Pseudohypopyon As a Feature of Multiple Myeloma

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

pathologic resemblence to a granu- 9-o’clock positions (Figure 1A-B). Mitochondria-Rich lar cell tumor. Results of more de- The tumor mass invaded the ante- Epithelioid Leiomyoma tailed immunohistochemical and rior chamber through the iris root. of the Ciliary Body electron microscopic studies showed The lens was indented and dis- smooth muscle differentiation and closed an associated posterior sub- Leiomyoma is a rare benign, smooth marked mitochondrial abundance of capsular cataract. There was no col- muscle–derived tumor that can arise the tumor, which was finally classi- lateral detachment of the retina, and from all parts of the uveal tract.1,2 fied as an epithelioid leiomyoma par- the posterior fundus and the optic This tumor can cause diagnostic ticularly rich in mitochondria. discs were normal in both eyes. Best- difficulties, because it may appear corrected visual acuity was 20/20 clinically as an amelanotic mela- Report of a Case. A 30-year-old OU, and intraocular pressure was 16 noma. Fewer than 30 leiomyomas Greek patient was referred to our mm Hg in both eyes. The flare val- of the ciliary body have been re- hospital because of a tumor of the ues of aqueous humor measured ported, but often these have not ciliary body in his right eye that had using a laser flare-cell meter (FC- been well documented by immuno- been detected on results of routine 1000; Kowa, Tokyo, Japan) were in- histochemical and/or electron ophthalmologic examination. No vi- creased in the right eye (19.8 counts microscopic studies. sual disturbances were found. The per 0.5 seconds; reference, Ͻ8 counts Herein we report an unusual patient was otherwise healthy, with per 0.5 seconds), indicating a com- variant of a ciliary body leiomyoma, no family history of any ocular or promised blood-aqueous barrier,3 which to our knowledge has not been systemic disease. but no other ocular abnormalities documented in the literature. This tu- Results of the clinical examina- were seen. Results of ultrasonogra- mor was clinically suspected of being tion showed a solid brownish tumor phy disclosed a solid 9.8ϫ8.2-mm a malignant melanoma, with histo- of the ciliary body between the 7- and tumor with low internal reflectiv-

A B

C D

Figure 1. A, Preoperative findings show a ciliary body tumor protruding through the iris root into the anterior chamber in a 30-year-old man. B, Gonioscopy of the tumor. C, Postoperative appearance after a 11.0ϫ11.3-mm en bloc excision and tectonic corneoscleral graft. D, Macroscopic appearance of the excised tissue with the rounded solid tumor. Dilated vessels are visible within the tumor mass along the cut surface.

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C D

Figure 2. A, Light microscopy shows a circumscribed tumor occupying the ciliary body stroma and covered by the ciliary epithelium (hematoxylin-eosin, original magnification ϫ10). B, The densely packed polygonal tumor cells show a strikingly granular eosinophilic cytoplasm (hematoxylin-eosin, original magnification ϫ375). C, The tumor cells are surrounded by prominent basement membranes (periodic acid–Schiff, original magnification ϫ250). D, A capillary network but little extracellular matrix is present between the tumor cells (Masson trichrome, original magnification ϫ250).

ity. Results of transillumination were dehyde and 1% glutaraldehyde and tumor occupied the stroma of the inconclusive. processed for light microscopy and ciliary body and was covered by the The clinical differential diag- transmission electron microscopy. intact, double-layered ciliary epithe- noses included malignant mela- Paraffin-embedded sections were lium. There was no invasion of the noma of the ciliary body with infil- stained with hematoxylin-eosin, pe- sclera (Figure 2A). The tumor was tration of iris and anterior chamber riodic acid–Schiff (PAS), Masson tri- well demarcated against the com- angle and adenoma of the nonpig- chrome, and Fontana-Masson. Im- pressed ciliary muscle, but continu- mented ciliary epithelium, although munohistochemistry was performed ity between the tumor and the most myogenic, neurogenic, and vascular using the streptavidin-biotin method anterior portion of the ciliary muscle neoplasms were also considered. Be- with antibodies against S-100 pro- was evident in some sections. cause evidence of tumor progression tein, desmin, smooth muscle ␣-ac- The tumor mass consisted of by means of history and tumor size tin, muscle-specific actin, vimentin, large, densely packed polygonal cells was found, we decided to perform an neuron-specific enolase, cytokera- with abundant cytoplasm and round- en bloc excision of the tumor. tin, glial fibrillary acid protein, HMB- to-oval uniform nuclei with moder- After cryocoagulation of the ad- 45, and CD68, with appropriate nega- ately prominent nucleoli. Mitotic fig- jacent retina, the tumor and the over- tive controls. Ultrathin sections were ures and necrotic or degenerative lying sclera in full thickness were ex- stained with uranyl acetate and lead changes were not observed. In sec- cised en bloc.4 A tectonic penetrating citrate. tions stained with hematoxylin- sclerokeratoplasty (11.0ϫ11.3 mm) Macroscopically, the excised eosin, the eosinophilic cytoplasm of was performed (Figure 1C) with an 9.0ϫ10.5-mm specimen showed a the tumor cells had a striking granu- extracapsular cataract extraction and completely resected, rounded, solid lar appearance (Figure 2B). Results posterior chamber lens implanta- brownish tumor of the ciliary body of PAS staining showed prominent tion. Postoperatively, a vitreous measuring 9ϫ8 mm in diameter and basement membranes surrounding hemorrhage occurred, and the pa- 5 mm in prominence, and resting on individual tumor cells but a PAS- tient had a best visual acuity of a normal sclera. Several dilated negative cytoplasm (Figure 2C). The 20/400 eight months after surgery. vessels were visible within the cytoplasm appeared red on results of Otherwise, the follow-up was un- pale yellow tumor mass along the the Masson trichrome staining (Fig- eventful. cut surface (Figure 1D). ure 2D). Fontana-Masson staining for The excised tissue block was By light microscopy, the well- melanin was negative. Little extra- fixed in buffered 4% paraformal- circumscribed, highly vascularized cellular matrix and a moderately de-

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C D

Figure 3. Results of immunohistochemistry show strong positive reactions for smooth muscle ␣-actin (A), desmin (B), and mitochondrial antigen (C) and a focally positive reaction for vimentin (D) (original magnifications ϫ250).

veloped capillary network were pres- and granular and lamellar inclu- mitochondria-rich epithelioid leio- ent between the densely packed sion bodies (Figure 4B). In addition myoma of the ciliary body with iris tumor cells. On the basis of light mi- to mitochondria, glycogen particles and anterior chamber invasion. croscopic criteria, the tumor was pre- (Figure 4B) and bundles of 9-nm liminarily classified as a granular cell myofilaments with characteristic fu- Comment. The clinically suspected tumor. siform densities (anchoring plaques) diagnosis of a malignant melanoma Immunohistochemistry showed were present in the peripheral cyto- or an epithelial tumor of the ciliary the tumor cells to be strongly posi- plasm in some of the tumor cells (Fig- body could not be confirmed on his- tive for smooth muscle ␣-actin ure 4C-D). Occasionally, lipid drop- topathologic and immunohisto- (Figure 3A), muscle-specific actin, lets and granules with particulate chemical examination using mela- desmin (Figure 3B), and mitochon- contents, presumably glycogeno- noma-specific and epithelial markers. drial antigen (Figure 3C); weakly somes, could be found among the mi- Instead, the light microscopic pat- positive for vimentin (Figure 3D), tochondria (Figure 4D). Lysosomal tern of the tumor cells strikingly re- neuron-specific enolase, and cyto- inclusions were only seldom seen. sembled that of a granular cell–type keratin; and negative for melanoma- Single smaller cells with prominent tumor. specific antigen (HMB-45), macro- Golgi complexes, cisterns of rough Large eosinophilic granular cells phage marker CD68, glial fibrillary endoplasmic reticulum, and clus- occurring in normal and neoplastic acidic protein, and S-100 protein. The ters of cytoplasmic granules resem- tissues have long been the subject of pattern of immunoreactivity was con- bling neurosecretory granules were speculation and controversy. Cyto- sistent with that of a tumor of smooth scattered between the mitochondria- plasmic granularity in tumor cells muscle origin, with the ciliary muscle laden cells. The tumor cells were sur- may be caused by an ultrastructural and blood vessels serving as internal rounded by continuous basement abundance of lysosomes (granular cell positive controls. membranes (Figure 4B-C). Specific tumors and granular cell myoblasto- Electron microscopy showed intercellular junctions could not be mas), mitochondria (oncocyto- that the cytoplasm of the distended observed. Few collagen fibers could mas), or other organelles, eg, micro- tumor cells was densely packed with be demonstrated in the sparse extra- crystals (alveolar soft part sarcomas), mitochondria (Figure 4A), which cellular space. smooth endoplasmic reticulum were enlarged and showed a num- The final diagnosis, based on (hepatocellular neoplasms), and se- ber of structural anomalies, eg, ab- electron microscopy and immuno- cretory granules (apudomas and normal and centrally stacked cristae histochemistry, was a particularly paragangliomas).5 Typical granular

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2 µm 1 µm C D

Figure 4. Results of transmission electron microscopy of the tumor cells. A, The cytoplasm of the distended tumor cells is packed with swollen mitochondria. B, Detail of tumor cells shows structural anomalies of mitochondria and glycogen granules (arrows). Arrowheads indicate the basement membrane. C, Myofilament bundles (MF) are present in the periphery of tumor cells, which are surrounded by a prominent basement membrane (arrowheads). D, Detail of tumor cells showing a prominent myofilament bundle (MF) with fusiform densities and a glycogenosome (arrow).

cell tumors are characterized by a myoblastoma of the iris and ciliary of immunohistochemical and ultra- PAS-positive cytoplasm, positive im- body.8 structural examinations. However, munoreactions for S-100 protein and Although the granular cells in electron microscopy has shown that neuron specific enolase, and in- our case were histologically indis- the apparent granularity and eosino- creased amounts of lysosomal inclu- tinguishable from those in typical philia of the tumor cells in the pres- sions (autophagosomes, myelin fig- granular cell tumors, PAS-negative ent case, detected using light micros- ures, and angulate bodies) by electron staining characteristics, immu- copy, were due to an augmentation microscopy, indicating a neuro- nonegativity of the cytoplasm for of mitochondria. The abundance of genic origin, most probably derived S-100 protein, and lack of lyso- mitochondria raised the possibility of from Schwann cells.6 These tumors somal structures distinguished the an oncocytoma,10 but this was not are known as rare tumors of the or- present case from a classic granular considered to be substantiated by the bit and ocular adnexa,7 but intraocu- cell tumor. The comparison with the location of the tumor below the cili- lar occurrence appears to be limited granular cell myoblastoma origi- ary epithelium or by the lack of epi- to a single report, based on light mi- nally described by Abrikossoff 9 thelial features such as desmosomes croscopic findings, of a granular cell remains superficial owing to a lack on electron microscopy.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Instead, the marked expression ectodermal tumors arising from the We thank Carmen Rummelt for of the myogenic markers desmin, ciliary muscle, which is a neural crest excellent technical assistance and smooth muscle actin, and muscle- derivative.2,22 Among the few cases Heinrich Witschel, MD, for helpful specific actin, the tumor location, and of mesectodermal leiomyomas of discussions at the Annual Meeting the electron microscopic demonstra- the ciliary body reported, various of German-speaking Ophthalmo- tion of myofilaments, subplasmalem- amounts of mitochondria, from Pathologists. mal fusiform densities, glycogen par- sparse to abundant, have been de- Corresponding author and re- ticles, and continuous basement scribed in the tumor cells.23-28 prints: Ursula Schlo¨tzer-Schrehardt, membranes clearly proved a myo- In concordance with these ob- PhD, Department of Ophthalmology, genic origin with smooth muscle servations and on the basis of our light University Erlangen-Nu¨rnberg, Schwa- differentiation of the tumor cells. microscopic, immunohistochemi- bachanlage 6, D-91054 Erlangen, Ger- Therefore, findings suggested a lei- cal, and ultrastructural findings, we many (e-mail: ursula.schloetzer@augen omyoma.1,2,11-13 The weak staining for diagnosed the tumor histopathologi- .imed.uni-erlangen.de). cytokeratin is difficult to interpret, but cally as an unusual granular cell vari- cytokeratin immunoreactivity has ant of a leiomyoma of the ciliary body. 1. Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia, Pa: WB Saunders been reported in smooth muscle and Positive desmin staining and focal Co; 1992:273-284. smooth muscle tumors.14 continuities between the tumor and 2. Shields JA, Shields CL, Eagle RC Jr, De Potter the circular portion of the ciliary P. Observations on seven cases of intraocular Leiomyomas exhibiting marked leiomyoma: the 1993 Byron Demorest Lec- granular changes (granular cell leio- muscle suggest its origin from the cili- ture. Arch Ophthalmol. 1994;112:521-528. myoma) have been rarely described ary muscle. The present case differs 3. Ku¨chle M, Nguyen NX, Naumann GOH. Quan- titative assessment of the blood-aqueous barrier at various extraocular locations, eg, from those of previous reports on in human eyes with malignant or benign uveal the breast or the urogenital tract.15-18 mesectodermal leiomyomas by the tumors. Am J Ophthalmol. 1994;117:521-528. These tumors showed polygonal or marked abundance of abnormal mi- 4. Naumann GOH, Rummelt V. Block excision of tumors of the anterior uvea. Ophthalmology. epithelioid rather than spindle- tochondria as its most prominent fea- 1996;103:2017-2028. shaped cells with granular eosino- ture. Thus, we believe that the term 5. Ghadially FN. Ultrastructural Pathology of the mitochondria-rich epithelioid leio- Cell and Matrix. Woburn, Mass: Butterworth- philic cytoplasm and smooth muscle Heinemann; 1997. differentiation. The granular cyto- myoma is the most accurate descrip- 6. Rodriguez-Ares T, Varela-Duran J, Sanchez- plasmic changes were generally re- tion of the tumor presented. Salorio M, Varela-Nunez R, Capeans-Tome C, Urdiales-Viedma M. Granular cell tumor of the lated to an increase in lysosomal el- Interestingly, the cells of the cir- eye (myoblastoma): ultrastructural and immu- ements within the neoplastic cells, cular and inner reticular portions of nohistochemical studies. Eur J Ophthalmol. thus resembling classic granular cell the ciliary muscle of cynomolgus 1993;3:47-52. 7. Jaeger MJ, Green WR, Miller NR, Harris GJ. schwannomas. However, some cases monkeys showed more mitochon- Granular cell tumor of the orbit and ocular ad- of leiomyoma, leiomyoblastoma, and dria and fewer myofibrils than cells nexae. Surv Ophthalmol. 1987;31:417-423. of the longitudinal portion.29 Al- 8. Cunha SL, Lobo FG. Granular cell myoblas- leiomyosarcoma have also been re- toma of the anterior uvea. Br J Ophthalmol. 1966; ported to disclose numerous mito- though not so pronounced, an in- 50:99-101. chondria filling the cytoplasm of the creased number of mitochondria 9. Abrikossoff A. Über Myome, ausgehend von der quergestreiften willku¨ rlichen Muskulatur. Vir- tumor cells and giving a granular ap- could also be demonstrated in the chows Arch. 1926;260:215-233. pearance by light microscopy.19,20 A circular part of the ciliary muscle in 10. Tallini G. Oncocytic tumors. Virchows Arch. large series of 70 smooth muscle neo- the present case and in normal hu- 1998;433:5-12. 11. Blodi FC. Leiomyoma of the ciliary body. Am J plasms from various body sites has man donor eyes, substantiating the Ophthalmol. 1950;33:939-942. shown that abundant mitochondria supposed origin of the tumor. 12. Sautter H, Bo¨ke W, von Domarus D, Demeler Although extremely rare, this U. Leiomyom des Ziliarko¨rpers. Klinischer, fluo- associated with a paucity of myofila- reszenzangiographischer und histologischer Be- ments represented a particular fea- case highlights the clinical and his- fundbericht. Klin Monatsbl Augenheilkd. 1979; ture of epithelioid smooth muscle tu- topathologic difficulties in diagnos- 175:704-710. 13. Meyer SL, Fine BS, Font RL, Zimmerman LE. mors, eg, epithelioid leiomyomas, ing ocular smooth muscle tumors Leiomyoma of the ciliary body: electron mi- leiomyoblastomas, or epithelioid and the definite need for electron microscopic verification. Am J Ophthalmol. 1968; components of leiomyosarcomas.21 croscopy and immunohistochemis- 66:1061-1068. 14. Brown DC, Theaker JM, Banks PM, et al. Cy- For instance, in 14 of 15 leiomyo- try to establish a correct diagnosis. tokeratin expression in smooth muscle and blastomas, the numerous mitochon- Local resection by means of en bloc smooth muscle tumors. Histopathology. 1987; excision has been proven to be ben- 11:477-486. dria were the most striking feature, 15. Abenoza P, Sibley RK. Granular cell myoma and virtually filling the cytoplasm to the eficial in the management of these schwannoma: fine structural and immunohis- exclusion of other organelles. Tu- tumors.4 tochemical study. Ultrastruct Pathol. 1987;11: 19-28. mor cells packed with mitochondria 16. Shimokama T, Watanabe T. Leiomyoma ex- contained fewer myofilaments and Ursula Schlo¨tzer-Schrehardt, PhD hibiting a marked granular change: granular cell were often round to polygonal in Anselm Ju¨nemann, MD leiomyoma versus granular cell schwannoma. Hum Pathol. 1992;23:327-331. shape. By contrast, spindle cells con- Gottfried O. H. Naumann, MD 17. Roncaroli F, Rossi R, Severi B, Martinelli GN, tained sparse mitochondria but nu- Erlangen, Germany Eusebi V. Epitheloid leiomyoma of the breast with granular cell change: a case report. Hum merous myofilaments. Pathol. 1993;24:1260-1263. Leiomyomas of the ciliary body This study was presented in part at the 18. Dobashi Y, Iwabuchi K, Nakahata J, Yanagi- have been generally classified into Annual Meeting of German-speaking moto K, Kameya T. Combined clear and granular cell leiomyoma of soft tissue: evidence of mesodermal tumors originating from Ophthalmo-Pathologists, Berlin, Ger- transformation to a histiocytic phenotype. His- vascular smooth muscle and mes- many, September 19, 2000. topathology. 1999;34:526-531.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 19. Hyde KE, Geisinger KR, Marshall RB, Jones TL. a 95% or better accuracy in the clini- a choroidal tumor that received 125I The clear-cell variant of uterine epithelioid leiomyoma: an immunohistologic and ultrastruc- cal diagnosis of malignant mela- brachytherapy as primary treatment tural study. Arch Pathol Lab Med. 1989;113: noma, and in some centers such as the of presumed malignant melanoma 551-553. Wills Eye Institute, Baltimore, Md,1 and that was identified as melanocy- 20. Nance K, Reddick RL. Epithelioid leiomyosar- comaofthesmallintestinewithoncocyticchange. and the Mayo Clinic, Rochester, toma after histopathologic examina- Arch Pathol Lab Med. 1987;111:1181-1182. Minn,2 96.3% and 97.7% accuracies, tion of the enucleated specimen. 21. Zukerberg LR, Cinti S, Dickersin GR. Mito- chondria as a feature of smooth muscle differ- respectively, have been reported. In entiation: a study of 70 smooth muscle 1990, a North American prospective Report of a Case. A 60-year-old tumors. J Submicrosc Cytol Pathol. 1990;22: randomized multicenter study group, woman was initially examined at the 335-344. 22. Jakobiec FA, Font RL, Tso MOM, Zimmermann the Collaborative Ocular Melanoma Mayo Clinic in 1990 and was found LE.Mesectodermalleiomyomaoftheciliarybody: Study (COMS) Group, reported a to have a pigmented 5ϫ4.5-mm cho- a tumor of presumed neural crest origin. Can- 99.5% accuracy in the diagnosis of roidal lesion exhibiting lipofuscin and cer. 1977;39:2102-2113. 3 23. Vogel M, Spitznas M, Waubke TN. Leio- choroidal melanoma. By 1998, the a collar-button configuration. Sub- myoma of the ciliary body. Albrecht Von Graefes COMS had enrolled more than 2300 retinal fluid associated with the tu- Arch Klin Exp Ophthalmol. 1978;209:89-98. 24. Croxatto JO, Malbran ES. Unusual ciliary body eyes into the study, and among the mor extended into the macula, re- tumor: mesectodermal leiomyoma. Ophthal- 1532 eyes randomized and enucle- ducing visual acuity (Figure 1). mology. 1982;89:1208-1212. ated, 1527 were found to have a cho- Results of fluorescein angiography 25. Takagi T, Ueno Y, Matsuya N. Mesectodermal leiomyoma of the ciliary body: an ultrastructural roidal melanoma, resulting in a diag- demonstrated patchy hypofluores- study. Arch Ophthalmol. 1985;103:1711-1714. nostic accuracy of 99.67%.4-6 The 5 cence and late tissue staining within 26. White V, Stevenson K, Garner A, Hungerford misdiagnosed cases included 4 ad- J. Mesectodermal leiomyoma of the ciliary body: the tumor. Results of ultrasonog- case report. Br J Ophthalmol. 1989;73:12-18. enocarcinomas that metastasized to raphy demonstrated a solid lesion 27. Shields JA, Shields CL, Eagle RC. Mesectoder- the choroid and 1 choroidal heman- with choroidal excavation and low mal leiomyoma of the ciliary body managed by partial lamellar iridocyclochoroidectomy. Oph- gioma. The low misdiagnosis rate in levels of internal reflectivity (A-scan thalmology. 1989;96:1369-1376. the COMS is a reflection of the level [Figure 2]). The tumor was 2.9 mm 28. Gloor BP, Daicker B, Gafner F. Leiomyoma of of expertise of the ophthalmologists thick. In accordance with the pa- the ciliary body: misdiagnosis leading to an un- conventional but successful surgical approach. participating in this study, but it also tient’s strong preference to have the Klin Monatsbl Augenheilkd. 1979;175:760-766. results from the study aim, which was tumor treated with brachytherapy, she 29. Flu¨ gel C, Ba´ra´ny EH, Lu¨ tjen-Drecoll E. Histo- to include only patients whose tu- chemical differences within the ciliary muscle was not enrolled in the COMS, and 125 and its function in accommodation. Exp Eye Res. mors could be adequately visualized I brachytherapy was adminis- 1990;50:219-226. and were believed to clearly fit the cri- tered. Three years after brachy- teria of malignant choroidal mela- therapy, extensive radiation retinopa- noma. The COMS reported 2 addi- thy was observed. Five years after tional misdiagnosed cases that brachytherapy, in 1996, the eye be- Mushroom-Shaped underwent enucleation after origi- came blind and painful owing to neo- Choroidal Melanocytoma nal treatment with iodine I 125 (125I) vascular glaucoma. The tumor mea- Mimicking Malignant brachytherapy. Both were melanocy- sured 3.2 mm in thickness by Melanoma tomas discovered in eyes that ini- ultrasonography. The eye was enucle- tially had been randomized to 125I ated. The differential diagnosis of malig- brachytherapy for presumed mela- On gross pathological examina- nant melanoma of the uveal tract con- noma, and both were later enucle- tion, findings included a black mush- tinues to challenge clinicians. In re- ated because of tumor growth.3 Simi- room-shaped mass immediately tem- cent decades, we have come to expect larly, we report an additional case of poral to the optic nerve, with a measurement of 7ϫ 7 ϫ 3mm (Figure 3). Histologically, it corre- sponded to a heavily pigmented choroidal tumor that had broken through Bruch’s membrane to infiltrate the overlying retina (Figure 4). Bleached sections showed a uniform population of large cells with abundant cytoplasm and small, bland nuclei consistent with the diagnosis of melanocytoma (Figure 5). Oc- casional inconspicuous nucleoli were present. Necrosis and mitotic fig- ures were not seen. The histocytic marker CD68 did not reveal foamy macrophages. Results of electron microscopy showed type II melanocytoma cells with small melanosomes Figure 1. Fundus photographs showing tumor with collar-button configuration, lipofuscin, and subretinal and premelanosomes measuring less fluid. than 1 µm in diameter (Figure 6).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Comment. Melanocytomas of the eye In this typical location, the clinical di- clinical feature. However, melano- may occur in any location within the agnosis of melanocytoma is usually cytomas involving the choroid are uveal tract, but most commonly they not a problem. However, the diag- unusual.9 Choroidal melanocyto- arise from pigmented cells that are in- nosis of this tumor elsewhere in the mas have been reported as part of corporated within the optic disc.7 Me- uveal tract may prove to be more of paraneoplastic syndromes (super ne- lanocytomas of the optic nerve head a challenge. In the ciliary body or iris, vus syndrome or bilateral diffuse are generally heavily pigmented and melanocytomas tend to be heavily uveal melanocytic proliferation syn- frequently have a feathered black edge pigmented, and the correct diagno- drome10-12), and in those cases, they that extends into the adjacent retina.8 sis is suspected on the basis of this tend to be very dark, multiple, and bilateral, and the correct diagnosis may be suspected clinically. A Several clinical features in our case, eg, the color, the presence of lipofuscin and subretinal fluid, and the collar-buttonconfiguration,suggested the clinical diagnosis of choroidal melanoma. In fact, the presence of a collar-buttonconfigurationisunusual in any tumor other than malignant melanoma, and its presence alone stronglysuggeststhatdiagnosis.How- ever,thisfindingisnotpathognomonic of melanoma; it has been reported in association with melanocytoma13 as well as a tumor of the retinal pigment epithelium.14 Tumor growth in this case also supported the diagnosis of malignant melanoma, as melanocytomas often remain clinically stable except when m occurring with the B super nevus syndrome.10,12,15 In our case, results of fluorescein angiography and ultrasonography also supported the diagnosis of melanoma. The fluorescein study showed patchy hyperfluorescence and late tissue staining of the tumor. A typical melanocytoma would be expected to obscure background fluorescein significantly, but this was not observed in our case. The ultra- Figure 2. Results of ultrasonography demonstrating solid lesion with choroidal excavation (A) and low sonographic features in our case internal reflectivity on A-scan (B). included a relatively low level of

Figure 3. Gross specimen showing the collar-button configuration of heavily Figure 4. Medium-power photomicrograph demonstrating the collar-button pigmented tumor that had broken through Bruch’s membrane. configuration of the tumor, resulting from the invasion through Bruch’s membrane into the retina. Retinal detachment, cystic degeneration, and exudates are observed (hematoxylin-eosin, original magnification ϫ100).

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Figure 5. Bleached sections showing neoplastic cells with small, Figure 6. Results of electron microscopy showing type II melanocytoma bland-appearing nuclei and abundant cytoplasm. Necrosis, mitosis, and cells with small melanosomes of less than 1 µm in diameter (lead citrate, nucleoli are absent (hematoxylin-eosin, original magnification ϫ200). original magnification ϫ26000).

internal reflectivity with acoustic hol- a composite tumor consisting of 2 dif- existed before radiation; however, the lowing and choroidal excavation, ferent cell populations. Melanocy- absence of necrosis and fibrosis sup- findings characteristic of a mela- toma occupied one side of the tu- port our impression that this neo- noma rather than a melanocytoma, mor, and malignant melanoma plasm was always a melanocytoma which has been observed to have high occupied the other. that mimicked a malignant mela- levels of internal reflectivity.16 Melanocytomas are generally noma. The classic histological appear- easily recognized by ophthalmic pa- ance of a melanocytoma, such as that thologists familiar with this entity. Ir- Dennis M. Robertson, MD seen in our case, is a heavily pig- radiation may alter the histological R. Jean Campbell, MD mented neoplasm with abundant cy- features of an intraocular tumor, con- Diva R. Saloma˜o, MD toplasmic pigment that obscures the founding interpretation of the cell Rochester, Minn nuclear features. Bleached sections type. In case of extensive tumor ne- disclose large, uniform cells with a crosis, one may not be able to recog- This study was supported in part by distinct cytoplasmic membrane, nize tumor type with certainty. Ra- a grant from Research to Prevent abundant cytoplasm, and a rounded, diation therapy may produce, in Blindness, Inc, New York, NY, and in small, bland-appearing nucleus that addition to tumor necrosis, a mac- part by the Mayo Foundation, Roch- may or may not contain an incon- rophage response with numerous ester, Minn. spicuous nucleolus.7 The difficul- pigment-laden histiocytes. The in- We thank Bonnie Ronken for sec- ties in differentiating the histologi- terpretation of such cells may prove retarial support and Cheryl Hann, MS, cal features of benign and malignant to be a challenge to the pathologist for support with the electron micros- pigmented lesions have long been during light microscopy. However, copy studies. recognized and have been the sub- histiocytic markers, eg, CD68, are Corresponding author and re- ject of individual publications.17,18 helpful in this differential diagnosis. prints: Dennis M. Robertson, MD, De- Is there an indication to per- Foamy macrophages were not seen partment of Ophthalmology, Mayo form a fine-needle aspiration (FNA) in our case, and histological exami- Clinic, 200 First St SW, Rochester, biopsy in this case? Fine-needle as- nation of the tumor showed little evi- MN 55905 (e-mail: robertson.dennis piration biopsy is generally reserved dence of necrosis 5 years after brachy- @mayo.edu) for cases with atypical clinical fea- therapy. Ultrastructural studies may tures, and since this case presented help support the diagnosis of mela- 1. Shields JA, McDonald PR. Improvements in the diagnosis of posterior uveal melanomas. Arch with clinical characteristics typical of nocytoma and differentiate between Ophthalmol. 1974;91:259-264. melanoma, FNA biopsy was not con- 2 types of melanocytoma cells. The 2. Robertson DM, Campbell RJ. Errors in the diagnosis of malignant melanoma of the cho- sidered. Even if an FNA biopsy had type II melanocytoma cells contain- roid. Am J Ophthalmol. 1979;87:269-275. been performed, we have no guar- ing small melanosomes were seen in 3. Albert DM, Marcus DM, for the Collaborative antee that a conclusive diagnosis our case (Figure 6). These cells are Ocular Melanoma Study Group. Accuracy of diagnosis in the Collaborative Ocular Mela- could be achieved because of the dif- considered more metabolically ac- noma Study: COMS report 1. Arch Ophthal- ficulties in obtaining diagnostic ma- tive than type I cells.20 mol. 1990;108:1268-1273. terial that properly samples the tu- In conclusion, this case illus- 4. Collaborative Ocular Melanoma Study Group. Design and methods of a clinical trial for a rare mor and because of difficulties trates the difficulty in differentiat- condition: the Collaborative Ocular Mela- interpreting the cells. Shetlar and col- ing a choroidal melanocytoma from noma Study: COMS report 3. Control Clin Tri- 19 als. 1993;14:362-391. leagues reported a case of choroi- a choroidal melanoma on the basis 5. Albert DM. The ocular melanoma story: LIII Ed- dal neoplasm diagnosed by means of of clinical features alone. It remains ward Jackson Memorial Lecture: part II. Am FNA biopsy. In that case, a diagno- uncertain whether the histological J Ophthalmol. 1997;123:729-741. 6. Albert DM, Diener-West M, Robinson N, sis of melanoma was rendered, but at features in this case accurately por- Grossniklaus HE, Green WR. Histopathologic enucleation the tumor proved to be trayed the tumor characteristics that characteristicsofuvealmelanomasineyesenucle-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 ated from the Collaborative Ocular Melanoma Study. Am J Ophthalmol. 1998;125:745-766. A B 7. Zimmerman LE. Melanocytes, melanocytic nevi, and melanocytomas: the Jonas S. Friedenwald Memorial Lecture. Invest Ophthalmol Vis Sci. 1965;4:11-14. 8. Zimmerman LE, Garron LK. Melanocytoma of the optic disc. Int Ophthalmol Clin. 1962;2:431- 440. 9. Shields JA, Font RL. Melanocytoma of the choroid clinically simulating a malignant melanoma. Arch Ophthalmol. 1972;87:396-400. 10. Ryll DL, Campbell RJ, Robertson DM, Brubaker SJ. Pseudometastatic lesions of the choroid. Oph- thalmology. 1980;87:1181-1186. 11. Barr CC, Zimmerman LE, Curtin VT, Font RL. Bilateral diffuse melanocytic uveal tumors as- Figure 1. Ophthalmoscopic appearance of the left eye depicting white intraretinal and subretinal sociated with systemic malignant neoplasms. hemorrhages in the temporal quadrant (A) and in the inferonasal quadrant (B). Arch Ophthalmol. 1982;100:249-255. 12. Bourruat FX, Othenin-Girard P, Uffer S, et al. Natural history of diffuse uveal melanocytic pro- Three unusual sequelae of long- Dilated ophthalmoscopic ex- liferation. Arch Ophthalmol. 1992;99:1698- standing vitreous hemorrhage are amination in the right eye revealed 1704. cholesterolosis bulbi (synchisis scin- prominent brown vitreous cells, 13. Lehman LJ, Hohberger GG, Buettner H, Camp- bell RJ. Necrotic melanocytoma of the cho- tillans), the formation of tubular vit- which obscured the retinal details and roid in a 2-year-old child. J Pediatr Ophthalmol reous cylinders, and hemoglobin prevented fundus photography. With Strabismus. 1997;34:40-43. 1 14. Fan JT, Robertson DM, Campbell RJ. Clinico- spherulosis. The last entity repre- indirect ophthalmoscopy, the optic pathologic correlation of a case of adenocarci- sents a spheroidal degradation prod- disc margins appeared sharp and flat. noma of the retinal pigment epithelium. Am uct of erythrocytes and was first de- Large white intraretinal and subreti- J Ophthalmol. 1995;119:243-245. 2 15. Joffe L, Shields J, Osher R, Gass JDM. Clinical scribed by Grossniklaus et al in an nal hemorrhagic infiltrates were vis- and follow-up studies of melanocytomas of the eye with a vitreous hemorrhage sec- ible in the mid periphery of the retina. optic disc. Ophthalmology. 1979;86:1067-1078. ondary to an idiopathic choroidal Examination of the left eye was simi- 16. Byrne SF, Green RL. Intraocular tumors. In: Cra- ven L, ed. Ultrasound of the Eye and Orbit. St Louis, neovascular membrane. Spherulo- lar, though there was less promi- Mo: Mosby–Year Book Inc; 1992:134-139, 180. sis was so named because of its his- nent overlying vitreous hemorrhage 17. Gass JDM. Problems in the differential diag- Figure 1 nosis of choroidal nevi and malignant melano- tologic resemblance to myospheru- ( ). mas: the XXXIII Edward Jackson Memorial Lec- losis, an inflammatory condition The differential diagnosis in- ture. Am J Ophthalmol. 1977;83:299-323. characterized by saclike clusters of cluded bilateral leukemic infiltrates, 18. Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma degenerating erythrocytes that have endogenous endophthalmitis, and/or and melanocytic nevi between expert patholo- been physically altered by exposure possible retinal opportunistic infec- gists. Hum Pathol. 1996;27:588-591. to a foreign substance — typically an tion. The patient underwent diagnos- 19. Shetlar DJ, Folberg R, Gass JDM. Choroidal ma- 3-5 lignant melanoma associated with a melano- antibiotic-containing ointment. tic and therapeutic pars plana vitrec- cytoma. Retina. 1999;19:346-348. The purpose of this article is to tomy in his right eye, with intravitreal 20. Juarez CP, Tso MOM. An ultrastructural study of melanocytomas (magnocellular nevi) of the document the clinical and patho- injection of 1.0 mg of vancomycin optic disc and uvea. Am J Ophthalmol. 1980; logical correlation of hemoglobin hydrochloride, 2.25 mg of ceftazi- 90:48-62. spherulosis in an eye with bilateral dime, and 5.0 µg of amphotericin B. white intraretinal and subretinal Vitreous cultures for bacteria and hemorrhages, along with an overly- fungi were negative, and cytology was Intravitreal Hemoglobin ing vitreous hemorrhage of a pa- negative for leukemic cells. Follow- Spherulosis: A Rare tient with CML. ing vitrectomy, his visual acuity im- Complication of Subretinal proved to 20/40 OD. Hemorrhage Report of a Case. A 39-year-old Af- Both undiluted vitreous and the rican American man experienced de- vitrectomy cassette were processed Hemoglobin spherulosis, a rare his- creased vision, with a greater deg- using the thin-prep technique, and tological finding, represents a spheri- radation of vision in the right eye the slides were stained with the cal degradation product of hemoglo- than in the left eye throughout one Papanicolau and Diff-Quik (Dade- bin. It has been described in a single month. His medical history was sig- Behring, Deerfield, Ill) methods. Cy- report as a vitreous hemorrhage origi- nificant for CML with associated tologic examination showed frag- nating from the subretinal space. We anemia (hemoglobin level, 8.1 g/dL) mented erythrocytes, ranging in describe an immunosuppressed pa- and thrombocytopenia (22ϫ103/ diameter from 2 to 4 µm. Larger tient with chronic myelogenous leu- µL), though the disease was be- (10-12 µm) dark brown globules kemia (CML) and associated throm- lieved to be in remission. On ocu- were observed, indicative of hemo- bocytopenia, with bilateral white lar examination, his uncorrected globin spherulosis (Figure 2). Rare intraretinal and subretinal hemor- visual acuity was counting fingers at inflammatory cells were identified. rhages, along with an overlying vit- 3 ft OD, and 20/40 OS. External and Neither tumor cells nor microor- reous hemorrhage. Cytologic exami- anterior segment examinations were ganisms were observed. Because of nation of a vitrectomy specimen unremarkable. Intraocular pres- the relatively small amount of ma- demonstrated hemoglobin spheru- sure was within normal limits, and terial, no additional studies (spe- losis. This represents only the sec- there was neither iris rubeosis nor cial stains and electron micros- ond report of this phenomenon. anterior chamber inflammation. copy) could be performed.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 tillans), the formation of tubular vitreous cylinders, and hemoglobin spherulosis.2 This last entity, which may be related to degenerative changes occurring to hemoglobin as it migrates from the subretinal space into the vitreous cavity, seems to be a poorly recognized phenomenon. Further studies are needed to support this hypothesis. The full ocular significance of this phenomenon is not fully known, though it may lead to a much more prolonged spontaneous clearance of hemorrhage from the vitreous cavity. We therefore recommend that vitrectomy specimens obtained from eyes with breakthrough subretinal hemorrhages be cytologically evalu- Figure 2. Vitrectomy specimen processed by the thin-prep technique, displaying 2- to 4-µm fragmented ated to rule out hemoglobin spheru- erythrocytes and intermixed with large dark brown globules, the largest ranging from 10 to 12 µm in losis. diameter (arrow indicates hemoglobin spherulosis) (Papanicolaou stain, original magnification ϫ100). Unfortunately,6monthsfollow- ing the pars plana vitrectomy surgery, Comment. McClatchie et al6,7 in Gass10,11 has described a yellow- the patient experienced a relapse of 1969 reported several East African brown material in the vitreous follow- hisCML.The patient died due to com- patients with inflammatory nod- ing hemorrhagic detachment of the plications of pneumonia. An autopsy ules involving muscular and subcu- retina and retinal pigment epithelium. was not performed. taneous tissues. Histologically, the He proposed that this material was lesions represented granulomatous composed of hemoglobin rather than Stephen G. Schwartz, MD inflammation surrounding “bags” of wholeblood,andhenotedthatthema- William F. Mieler, MD spherules, each spherule being terial may also stain the iris stroma, Eric R. Holz, MD slightly larger than an erythrocyte. resulting in heterochromia in a lightly Bita Esmaeli, MD This condition was given the de- pigmented patient. The mechanism of Paul S. Ragsdale, CRA scriptive term myospherulosis. anteriormigrationofsubretinalhemo- Ramon L. Font, MD Eight years later, Kyriakos3 used globin may be similar to that which Houston, Tex the term to describe a histologically causes corneal blood staining follow- similar inflammatory condition of the ing a hyphema. Supported in part by a grant from the nose, paranasal sinuses, and middle Since his initial publication, Retina Research Foundation, Hous- ear. His work, as well as the work of Grossniklaus has noted 2 addi- ton, Tex, and by an unrestricted grant of subsequent investigators4,5 dem- tional cases, although these were not from Research to Prevent Blindness onstrated the contents of the sac- formally reported.2 Our patient, Inc, New York, NY. like structures to be erythrocytes al- therefore, represents only the sec- Dr Schwartz is currently with the tered by a foreign substance, typically ond reported case of intravitreal he- Department of Ophthalmology at the an antibiotic-containing ointment. moglobin spherulosis in the litera- Medical College of Virginia Campus Today, myospherulosis is often a sur- ture. It is significant that in our of Virginia Commonwealth Univer- gical complication and has been de- patient, the vitreous hemorrhage also sity, Richmond. scribed in numerous tissues, includ- seems to have originated in the sub- Corresponding author: William ing the upper eyelid8 and caruncle.9 retinal space, which may explain the F. Mieler, MD, Cullen Eye Institute, In 1988, Grossniklaus et al2 de- pathogenesis of the spherule forma- Baylor College of Medicine, 6565 Fan- scribed a unique hemoglobin deg- tion. Our patient had at least 2 risk nin St, NC-205, Houston, TX 77030 radation product recovered from a factors for the vitreous hemor- (e-mail: [email protected]). vitreous hemorrhage in an eye with rhage, including the underlying 1. Spraul CW, Grossniklaus HE. Vitreous heman idiopathic choroidal neovascu- CML, along with thrombocyto- orrhage. Surv Ophthalmol. 1997;42:3-39. lar membrane. They named the con- penia. With the white intraretinal 2. Grossniklaus HE, Frank KE, Farhi DC, Jacobs dition hemoglobin spherulosis be- and subretinal hemorrhages, it was GJ, Green WR. Hemoglobin spherulosis in the vitreous cavity. Arch Ophthalmol. 1988;106: cause of its histologic resemblance presumed that the intraocular hem- 961-962. to myospherulosis. The mecha- orrhages had been present for an 3. Kyriakos M. Myospherulosis of the paranasal sinuses, nose and middle ear: a possible iatrogenic nism of the spherule formation is extended period. disease. Am J Clin Pathol. 1977;67:118-130. unknown, although they hypoth- As discussed previously, 3 un- 4. Rosai J. The nature of myospherulosis of the esized that the initial subretinal lo- common complications of long- upper respiratory tract. Am J Clin Pathol. 1978; 69:475-481. cation of the blood may have played standing vitreous hemorrhage are 5. Beuret J. Myospherulosis [letter]. Am J Clin a role. cholesterolosis bulbi (synchisis scin- Pathol. 1979;71:130.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 6. McClatchie S, Waambo MW, Bremner AD. left pupil was slightly irregular, and disc swelling. Although the lesion Myospherulosis: a previously unreported disease? Am J Clin Pathol. 1969;51:699-704. there was evidence of low-grade an- was simulating a hypopyon, there 7. McClatchie S, Bremner AD. Unusual subcuta- terior chamber activity (indicated by was no strong evidence of an in- neous swellings in African patients. East Afr Med a few cells and mild flare) with sec- fective underlying cause, so the pa- J. 1969;46:625-633. 8. Biedlingmaier JF, Aronsky MA, Whelen PJ. ondary localized posterior syn- tient began taking mild topical Myospherulosis of the upper eyelid as a com- echiae. However, the most striking steroids (0.5% prednisolone oph- plication of endoscopic sinus surgery. Am J Rhi- nol. 1997;11:345-347. clinical abnormality was a white, thalmic drops, 4 times daily). A 9. Kini U, Babu MK. Ocular spherulocystosis. solid, well-demarcated pseudohy- sample of the infiltrate was ob- J Clin Pathol. 1996;49:857-858. popyon of undetermined source oc- tained through a corneal paracen- 10. Gass JDM. Pathogenesis of disciform detachment of the neuroepithelium, III: senile disci- cupying the inferior anterior cham- tesis. Cytology results confirmed the form macular degeneration. Am J Ophthalmol. ber and slightly extending medially presence of monoclonal plasma cell 1967;63:617-644. (Figure 1). There was no evi- infiltration. The patient underwent 11. Gass JDM. Stereoscopic Atlas of Macular Dis- eases: Diagnosis and Treatment. 4th ed. St Louis, dence of crystals within the cornea 10 courses of radiotherapy to the left Mo: Mosby-Year Book; 1997. or infiltration of the iris. Intraocu- orbit with subsequent complete reso- lar pressures were within normal lution of the pseudohypopyon limits, and ophthalmoscopy results (Figure 2). After treatment be- were unremarkable in both eyes, gan, the cellular activity in the an- Pseudohypopyon with the absence of retinal venous terior chamber and the pseudohy- as a Feature of stasis, cotton-wool spots, or optic popyon resolved, and the patient’s Multiple Myeloma

Multiple myeloma is a malignancy of the immune system that infre- quently involves the eye. Cysts of the ciliary body and retinal vascular lesions represent the most common ocular manifestations in myeloma patients.1 This report documents the first case of anterior chamber infiltration–simulating hypopyon (pseudohypopyon) in multiple myeloma.

Report of a Case. A 72-year-old white man was referred by his he- matologists for anterior segment evaluation. Hyperemia and sore- ness of his left eye, accompanied by blurred vision, had been noted over the preceding 3 weeks. The patient Figure 1. White, solid, anterior chamber infiltrate–simulating hypopyon. had been diagnosed with multiple myeloma 2 months previously following prolonged fatigue, acute re- nal insufficiency, and high levels of serum calcium and IgG. Subse- quently, he received 3 courses of vin- cristine sulfate, doxorubicin hydrochloride, and methylprednisolone (VAMP) chemotherapy, which resulted in considerable decrease of the paraprotein (IgG). His ocular symp- toms developed 2 weeks after the last course of chemotherapy, while he was taking oral amitriptyline hydrochloride, ciprofloxacin hydrochloride, and acyclovir. On examination, his corrected visual acuity was 20/30 OD and 20/40 OS. Both corneas were clear, and his left conjunctiva was hyperemic, although there was no Figure 2. Immunoperoxidase on a cytospin of fluid revealing ␬ light chain restriction within a monoclonal conjunctival venous sludging. His population of plasma cells (original magnification ϫ320). Courtesy of Alastair Deery, FRCPath.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 visual acuity improved to 20/30 in tween the oncologists and ophthal- patients responded to treatment with the affected eye. mologists who treat such patients is topical corticosteroids and mydri- mandatory for prompt diagnosis and atics, without recourse to further an- Comment. Multiple myeloma is the effective management. tiviral treatment; they did not com- most common of the plasma cell dys- monly experience a subsequent crasias characterized by monoclo- Paris G. Tranos, ICO attack of ARN. To our knowledge, nal gammopathy and osteolytic bone Petros S. Andreou, FRCOphth this is the first report of isolated re- lesions.2 Ocular involvement in pa- Sanjeewa S. Wickremasinghe, current AU following healed ARN. tients with multiple myeloma has MRCOphth Acute retinal necrosis is a ful- been well described.1 The ocular John D. Brazier, FRCOphth minant viral retinitis first de- manifestations may be divided into London, England scribed in 1971 by Urayama et al1 in 2 groups: those attributable to my- Japan, where it was initially known eloma infiltration in and about the Corresponding author and reprints: as Kirisawa uveitis. The American eye, and the ocular consequences of Paris G. Tranos, ICO, Department of Uveitis Society’s diagnostic criteria hematologic and serum protein ab- for ARN include the following: 1 or 3 4 Ophthalmology, Royal Free Hospital normalities. Bronstein reported Medical School, Pond Street, London more foci of retinal necrosis with dis- plasma cells floating free in the an- NW3 2QG, England (e-mail: crete borders commonly in the pe- terior chamber and adhering to the [email protected]). ripheral retina that show rapid cir- posterior cornea. Infiltration of the cumferential progression, dense iris has also been reported, simulat- 1. Knapp AJ, Gartner S, Henkind P. Multiple my- vitritis, AU, and occlusive vasculi- ing a nongranulomatous uveitis.5 eloma and its ocular manifestations. Surv Oph- tis.2 Other features that may be as- thalmol. 1987;31:343-351. However, to our knowledge, this is 2. Orellana J, Friedman AH. Ocular manifesta- sociated but are not required for the the first report of a myeloma pa- tions of multiple myeloma, Waldenstro¨m’s mac- diagnosis include optic neuritis or roglobulinemia, and benign monoclonal gam- tient with a well-formed, solid in- mopathy. Surv Ophthalmol. 1981;26:157-169. papillitis with subsequent optic at- filtrate in the anterior chamber that 3. Bataille R. Localized plasmacytomas. Clin Hae- rophy, early retinal detachment, and resembles a hypopyon (pseudo- matol. 1982;11:113-122. scleritis.2 The usual causative organ- 4. Bronstein M. Ocular involvement in multiple my- hypopyon). A pseudohypopyon is eloma. Arch Ophthalmol. 1955;55:188-192. ism is varicella-zoster virus, but her- characterized by its persistence and 5. Shakin EP, Augsburger JJ, Eagle RC Jr, et al. Mul- pes simplex virus (HSV) types 1 and irregular contour, which suggest tiple myeloma involving the iris. Arch Ophthal- 2 and cytomegalovirus have been mol. 1988;106:524-526. 3 clumping of neoplastic cellular ma- 6. Ells A, Clarke WN, Noel LP. Pseudohypopyon implicated. The diagnosis may be terial rather than the layering of neu- in acute myelogeneous leukemia. J Pediatr Oph- confirmed by the detection of viral thalmol Strabismus. 1995;32:123-124. trophils, as in anterior uveitis. 7. Shields CL, Shields JA, Gross NE, Schwartz GP, DNA by polymerase chain reaction Resolved blood remnants and Lally SE. Survey of 520 eyes with uveal metas- of a vitreous biopsy specimen or by neoplastic infiltrates may give rise to tases. Ophthalmology. 1997;104:1265-1276. the identification of intraocular an- 8. Fay AM, Leib ML, Fountain KS. Multiple my- a comparable appearance. Neoplas- eloma involving the orbit. Ophthal Plast Recon- tibody. tic infiltrates can be caused by acute str Surg. 1998;14:67-71. Acute retinal necrosis may oc- or chronic leukemias or juvenile casionally follow a mild self- xanthogranuloma, or they may be an limiting course, but in general re- atypical manifestation of retinoblas- quires aggressive treatment with tomas. In addition, metastatic car- Anterior Uveitis After high-dosage intravenous acyclovir or cinomas of the iris, which typically Healed Acute Retinal famciclovir, which may reduce the appear as solid, amelanotic masses, Necrosis incidence of the development of occasionally are discohesive and bilateral disease.4 High-dosage oral shed cells that form a hypopyon in Acute retinal necrosis (ARN) is a vi- prednisolone may be required, the anterior chamber.6,7 ral retinitis occurring predomi- particularly if optic disc swelling is Treatment of multiple my- nantly in immunocompetent per- present. To reduce the risk of reti- eloma is predominantly directed to- sons. Clinical diagnosis is based on nal detachment, prophylactic laser ward the systemic disease, and che- the presence of 1 or more periph- demarcation may be performed motherapy and radiotherapy are very eral foci of retinal necrosis that show around necrotic foci. Despite such effective in reducing the tumor rapid circumferential progression treatment, the prognosis for main- mass.8 In our patient, radiotherapy and often result in early retinal de- taining vision is generally poor. Vi- resulted in complete resolution of tachment. Characteristically, the ac- sual loss results from early retinal de- the anterior chamber infiltrate with tive phase is associated with ante- tachment, papillitis with secondary subsequent improvement of his vi- rior chamber inflammation and optic atrophy, or extensive necro- sual acuity. vitritis. We report a series of cases sis involving the macula. Our case of a solid anterior in which recurrent anterior uveitis Recurrence of ARN is docu- chamber infiltrate broadens the clini- (AU) occurred in the absence of re- mented, and second-eye involve- cal spectrum of multiple myeloma currence of posterior segment in- ment may occur several years later.5 and emphasizes that tumor infil- flammatory activity or retinitis, af- However, the recurrence of AU in trates should be considered in the ter the initial episode of healed ARN. the absence of active ARN, vitritis, differential diagnosis of any atypi- No patient was infected with hu- or retinitis has not been reported, to cal hypopyon. Close cooperation be- man immunodeficiency virus. All our knowledge.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 1. Characteristics of Acute Retinal Necrosis (ARN) in Patients Who Subsequently Developed Isolated Anterior Uveitis (AU) After Healed ARN*

Unilateral Duration of Patient Age, y/Sex vs Bilateral Episode, mo Recurrence of ARN Retinal Detachment Other Features 1 51/F Bilateral 2 Fellow eye 1 mo later No None 2 62/F Unilateral 6 No Yes None 3 23/F Bilateral 2 Fellow eye 14 y later Yes (right eye) Scleritis (anterior and posterior) 4 63/F Unilateral 72 No No None 5 65/F Unilateral 3 No No Old HSV and keratitis 6 43/M Unilateral 3 No No Old HSV and keratitis 7 35/F Unilateral 3 Recurrent ARN 4 mo after No Papillitis and cystoid macula resolution of AU edema

*HSV indicates herpes simplex virus.

Report of Cases. A retrospective a history of uveitis as a child be- 3+ cells and flare during the initial epi- case-note analysis of patients seen by tween age 5 and 14 years and an iso- sode of ARN. The isolated AU that fol- the Moorfields Eye Hospital’s uve- lated episode during pregnancy at age lowed was much less severe (1+ cells itis service, London, England, was 22. She had not had symptomatic AU and 1+ flare). Three patients had 2+ undertaken. Between 1992 and for 33 years before the development cells and flare during the initial ARN, 1998, 19 patients with classic ap- of ARN. Patient 6 had had recurrent 1 subsequently developing AU with pearance of ARN were identified. AU following dendritic ulceration be- 2+ cells and 2+ flare but the other 2 Ten were women and 9 were men, tween age 1 and 30 years. He had not having a milder (1+ cells and flare) AU with a mean age of 44 years (range, had symptomatic AU for 13 years after resolution. The remaining 3 pa- 18-79 years). No patients were in- before the episode of ARN. Another tients had mild (1+ cells and flare) AU fected with human immunodefi- patient had recurrent AU after ARN associated with the initial ARN and ciency virus. The causative organ- associated with recurrent severe similarly mild (1+ cells and flare) sub- ism was determined in 5 patients by scleritis. sequent isolated AU. One patient had polymerase chain reaction of a vit- One patient developed a sec- fine keratoprecipitate at the time of reous biopsy specimen. Of these, 1 ond episode of ARN in the same eye the ARN but not in subsequent at- was due to HSV-1; 2, to HSV-2; and after the initial episode had healed tacks of AU, and another patient de- 2, to varicella-zoster virus. Four pa- and following a subsequent epi- veloped fine keratoprecipitate with tients had bilateral disease. sode of the isolated AU. However, the subsequent AU. With the recur- Nine patients developed reti- this second episode of ARN oc- rent AU, one patient developed mild nal detachment (2 bilateral), and all curred 4 months after complete reso- posterior synechiae, but another de- but 1 underwent retinal reattach- lution of isolated AU. This was fol- veloped extensive posterior syn- ment surgery. Six patients had op- lowed by another attack of isolated echiae followed by iris bombe´ and re- tic disc swelling; 5 of these went on AU 3 months after the second epi- quired laser peripheral iridectomy. to develop a retinal detachment. sode of ARN had completely re- The 2 patients with prior herpetic an- All were treated with a stan- solved, lasting 1 month. Five months terior segment involvement had seg- dard regimen of 7 days of intrave- later, she had another episode of iso- mental iris atrophy. nous acyclovir (10 mg/kg of body lated AU in the absence of vitritis or All responded to treatment with weight 3 times a day) followed by ei- retinitis, but this was accompanied topical corticosteroids and mydriat- ther 800 mg of oral acyclovir 5 times by cystoid macula edema. Follow- ics without additional antiviral treat- daily or1goforal valcyclovir 3 times ing an orbital floor injection of meth- ment, and the AU did not herald a daily for 6 to 12 weeks, in conjunc- ylprednisolone acetate, the AU and further attack of ARN. Only 1 pa- tion with oral prednisolone at a start- deficiency resolved within 4 months. tient with AU after healed ARN had ing dose of 40 to 80 mg. Patients with The cystoid macula edema re- previously had a polymerase chain re- severe intraocular inflammation re- curred 1 month later, but with fur- action done on a vitreous biopsy ceived cyclosporine in addition to cor- ther treatment resolved completely specimen; this yielded HSV-1 DNA. ticosteroids. In all cases, the initial in- within another 6 months. This was a patient with preceding flammatory process resolved within The AU seen after resolution of herpetic anterior chamber involve- 3 to 6 months of treatment. ARN was generally consistent with ment (patient 6). The characteris- Of the 19 patients, 7 developed that seen initially, with similar or less tics of the ARN are summarized for AU in the absence of vitritis or new severe inflammation. Five of the 7 pa- each patient in Table 1. An outline foci of retinitis after complete reso- tients had nongranulomatous AU in of the subsequent clinical course and lution of the initial inflammation. Two the initial attack and in all episodes episodes of AU is given in Table 2. patients had a history of herpetic re- of recurrent AU. Two patients with In this study, the occurrence of current AU before the development granulomatous AU in the initial at- AU following healed ARN was not re- of ARN, but the AU had been dor- tack went on to have nongranuloma- lated to the severity of the initial epi- mant for several years. Patient 5 had tous recurrent AU. Only 1 patient had sode of ARN. In a multiple logistic re-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 tute of Ophthalmology, Moorfields Eye Table 2. Characteristics of Anterior Uveitis Occurring After Healed Acute Retinal Hospital, City Road, London EC1V Necrosis (ARN) 2PD, England (e-mail: s.lightman@ucl .ac.uk). Onset After No. of Healed Duration, Vitritis or Recurrent ARN 1. Urayama A, Yamada N, Sasaki T, et al. Unilat- Patient Episodes ARN, mo mo Retinitis or Sequelae eral acute uveitis with retinal periarteritis and 1 1 5 2 No No detachment. Jpn J Clin Ophthalmol. 1971;25:607- 619. 2 2 6, 9 1, 3 No No 2. Holland G, and the Executive Committee of the 3 10 3-264 1-3 No Recurrent American Uveitis Society. Standard diagnostic cri- scleritis teria for the diagnosis of the acute retinal necro- 4 1 2 1 No No sis syndrome. Am J Ophthalmol. 1994;117:663- 5 5 9-60 24 No No 667. 6 2 1, 3 1, 2 No No 3. Rugger-Brandle E, Roux L, Leuenberger PM, et al. Bilateral ARN: identification of the pre- 7 1 4 1 No Second episode sumed infectious agent. Ophthalmology. 1984; of ARN 91:1648-1658. 4. Palay DA, Sternberg P Jr, Davis J, et al. De- crease in the risk of bilateral acute retinal necrosis by acyclovir therapy. Am J Ophthalmol. gression analysis, severity factors, could be a secondary immune event. 1991;112:250-255. including duration of ARN, pres- Similar to the sensitization to retinal 5. Schlingemann RO, Bruinenberg M, Wertheim- ence or absence of bilateral disease, S antigen following panretinal pho- van Dillen P, Feron E. Twenty years’ delay of fellow eye involvement in herpes simplex virus type relapse of ARN, optic disc swelling, tocoagulation, the destruction of reti- 2–associated bilateral acute retinal necrosis syn- and retinal detachment, were stud- nal tissue may release antigen that drome. Am J Ophthalmol. 1996;122:891-892. ied. The occurrence of AU following may incite the production of antibod- healed ARN did not show a statisti- ies against ocular tissue. Molecular cally significant association with any mimicry between T cells specific for of these factors, but a larger sample the virus could be implicated, cross- Pseudomonas size would be required to evaluate this reacting with ocular tissue, the mo- aeruginosa–Related conclusively. lecular structure of which may be na- tive, altered, or rendered manifest by Postoperative Comment. In this retrospective clini- the initial tissue damage. As this Endophthalmitis Linked cal study, we found that healed ARN phenomenon does not occur in all to a Contaminated may be followed by recurrent AU in patients with ARN, there may be a Phacoemulsifier the absence of posterior segment in- genetic predisposition to the devel- flammation or a recurrence of ARN. opment of recurrent AU following Cataract extraction is a commonly This phenomenon could be either a healed ARN. performed operation in the United direct effect of the virus itself, per- Two of the 7 patients in this se- States, with 1.3 million procedures sistent or reactivated, or a second- ries with recurrent AU had had ante- performed annually. Postoperative ary immunological effect. In this rior segment herpetic disease that pre- endophthalmitis is a potentially dev- study, 7 of 19 patients with ARN de- dated the ARN. As a history of ocular astating complication, with an inci- veloped recurrent AU. Only 1 of the herpetic disease or cold sores is rare dence of approximately 0.1% to 7 developed a second episode of inpatientswithARN,itispossiblethat 0.3%.1,2 We report herein an evalu- ARN. This observation does not fa- previous herpetic anterior segment ation of an outbreak of postopera- vor a hypothesis of recurrent low- involvement, even several years ear- tive endophthalmitis. grade herpetic infection or a latent lier, could predispose patients with This outbreak was investi- herpetic infection resulting in an in- ARN to the development of recurrent gated by the North Carolina State- termittent inflammatory response AU after resolution of the ARN. wide Program for Infection Control analogous to the recurrence of the Recurrent AU may follow healed and Epidemiology. Patient cultures common cold sore. Furthermore, in ARN without evidence of recurrent were performed in a hospital micro- 1 patient, the anterior chamber was herpetic involvement. It is possible biology laboratory. Environmental tapped at the time of an episode of that the destructive retinitis results in cultures were processed as follows. subsequent AU, and HSV DNA was an autoimmune response, and recur- Medication vials and water samples not detected by polymerase chain re- rent anterior chamber immune- were processed by filtration using a action. This patient did not have a mediated inflammation can occur. disposable filter (MSI Savur Analyti- history of herpetic disease or AU be- cal filter; Osmonics, Minnetonka, fore ARN. Similarly, this would not Marie Comer, MRCP, FRCOphth Minn) placed on either sheep blood support recurrent low-grade persis- Stephanie Young, FRACO, FRACS or D/E-neutralizing agar. Fluids too tent herpetic infection as a likely Susan Lightman, PhD, FRCP, viscous for filtration (eg, Keri Lo- cause, but clearly a negative result FRCOphth tion) were plated directly onto suit- in 1 case does not conclusively ne- London, England able media. Environmental sur- gate the low-grade infection hypoth- faces (eg, sink drains) were cultured esis in the other patients. Corresponding author: Susan Light- using a sterile swab premoistened We therefore hypothesize that man, PhD, FRCP, FRCOphth, Depart- with trypticase soy broth and then isolated AU following healed ARN ment of Clinical Ophthalmology, Insti- plated directly onto appropriate agar.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 1. Clinical Characteristics of Patients Who Underwent Cataract Extractions on the Outbreak Day*

Patient No.†

Clinical Characteristic 1 2 345 678 9 Demographic features Age, y 74 70 83 84 64 61 66 48 85 Sex Male Female Female Female Female Male Male Male Male AODM Yes Yes No No No No No No No Operative features Eye involved Right Left Right Left Right Right Left Right Left Lens implanted Yes No Yes Yes Yes Yes Yes Yes No Cataract extraction method Phaco Corneal Phaco Phaco Phaco Phaco Phaco Phaco Corneal relaxation transplantation Phacoemulsification time, s 57 NA 42 44 25 37 39 22 NA Endophthalmitis onset POD 1 NA POD 1 NA POD 1 (PM) POD 3 NA POD 2 NA Cultures Site AC NA AC NA PC PC NA PC NA Results NG NA PA‡ NA PA PA NA PA and PM NA Intravitreal antibiotic therapy§ Without vitrectomy 1 NA 1 NA 0 1 NA 0 NA With vitrectomy 1 NA 1 NA 2 1 NA 2 NA Visual acuity Preoperative 20/50 NA 20/100 NA 20/50−1 20/400 NA 20/200 NA Postoperative Worst HM NA HM NA HM HM NA HM NA Best 20/30 NA 20/20 NA 20/20࿣ 20/20 NA 20/20 NA

*AODM indicates type 2 diabetes mellitus; Phaco, cataract extraction using phacoemulsification; POD, postoperative day; PM, Proteus mirabilis (2 colonies); AC, anterior chamber; PC, posterior chamber (vitreal tap); NG, no growth; PA, Pseudomonas aeruginosa; HM, hand movements; and NA, data not applicable. †The operative order is the same as the patient number. ‡In addition, ␣-hemolytic streptococcus and Enterococcus species grew from the broth only. §Data are given as the number of times therapy was administered. ࿣This patient experienced late development of retinal detachment.

To determine the relatedness of Pseudomonas aeruginosa isolates, we Table 2. Results of Environmental Cultures performed pulsed-field gel electrophoresis using standard tech- Environmental Culture Results niques. Cultures Obtained 9 d After the Outbreak The North Carolina Statewide Air tubing No growth Program for Infection Control and Povidone-iodine (Betadine) solutions* No growth Epidemiology was notified on Oc- Povidone-iodine (Betadine) and isotonic sodium No growth tober 14, 1999, about a cluster of chloride solution Balanced salt solution* No growth cases of postoperative endophthal- Sterile water vial No growth mitis. Preliminary data obtained via Sterile vancomycin hydrochloride No growth telephone revealed that 5 of 7 pa- Wydase No growth tients who underwent a cataract ex- Phenylephrine hydrochloride No growth traction with phacoemulsification BioLon hyaluronate sodium No growth Keri Lotion No growth and implantation of an intraocular Scrub sink drain Growth, not Pseudomonas lens on October 11, 1999 (out- Starr surgical pens Nos. 1 and 2 Growth, not Pseudomonas break day), had developed postop- Water pick Growth, not Pseudomonas erative endophthalmitis (Table 1). Tap water in the autoclave room Growth, not Pseudomonas Sink aerator from the dirty utility room Growth, not Pseudomonas Patients were seen postoperatively Scrub sink drain Pseudomonas aeruginosa (nonoutbreak strain) with severe pain in the involved eye, Scrub sink P aeruginosa (nonoutbreak strain) conjunctival hyperemia, and de- Internal tubing phacoemulsifier P aeruginosa (outbreak strain) creased visual acuity. Cultures Obtained 14 d After the Outbreak Prednisone acetate suspension No growth Report of Cases. All infected pa- Erythromycin ophthalmic ointment No growth tients had undergone cataract ex- Starr surgical pen No. 3 No growth traction in the right eye, and all non- Tropicamide (Mydriacyl) No growth Cyclogyl No growth infected patients had undergone Proparacaine hydrochloride (Alcaine) No growth cataract extraction in the left eye Phenylephrine hydrochloride No growth (P=.048, 2-tailed Fisher exact test). Brimonidine tartrate (Alphagan) No growth All cataract procedures were per- Ofloxacin (Ocuflox) No growth formed using automated phacoemul- Pilocarpine hydrochloride No growth sification with a phacomachine *Obtained 3 times.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 extraction are linked to use of con- 14 13 12 11 10 9 8 7 6 5 4 3 2 1 taminated multidose vials or irrigat- ing solutions and to an intrinsically contaminated intraocular lens; re- cently, 2 European outbreaks were linked to use of a contaminated phacoemulsifier.3,4 We demonstrated that all in- fecting strains of P aeruginosa were identical by pulsed-field gel electrophoresis. Patient 1’s culture did not yield P aeruginosa, but only the aqueous humor was cultured. In patients with endophthalmitis, cultures of the aqueous humor are less sensitive than cultures of the vitreous. We believe that the additional organisms cultured from patient 3 represented contaminants. We believe that the phacoemulsifier was the source of this outbreak. All patients who underwent an operation on their right eye developed infection, while all patients who underwent an operation on their left eye were uninfected. The operating room was set up in such a way that the phacoemulsifier was placed on the patient’s right side. Thus, when the left eye was oper- ated on, the tubing for the phaco- Figure 1. Pulsed-field gel electrophoresis of Pseudomonas aeruginosa isolates. The sources of the emulsifier was stretched more taut. isolates in each lane are as follows: 1, ␭ ladder; 2, patient 5 (outbreak strain a); 3, patient 5 (outbreak strain a); 4, patient 5 (outbreak strain a); 5, unrelated patient isolate (strain b); 6, patient 3 (outbreak This may have led to gravity back- strain a); 7, patient 8 (outbreak strain a); 8, patient 8 (outbreak strain a); 9, patient 6 (outbreak strain a); flow of contaminated fluid during 10, right scrub sink (strain c); 11, interior tubing of the phacoemulsifier (outbreak strain a); 12, unrelated operations on the right eye and environmental isolate (strain d); 13, unrelated environmental isolate (strain d); and 14, scrub sink drain might explain the significantly dif- (strain c). ferent infection rates between left and right eyes. (AMO Diplomax; Allergan Inc, Ir- Thefluidpathwaysofthephaco- Contamination of the internal vine, Calif) that used a peristaltic emulsifier are shown in Figure 2A. tubing of 3 different models of pump, followed by implantation of The outflow tubing is connected via phacoemulsifiers that used a peri- a Starr foldable silicone intraocular a T fitting to a pressure transducer staltic pump was first demon- lens. All patients received 0.3% and air valve system that is housed strated in 1986.5 Under certain ofloxacin drops, 3 times per day, within the machine (Figure 2B). Us- vacuum settings, air was intro- postoperatively. ing methylene blue, we investi- duced into the aspiration catheter Following notification of this gated conditions that might lead to from the machine, and during this outbreak, we recommended that no retrograde flow from the internal venting process, previously seques- additional operations be per- tubing to the handpiece. Disrupt- tered fluids in the machine could be formed. Multiple environmental cul- ing the sealed connection of the in- regurgitated back into the aspira- tures were obtained on days 9 and ternal tube from the pressure trans- tion catheter, resulting in potential 14 after the outbreak (Table 2). The ducer was effective in producing transmission of pathogens. de Kasper P aeruginosa isolates from 4 pa- almost immediate reflux that and colleagues6 investigated the con- tients and 3 environmental sites were reached the handpiece within 2 min- tamination rates of automated evacu- compared using pulsed-field gel elec- utes. ation systems equipped with an in- trophoresis (Figure 1). All pa- ternal vacuum control manifold tient isolates and the strain isolated Comment. Postoperative endoph- compared with a system equipped from the phacoemulsifier’s internal thalmitis is a potentially devastat- with a modified external vacuum tubing were identical. The strains of ing complication of cataract sur- control manifold that was steril- P aeruginosa isolated from the scrub gery, with an incidence of 0.08% to ized between patients; 2+ to 4+ bac- sink and its drain were identical, but 0.30%.1,2 Multiple P aeruginosa– terial growth was found in all speci- differed by multiple bands from the related outbreaks of postoperative mens from the internal vacuum patient strains. endophthalmitis following cataract control manifold system. They

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 A rograde flow. This might occur with a leak at one of the fittings, a small defect in the transducer, or an in- BSS termittently sticking air valve. To our knowledge, this represents the third outbreak of postoperative endophthalmitis due to P aeruginosa linked to use of a con- Fluid Valves taminated phacoemulsifier and the Inflow first report from North America. All Reflux Line Pressure manufacturer’s recommendations re- Transducer garding machine maintenance were Handpiece Outflow followed. These 3 outbreaks linked AV to a contaminated phacoemulsifier Case suggest that this device may need to be redesigned to reduce the likeli- P hood of contamination or that additional disinfection methods may need W to be routinely used.

Karen K. Hoffmann, MS David J. Weber, MD, MHA, MPH B Maria F. Gergen, MT(ASCP) William A. Rutala, PhD Chapel Hill, NC George Tate, MD Charlotte, NC

None of the authors has any finan- cial interest in the company that manu- factured the phacoemulsifier described in this article. We thank Marlene Durand, MD, for reviewing the manuscript. Corresponding author and reprints: David J. Weber, MD, MHA, MPH, University of North Carolina at Chapel Hill, Campus Box 7030, Bur- nett-Womack, Room 547, Chapel Hill, NC 27599-7030 (e-mail: dweber@ unch.unc.edu).

1. Weber DJ, Durand M, Rutala WA. Nosocomial Figure 2. A, Schematic view of the fluid channels of the phacoemulsifier. BSS indicates balanced salt ocular infections. In: Mayhall GC, ed. Hospital Epi- solution; AV, air valve; P, peristaltic pump; and W, waste disposal container. Tubing to the right of the demiology and Infection Control. 2nd ed. Philadel- “case” is within the interior of the machine. B, The internal tubing of the phacoemulsifier. S indicates phia, Pa: Williams & Wilkins; 1999:287-299. 2. Durand ML, Heier JS. Endophthalmitis. Curr Clin pressure sensor; T, internal tubing; F, filter; and V, air valve. Top Infect Dis. 2000;20:271-297. 3. Cruciani M, Malena M, Amalfitano G, Monti P, Bonomi L. Molecular epidemiology in a cluster emphasized that “the observed Using methylene blue, we dem- of post-operative Pseudomonas aeruginosa endophthalmitis. Clin Infect Dis. 1998;26:330-333. contamination of intraocular sur- onstrated the possibility of retro- 4. Zaluski S, Clayman HM, Karsenti G, et al. Pseu- gery machines is not related to a grade flow when the internal tub- domonas aeruginosa endophthalmitis caused by specific company but must be ing was disconnected from the contamination of the internal fluid pathway of a phacoemulsifier. J Cataract Refract Surg. 1999; attributed to the technical con- transducer. Although the machine 25:540-545. stituent of an inbuilt and inacces- would not pass normal preopera- 5. Clayman HM, Parel J-M, Miller D. Bacterial recovery from automated cataract surgical equip- sible internal vacuum control tive checks with this malfunction, it ment. J Cataract Refract Surg. 1986;12:158-161. manifold that exists in a wide vari- seems plausible that a small leak 6. de Kasper HM, Grasbon T, Kampik A. Auto- ety of types of automated intra- might have a similar or intermit- mated surgical equipment requires routine disinfection of vacuum control manifold to ocular surgery machines of several tent result, and the machine could prevent postoperative endophthalmitis. Oph- producers.”6(p690) still pass the check yet lead to ret- thalmology. 2000;107:685-690.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 examination revealed mild anterior at the posterior hyaloid near the disc, Intraocular Hemorrhages chamber cells and anterior vitritis in a new preretinal hemorrhage over the Due to Warfarin- both eyes. Funduscopic examina- disc and the papillomacular nerve fi- Fluconazole Drug tion revealed vitreous haze and mul- bers, and macular striae (Figure 2). tiple fluffy cotton-ball chorioretinal Examination of the left eye revealed a Interaction in a Patient opacities predominantly in the left eye massive hemorrhagic choroidal de- With Presumed Candida (Figure 1). A diagnosis of bilateral tachment confirmed by B-scan ultra- Endophthalmitis Candida endophthalmitis was made. sound (Figure 3). Laboratory evalu- The patient received an intravitre- ationrevealedamarkedlyelevatedpro- Fluconazole is a triazole antifungal ous injection of 5 µg of amphoteri- thrombintimeof67.8seconds(normal effective against Candida endoph- cin B in the left eye after vitreous bi- range, 9.9-13.0 seconds). The warfa- thalmitis. It potentiates the antico- opsy, and was administered 400 mg rinwasdiscontinuedandthemedicine agulant effect of warfarin sodium.1 of oral fluconazole daily by the in- service was consulted. The patient de- fectious disease service. Vitreous bi- clined surgical drainage of the choroi- Report of a Case. A 44-year-old man opsy revealed leukocytes on Gram dal hemorrhage in the left eye. experienced worsening vision and stain, but fungal culture revealed no Two months later, the patient’s floaters in both eyes for 1 month. His growth. visual acuity further decreased to medical history included alcohol- Two weeks later, he had de- counting fingers at 2 ft OD. Fundu- ism and pancreatitis. He had been ad- creased vision in his left eye. Medica- scopic examination of his right eye mitted to another hospital for paren- tionsincluded2.5mgofwarfarindaily, revealed a dense vitreous hemor- teral hyperalimentation via a central 400 mg of fluconazole daily, and 1% rhage with ochre staining of the pos- line, complicated by a deep venous prednisolone acetate 4 times daily in terior hyaloid. He underwent pars thrombosis of his internal jugular vein both eyes. Visual acuity decreased to plana vitrectomy in that eye, and requiring anticoagulation with war- counting fingers at 7 ft OD and light postoperative visual acuity im- farin. His visual acuity without cor- perception OS. Funduscopic exami- proved to 20/20 OD without correc- rection was 20/400 OD and count- nation of his right eye revealed de- tion (Figure 4). ing fingers at 3 ft OS. Slitlamp creased vitritis, cotton-ball opacities Comment. Massive subretinal and vitreous hemorrhages have been re- A B ported as complications of anticoagulation in patients with age- related macular degeneration (ARMD).2,3 El Baba et al3 reported that 19% of the patients with ARMD who developed massive intraocular hemorrhages were taking warfarin or aspirin. Histopathological analysis revealed that rupture of choroidal vessels in disciform scars ac- counted for the massive hemorrhages.2 Our patient’s preretinal and Figure 1. A, Fundus photograph of the right eye showing mild vitreous haze, a small preretinal vitreous hemorrhage in his right eye hemorrhage, and a few fluffy, white chorioretinal infiltrates. B, Left fundus photograph showing multiple chorioretinal infiltrates and marked vitreous haze. and the choroidal hemorrhage in his left eye probably resulted from the coagulopathy due to the warfarin- fluconazole interaction. Abnormal

Figure 2. Fundus photograph of the right eye showing an increased preretinal hemorrhage extending from the optic nerve to the macula and an improvement in vitreous haze and chorioretinal infiltrates. Figure 4. Fundus photograph of the right eye following pars plana vitrectomy, showing a mild Figure 3. B-scan ultrasound of the left eye, epiretinal membrane and fibrovascular tissue at showing massive choroidal hemorrhage. the optic nerve.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 vessels of chorioretinal scars caused hemorrhages related to warfarin- Lomas Blvd NE, Albuquerque, NM by Candida endophthalmitis may be fluconazole drug interaction. Pro- 87131-5341 (e-mail: vmootha@salud the source of the hemorrhages in our thrombin times must be monitored .unm.edu). patient. The cytochrome P4502C9 closely when fluconazole is coad- 1. Seaton TL, Celum CL, Black DJ. Possible poten- enzyme metabolizes many drugs, in- ministered with warfarin. tiation of warfarin by fluconazole. DICP. 1990; cluding warfarin.4 Fluconazole sig- 24:117-118. 2. Brown GC, Tasman WS, Shields JA. Massive sub- nificantly inhibits cytochrome V. Vinod Mootha, MD retinal hemorrhage and anticoagulant therapy. P4502C9 and potentiates the cou- Mark L. Schluter, MD Can J Ophthalmol. 1982;17:227-230. 4 3. El Baba F, Jarrett WH, Harbin TS, et al. Massive madin effect. Since 1990, the non- Arup Das, MD, PhD hemorrhage complicating age-related macular de- ophthalmic literature has con- Albuquerque, NM generation: clinicopathologic correlation and role tained reports of the adverse effects of anticoagulants. Ophthalmology. 1986;93:1581- 1592. of warfarin-fluconazole drug inter- Corresponding author: V. Vinod 4. Miners JO, Birkett DJ. Cytochrome P4502C9: an action.1 To our knowledge, this is the Mootha, MD, University of New enzyme of major importance in human drug me- first reported case of intraocular Mexico Health Sciences Center, 2211 tabolism. Br J Clin Pharmacol. 1998;45:525-538.

From the Archives of the ARCHIVES

A look at the past...

Kopff (Paris): A Case of Bilateral Optic Neuritis Caused by Influenza Ending in Recovery he optic neuritis appeared on the sixth day of the disease with reduc- tion of vision to the ability to count fingers, mydriasis, and papillo- T retinitis. The treatment consisted in the use of leeches, quinine, calo- mel, and milk diet. Four months later the vision of the right eye rose to 8/10, and that of the left to 7/10.

Reference: Berger E. Report of the ophthalmological section of the 13th Inter- national Medical Congress in Paris, August 2-9, 1900. Arch Ophthalmol. 1901;30:190.

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