Nodular Scleritis in a Patient with Pyoderma Gangrenosum

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

leukemia that manifested initially as cyte marker), cytokeratin (epithe- Acute Myeloid Leukemia an epibulbar mass. lial marker), and melanoma mark- Manifesting Initially ers HMB-45 and S100 protein. A stain as a Conjunctival Mass Report of a Case. A 47-year-old Af- for myeloperoxidase was weakly posi- rican American man with acquired tive, and the Leder chloroacetate es- in a Patient With immunodeficiency syndrome (AIDS) terase stain disclosed cytoplasmic Acquired Immunodeficiency who was being treated with highly ac- granules in tumor cells evincing Syndrome tive antiretroviral therapy devel- granulocytic differentiation (Figure oped bilateral pink conjunctival le- 2B). The findings were consistent The ophthalmic manifestations of sions during a 2-week period. There with granulocytic or myeloid sar- human immunodeficiency virus were 3 lesions noted on the bulbar coma. Myeloid sarcoma indicates tis- (HIV) infection range from mollus- conjunctiva of each eye (Figure 1). sue involvement by acute myeloid cum contagiosum of the eyelid to The subconjunctival tumors mea- leukemia cells. cotton-wool spots of the retina.1-4 sured up to 7 mm in basal diameter The patient reported previous Additionally, HIV infection is asso- and 2 mm in thickness and had no small subcutaneous lesions on his ciated with several opportunistic apparent intrinsic vasculature. Di- arms, back, abdomen, and legs, most cancers of the eye and orbit,2 includ- lated, tortuous blood vessels fed each of which had appeared and re- ing conjunctival squamous cell car- tumor. Visual acuity was 20/20 OU, gressed during the prior 10 weeks. cinoma,3 Kaposi sarcoma,4 and non- and both fundi were normal. An excisional biopsy specimen of Hodgkin lymphoma.4 In this report, Excisional biopsy of one of the one of the skin tumors originally was we illustrate the rare association of lesions was performed to role out Ka- diagnosed elsewhere as a high- HIV infection with acute myeloid posi sarcoma, non-Hodgkin lym- grade lymphoma, but the tumor was phoma, leukemia, or an opportunis- reclassified by the National Cancer tic infection. Routine histopathologic Institute as an immature hemato- examination showed a diffuse infil- poietic malignancy consistent with trate of poorly differentiated malig- myeloid sarcoma with monocytic nant cells that had large, irregular ve- differentiation. Additional immu- sicular nuclei, prominent nucleoli, nohistochemical studies per- and relatively abundant cytoplasm formed at the National Cancer In- (Figure 2A). The cells showed posi- stitute confirmed that the tumor cells tive immunoreactivity for CD43 (my- were reactive for lysozyme, KP-1, eloid marker), lysozyme (leukocyte and CD43 but were negative for marker), and KP-1 (CD68, mono- CD20 (B lymphocyte marker), cyte cytoplasmic antigen marker). CD79A (B lymphocyte marker), my- They stained negative for lympho- eloperoxidase (leukocyte marker), Figure 1. The left eye of a patient with acquired immunodeficiency syndrome shows a pink bulbar cyte markers CD20 (B lymphocyte CD30 (B lymphocyte, T lympho- subconjunctival mass with dilated feeder vessels. marker) and UCHL-1 (T-lymphocyte, and monocyte marker), CD34

A B

Figure 2. A, A photomicrograph shows a section of conjunctival granulocytic sarcoma with large cells, prominent nuclei, eosinophilic nucleoli, and relatively abundant cytoplasm (hematoxylin-eosin, original magnification ϫ250). B, A photomicrograph of a section of conjunctival granulocytic sarcoma stained with Leder chloroacetate esterase demonstrates the presence of cytoplasmic lysozyme granules (original magnification ϫ250).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 (pluripotent progenitor cell marker), Acute myeloid leukemia oc- delphia (Dr C. L. Shields), the Macula and human herpesvirus 8. In situ hy- curs most commonly in white men, Foundation, New York, NY (Dr C. L. bridization studies for Epstein-Barr and its incidence increases with age. Shields), the Paul Kayser Interna- virus were negative. A bone mar- The average age at diagnosis is older tional Award of Merit in Retina Re- row biopsy and aspiration showed than 65 years.5 The initial symp- search, Houston, Tex (Dr J. A. hypocellular marrow with left- toms of acute myeloid leukemia in- Shields), and the Noel T. and Sarah shifted myelopoiesis. The periph- clude fatigue, weight loss, bleed- L. Simmonds Endowment for Oph- eral blood smear contained rare ing, easy bruising, and susceptibility thalmic Pathology, Wills Eye Hospi- immature hematopoietic cells con- to infection. The incidence of acute tal, Philadelphia (Dr Rice). sistent with myeloid origin. The pa- myeloid leukemia in patients with Corresponding author: Carol L. tient was treated with chemo- AIDS is approximately 2-fold com- Shields, MD, Oncology Service, Wills therapy with initial favorable results, pared with the general popula- Eye Hospital, 900 Walnut St, Phila- but systemic involvement was found tion.6 Acute myeloid leukemia is delphia, PA 19107. 5 months later, and the patient de- caused by numerous nonrandom 1. Cunningham ET, Margolis TP. Ocular manifes- clined further treatment. chromosomal abnormalities, the ma- tations of human immunodeficiency virus in- jority of which are translations, and fection. N Engl J Med. 1998;339:236-244. environmental carcinogens.5 2. Purtilo DT. Opportunistic cancers in patients Comment. Patients with AIDS have with immunodeficiency syndromes. Arch Pathol impaired cellular immunity that can Granulocytic sarcoma is a vari- Lab Med. 1987;111:1123-1129. lead to opportunistic infections and ant of acute myeloid leukemia that 3. Winward KE, Curtin VT. Conjunctival squa- 1,2 mous cell carcinoma in a patient with human im- malignancies. Previously pub- occurs as an invasive solid mass, most munodeficiency virus infection. Am J Ophthal- 7 lished reports have shown a relation- frequently in bone. Zimmerman and mol. 1989;107:554-555. ship between AIDS and conjuncti- Font7 described 33 patients with 4. Tunc M, Simmons M, Char D, Herndier B. Non- Hodgkin’s lymphoma and Kaposi’s sarcoma in val malignancies such as Kaposi granulocytic sarcoma of the ocular an eyelid of a patient with acquired immunode- sarcoma, non-Hodgkin lymphoma,4 tissues, involving the orbit (26 pa- ficiency syndrome. Arch Ophthalmol. 1997;115: 3 tients), eyelid (4 patients), lacrimal 1464-1466. and squamous cell carcinoma. These 5. Giles FJ, Koeffler PH. Myeloid neoplasms. In: ocular malignancies found in pa- gland (3 patients), uveal tract (2 pa- Haskell CM, ed. Cancer Treatment. 4th ed. Phila- tients with AIDS are suspected to be tients), and conjunctiva (1 patient). delphia, Pa: WB Saunders; 1995:905-921. 1-4 6. Sutton L, Guenel P, Tanguy ML, et al. Acute my- of viral origin. There is evidence In 52% of these patients, hemato- eloid leukaemia in human immunodeficiency vi- linking squamous cell carcinoma to logic evidence of leukemia was pres- rus–infected adults: epidemiology, treatment fea- human papillomavirus.3 Kaposi sar- ent at diagnosis. In 88% of patients, sibility, and outcome. Br J Haematol. 2001;112: 900-908. coma–associated human herpesvi- the ophthalmic lesion was the ini- 7. Zimmerman LE, Font RL. Ophthalmic manifes- rus 84 and Epstein-Barr virus2 have tial sign of leukemia. In a series of 121 tations of granulocytic sarcoma (myeloid sar- children from Turkey with acute my- coma or chloroma). Am J Ophthalmol. 1975;80: been detected in Kaposi sarcoma and 975-990. lymphoma tissue, respectively. It has elomonocytic leukemia (M4), 27% 8. Cavdar AO, Babacan E, Go¨szdas¸og˘lu S, et al. High been postulated that HIV may play a presented with granulocytic sar- risk subgroup of acute myelomonocytic leuke- 8 mia with orbito-ocular granulocytic sarcoma in permissive role by allowing these vi- coma in either the orbit or eyes. Turkish children. Acta Haematol. 1989;81:80-85. ruses to evade the host immune sys- The pink conjunctival tumors tem and proliferate.2 Epstein-Barr vi- present in our patient were initially rus and human herpesvirus 8 were suspicious for Kaposi sarcoma, lym- not detected in our patient’s tumor, phoma, or leukemia. All 3 malig- In Vivo Confocal however. nancies can be associated with HIV Microscopy of the Cornea According to the French- infection. The immunodeficient pain Nephropathic Cystinosis American-British classification of tient should be watched carefully for acute leukemia, acute myeloid leu- opportunistic infections and malig- We report a case of nephropathic kemia is classified into 9 different nancies. Appropriate diagnosis is cystinosis, with corneal crystals, im- subtypes depending on the morpho- crucial for providing proper treat- aged and analyzed by in vivo con- logical and cytochemical character- ment. Thus, in addition to Kaposi focal microscopy. The subject had istics of cells.5 These subtypes range sarcoma, non-Hodgkin lymphoma, a visual acuity of 6/6 OU. Slitlamp from M0 (acute myeloid leukemia and squamous cell carcinoma, acute biomicroscopy revealed dense, hy- without cytologic maturation) to M7 myeloid leukemia should also be rec- perreflective cysteine crystals cor- (acute megakaryocytic leukemia). ognized as a conjunctival malig- responding to a “Gahl score” of 2.75 The most commonly diagnosed sub- nancy associated with AIDS. to 3.00 in both eyes. In vivo confo- type is the M2 type (30% of pa- cal microscopy highlighted dense, tients) in which the cells show sig- Jeffrey A. Nau, MMS polyhedral crystals throughout the nificant maturation. Morphological Carol L. Shields, MD posterior stroma and crisscrossing and immunohistochemical findings Jerry A. Shields, MD crystals of similar density through- in our patient appeared most consis- Ralph C. Eagle, MD out the anterior stroma. Quantita- tent with subtype M5, acute mono- Edgar Rice, MD tive assessment suggested that crys- cytic/monoblastic leukemia (10% of Philadelphia, Pa tal density was lowest in the middle patients). Interestingly, M5 is the leu- stroma. The longitudinal and trans- kemic subtype most often associ- This study was supported by the Eye verse diameters of a total of 100 crys- ated with soft tissue involvement. Tumor Research Foundation, Phila- tals for anterior and posterior stro-

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C D

Figure 1. Slitlamp biomicroscopy of the cornea demonstrating dense hyperreflective cysteine crystals distributed throughout the entire cornea of the right (A) and left (B) eyes. Careful examination of the optical section reveals random distribution of the crystals throughout corneal thickness (C and D).

mal layers were measured and of 22 years. From the age of 1 year Careful examination of the optical analyzed. The advantages of in vivo he was treated with oral cyste- section revealed a random distribu- confocal microscopy for microstruc- amine hydrochloride that was tion of the crystals throughout the tural analysis of a living human cor- changed to oral cysteamine bitar- corneal thickness; however, there nea might provide useful informa- trate because of a manufacturer’s was apparently greater density to- tion about the natural history of change in 1999. He has always been ward the limbus (Figure 1). crystal deposition and growth aware of having photophobia but re- Crystals were also identified throughout the stromal layers in sub- ported a worsening of his symp- over the anterior surface of the iris. jects with cystinosis. toms following the change in his sys- Intraocular pressures were 12 and 13 Infantile nephropathic cystino- temic medication; however, because mm Hg, OD and OS, respectively, sis may affect vision due to corneal of serious life-threatening prob- and there were no signs of poste- disease, retinopathy, or glaucoma.1 lems, his eye symptoms have been rior segment involvement. Of these 3 complications, glau- considered less important. Unfor- coma is the one most commonly as- tunately, the subject cannot be of- Results. The methodology for in sociated with significant visual loss fered treatment with topical cyste- vivo confocal examination has been in adult subjects.2 Corneal crystals amine drops because the medication published previously.5 In the case re- may be observed as early as age 1 is currently not registered in New ported herein, 4 passes at a 900-µm year, but they generally have a be- Zealand. working distance were used. To nign course and rarely cause severe The subject’s examination in minimize image glare and reflec- visual loss, although photophobia is our unit included photobiomicros- tions from the hyperreflective crys- a common symptom.3 Recently, cor- copy, in vivo confocal microscopy, tals, the intensity of the light was de- neal crystals have been successfully tonometry, and fundus dilatation. creased to approximately half the treated with cysteamine drops.3,4 The subject had a visual acuity of 6/6 usual intensity for human subjects. OU. Slitlamp biomicroscopy re- The bright reflections prevented vi- Report of a Case. A 24-year-old man vealed dense, hyperreflective cyste- sualization of the cellular elements received a diagnosis of cystinosis at ine crystals corresponding to a score of the stroma, but the endothelial the age of 14 months and under- of 2.75 to 3.00 in both eyes based on mosaic and superficial epithelial lay- went renal transplantation at the age the library published by Gahl et al.3 ers were clearly recognizable. Only

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D E F

Figure 2. In vivo confocal microscopy demonstrated dense, polyhedral crystals in the region in front of Descemet membrane (A). Anteriorly, a few larger crystals were highlighted, and most of the smaller crystals were needle shaped (B-D). Crystals in the anterior fifth of the stroma were more crisscrossing and less bright than the crystals in the posterior stroma (E and F).

the central cornea was examined be- middle stroma (Figure 2). The cor- tral cornea to be best for analysis in cause the reflections from the pe- neal endothelium and epithelium ap- our subject, but we believe that this ripheral cornea were very bright. peared to be normal in respect to site may be beneficial for several rea- Two acquisitions were performed for structure and cell density; how- sons: the central cornea is thinner each eye and a total of 900 images ever, stromal keratocytes were shad- with fewer crystals, providing easier were saved onto a hard disk drive. owed by the crystals thus making structural discrimination and mea- Despite being very photophobic the evaluation impossible. surement, the examination can be re- subject had no difficulties undergo- peated using the pupillary margin as ing the examination. Comment. The cornea has been a landmark, and, finally, the dynam- In vivo confocal microscopy vi- called “the window to cystinosis”; ics of the central cornea may be more sualized the crystals in detail and their however, the cause for the severity closely associated with the pa- appearance in both eyes was very and progression of the corneal pre- tient’s symptoms such as photo- similar. Immediately in front of Des- sentation is still not clear.3 It has phobia and glare. In addition, the cemet membrane the crystals were been proven that cysteamine drops examination by in vivo confocal mi- dense and polyhedral, the longitudi- may have a beneficial effect in up to croscopy is relatively quick (2-5 min- nal and transverse diameters mea- 62% of symptomatic patients and pa- utes) and in this report our subject suring 85±37 µm to 43±29 µm tients with recurrent erosion syn- coped well with the procedure with (mean±SD) (n=50 measurements), drome.3 However, the effect of the no unusual symptoms. respectively. Anteriorly, a few larger medication has been evaluated An alternative method of ex- crystals were highlighted; however, “semiquantitatively” on the basis of amination in these subjects is ultra- most of the smaller crystals were clinical photography.3 sound biomicroscopy (UBM).2 The needle shaped. Crystals in the ante- We report the application of in advantage of this technique is visu- rior fifth of the stroma appeared to be vivo confocal microscopy for imag- alization of a larger area of the cor- crisscrossing and of similar density, ing both corneas of a subject who has nea and adjacent structures includ- with longitudinal and transverse di- nephropathic cystinosis. By careful ing the conjunctiva, iris, anterior ameters measuring 57±41 µm to modulation of the confocal set- chamber angle, and lens.2 How- 21±17 µm (mean±SD) (n=50 mea- tings, the crystals can be visualized ever, owing to low magnification, surements), respectively. However, in detail, providing an excellent op- comparable to the conventional slit- quantitative assessment suggested portunity for qualitative and quan- lamp, UBM provides only a semi- that crystal density was lowest in the titative analysis. We found the cen- quantitative analysis of the corneal

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 crystals.2 Our report demonstrates ment of corneal cystine crystals in cystinosis. Mol medical history was significant for Genet Metab. 1998;64:237-242. the advantage of in vivo confocal mi- 5. Grupcheva CN, Craig JP, Sherwin T, McGhee obesity and hypothyroidism; the lat- croscopy, not only in visualizing the CN. Differential diagnosis of corneal oedema as- ter was being treated with levothy- crystals but also in accurately mea- sisted by in vivo confocal microscopy. Clin Exp roxine sodium. On examination, vi- Ophthalmol. 2001;29:133-137. suring their dimensions. In vivo con- sual acuity was 20/25 OU. There was focal microscopy will equally cover no afferent pupillary defect, and color the same age groups as previously Lymphoepithelial Carcinoma vision was normal. The left eye was examined by UBM (Ͼ16 years); of the Lacrimal Gland proptotic, and Hertel exophthalmom- however, it might provide better etry measurements were 14 mm OD follow-up of the corneal changes The association of benign lympho- and 20 mm OS across a base of 100 especially following application of epithelial lesions with Sjo¨gren syn- mm. There was mild-to-moderate re- 2 cysteamine eyedrops. drome is well recognized; how- sistance to retropulsion of the left Our in vivo confocal observa- ever, such lesions can also develop globe. The patient was orthophoric tions of the distribution of the cor- in patients without clinical fea- in all gaze positions except for left neal crystals throughout the cor- tures of this syndrome.1 The lym- gaze, where she had a 15-diopter eso- neal thickness (z-dimension) did not phoid infiltrate or the epithelial com- tropia. Ductions were full except for concur with the slitlamp observa- ponent of the lymphoepithelilal a 20% limitation of left eye abduc- tions. In the latter the crystals ap- lesions can undergo malignant trans- tion. Visual field and funduscopy peared to be evenly distributed formation, resulting in B-cell lym- findings were unremarkable. The throughout the optical slice, whereas, phomas or lymphoepithelial carci- clinical impression was a benign confocal microscopy highlighted noma. The development of such mixed tumor of the lacrimal gland. greater density anteriorly and pos- carcinomas in the salivary glands and Computed tomographic scans of the teriorly, with least crystal density in other sites has been amply docu- orbit showed an enlarged left lacri- the middle stroma. By isolating the mented.2-5 Recently, Bloching et al6 mal gland without bone involve- area of interest, confocal micros- briefly described a lacrimal gland tu- ment, and magnetic resonance im- copy offers the advantage of mini- mor, which they called “lymhoepi- aging scans revealed a solid, 3-cm mizing the effect of adjacent re- thelioma-like carcinoma.” The tu- mass in the region of the lacrimal gions and in the future might provide mor they described could be the first fossa. The mass was somewhat useful information about the natu- reported case of lymphoepithelial homogenous with respect to signal, ral history of crystal deposition and carcinoma. In the present article, we and enhanced with gadolinium growth throughout the stromal lay- describe in detail the clinical and his- (Figure 1). The patient underwent ers in subjects with cystinosis. topathologic features of a primary en bloc excision via Kronlein lateral lacrimal gland lymphoepithelial car- orbitotomy, and the entire mass was Christina N. Grupcheva, MD cinoma with immunohistochemi- removed with care to avoid rupture Susan E. Ormonde, FRCOphth cal and molecular analysis. of the pseudocapsule of the pre- Charles McGhee, PhD, FRCOphth sumed benign mixed-cell tumor. Auckland, New Zealand Report of a Case. A 63-year-old However, there was adherence to the white woman visited an ophthal- posterior lateral scleral wall that re- The study was supported in part by an mologist with a history of dry eyes, quired shaving off the sclera. The pa- unrestricted grant from the Maurice “fullness” around the superotempo- tient subsequently received 3500 rad and Phyllis Paykel Trust. ral aspect of the left eye, proptosis, (35 Gy) rad) of radiotherapy to the The authors have no financial in- and binocular horizontal diplopia on left orbit. Six months following the terest to declare. left gaze, during the past several treatment, she had full levator func- Corresponding author: Charles months. She gave no reports of pain, tion and 20/25 visual acuity without McGhee, PhD, FRCOphth, Discipline local tenderness, or headache. Her recurrence or metastasis. of Ophthalmology, University of Auck-

land, Private Bag 92019, Auckland, A B New Zealand (e-mail: c.mcghee@ auckland.ac.nz).

1. Reese PD. Corneal crystals in nephropathic cystinosis [commentary]. N Engl J Med. 1987;317: 772. 2. Mungan N, Nischal KK, Heon E, MacKeen L, Balfe JW, Levin AV. Ultrasound biomicroscopy of the eye in cystinosis. Arch Ophthalmol. 2000; 118:1329-1333. 3. Gahl WA, Kuehl EM, Iwata F, Lindblad A, Kaiser- Kupfer MI. Corneal crystals in nephropathic cystinosis: natural history and treatment with cysteamine eyedrops. Mol Genet Metab. 2000;71: 100-120. 4. Iwata F, Kuehl EM, Reed GF, McCain LM, Gahl WA, Kaiser-Kupfer MI. A randomized clinical trial of topical cysteamine disulfide (cysta- Figure 1. A, Computed tomographic scan of the left orbit shows a large mass occupying the lacrimal mine) versus free thiol (cysteamine) in the treat- fossa and lateral orbit. B, Magnetic resonance imaging scan of the left orbit shows a large lacrimal mass.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 On immunohistochemical analysis, the epithelial component stained positive with Pan-keratin (Ventana Medical Systems Inc, Tuc- son, Ariz), and the lymphoid infiltrate was positive for common leukocyte antigen (Figure 4). These stains confirmed the presence of permeated leukocytes in the nests of epithelial cells. The lymphoid-rich stroma were mainly stained with CD-3 (Pan T-cell marker; Figure 5 A). The CD-68–positive (macrophage marker) cells were seen encircling the lobules and cords of neoplastic cells (Figure 5 B). The CD-20–positive (B-cell marker) cells were present mainly in the lymphoid follicles, whereas the CD-3– Figure 2. The orbital mass shows fibrous septa, with islands of malignant epithelial cells surrounded by positive cells were widely distrib- lymphoid cells (hemotoxylin-eosin, original magnification ϫ63). Note the presence of lacrimal gland acini with lymphocytic infiltration in the lower part of the illustration. Inset, Abnormal mitotic figure uted. This heterogeneous lymphoid (hemotoxylin-eosin, original magnification ϫ400). and mononuclear cell infiltration was also noted in the lacrimal gland tissue present at the periphery of the tumor (Figure 2). The morphologic features, in addition to the immunohistochemical results, were supportive of the diagnosis of lymphoepithelial carcinoma of the lacrimal gland. Immunohistochemical (DAKO, Carpinteria, Calif) and in situ hybridization tests to detect Epstein- Barr viral antigen and the viral ge- nome gave negative results (Enzo Di- agnostics, Farmingdale, NY). The polymerase chain reaction (PCR) using paraffin-embedded sections of the tumor, and primers specific for Epstein-Barr virus (forward primer L1 [5Ј-GTTAGATCTTACCAAG- TAAGCA-3Ј] and reverse primer L2 [5Ј-TTATGAGTGACTGGACTG- 7 Figure 3. An island of carcinoma cells surrounded and permeated by lymphocytes. Note the presence of GAGGA-3Ј]) showed the absence fibrous strands partly surrounding the carcinoma island (hemotoxylin-eosin, original magnification ϫ220). of amplified products.

The orbital tumor was roughly (Figure 3). The undifferentiated Comment. The present case shows oval and measured 31ϫ29ϫ28 mm. epithelial cells showed indistinct cell the typical histopathologic features The mass appeared partially encap- boundaries and eosinophilic cyto- of lymphoepithelial carcinoma, char- sulated, and the cut surface was tan- plasm containing large vesicular nu- acterized by islands of undifferen- white. Histologic examination of the clei and prominent nucleoli. There tiated large carcinoma cells perme- tumor revealed a circumscribed mass were frequent abnormal mitotic ated and enveloped by an admixture containing irregularly shaped nests figures (Figure 2, inset). The carci- of T lymphocytes, macrophages, and of epithelial cells, dense lympho- noma cells formed cords, small ir- a few B lymphocytes (Figures 2 and cytic infiltrates, lymphoid follicles regular nests, and syncytial aggre- 5). These histologic features are vir- containing germinal centers, and fi- gates, distinctly surrounded by tually identical to those seen in lym- brous tissue stroma (Figure 2). The lymphoid-rich stroma (Figure 3). phoepithelial carcinomas occur- epithelial nests were frequently per- The lymphoid infiltrate was primar- ring in the salivary glands and other meated by lymphocytes, and small ily made up of small lymphocytes ad- sites.2-4 Under low magnification, the islands of these epithelial cells were mixed with a few plasma cells and lacrimal gland carcinoma showed in- widely separated by the lymphoid occasional polymorphonuclear leu- distinct epithelial components and infiltrates and fibrous septae kocytes and eosinophils. distinct heavy infiltration of lym-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 phoid cells, simulating a lym- A B phoma. Higher magnification disclosed nests of malignant epithelial cells, exhibiting eosinophilic cytoplasm with ill-defined cell borders and frequent abnormal mitotic figures (Figure 2, inset). Although lacrimal gland acini were seen juxta- posed to the malignant epithelial lobules, the lacrimal gland acini did not show epimyoepithelial proliferation, but focal lymphocytic infiltration was present. These features, as well as the gross appearance of the lacrimal gland, suggest that the tumor arose de novo from the lacrimal gland rather than from a preexisting benign lymphoepithelial lesion. Although the patient was not given a workup for Sjo¨ gren syn- Figure 4. A, Carcinoma cells stain positive with Pan keratin. B, Lymphoid infiltrate showing positive ϫ drome, her history of unilateral dry staining with common leukocyte antigen (immunoperoxidase, original magnification 220). eye in the involved eye, unaccom- panied by dryness in any other body part, makes the diagnosis of Sjo¨ - A B gren syndrome less likely, and ac- cordingly supports a de novo origin of the tumor. There is a proclivity for the occurrence of nasopharyngeal and salivary gland lymphoepithelial carcinomas in individuals with Mon- golian ancestry. The carcinoma can also develop in individuals with non-Mongolian ancestry, but this group constitutes less than 15% of such carcinomas.2 The tumor affects both sexes, with a female- male ratio of 1.5:1.0. Familial clus- tering of nasopharyngeal lymphoepithelial carcinomas has been previously reported.2 The age at diagnosis ranges from 10 to 86 years, Figure 5. Immunohistochemical staining shows many T lymphocytes (A) and many macrophages with a median age of approxi- encircling the tumor cells (B) (original magnification ϫ220). mately 40 years.2 Although the present patient with the lacrimal gland nohistochemical stain, in situ mediated immunity and the cyto- lymphoepithelial carcinoma was a hybridization, and PCR methods. kines generated by these cells may 63-year-old woman, she has no The characteristic lymphoid in- contribute to long-term survival.2 known Mongolian lineage, and there filtration seen in lacrimal gland car- Lymphoepithelial carcinoma is no history of the occurrence of cinoma consists primarily of T lym- shows histopathologic features simi- such tumors in her family. phocytes, followed by CD-68– lar to those noted in benign lym- Lymphoepithelial carcino- positive macrophages and B phoepithelial lesions; however, the mas, in particular those occurring in lymphocytes (Figure 5). The pre- former is distinguished by the pres- the nasopharynx, are often associ- dominant presence of T-lineage cells ence of malignant cytologic fea- ated with Epstein-Barr virus infec- suggests that cell-mediated immu- tures in the epithelial structures and tion.2,8,9 Such an association is pres- nity may play a role in the tumor by the invasion of adjacent tissues. ent in a significant number of progression and metastasis. Over- Large-cell lymphomas, histiocytic individuals with Mongolian ances- all, irrespective of their site of ori- neoplasms, and amelanotic mela- try, but it is rarely seen in non- gin, lymphoepithelial carcinomas noma need to be considered in the Mongolian people.2 The tumor carry a better prognosis than simi- differential diagnosis, but immuno- samples from this patient were nega- lar carcinomas that are devoid of histochemical methods can distin- tive for Epstein-Barr virus infec- such lymphoid infiltration. It has guish these tumors from lympho- tion when examined by the immu- been proposed that the T-cell– epithelial carcinoma.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Because of the rarity of lym- 9. Iezzoni JC, Gaffey MJ, Weiss LM. The role of Ep- months prior to this, she had an al- stein-Barr virus in lymphoepithelioma-like car- phoepithelial carcinomas of the lac- cinomas. Am J Clin Pathol. 1995;103:308-315. lergic blepharitis when she re- rimal gland, optimal therapy is un- ceived new spectacles. On exami- known. The rationale for therapy in nation, she was found to have our patient was based on the clini- superficial punctate keratopathy, al- cal experience with the more com- Diffuse Hyperplasia though tear function was normal. mon lesion in the salivary gland, of Intratarsal Ectopic Her visual acuity was 20/120 OD and which shows improved survival with Lacrimal Gland Tissue 20/80 OS, and the intraocular pres- surgical excision of the mass, fol- sure was normal in both eyes. Mild lowed by irradiation.2 Although lym- background diabetic retinopathy was phoepithelial carcinoma rarely Diffuse bilateral ectopia of lacrimal noted on funduscopy. Extraocular occurs in the lacrimal gland, our im- gland tissue in the tarsal plate has not movements and eyelid function were munohistochemical and molecular been recorded previously, to our normal. On eversion, the upper tar- studies suggest that its pathogen- knowledge. This abnormality was sal conjunctiva on each side con- esis at this site may be independent studied in tissue removed from a tained numerous concretions, and of previous Epstein-Barr virus in- middle-aged female patient who had deeper in the tarsal plate there were fection. bilateral nongranulomatous con- multiple small mounds (Figure 1). junctivitis and superficial punctate The lower tarsus was normal on each Narsing A. Rao, MD keratopathy. In addition, the pa- side. A biopsy specimen was ob- Elizabeth Kaiser, MD tient had microcore myopathy, hy- tained from the tarsal plate on the Peter A. Quiros, MD pertension, and brittle diabetes left side, and following the initial Alfredo A. Sadun, MD, PhD mellitus. Clinical investigation re- pathologic analysis, the left tarsal Robert F. See, MD vealed surface irregularities in the plate was resected. The keratocon- Los Angeles, Calif tarsal plate, and morphologic stud- junctivitis settled in the left eye. ies demonstrated large ectopic glands There was a similar clinical out- This study was supported in part by throughout the tarsal plate. Chronic come after the right tarsal plate was grant EY03040 from the National Eye inflammatory cell infiltration was resected. Institute, Bethesda, Md, and by a grant present in the periacinal fibrous tis- The patient had severe insulin- from Research to Prevent Blindness, sue, and this progressed to fibro- dependent diabetes for 21 years. New York, NY. fatty replacement of the glandular Since 1995, she had complained of Corresponding author and re- tissue. Dilatation of the ductules sug- progressive weakness in her limb prints: Narsing A. Rao, MD, Doheny gested that blockage of the acinar se- muscles. When she attended the Eye Institute, 1450 San Pablo St, DVR- cretions led to, or was caused by, Tennent Institute (Glasgow, Scot- 211, Los Angeles, CA 90033 (e-mail: chronic inflammation in the over- land), she was unable to lift herself [email protected]). lying conjunctival stroma. The from her wheelchair; her shoulder symptoms were relieved after exci- muscles were extremely wasted. A 1. Font RL, Yanoff M, Zimmerman LE. Benign lymphoepithelial lesion of the lacrimal gland and its sion of both tarsal plates. muscle biopsy in 1995 revealed a mi- relationship to Sjo¨gren’s syndrome. Am J Clin Ectopic lacrimal glands on the crocore myopathy (David Doyle, Pathol. 1967;48:365-376. bulbar conjunctiva within the uveal MD, Institute of Neurological Sci- 2. Ellis GL, Auclair PL. Lymphoepithelial carcinoma. In: Rosai J, Sobin LH, eds. Atlas of Tumor tract and on the surface of the cor- ences, Glasgow). Pathology. 3rd ed. Washington, DC: Armed nea are a well-recognized source of The patient is a carrier of cys- Forces Institute of Pathology; 1995:311-318. 3. Dadmanesh F, Peterse JL, Sapino A, Fonelli A, choristomatous tumors, which are tic fibrosis and she has 1 daughter Eusebi V. Lymphoepithelioma-like carcinoma of usually identified in early child- who is also a carrier and 1 grand- the breast: lack of evidence of Epstein-Barr vi- hood.1 When ectopic lacrimal gland son who is asthmatic and requires rus infection. Histopathology. 2001;38:54-61. 4. Ferlicot S, Plantier F, Rethers L, Bui AD, Wech- tissue gives rise to tumors in the or- an inhaler but does not have cystic sler J. Lymphoepithelioma-like carcinoma of the bit, the age of the patient may vary fibrosis. The daughter and the grand- skin: a report of 3 Epstein-Barr virus (EBV) – between childhood and middle age. son do not have ocular disease. negative additional cases: immunohistochemical study of the stroma reaction. J Cutan Pathol. Retention of secretions at this site has The biopsy specimen mea- 2000;27:306-311. led to the formation of pseudotu- sured 4ϫ2ϫ2 mm, and the left and 5. Thalacker U, Takacsi-Nagy L, Godeny M, Varga 2 S, Horvai G, Kulka J. Lymphoepithelial carci- mors. In this report, we describe a right tarsal plate resections mea- noma of the nasolacrimal duct: a case report. La- diffuse bilateral hyperplasia of ec- sured approximately 12ϫ8ϫ5 mm. ryngorhinootologie. 1995;74:765-767. topic lacrimal gland tissue within the Each specimen was fixed in 2% buf- 6. Bloching M, Hinze R, Berghaus A. Lymph- epithelioma-like carcinoma of the lacrimal upper tarsal plates in association fered glutaraldehyde, and samples gland. Eur Arch Otorhinolaryngol. 2000;257: with chronic keratoconjunctivitis. were obtained for routine paraffin 399-401. histologic analysis (hematoxylin- 7. Takeuchi H, Kobayashi R, Hasegawa M, Hirai K. Detection of latent Epstein-Barr virus (EBV) DNA Report of a Case. A 58-year-old eosin and periodic acid–Schiff in paraffin sections of nasopharyngeal carcino- woman had poorly controlled dia- stains). For conventional transmis- mas expressing no EBV-encoded small RNAs using in situ PCR. Arch Virol. 1997;142;1743- betes for many years. She was re- sion, electron microscopy using to- 1756. ferred by specialists in diabetes to the luidine blue for semithin sections 8. Kim I, Kim YS, Kim HK, Chae YS, Yoem BW, Kim university eye department because was performed. The morphologic I. The detection of Epstein-Barr virus in the lesions of salivary glands. Pathol Res Pract. 1999; she complained of a reduction in vi- features were essentially the same in 195:407-412. sion and severe photophobia. Twelve each of the specimens.

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Figure 1. The appearances of the right (A) and left (B) upper tarsal plates. Note the pale nodular areas beneath the yellow concretions.

A B

Figure 2. A, A lobule of lacrimal gland tissue with a disorderly arrangement of the acini is located in the tarsal plate beneath the conjunctival stroma, which contains a nongranulomatous infiltrate. The acinar tissue is atrophic and surrounded by fibrous bands. Fibrofatty tissue surrounds the lobule (hematoxylin-eosin; original magnification ϫ100). B, In some lobules, the acinar cells retain eosinophilic cytoplasm in contrast to those in a lobule that is almost entirely replaced by fibrous tissue. Note the dilated ductules in the lobules (hematoxylin-eosin; original magnification ϫ100).

In some areas, the conjunctival ent within the glands and superfi- cal part of the cell (Figure 4A). The epithelium was hyperplastic and gob- cial stroma. The acinar cells pos- intercellular attachment systems and let cells were plentiful, while else- sessed eosinophilic cytoplasm in some the basal lamina were identifiable but where the epithelium was atrophied lobules, but in many atrophic lob- the apical microvillar surface was orulcerated.Surfacestratificationwas ules the cells were small and the cy- flattened. The hyperplastic acini con- not present, and the pattern was not toplasmic staining was weaker. In the tained cells that were enlarged by that of keratoconjunctivitis sicca. The well-preserved lobules, the acini ap- swollen mitochondria, accompa- superficial stroma contained a dense peared to be hyperplastic and the nor- nied by irregular distribution of the nongranulomatous chronic inflam- mal cuboidal architecture of the epi- secretory granules and the orga- matory infiltrate and dilated lym- thelial cells was lost (Figure 3). In nelles throughout the cytoplasm phatics. Pseudoglands of Henle were some areas, the acini were sur- (Figure 4B). In the latter acini, the prominent and many were en- rounded by fibrous tissue and ap- normal intercellular attachments larged by concretions. The tarsal peared shrunken and distorted. The were disorganized, and in parts, the plate contained large ectopic lacri- presence or absence of secretory gran- basement membrane was lost. Myo- mal gland elements, which re- ules was easily determined in appro- epithelial cells, nonmyelinated nerve tained identifiable architecture and priately stained semithin sections; fibers, and lymphocytes were in the almost extended to the surface epi- many acinar cells were devoid of these interstitium. Viral particles and bac- thelium (Figure 2). In most het- organelles. The ductules were of nor- terial and fungal elements were not erotopic glands, there was no evi- mal appearance. In fortuitous sec- identified. dence of a hilum, and the acinar tion planes it was possible to see a tu- tissue was distorted and infiltrated buloacinar architecture (Figure 3). Comment. The presence of numer- by fibrous tissue that contained a At the ultrastructural level, the ous lacrimal gland elements within lymphocytic infiltrate. Fibrofatty tis- cuboidal acinar cells contained lipid the tarsal plates in the specimens sue surrounded and penetrated some droplets and a variable number of se- analyzed in this case of chronic kera- lobules. Dilated ductules were pres- cretory granules located in the api- toconjunctivitis was an unex-

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C D

Figure 3. A, While some acini possess a cuboidal monolayer, others are filled by cells that are irregularly arranged (hematoxylin-eosin; original magnification ϫ350). B, Dense fibrous tissue distorts the surviving acini (toluidine blue/semithin section; original magnification ϫ200). C, The tubuloacinar pattern in the lobules demonstrates the similarity of the tissue to accessory lacrimal gland tissue. Note the secretory granules in the acinar cells (toluidine blue/semithin section; original magnification ϫ350). D, Cells with vacuolated cytoplasm are within the acini (toluidine blue /semithin section; original magnification ϫ400).

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Figure 4. A, At the ultrastructural level, many cells maintain normal architecture although isolated cells are distended by degenerate mitochondria and lipid inclusion bodies (original magnification ϫ3200). B, The acinus is filled by disorganized cells with abnormally distributed organelles and distended mitochondria (original magnification ϫ1900).

pected finding. The glands were sible to demonstrate dilatation of the been engineered to overexpress fibro- identified beneath the concretions ducts and retention of secretion in blastic growth factor 7, ectopic glands overlying the center of the tarsal the ductules so that inspissation will form in the cornea, and ectopic plate. This excluded the possibility could be an acceptable explanation lacrimal buds will form in ocular ex- that the lacrimal gland elements were for the periacinal inflammatory in- plants that are exposed to fibroblas- the normal accessory lacrimal glands filtrate. An alternative possibility is tic growth factor 10.8,9 It is not un- of Wolfring, which are located in the that there could have been an ex- reasonable to suggest that growth upper end of the tarsal plate and are tension from the inflammatory pro- factors could have entered the tarsal usually small and inconspicuous. In cess in the conjunctiva. plate to stimulate proliferation in pre- the accessory lacrimal glands lo- At the ultrastructural level, it existing ectopic acinar cells in the 12- cated in normal sites, the acini and was of interest to compare the fea- month period during which there was tubules contain cells that form epi- tures of ectopic glands with those of chronic inflammation in the tarsal thelial monolayers in a tubuloepi- normal accessory glands3 and an in- conjunctiva. thelial pattern (unlike the tubuloac- traocular lacrimal gland choris- The fact that the patient is a car- inar pattern of the lacrimal gland).3 toma.6 There was much similarity rier for cystic fibrosis could be a con- Thus, the intratarsal glands should among the 3 entities but the main tributory factor in the patient’s kera- be regarded as ectopic accessory lac- differences were the presence of an titis. One study10 has shown that rimal glands. inflammatory infiltrate in the ectop- patients with full-blown cystic fi- In some lobules, periacinal fi- ic tarsal glands and the changes that brosis have severe xerophthalmia, al- brosis was prominent and there was had occurred in the acinar cells. though a carrier status is not gener- evidence that continuing inflamma- Within individual acini, there was ally recognized as a risk factor for tion had led to fibrofatty replace- cytoplasmic rarefaction and vacu- ocular surface problems. In cystic fi- ment of preexisting ectopic lacri- ole formation in degenerating cells, brosis, ocular surface disease may be mal glands. The presence of chronic a feature that is absent from descrip- the consequence of vitamin A defi- inflammation and repair in the ec- tions of accessory glands3 or a cho- ciency due to malabsorption, or to topic lacrimal tissue in the tarsal ristoma.6 One feature of normal changes in the production or stabil- plate was similar to that found in the accessory lacrimal glands is an ir- ity of the tear film. In our case, some ectopia of lacrimal gland tissue in the regular distribution of secretory sectors of the conjunctival epithe- orbit, where presumably there was granules3: this was a common fea- lium were hyperplastic with numer- obstruction to outflow secretion.2 In ture in many of the cuboidal and hy- ous goblet cells; this supports the contrast, the lacrimal gland compo- perplastic acinar cells in the speci- clinical observation that the pa- nent of a choristoma in the upper mens in our case. tient did not have keratoconjuncti- eyelid possessed normal histologic Hyperplasia in the acini of the vitis sicca. characteristics,4 presumably be- ectopic lacrimal glands could be ex- The association of ocular sur- cause tear flow was not obstructed. plained by the chronic nongranulo- face disease with a muscle wasting In many of the case reports of intra- matous inflammation in the conjunc- disease is intriguing but probably ir- ocular lacrimal gland choristo- tival stroma and eyelids, leading to the relevant. Microcore myopathy or mas,5 the acinar architecture was de- production of growth factors, eg, fi- multicore myopathy is manifest as scribed as being well preserved and broblastic growth factor, which has central areas within enlarged muscle inflammatory infiltration was mini- been identified in the normal lacri- fiber in which there is negative stain- mal, although cyst formation was mal gland after damage to the cor- ing for phosphorylation, adenosine common. In our case, it was pos- nea.7 In transgenic mice that have triphosphatase, and glycogen. In

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 these areas, mitochondria are ab- 5. Kluppel M, Muller W, Sundmacher R. Lacri- duration in her right eye. On admis- mal gland choristoma of the iris. Arch Ophthal- sent and the Z-bands exhibit stream- mol. 1999;117:110-111. sion, the patient’s best-corrected vi- ing on electron microscopy.11 A few 6. Ghadially FN, Chisholm IA, Lalonde GM. Ul- sual acuity was 20/60 OD and 20/20 case reports refer to ocular disease trastructure of an intraocular choristoma. J Sub- OS. She also had a right relative af- microsc Cytol. 1986;18:189-198. confined to weakness in the extra- 7. Schechter J, Wallace M, Carey J, Chang N, ferent pupillary defect. Slitlamp ex- ocular muscles but, as in the pres- Trousdale M, Wood R. Comeal insult affects amination of both eyes was unre- the production and distribution of FGF-2 ent case, the extraocular muscles within the lacrimal gland. Exp Eye Res. 2000; markable. Applanation tonometry were probably unaffected in most. 70:777-784. disclosed an intraocular pressure of There is no evidence in the litera- 8. Lovicu FJ, Kao WW, Overbeek PA. Ectopic 14 mm Hg OD and 18 mm Hg OS. gland induction by lens-specific expression of ture of external eye disease in mi- keratinocyte growth factor (FGF-7) in trans- Ophthalmoscopic examination of the crocore myopathy, although in one genic mice. Mech Dev. 1999;88:45-53. patient’s right eye showed the pres- report, a 15-year-old patient with 9. Makarenkova HP, Ito M, Govindarajan V, et al. ence of a central RVO (Figure 1A), FGF10 is an inducer and Pax6 a competence myopathy was described as having factor for lacrimal gland development. Devel- which was confirmed by fluores- features of ectodermal dysplasia, opment. 2000;127:2563-2572. cein angiography (Figure 1B). Fun- 10. Castagna I, Roszkowska AM, Fama F, Sini- conical teeth, scaly skin, and sparse cropi S, Ferreri G. The eye in cystic fibrosis. Eur dus examination of the left eye re- hair, without evidence of ocular sur- J Ophthalmol. 2001;11:9-14. vealed a normal posterior pole. One face disease.12 11. Rowe PW, Eagle M, Pollitt C, Bullock RE, week later, visual acuity in the right Bushby KM. Multicore myopathy: respiratory The most acceptable proposal failure and paraspinal muscle contractures are eye deteriorated to 20/200 as well as for the pattern of disease in our case important complications. Dev Med Child Neu- the fundus aspect (Figure 1C). Her is that the ectopic lacrimal glands rol. 2000;42:340-343. family medical history had some re- 12. Gordon CP, Litz S. Multicore myopathy in a pa- were present at birth and were in- tient with anhidrotic ectodermal dysplasia. Can markable points. At age 35 years, she nocuous, but the isolated attack of J Anaesth. 1992;39:966-968. suffered from deep-vein thrombosis blepharoconjunctivitis initiated con- in her right leg. Her father had an is- junctival stromal inflammation and chemic stroke at the age of 51 years fibrosis, which led to ductal com- and died at 56 years. Alcohol abuse pression, retention of secretions, and and cigarette smoking were ex- consequent chronic inflammation in Idiopathic Central Retinal cluded as well. the ectopic glands. This started a vi- Vein Occlusion in 2 Eleven months later, the pa- cious circle of conjunctivitis and dac- Siblings With the 20210 tient’s 41-year-old brother (patient 2) ryoadenitis that was self-propagat- G→A Prothrombin Variant was admitted to our department with ing. Resolution of the keratitis after a diagnosis of papillophlebitis in his resection of the tarsal plate (by re- Genetic variations in clotting factor left eye (Figure 2). Best-corrected moving inflamed tissue) supports genes may be very important in both visual acuity was 20/30 OS and 20/20 this explanation. venous and arterial thrombosis. In- OD. Slitlamp examination did not herited thrombophilia has been as- disclose any abnormality in the an- William R. Lee, MD sociated with a deficiency of antico- terior segment of either eye. Dorothy A. Aitken agulant proteins such as protein C, Complete ophthalmic history Colin M. Kirkness, FRCS protein S, antithrombin III (AT III), and examination, as well as general Glasgow, Scotland and factor V Leiden mutation.1 medical history and physical exami- Another procoagulant muta- nations investigating factors associ- This report was presented at the com- tion, located in the 3Ј-untranslated ated with an increased risk of reti- bined European Ophthalmic Pathol- region of the prothrombin (PT) gene nal vein occlusion, were obtained in ogy Society/Verhoeff-Zimmerman So- 20210 G→A PT mutation has re- both patients and were negative. ciety Meeting, Zurich, Switzerland, cently been associated with an in- Laboratory testing, including a com- June 10, 2001. creased risk of venous thrombo- plete blood cell count, serum chem- Corresponding author: William R. sis.2 Franco et al3 thought the istries, glucose tolerance, hemoglo- Lee, MD, Tennent Institute of Ophthal- prevalence of the PT G→A muta- bin electrophoresis, erythrocyte mology, Gartnavel General Hospital, tion was found to be 2- to 7-fold sedimentation rate, serum lipids, 1053 Great Western Rd, Glasgow G12 higher among patients with athero- quantitative immunoglobulins, an- OYN Scotland (e-mail: wrl1v@clinmed sclerotic disease than in healthy con- tinuclear and anticardiolipin anti- .gla.ac.uk). trols. Heterozygosity for the 20210 body titers, human immunodefi- A allele was reported to be associ- ciency virus (HIV) serology, presence 1. Green WR. The uveal tract. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Text- ated with increased PT (factor II of of lupus anticoagulant, and syphilis book. Philadelphia, Pa: WB Saunders; 1996: coagulation) and venous thrombo- serology, had normal results. Com- 1502-2485. embolism.2-4 We report 2 cases of mon coagulation tests (PT, acti- 2. Green WR, Zimmerman LE. Ectopic lacrimal gland tissue. Arch Ophthalmol. 1967;78:318- retinal vein occlusion (RVO) in 2 vated partial thromboplastin time, fi- 327. siblings who tested positive for the brinogen) and studies for congenital 3. Seifert P, Spitznas M, Koch F, Cusumano A. The architecture of human accessory lacrimal glands. clotting factor II 20210 A variant. causes of hypercoagulability, includ- Ger J Ophthalmol. 1993;2:444-454. ing AT III, protein C, protein S, re- 4. Gordon AJ, Patrinely JR, Knupp JA, Font RL. Report of a Case. A 38-year-old sistence to activated protein C defi- Complex choristoma of the eyelid containing ectopic cilia and lacrimal gland. Ophthalmol- white woman (patient 1) reported ciencies, and factor V Leiden ogy. 1991;98:1547-1550. painless decrease in vision of 2 days’ mutation, were also within normal

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Figure 1. A, Fundus photograph of the right eye, showing a central retinal vein occlusion with venous tortuosity, disc edema, cotton-wool spots, and hemorrhages in all quadrants. B, Fundus angiogram of the right eye (292 seconds of fluorescein injection). C, Fundus photograph of the same right eye, showing a central retinal vein occlusion 1 week later. Disc swelling, venous engorgement with flame-shaped hemorrhages on the disc and the surrounding retinal tissue.

limits. Additionally, the 2 siblings the 20210 A allele is associated with were tested for the PT 20210 A vari- a 25% increase in circulating PT lev- ant. Only the latter test was positive els.2-4 Secondly, these elevated PT lev- for the heterozygous form of the PT els are associated with increased 20210 A gene in both cases. The same thrombin formation and activation of heterozygous condition was demon- the coagulation.3 Franco et al3 de- strated in one of their nieces, but she tected plasma PT levels in carriers had no clinical manifestations. The (1.26±10 U/mL) were higher than in 20210 A allele of the PT gene was de- noncarriers (1.03±1 U/mL, P=.02). tected by PCR amplification of a A “prothrombic” interpretation is also 142-bp (base pair) fragment, includ- in keeping with the fact that 20210 Figure 2. Fundus photograph of the left eye ing nucleotide 20210, using a down- mutation was originally described as (male sibling) showing a less severe disc stream mutagenic primer that intro- a risk factor for venous thrombosis, edema, hyperemia, and venous engorgement. duced a recognition site for the a fact that has been confirmed in Papillophlebitis. restriction enzyme Hind III, where ad- other recent studies.3,4 enine was present at position 20210. In our patients, this mutation On the other hand, previous leads to an increase in plasma PT rate studies have documented that an el- of the order of 30% too. In these 2 evated plasma homocysteine levels cases, who tested positive for the may be a risk factor for RVO.5 Ho- 20210 A mutation, the plasma PT mocysteinemia was investigated in levels were 1.62 U/mL (normal this family too, but only the first case plasma PT levels=1.0 U/mL) and of RVO showed a higher plasma ho- 1.51 U/mL, respectively. They were mocysteine level than the second performed by a thromboplastin- case of RVO and in their niece (14.8 based assay using factor II – defi- µmol/L vs 9.4 µmol/L and 9.3 cient plasma (Instrumentation Labo- Figure 3. Fundus photograph of the right eye µmol/L, respectively). Homocyste- ratory UK, Warrington, England) on (female sibling) 10 months later, with a ine levels were determined by high- a Sysmex CA 6000 (Globe Scien- reduction of retinal edema and macular atrophy. performance liquid chromatogra- tific Inc, Paramus, NJ) coagulation phy with electrochemical detection. analyser. Our patients represent a to RVO. We have found higher At a follow-up period of 10 documented association between plasma levels of homocysteina in the months, patient 1’s visual acuity was RVO and the 20210 G→A heterozy- woman with RVO compared with stablized (20/200 OD). Figure 3 gous genotype. Even if this correla- the second case of RVO. A fact that shows a fundus photograph of the tion cannot be demonstrated solely is known as a possible new risk fac- right eye. In contrast, her brother, by these patients, the history of deep- tor for RVO.5 patient 2, had improved visual acu- vein thrombosis at age 37 years fur- A laboratory evaluation for co- ity to 20/20 OS (4 months after his), ther supports the presence of a spe- agulophaty, including the PT 20210 with total spontaneous resolution of cific thrombophilic disorder in one A variant and homocysteinemia, may the retina lesions. of these patients. Although we can- be considered in young patients with not conclude that the RVO was a di- RVO or in older patients with RVO, Comment. The mutation of PT G→A rect result of the 20210 G→A mu- especially those without obvious variant is linked to an increased tation, this association was the only venous thrombosis risk factors and co- thrombotic tendency,2 and has been known risk factor for thromboem- agulopathies. Thus, this PT gene se- associated with both artery and ve- bolism we found in these 2 pa- quence variation and the homocys- nous disease.3,4 This feature is prob- tients. But this association, PT 20210 teine plasma levels add to the list of ably mediated by various condi- A variant and RVO, is strengthened recognized genetic risk factors for tions. Firstly, the heterozygosity for in the first case by another relative thrombophilia. Additional genetic in-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 vestigations in a sufficiently large also cause endophthalmitis in immu- ment, the patient was hospitalized number of patients are needed to es- nosuppressed individuals.2 for fever and pneumonia and can- tablish the presence of a significant Ocular signs may be the first didal skin infections. The results of correlation between mutations of manifestation of leukemia or may be all fever work-ups were negative. the PT gene, homocysteinemia, and a manifestation of relapsed leuke- Four weeks prior to our exami- RVO. mia. Although the choroid is the nation, at the end of his induction most frequently affected ocular site course, the patient had a red, pain- Cristina Peris-Martıńez, MD in histopathologic studies,3 choroi- less left eye. He was diagnosed as hav- Manuel Dıáz-Llopis, MD, PhD dal involvement may not be evi- ing anterior uveitis of the left eye and Jose´ L. Menezo, MD, PhD dent clinically. Leukemic retinopa- was treated with 1% topical pred- Valencia, Spain thy, infiltrates, microaneurysms, nisolone acetate. The patient started orbital and eyelid involvement,3,4 receiving systemic dexamethasone. Reprints: Cristina Peris-Martıńez, 5 MD, Avda, Autopista del Saler 12, 3a leukemic hypopyon, retinal detach- The day prior to our examination, the ment,6 and optic nerve head infil- patient was noted to have esotropia planta, Puerta 7, University Hospital 7 “La Fe,” Department of Ophthalmol- tration by leukemic cells have also and stated that he could not see from ogy, 46013 Valencia, Spain (e-mail: been reported. Optic nerve involve- his left eye. The patient did not have [email protected]). ment occurs mainly in children with any systemic complaints. He denied acute lymphocytic leukemia.3 It is headache, nausea, or vomiting. occasionally seen on routine exami- On examination, the child was 1. Vine AK, Samama MM. Screening for resis- tance to activated protein C and the mutant gene nation without ocular complaints afebrile, with a visual acuity of 20/25 for factor V: Q506 in patients with central reti- such as pain.7 Edema, hemorrhage, OD and no light perception OS. nal vein occlusion. Am J Ophthalmol. 1997;124: 673-676. and retrolaminar infiltration of the Twenty prism diopters of esotropia 2. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. optic nerve head may be present. In was noted with full motility. An am- A common genetic variation in the 3N untrans- the case of leukemic optic nerve in- aurotic 4+ relative afferent pupil- lated region of the prothrombin gene is associated with elevated plasma prothrombin levels and volvement, radiation therapy should lary defect of the left eye was pres- an increase in venous thrombosis. Blood. 1996; be initiated promptly.7 ent. The left cornea disclosed mild, 88:3698-3703. diffuse anterior stromal haze with 3. Franco RF, Trip MD, Ten Cate H, et al. The 20210 G to A mutation in the 3N untranslated Report of a Case. A 3-year-old boy 360° of posterior synechia. There region of the prothrombin gene and the risk for was referred to the Bascom Palmer was no hypopyon. The right eye was arterial thrombotic disease. Br J Haematol. 1999; 104:50-54. Eye Institute (Miami, Fla) for de- unremarkable. 4. Peris-Martıńez C, Avin˜ o-Martıńez J, Dıáz- creased vision in the left eye and eso- Indirect ophthalmoscopy of the Llopis M, Espan˜ a Gregori E, Menezo JL, Vaya´ tropia of 2 days. Two months prior left eye through a small pupil dis- A. Branch retinal vein occlusion associated with the 20210 G to a prothrombin variant. Eur J Oph- to this examination, the patient was closed 3+ vitreous haze. The right eye thalmol. 2000;10:177-179. diagnosed as having acute lympho- was unremarkable. Echography re- 5. Martin SC, Rauz S, Marr JE, Martin N, Jones AF, cytic leukemia without central ner- vealed dense vitreous opacities and Dodson PM. Plasma total homocysteine and retinal vascular disease. Eye. 2000;14:590-593. vous system involvement. He had a pedunculated retinal lesion ante- undergone 2 uneventful courses of rior to the optic nerve head, with sub- induction therapy, including dexa- retinal extension (Figure 1). Re- methasone and intrathecal metho- sults of magnetic resonance imaging Endogenous Fungal trexate. During the course of treat- of the brain and orbits, using gado- Retinitis in a Patient With Acute Lymphocytic Leukemia Manifesting as Uveitis and Optic Nerve Lesion

Ocular infections continue to be an increasingly common complication in immunosuppressed patients. En- dophthalmitis has been reported in immunosuppressed patients and patients who use intravenous drugs. Candida albicans is the most frequent cause of endogenous mycotic endophthalmitis.1 Other organisms include the Aspergillus and Fusarium species, Cryptococcus neoformans, Coccidioides immitis, Sporotrichum schenckii, Blastomyces dermatitidis, and Histoplasma capsulatum.1 Non- fungal organisms, such as the Pseu- Figure 1. Echography of the left eye reveals a pedunculated lesion anterior to the optic nerve head. domonas and Salmonella species, may Adjacent subretinal involvement is present.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 linium contrast medium, were con- (Figure 3). Light microscopic ex- sistent with a lesion anterior to the amination of the left eye disclosed left optic nerve head without cen- an endophytic peripapillary retinal tral nervous system involvement. lesion measuring 5.0 mm in height Examination with the patient and 4.0 mm in base. The lesion con- anesthetized revealed a yellow, creamy tained fungal elements, a focus of pedunculated retinal lesion adjacent central necrosis, and an acute and to the anterior optic nerve head, with chronic inflammatory cell infiltrate. a dense overlying vitritis (Figure 2). An acute and chronic inflammatory Fungal endophthalmitis was sus- cell infiltrate was present over the pected, and enucleation of the left eye apex of the lesion, with extension into Figure 2. Examination under anesthesia reveals a with implantation of a hydroxyapa- the vitreous. No leukemic cells were yellow pedunculated retinal lesion adjacent to the tite implant was performed. identified (Figure 4A and B). The optic nerve head, with a dense vitritis in the left eye A specimen of the enucleated iris, angle, ciliary body, and lens were (RetCam 120, Massey Research, Dublin, Calif). eye and the lesion were sent for cul- unremarkable. The inner retina con- ture. Enucleation was selected as the tained a chronic inflammatory cell in- diagnostic, therapeutic surgery of filtrate in the area of the lesion. Reti- choice because of the absence of light nal vasculitis was focally present. The perception and the possibility of an choroid, sclera, and optic nerve were intraocular malignancy. The remain- unremarkable. der of the tissue was placed in 10% Gomori methenamine silver neutral buffered formalin, pro- stain disclosed a dense collection of cessed, and sectioned serially through fungal elements suggestive of can- the retinal lesion. Blood cultures were didal infection (Figures 4C and D). obtained. Cultures of the intraocular con- Gross examination of the left tents at the time of enucleation were eye disclosed an endophytic yellow negative for organisms as were 2 Figure 3. Gross examination after enucleation discloses a yellow retinal mass anterior to the retinal mass in the posterior pole blood cultures. A systemic work-up optic nerve head. anterior to the optic nerve head for possible sources of fungus was

A B

C D

Figure 4. A, Histopathologic examination of the left eye discloses an endophytic fungating retinal lesion with superficial extension into the optic nerve (hematoxylin-eosin; original magnification ϫ2). B, At the apex of the lesion, a moderate number of acute inflammatory cells extends into the vitreous cavity (hematoxylin-eosin; original magnification ϫ10). C, A dense collection of fungal elements within the retinal lesion was present (gomori methenamine silver; original magnification ϫ4). D, High-power micrograph of the fungal elements within the retinal lesion (gomori methenamine silver; original magnification ϫ40).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 negative, with the exception of a Our patient showed no evi- resolved cutaneous candidal in- dence of central nervous system leu- Bilateral Multifocal fection. kemic involvement and no evi- Chorioretinopathy dence of leukemic recurrence. He in a Woman had a history of a skin rash second- Comment. Intraocular fungal in- With Cutaneous fections are uncommon. Fungal ary to Candida, which presump- Malignant Melanoma endophthalmitis has been most tively was felt to be the source of in- commonly reported in immuno- fection. suppressed individuals and pa- This case demonstrates the im- Melanoma-associated retinopathy tients who use intravenous drugs. portance of careful ophthalmic ex- (MAR) is a paraneoplastic retinopa- The most common organisms are amination of immunosuppressed pa- thy that occurs predominantly in from the Candida species. Candida tients, particularly those undergoing males as a distal effect induced by endophthalmitis has been re- chemotherapy for hematologic ma- the immune system’s response to a ported as a complication of dis- lignancies. Distinguishing between cutaneous malignant melanoma seminated fungal infection in a infectious and neoplastic recur- (CMM).1 Onset and survival differ patient with acute nonlymphocytic rence in patients with hematologic markedly, with associated vision leukemia.8 malignancies may be difficult and re- problems occurring, on average, 3.6 Leukemic recurrences are rare quires careful clinical evaluation as years (range, 2 months to 19 years) and may be indicated by retinal ves- well as systemic work-up to ascer- following the diagnosis of CMM, and sel changes, hemorrhages, and leu- tain the cause. 1.9 years (range, 1 month to 15 kemic infiltration. Of 657 children years) subsequent to the finding of diagnosed as having acute leuke- Alice Song, MD metastases. Survival time following mia, 52 (9%) had ocular abnormali- Sander R. Dubovy, MD the diagnosis of CMM is 5.9 years ties. Retinal hemorrhages were pres- Audina M. Berrocal, MD on average, ranging from 1 to 19.5 ent in 19 (37%) of 52 patients. Timothy Murray, MD years.1 The MAR syndrome typi- Invasion of the optic nerve, retina, Miami, Fla cally manifests as a sudden onset of iris, or orbit occurred in 29 (56%) disabling glare or night blindness that of those patients.4 is thought to result from the pro- In our patient, the presence of Corresponding author and reprints: duction of autoantibodies reactive a retinal lesion with overlying vitri- Timothy Murray, MD, Department of with retinal depolarizing bipolar 2 tis was discovered after a thorough Ophthalmology, Bascom Palmer Eye cells. While the physical appear- ocular examination. This patient had Institute, University of Miami School ance of the retina is frequently nor- retinal infiltration with fungal ele- of Medicine, PO Box 016880, Miami, mal, changes in the retinal pigment ments, retinal, and subretinal infil- FL 33101. epithelium (RPE), such as a slight tration of acute and chronic inflam- mottling, have been reported1,3 matory cells, necrosis, and retinal 1. Patel AS, Hamady RK, Rodrigues M, Rajago- together with optic disc pallor, reti- palan S, Elman MJ. Endogenous Fusarium en- vasculitis. Optic nerve infiltration dophthalmitis in a patient with acute lympho- nal vessel attenuation, and the pres- has been reported to occur mainly cytic leukemia. Am J Ophthalmol. 1994;117: ence of vitreous cells.1 Melanoma- in children with acute leukemia, par- 363-368. associated retinopathy with retinal 2. Weinstein JM, Elliott J, Tilford RH. Meta- ticularly in acute lymphocytic leu- static endophthalmitis due to Salmonella periphlebitis has also been de- kemia.9,10 Because of the vitritis and typhimurium. Arch Ophthalmol. 1982;100: scribed in a patient,4 which further 293-295. the intraocular mass in an immuno- 3. Rosenthal AR. Ocular manifestations of leuke- illustrates the diversity of findings compromised patient, an opportu- mia. Ophthalmology. 1983;90:899-905. that accompany this syndrome. Here nistic ocular infection was sus- 4. Ridgway EW, Jaffe N, Walton DS. Leukemic we report a woman with MAR with ophthalmopathy in children. Cancer. 1976;38: pected. 1744-1749. unusual fundus findings not previ- A diagnostic enucleation was 5. Jankovic M, Masera G, Uderzo C, et al. Recur- ously described to our knowledge. performed to determine whether the rences of isolated leukemia hypopyon in a child with acute lymphoblastic leukemia. Cancer. ocular mass contained leukemic 1986;57:380-384. Report of a Case. A 33-year-old cells, infectious organisms, such as 6. Primack JD, Smith ME, Tychsen L. Retinal white woman had a 4-week history detachment in a child as the first sign of fungus, or both. A globe-conserv- leukemic relapse: histopathology, MRI find- of sudden-onset bilateral disabling ing biopsy would likely not have re- ings, treatment, and tumor-free follow up. glare and night blindness in June vealed positive cultures and would J Pediatr Ophthalmol Strabismus. 1995;32: 2000. While she could still make out 253-256. have been interpreted as nondiag- 7. Kaikov Y. Optic nerve head infiltration in acute her surroundings she described a nostic, leading to a therapeutic di- leukemia in children: an indication for emer- white, central scotoma, and experi- lemma (in the face of negative cul- gency optic nerve radiation therapy. Med Pe- enced photopsias on closing her eyes. diatr Oncol. 1996;26:101-104. tures from direct enucleation of a 8. Greene WH, Wiernik PH. Candida endoph- The patient had a history of fa- portion of the lesion and surround- thalmitis. Am J Ophthalmol. 1972;74:1100- milial dysplastic nevus syndrome. 1102. ing ocular tissue). A patient with 9. Rosenthal AR, Egbert PR, Wilbur JR, Probert She was first diagnosed with CMM acute lymphocytic leukemia with JC. Leukemic involvement of the optic nerve. (nodular malignant melanoma; tu- both endogenous Fusarium endoph- J Pediatr Ophthalmol. 1975;12:84-93. mor thickness, 2.0 mm; Clark level 10. Brown GC, Shields JA, Augsburger JJ, Serota thalmitis and leukemic ocular infil- FT, Koch P. Leukemic optic neuropathy. Int III) in 1996. In 1997, the right ovary trates has been reported.1 Ophthalmol. 1981;3:111-116. had to be removed due to metasta-

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Figure 1. June 2000. Color photographs of the posterior pole, showing multiple well-circumscribed detachments of the retinal pigment epithelium in both eyes (A, right eye; B, left eye), each of which contains a small yellow-orange lesion.

A B C

1′ 3″ 9′ 23″ 2′ 17″

Figure 2. Early-phase (A) and late-phase (B) fluorescein angiography of the left eye, depicting a mild hyperfluorescence that did not increase in leakage. C, indocyanine green angiography of the left eye, with staining extending the area of the retinal pigment epithelium detachments.

sis. At this time, she received im- fluorescence in the areas of the RPE 10% loss of visual function. The tol- munotherapy with anti-idiotypic detachment. Indocyanine green an- erance for normality lies between −2 melanoma–specific mouse antibod- giography showed multifocal stain- dB and +2 dB. The LV indicates lo- ies, interleukin 2, and granulocyte ing, extending the areas of the RPE calized damage. It is calculated from macrophage colony stimulating fac- detachments (Figure 2). the individual deviation of all mea- tor.5 Her tumor status at that time Testing of the visual fields failed sured locations from the MD value. was stage IV, pT3, N0, M1b (Union to reveal any corresponding dys- In combination with a normal MD, Internationale Contre le Cancer function. On kinetic perimetry a value greater than 6 dB2 signifies classification). The patient had not (Goldmann III/4; Haag Streit, Bern, a localized defect. been taking systemic steroids and did Switzerland), the visual field of ei- Nyctometry (Rodenstock, Mu- not experience hypertension or re- ther eye extended to 70° caudally, nich, Germany) provides informa- nal problems. 50° cranially, 80° temporally, and 50° tion on vision in dim light and thus On examination, visual acuity nasally. Testing of the central 30° us- can be seen as an indicator for the was 20/20 OU. The intraocular pres- ing static perimetry (Octopus d32; quality of night vision. Increasingly sure was 8 mm Hg OU. A nevus was Interzeag AG, Schlieren, Switzer- weaker contrasts are presented at a observed on the right lower eyelid. land) revealed the following: mean particular adaptation level; thus, sen- Results of slitlamp examination of the defect (MD), 2.8 dB; loss variance sitivity to different illumination is anterior segment were otherwise un- (LV), 5.4 dB2 OD, and MD, 4.4 dB; tested. In our patient, on nyctom- remarkable. On ophthalmoscopy, le- LV, 7.1 dB2 OS. At a follow-up 2 etry, stimuli with a decreasing con- sions suggestive of multiple well- months later, these values were as trast of 1:23.5, 1:5.0, 1:2.7, 1:2.0, circumscribed detachments of the follows: MD, 0.9 dB; LV, 4.1 dB2 OD, 1:1.66, and 1:1.46 were presented, RPE were seen on the posterior pole and MD, 1.7 dB; LV, 3.8 dB2 OS. The first without glare (surrounding lu- of both eyes (Figure 1). Each de- MD and LV are comparative mea- minance: 0.032 candela [cd]/m2)and tachment contained a small yellow- sures that represent the difference then with glare (surrounding lumi- orange lesion. between the age-corrected normal nance: 0.1 cd/m2, glare source with a Fluorescein angiography data and the actual measured re- diameter of ∼15 minutes of arc, a 3° showed stable hyperfluorescent spots sults. The MD is an index related to angle of glare, and a corneal lumi- in some of the small yellow-orange le- global damage whereby a loss of 1 nance of 0.35 lux). While most sions, as well as a stable, mild hyper- dB corresponds to approximately a healthy young people can easily see

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 a contrast of 1:2.7 with or without scotopic b-wave amplitude (lumi- multifocal ERG of our patient are glare, our patient could not detect any nance: 0.0025 cd/m2; 16.5 µV OD, comparable with the reduced cen- stimulus either with or without glare. 20.7 µV OS [normal, Ͼ110 µV]) tral amplitudes observed in the mul- Electrophysiologic testing (pat- (Figure 3A). The a wave was nor- tifocal ERG of patients with MAR,6 tern electroretinogram [P-ERG], mal with a maximal response am- but reduced amplitudes (Figure 4) Ganzfeld ERG [Haag Streit], and plitude of 35.4 µV OD and 45.9 µV were not found in all areas of reti- electro-oculogram [Medelec, Sur- OS (normal range, 33-48 µV; lumi- nal lesions (Figure 1). rey, England]) was performed ac- nance, 2.8 cd/m2). Retinal function The patient’s serum was evalu- cording to the standard of the In- evaluation by multifocal ERG ated by indirect immunohistochemi- ternational Society for Clinical (mfERG) (VERIS; Electro-Diagnos- cal analysis on 6-µm sections of rhe- Electrophysiology of Vision. The tic Imaging, San Mateo, Calif) (Lmax sus monkey at a dilution of 1:100. electro-oculogram results were 200 cd, Lmean 100 cd) showed re- Antibody reactions were visualized within the normal range, with an duced amplitudes in the central 4° using fluorescein-isothiocyanate con- Arden ratio of 1.9 OD and 2.4 OS. OU where the mean amplitude N1P1 jugated rabbit-antihuman polyva- The P-ERG showed normal am- (first negative to first positive peak) lent ␥-globulins (Sigma F4637; plitudes for N35P50 (3.05 µV OD, was 24.1 nV/degrees2 (deg2) OD and Sigma, St Louis, Mo) at a dilution of 1.7 µV OS [normal range, 1.46-4.9 24.4 nV/deg2 OS (Figure 4A). This 1:500. Serologic examination re- µV]) and for P50N95 (7.1 µV OD, contrasts with the mean (SD) revealed abnormal immunologic activ- 4.9 µV OS [normal range, 2.0-8.6 sponse of 69.0 (22.1) nV/degrees2 ity consistent with MAR, showing a µV]) as well as normal latencies (eg, (deg2) in the central 4° of a normal focus of antibody reactions within the P50: 53.9 ms OD, 51.6 ms OS [nor- reference control group of 15 indi- inner nuclear layer, where the nu- mal range, 49-59 ms]). viduals of similar age. clei of the bipolar cells are located. The Ganzfeld ERG showed a The central distribution of the Western blot reactions on an ex- selective reduction of the isolated rod reduced amplitudes observed in the tract of rhesus optic nerve revealed additional abnormal antibody activ- A 100 B 600 ity with myelin basic protein. 80 500 Intensive examination in Oc- 60 400 tober 2000 led to the recognition and

40 300 removal of a metastasis in the lymph V

µ nodes of the right axilla (radical 20 200 lymph node dissection, 3 of 7 lymph 0 100 nodes were positive) followed by –20 0 chemotherapy with vindesine. –40 –100 In December 2000, the mfERG 0 30 60 90 120 150 180 210 240 270 300 030 60 90 120 150 180 210 240 270 300 recordings showed an improve- Milliseconds Milliseconds ment of the central amplitudes, with Figure 3. Ganzfeld electroretinogram (ERG) (Haag Streit, Bern, Switzerland) showing isolated rod the mean amplitude N1P1 (first scotopic b-wave. A, June 30, 2000. Initial selective reduction of the isolated rod scotopic b-wave Ͼ negative to first positive peak) im- amplitude: 16.5 µV OD, 20.7 µV OS (normal, 110 µV). One scaling unit depicts 20 µV. B, July 3, 2001. 2 The isolated rod scotopic ERG b-wave amplitude recovered to 164 µV OD and 204 µV OS (normal, Ͼ110 proving to 33 nV/deg OD and µV). One scaling unit depicts 100 µV. 28.3 nV/deg2 OS, in contrast with a

A KI-Traces B KI-Traces Control Control

R L R L

Patient Patient

200 nV 200 nV 0 80 ms 0 80 ms

Figure 4. Testing of the central retinal cone function with the multifocal electroretinogram (VERIS; Electrodiagnostic Imaging, San Mateo, Calif, Lmax 200 candela (cd), Lmean 100 cd, stimulation of the central 50° of the retina). A, The top shows a normal first-order trace array (left eye) for comparison. The bottom shows the patient’s recordings (June 2000) show reduced amplitudes in the central 4°(central 7 waveforms). B, The top shows a normal first-order trace array (left eye) for comparison. The bottom shows the patient’s recordings obtained 6 months later (December 2000) show improved response amplitudes in the central 4°(central 7 waveforms). However, amplitudes in the central 4° are still reduced when compared with the normal trace array .

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Figure 5. July 2001. Color photographs show the detachment to have resolved, while the yellow-orange lesions appear to have consolidated continuously. A, Right eye; B, left eye.

A B

28′ 58″ 29′ 8″

Figure 6. Autofluorescence in the lesions of the left eye (A) and fluorescein angiography of the left eye (B). There is a marked blocking of the choroidal filling, with intact filling of the retinal vessels.

responsemean(SD)of69.0(22.1)nV/ 1.46-4.9 µV]) as well as for P50N95 closed her eyes. This effect indi- deg2 in the control group (Figure 4B). (7.02 µV OD, 4.89 µV OS [normal cated choroidal malfunction. In April 2001, the patient was range, 2.0-8.6 µV]). The latencies of On further follow-up in Febru- able to see the bright background P50 also remained within the nor- ary 2002, the patient reported im- disc on which the stimulus was pre- mal range (53.3 ms OD, 52.1 ms OS proved night vision and a lessened sented during nyctometry for the [normal range, 49-59 ms]). sensitivity to glare. However, she first time, although she still could not On ophthalmoscopy, the de- complained of a recent onset of cen- detect the stimulus itself. tachments of the RPE had resolved tral metamorphopsia in the left eye. At a follow-up nyctometry in while the yellow-orange lesions ap- Visual acuity was 20/16 OD and 20/40 July 2001, vision in the right eye had peared to have increased in size and OS. When examined by nyctometry, improved to where it could resolve density (Figure 5). These lesions it was found that the right eye could a contrast of 1:2.7 without glare; with showed autofluorescence, which now resolve a contrast of 1:2.7 with- glare, however, no contrast stimu- may indicate lipid deposits in the out glare and of 1:5 with glare, but the lus was seen. The left eye was still un- RPE or inner choroid (Figure 6). left eye was still unable to detect any able to detect any stimulus, either Fluorescein angiography showed a stimulus either with or without glare. with or without glare. Visual acuity marked blocking of the choroidal On ophthalmoscopy, the yel- and visual fields had remained stable. filling, with intact filling of the reti- low-orange deposits appeared to The isolated rod scotopic ERG nal vessels (Figure 6). The clini- be reduced in size and density b-wave amplitude also recovered to cally apparent lesions therefore ap- (Figure 7). Fluorescein angiogra- 164 µV OD and 204 µV OS, respec- peared to predominate in the RPE phy continued to show a blocking of tively. The P-ERG continued to show and/or inner choroid. The patient the choroidal filling, with intact fill- normal amplitudes for N35P50 (2.91 was aware of a negative scotoma in ing of the retinal vessels in the area µV OD, 1.66 µV OS [normal range, the area of the lesions when she of these lesions. Small filling defects

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1′ 23″ 4′ 11″

17′ 7″ 2′ 26″

Figure 7. February 2002. A, Color photographs show the yellow-orange lesions, which appear reduced in size. B, Corresponding fluorescein angiography. C, Indocyanine green angiography. Right eye, top row; left eye, bottom row.

A B

2′ 21″

C D

1′ 8″

Figure 8. June 2002. Right (A and B) and left (C and D) eyes. A and C, Color photographs depict the yellow-orange lesions, which appear even more reduced in size than in Figure 7. This can be appreciated more when their autofluorescence is viewed (B and D).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 were seen by indocyanine green an- metry between the left and right eye We thank Anita Leys, MD, PhD, giography. Neither fluorescein angi- and may develop over several years.8,9 and Mary van Schooneveld, MD, PhD, ography nor indocyanine green Our patient had no familial history for their helpful comments. angiography revealed a choroidal neo- of Best disease; in contrast, she ex- We have no proprietary interest vascular membrane or macular perienced a regression of RPE de- in any of the products mentioned. edema. The reduced central vision in tachments in association with the Corresponding author: Anja M. the left eye was thought to be sec- removal of secondary melanoma me- Palmowski, MD, Department of ondary to the observed central pig- tastases. Ophthalmology, Saarland Univer- ment epithelial changes. The vitelliform detachments of sity Hospital, D-66421 Homburg/ At the latest follow-up in June the RPE in Best disease have been Saar, Germany (e-mail: auapal 2002, the patient reported im- described as acquiring a yellow dis- @med-rz.uni-sb.de). proved central metamorphopsia in coloration and blocking choroidal 1. Keltner JL, Thirkill CE, Yip PT. Clinical and the left eye. Visual acuity was stable fluorescence on fluorescein angiog- immunologic characteristics of melanoma- (20/16 OD 20/40 OS). When exam- raphy.10 We found no “egg yolk” or associated retinopathy syndrome: eleven new ined by nyctometry, it was found “scrambled lesion”typical of Best dis- cases and a review of 51 previously pub- 8 lished cases. J Neuroophthalmol. 2001;21: that the right eye could resolve a ease in our patient. In addition, the 173-187. contrast of 1:1.46 without glare and vitelliform stage of her RPE detach- 2. Berson EL, Lessell S. Paraneoplastic night blindness with malignant melanoma. Am J Oph- of 1:5 with glare. The left eye was ments did not block choroidal fluo- thalm. 1988;106:307-311. now able to detect a contrast of 1:5 rescence on fluorescein angiog- 3. Borkowski LM, Grover S, Fishman GA, et al. without glare. With glare, the left raphy; blocking only occurred Retinal findings in melanoma-associated retinopathy. Am J Ophthalmol. 2001;132:273- eye still could not resolve the following resolution of the RPE de- 275. stimulus. On ophthalmoscopy, the tachments and following the depo- 4. Remulla JF, Pineda R, Gaudio AR, et al. Cuta- sition of lipids. It is unlikely that our neous melanoma-associated retinopathy with yellow-orange deposits appeared retinal periphlebitis [letter]. Arch Ophthalmol. further reduced in size and density patient suffers from multifocal vi- 1995;113:854-855. (Figure 8). To date, further elec- telliform Best disease. The combi- 5. Perillo A, Pierelli L, Scambia G, et al. Periph- eral blood progenitor cell collection after epi- trophysiologic examinations were nation of MAR and bilateral multi- rubicin, paclitaxel, and cisplatin combination not performed. focal chorioretinopathy we described chemotherapy using EPO-based cytokine regi- represents an additional example of mens: a randomized comparison of G-CSF and sequential GM-/G-CSF. Transfusion. 2001;41: Comment. We describe a patient the pathologic and immunologic het- 647-680. with MAR who experienced subjec- erogeneity that continues to emerge 6. Haus AH, Palmowski AM, Allgayer R, et al. Mul- in descriptions of the MAR syn- tifocal ERG (MF-ERG) in patients with cuta- tive improvement of her night vi- neous malignant melanoma (CMM). Invest Oph- sion and of her glare sensitivity fol- drome. thalmol Vis Sci. 2001;42:S462. lowing removal of metastasis and 7. Lei B, Bush RA, Milam AH, et al. Human melanoma-associated retinopathy (MAR) anti- treatment with chemotherapy. This Anja M. Palmowski, MD bodies alter the retinal ON-response of the mon- recuperation could also be observed Arno H. Haus key ERG in vivo. Invest Ophthalmol Vis Sci. 2000; in the normalization of a previously Claudia Pfo¨hler, MD 41:262-266. 8. Miller SA. Multifocal Best’s vitelliform dystro- abnormal rod-isolated scotopic b- Uwe Reinhold, MD phy. Arch Ophthalmol 1977;95:984-990. wave response as well as in the im- Rainer Allgayer, Dipl Phys 9. Maloney WF, Robertson DM, Duboff SM. He- Wolfgang Tilgen, MD reditary vitelliform macular degeneration: vari- provement of nyctometry results. able fundus findings within a single pedigree. This recovery is consistent with the Klaus W. Ruprecht, MD Arch Ophthalmol. 1977;95:979-983. recent experimental findings of Lei Homburg/Saar, Germany 10. Ciulla T, Frederick AJ. Acute progressive mul- 7 tifocal Best’s disease in a 61-year-old man. Am et al, who found electrophysiologic Charles E. Thirkill, PhD J Ophthalmol. 1997;123:129-131. dysfunction typical of MAR to be a Sacramento, Calif transient effect following intravit- real injection of MAR serum into the eye of a monkey. This research was supported by grants Photodynamic Therapy Furthermore, our patient’s case DFG Pa 609/2 from the Deutsche For- is remarkable in that she had un- schungsgemeinschaft, Bonn (Dr Pal- in Adult-Onset Vitelliform usual fundus findings on initial mowski); 1P30 EY12576-01 from the Macular Dystrophy examination, the origin of which National Eye Institute, Washington, Misdiagnosed as Choroidal remains unclear at present. The find- DC (Dr Thirkill); and Research to Pre- Neovascularization ings in our patient may be com- vent Blindness, New York, NY (Dr pared with those of Best disease, Thirkill). In adult-onset vitelliform macular where multifocal vitelliform le- This research was presented in dystrophy (AOVMD), the yellow- sions of various size, similar to those part at the International Society for ish subretinal material accumu- we describe, may also occur. Mul- Clinical Electrophysiology of Vision at lating at the fovea may cause late tifocal vitelliform Best disease may the meeting of the Association for Re- hyperfluorescence, both with fluo- also occur sporadically and may search in Vision and Ophthalmology, rescein angiography and with in- show normal electro-oculogram re- Fort Lauderdale, Fla, April 28, 2001, docyanine green angiography,1,2 sults, as were found in our patient. and at the meeting of the European sometimes simulating choroidal neo- In Best disease, vitelliform RPE de- Neuro-Ophthalmological Society, Tu¨b- vascularization (CNV). We report 3 tachments can show a marked sym- ingen, Germany, July 22, 2001. cases of AOVMD misdiagnosed as

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D E F

Figure 1. A, Vitelliform submacular lesion with red-free photograph in case 1 immediately before photodynamic therapy. Middle-phase fluorescein angiogram shows a stellate hypofluorescent lesion with mild foveal hyperfluorescence that was misdiagnosed as choroidal neovascularization, B, Three months after photodynamic therapy, the vitelliform lesion had disappeared (C and D); the picture was unchanged after 1 year of follow-up (E and F). Visual acuity was 20/30 and remained stable throughout the follow-up.

classic CNV secondary to age- months later, the subretinal mate- graphic aspect of the left macula was related macular degeneration that rial had disappeared, leaving in also stable. were treated with photodynamic place RPE mottling (Figure 1C); Case 3. Bilateral macular RPE therapy (PDT). visual acuity was unchanged. Fluo- atrophy associated with reticular hy- rescein angiography showed mild perpigmentation were seen in both Report of Cases. Case 1. A 71-year- window defect at the left macula fundi of a 65-year-old man. The left old woman reported vision loss in (Figure 1D). With OCT, the foveal fovea had yellowish subretinal ma- her right eye. Examination showed profile was restored because of terial causing early, stellate blocked atrophy of the choriocapillaris, and disappearance of the subretinal fluorescence with fluorescein angi- yellowish subretinal material was mound (Figure 2B). One year after ography, followed by abundant late seen in the left eye (Figure 1A). PDT, visual acuity, as well as angio- leakage. Best-corrected visual acu- Best-corrected visual acuity was graphic and OCT findings (Figure ity was 20/600 OD and 20/100 OS. 20/200 OD and 20/30 OS. Fluores- 1E and F, and Figure 2C), were The left eye received PDT because cein angiography showed early substantially unchanged. of suspected CNV. We obtained blocked fluorescence at the left Case 2. A 74-year-old woman fluorescein angiograms as early as 1 macula, with perimacular stellate had a vitelliformlike lesion in her left month after PDT. Although the an- aspect and mild late hyperfluores- eye on clinical examination. The giographic picture was substan- cence (Figure 1B). Indocyanine right eye displayed a roundish area tially unchanged, we observed re- green angiography also showed late of chorioretinal atrophy at the sorption of the yellowish subretinal hyperfluorescence that was also macula. The subretinal macular de- material, and this aspect was main- misinterpreted as CNV. Optical posits showed early, stellate blocked tained during the following months. coherence tomography (OCT) fluorescence, and marked late leak- Visual acuity was 20/100 soon after revealed foveal hyperreflective age in the left eye. The left eye re- PDT, and was measured as 20/60 elevation of the profile of the reti- ceived PDT because of suspected after 6 months. Thereafter, it de- nal pigment epithelium (RPE)– CNV. Visual acuity in the left eye clined to 20/400 because of dense Bruch membrane–choriocapillaris was 20/40 before PDT and through- subcapsular cataract. Cataract complex (Figure 2A). The patient out the following year, and no fur- extraction was advised approxi- received PDT in her left eye. Three ther PDT was applied. The angio- mately 1 year after PDT.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 A though this may be seen in the long- tender sterile pustules with central term in some eyes with AOVMD, it necrosis. We report a case of nodu- could also be hypothesized that the lar scleritis due to pyoderma gan- rather rapid resorption of the sub- grenosum and our experience ex- retinal material is due to RPE stimu- cising the lesion. lation by PDT, which is known to cause RPE damage followed by re- Report of a Case. A 39-year-old generation experimentally.4,5 woman complained of redness and In conclusion, we showed that a foreign body sensation in her right AOVMD can be misinterpreted as eye. She also had a large 8ϫ20-cm B CNV. Only practitioners experi- ulcer involving her right lower leg. enced in clinical examination and Her medical history is significant for fluorescein interpretation of macu- pyoderma gangrenosum, hemo- lar degeneration should be perform- lytic anemia, large granular lympho- ing PDT. cytic disorder, nasopharynx papil- lomatosis, and occasional migratory Ugo Menchini, MD arthralgias. Findings from slitlamp Giovanni Giacomelli, MD examination revealed a large ery- Stefania Cappelli, MD thematous, raised scleral nodule ad- Fabrizio Giansanti, MD jacent to the temporal limbus of the C Florence, Italy right eye (Figure 1). The nodule Andrea Romani, MD was tender and had an irregular sur- Arezzo, Italy face similar to a papilloma. The nodular scleritis appeared Corresponding author: Ugo Menchini, while the patient was receiving MD, Department of Oto-Neuro- intravenous cyclosporine and Ophthalmological Surgical Sciences, methylprednisolone for the pyo- Eye Clinic II, University of Florence, derma gangrenosum ulcer of her Figure 2. Case 1. Optical coherence tomography Viale Morgagni 85, 50134 Florence, before photodynamic therapy (A) shows a leg. Because of the papilloma-like hyperreflective subretinal elevation at the level of Italy (e-mail: [email protected]). appearance of the scleral nodule, the fovea, with preservation of the physiological she was treated with topical cidofo- neuroepithelial depression. Three months later, 1. Gass JDM. Pattern dystrophies of the RPE: adult- onset foveomacular vitelliform dystrophy. In: Ste- the subretinal deposits had disappeared, and the vir in addition to topical cyclospor- reoscopic Atlas of Macular Diseases: Diagnosis and ine and prednisolone acetate. After retinal pigment epithelium profile was almost Treatment. Vol 1. St Louis, Mo: CV Mosby Co; restored or rectilinear (B), with no change after 1997:316-321. poor response to 3 weeks of medi- 1 year (C). 2. Lanzetta P, Virgili G, Menchini U. Indocyanine cal treatment, a diagnostic/thera- green angiography in vitelliform macular lesions. Ophthalmologica. 1996;210:189-194. peutic excisional biopsy was per- Comment. Adult-onset vitelliform 3. Dubovy SR, Hairston RJ, Schatz H, et al. Adult- formed. Bacterial, viral, and fungal macular dystrophy is a subtype of onset foveomacular pigment epithelial dystro- cultures from the biopsy specimen phy: clinicopathologic correlation of three cases. pattern dystrophy that resembles Retina. 2000;20:638-649. were all negative for organisms. Best dystrophy, in which smaller vi- 4. Schmidt-Erfurth U, Hasan T, Gragoudas E, Mi- The specimen showed an inflam- telliform lesions are usually seen in chaud N, Flotte TJ, Birngruber R. Vascular tar- matory cellular infiltration of the geting in photodynamic occlusion of subretinal middle-aged or elderly individu- vessels. Ophthalmology. 1994;101:1953-1961. tissue diagnostic of diffuse neu- als.1 Lipofuscin material on either 5. Lin SC, Lin CP, Feld JR, Duker JS, Puliafito CA. trophilic mucositis, consistent The photodynamic occlusion of choroidal ves- side of the RPE, as well as basal lami- sels using benzoporphyrin derivative. Curr Eye with pyoderma gangrenosum nar and basal linear deposits, were Res. 1994;13:513-522. (Figure 2 and Figure 3). The observed throughout the macula nodular scleritis resolved after the in a recent clinicopathologic corre- excisional biopsy. Topical cortico- lation.3 steroid was tapered and its use dis- We saw 3 patients in whom a Nodular Scleritis continued over a 2-month period. vitelliform macular lesion had been in a Patient With Therapy with systemic corticoste- treated with PDT because of misdi- Pyoderma Gangrenosum roids and cyclosporine were con- agnosed CNV. Photodynamic tinued for the treatment of the therapy did not seem to cause any Pyoderma gangrenosum is a rare leg ulcer, which remained stable adverse effects despite the fact that chronic reactive inflammatory dis- during therapy without complete it was done in the setting of no CNV, order that involves ulceration of the resolution. No new skin lesions no intraretinal fluid, and possibly skin, is commonly associated with appeared during this period. She compromised choriocapillaris. Vi- inflammatory bowel disease and ar- had no evidence of recurrence of sual acuity was stable or possibly thritis, and occurs mostly in women. the scleritis during the following 7 improved in all 3 instances. In 2 of The ulcerative lesions of pyoderma months (Figure 4). 3 cases, the vitelliform subretinal gangrenosum are typically at the site material disappeared within 1 to of minor trauma and begin as small Comment. Pyoderma gangreno- 3 months of PDT treatment. Al- erythematous papules progressing to sum is an autoimmune condition, re-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Figure 1. Initial slitlamp photograph of a scleral nodule adjacent to the limbus of the right eye. The yellow, elevated lesion with prominent vessels is surrounded by focal conjunctival hyperemia.

Figure 2. Microscopic section of the scleral nodule showing submucosal connective tissue with inflammatory cells that consisted mostly of neutrophils (white arrow). A vessel is seen (black arrow) (hematoxylin-eosin, original magnification ϫ20).

Figure 3. High-magnification microscopic section showing diffused neutrophilic infiltration consistent with pyoderma gangrenosum (white arrow). A vessel is noted (black arrow). No abscess or infectious agent is observed (hematoxylin-eosin, original magnification ϫ40).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 sistent with, but not specific to, pyoderma gangrenosum.2 Patients with ocular involvement of pyoderma gangrenosum have responded to a variety of treatments. Three reported cases of ulcerative keratitis have been treated successfully with oral and topical coritcosteroids, oral cyclo- phosphamide, and oral azathio- prine.3,4 A case of scleral ulceration responded to cryotherapy and systemic cortisone.5 Our case of nodular scleritis resolved with a combination of an excisional biopsy with adjunctive systemic and topical immunosuppressants.

Maria M. Braun, MD Ira G. Wong, MD, MS Figure 4. Slitlamp photograph of the same area of conjunctiva seen in Figure 1, 3 months after excisional Christopher N. Ta, MD biopsy. The conjunctiva is flat with no ulceration or chemosis, and only minimal hyperemia. Stanford, Calif

sulting in painful skin ulceration af- tional inflammation or ulceration Corresponding author and reprints: ter minor trauma. It is commonly but rather in the resolution of the Christopher N. Ta, MD, Department associated with inflammatory bowel scleritis, possibly because of the of Ophthalmology, Stanford Univer- disease and arthritis, and approxi- preoperative and postoperative sity, 900 Blake Wilbur Dr, Room mately 10% of patients may have an treatments with cyclosporine and W3002, Stanford, CA 94304 (e-mail: IgA monoclonal gammopathy.1 Ma- corticosteroids. Of the 4 cases of pyo- [email protected]). lignancies such as leukemia and lym- derma gangrenosum–related ulcer- phoma have also been associated ative keratitis and scleritis we re- 1. Powell FC, Schroeter AL, Su WP, Perry HO. Pyo- 3-5 derma gangrenosum and monoclonal gammopa- with pyoderma gangrenosum. viewed, only 1 required biopsy, thy. Arch Dermatol. 1983;119:468-472. The results of skin biopsies which did not result in ulceration.5 2. Powell F, Collins S. Pyoderma gangrenosum. Clin have led to formation or enlarge- Biopsy specimens and tissue Dermatol. 2000;18:283-293. 2 3. Bishop P, Tullo A. Pyoderma gangrenosum and ment of ulcers. Because of this risk, cultures are important in exclud- necrotizing sclerokeratitis. Cornea. 1998;17:346- the nodular scleritis was initially ing other conditions that can mimic 347. 4. Brown BA, Parker CT, Bower KS. Effective ste- treated with immunosuppressants. pyoderma gangrenosum, such as an roid-sparing treatment for peripheral ulcer- Owing to the lack of response to infected ulcer. In this current case ative keratitis and pyoderma gangrenosum. Cor- medical treatment, an excisional bi- report, histopathologic findings of nea. 2001;20:117-118. 5. Happle R, Schiffer H, Kovary P. Ocular involve- opsy of the scleral nodule was per- inflammatory cell infiltrate with or ment in pyoderma gangrenosum. Arch Derma- formed that did not result in addi- without abscess formation is con- tol. 1977;113:1612.

From the Archives of the ARCHIVES

ight having within forty-eight hours grown steadily S worse leading to almost entire blindness, com- mencing to improve immediately after forcible massage— that is, pressure against the eyeball, with scarcely any other treatment, we may fairly claim that this exceptional recovery has been improved circulation from massage of the eye.

Reference: Barkan A. Case of embolism (thrombosis?) of a branch of the central retinal artery treated with forcible massage recovery. Arch Ophthalmol. 1902;31:1.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 of their relevant pharmacokinetic and pharmacody- important yet complex task because of the ease of acces- namic properties. Furthermore, consideration of factors sibility of such agents. Additionally, and perhaps of greater such as biological variability and dose-response, which significance, it is unknown how the results of ongoing express therapeutic action in terms of efficacy as well as prospective trials of vitamin and nutrient therapy for dis- toxicity, are in large part poorly defined within the AREDS orders other than AMD will affect those currently fol- study design. Characterization of the pharmacologic re- lowing AREDS recommendations.4 sponse to various high-dose vitamin and nutrient ad- Vitamins and nutrients are not only ubiquitous in ministration requires stringent assessment of popula- nature and easily obtained from nourishing diets, they tion-, disease-, and formulation-specific variables that may are also aggressively marketed by pharmaceutical com- influence the occurrence of adverse effects in ways not panies eager to promote perceived as well as validated described in the AREDS. claims of health benefit. In addition, the clever market- For example, changes in drug disposition with age ing strategies of pharmaceutical companies, such as those are characterized by alterations in lean body mass, which promoting doses that “exceed AREDS recommenda- influences the volume of distribution and partition co- tions,” demonstrate the need for clinicians to closely moni- efficients pertinent to fat-soluble vitamins, particularly tor vitamin and nutrient intake. I believe that the AREDS ␣-tocopherol. Furthermore, individuals who use vita- findings are inadequate in the elucidation of clear and min A1 as a source of beta-carotene should be advised concise safety guidelines for entities that are largely un- that absorption of vitamin A1 (retinol) varies consider- regulated and widely promoted with an array of ingre- ably depending on the formulation of the preparation as dients, formulations, and equivalency provided for pub- well as the amount of dietary fat an individual typically lic interpretation. ingests.2 In addition, febrile infections and stress may markedly decrease serum retinol, whereas chronic re- Bruce I. Gaynes, OD, PharmD nal disease may result in significantly elevated serum reti- Chicago, Ill nol, requiring the need for an alteration in intake.3 Moreover, the AREDS neglects to discuss assign- ment of causality, as well as the temporal relationship The author has no relevant financial interest in this article. and outcome of reported adverse events, particularly those noted as “circulatory.” Furthermore, discussion of ad- 1. Age-Related Eye Disease Study Research Group. A randomized, placebo- controlled, clinical trial of high-dose supplementation with vitamins C and ditive or synergistic effects, either observed or poten- E, beta carotene, and zinc for age-related macular degeneration and vision tial, of the AREDS therapy with various prescription and loss. Arch Ophthalmol. 2001;119:1417-1436. 2. Nutrients and nutritional agents: facts and comparisons. In: Drug Facts and nonprescription products is lacking. The AREDS also does Comparisons. St Louis, Mo: Wolters Kluwer Co; 2002:6-7. not address the need for continuing surveillance of the 3. Marcus R, Coulston AM. Fat soluble vitamins. In: Hardman JG, Limbird LE, safety of vitamin and nutrient therapy for AMD in terms eds. Goodman and Gilman’s the Pharmacologic Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:1780-1781. of elucidation of unexpected idiosyncratic reactions, an 4. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. J Urol. 2001;166:1311-1315.

Correction

Author Name Omitted. In the Clinicopathologic Reports, Case Reports, and Small Case Series article titled “Photodynamic Therapy in Adult-Onset Vitel- liform Macular Dystrophy Misdiagnosed as Choroidal Neovascularization,” published in the December issue of the ARCHIVES (2002;120:1761-1763), Gianni Virgili, MD, was omitted and should have been listed in the signature block as the last author.

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