Infectious Scleritis After Use of Immunomodulators

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

blastoma during childhood,1 but livered dose of 5000 rad (50 Gy; 330 Late Malignant Melanoma other multiple ophthalmic malig- rad [3.3 Gy] per fraction) with good After Treatment of nancies in the same patient are a very local tumor control. During follow- Rhabdomyosarcoma of the rare occurrence. We report the case up, the patient developed cataract of a patient who had 2 distinct tu- and strabismus and underwent un- Orbit During Childhood mors involving her left orbit. A child- eventful surgical treatment for cata- A 27-year-old woman developed ma- hood sarcoma was followed 21 years ract. Her final visual acuity was 20/ lignant orbitoconjunctival mela- later by a malignant melanoma. 200 because of macular retinal noma in her left eye 21 years after alterations that were probably sec- treatment of a left orbital embryo- Report of a Case. In 1971, a 6-year- ondary to radiation retinopathy. A nal sarcoma with systemic chemo- old girl developed a tumor in her left surgical procedure to correct stra- therapy and radiation therapy to the orbit. A specimen from an inci- bismus was then performed in 1982, orbit. The coexistence of these 2 ma- sional biopsy of the mass showed and regular follow-up was per- lignancies in the same orbit is very evidence of embryonal sarcoma formed by her ophthalmologist. rare. It may be coincidental, but a ge- (Figure 1A and B). The patient re- In July 1992, at age 27 years, the netic predisposition or late adverse ceived multidrug systemic chemo- patient developed a slowly growing, effects of childhood cancer treat- therapy (including dactinomycin) painless, temporal conjunctival mass ments cannot be excluded. and radiation therapy to the orbit. of the left eye. The patient was then Second malignant tumors can Radiation therapy consisted of an referred to our clinic in September occur in patients treated for retino- exclusive anterior beam with a de- 1992. At that time, she had a slightly

A B

C D

Figure 1. A and B, Biopsy specimen of an orbital lesion, embryonal sarcoma, shows syncytial arrangement of poorly differentiated embryonic mesenchymal cells dispersed in edematous or fibrous stroma (hematein-eosin saffron, original magnification ϫ10 [A] and ϫ40 [B]). C and D, Orbital exenteration because of malignant melanoma shows highly cellular proliferation of fusiform malignant cells with atypical nuclei and prominent nucleoli (hematein-eosin saffron, original magnification ϫ10 [A] and ϫ40 [B]).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 pigmented bulbar conjunctival mass logic features and immunopheno- tiva as far as the limbus. The surgical in the temporal area (Figure 2) with type were compatible with the diag- margins were free of tumor. posterior extension on computed to- nosis of malignant amelanotic The patient was then fitted with mography (Figure 3). There were melanoma (tumor cells were posi- transcutaneous implants and a mag- no palpable preauricular or subman- tive for S100 protein and negative for netic retained prosthesis with satis- dibular nodes. Systemic workup vimentin, desmin, actin, myoglo- factory aesthetic results. Regular ruled out metastasis. A biopsy speci- bin, and cytokeratin). The patholo- systemic and ophthalmologic fol- men of the lesion revealed a conjunc- gical characteristics of the exen- low-up was uneventful until Janu- tival malignant melanoma, and the teration specimen confirmed the ary 1999, at which time the patient patient underwent orbital exentera- diagnosis of melanoma (Figure 1C complained of persistent nasal ob- tion in October 1992. Histological ex- and D). The mass was located in the struction. Examination revealed a amination of the biopsy specimen lower conjunctival fornix and ex- mass in the left nasal fossa and max- showed proliferation of malignant tended inferiorly to involve theor- illary sinus (Figure 4). Surgical pleomorphic cells whose morpho- bicularis muscle and bulbar conjunc- treatment consisted of maxillec- tomy with immediate reconstruc- tion with latissimus dorsi free-flap, and pathological examination confirmed the presence of malignant melanoma (Figure 5A and B). One year later, a sinus relapse was observed on a follow-up computed tomographic scan. The patient underwent a salvage operation, and pathological examination confirmed the presence of melanoma (Figure 5C and D). Dissemi- nated hepatic and bone metastases appeared in August 2000. The patient is currently receiving systemic chemotherapy with interferon and temozolomide.

Comment.Theassociationofembryo- nal sarcoma and melanoma in the Figure 2. Slightly pigmented mass adjacent to the temporal region of the left eye. same orbit is a very rare occurrence;

Figure 3. Computed tomographic scan of the left orbit shows posterior Figure 4. Computed tomographic image shows recurrent malignant extension of the mass. melanoma involving the orbital apex, left ethmoidal and maxillary sinuses, and nasal fossa.

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C D

Figure 5. A and B, Maxillary recurrence of malignant melanoma shows proliferation of large epithelioid cells (hematein-eosin saffron, original magnification ϫ10 [A] and ϫ40 [B]). C, Sinus relapse of malignant melanoma shows epithelioid-type cells (hematein-eosin saffron, original magnification ϫ20). D, Significant expression of a melanoma-related antigen (HMB 45, ϫ20).

to the best of our knowledge, the lit- dren with soft-tissue sarcomas, the in- (rhabdomyosarcoma and malignant erature reports only 1 other case of cidence of second malignant neo- melanoma) occurring in the same pa- orbital melanoma 45 years after suc- plasms was estimated to be 7.5%, but tient at an interval of 20 years; it fur- cessful treatment of rhabdomyosar- these authors reported only 1 case of ther emphasizes the current concern coma.2 The appearance of second melanoma.6 about childhood cancer treatments tumors after treatment of rhabdomyo- The metachronous appearance that might cause severe late effects, es- sarcoma is also a very rare event. In of 2 primary malignancies may be due pecially second cancers. their series describing long-term to several causes. It could be an inci- follow-up of children treated for or- dental occurrence, or it may be related Livia Lumbroso, MD bital rhabdomyosarcoma, Oberlin et to a genetic predisposition. The role Brigitte Sigal-Zafrani, MD al3 did not describe any patient with of previous cancer treatments (che- Thomas Jouffroy, MD a second neoplasm (median follow- motherapy and radiation therapy) Christine Levy, MD up, 8 years). Paulino et al,4 in a smaller cannot be excluded. Jose´ Rodriguez, MD series but with a longer follow-up, de- The possibility of a radioin- Laurence Desjardins, MD scribed a mucoepidermoid carcinoma duced tumor is supported by the pre- Paris, France of the parotid gland occurring at the existing homolateral lesion treated border of the radiation field after ra- by a combination of radiation Corresponding author and reprints: diotherapy of the supraglottic larynx. therapy and chemotherapy; the le- Livia Lumbroso, MD, Institut Curie, An epidermoid carcinoma was de- sion also occurred in the radiation 26 Rue d’Ulm, 75005 Paris, France scribed9yearsafterchemotherapyand field several years after initial treat- (e-mail: [email protected]). radiation therapy for rhabdomyosar- ment. However, the possibility of a coma, and this lesion was attributed genetic predisposition cannot be ex- 1. Abramson DH, Frank CM. Second nonocular 5 tumors in survivors of bilateral retinoblastoma: to radiation therapy. However, the cluded in our patient, despite the ab- a possible age effect on radiation-related risk. various second malignant neoplasms sence of a family history of cancer. Ophthalmology. 1998;105:573-580. described after treatment of rhabdo- This case report describes and 2. Leff SR, Henkind P. Rhabdomyosarcoma and late malignant melanoma of the orbit. Ophthalmol- myosarcomadonotincludemalignant documents the very rare occurrence ogy. 1983;90:1258-1260. melanoma.4,5 In a recent study on chil- of 2 distinct orbital malignancies 3. Oberlin O, Rey A, Anderson J, et al. Treatment

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 of orbital rhabdomyosarcoma: survival and late angle tumors in the same eye after of systemic malignancy. The tumor effects of treatment results of an international workshop. J Clin Oncol. 2001;19:197-204. treatment. The angle tumors simu- was treated with a radioactive 4. Paulino AC, Simon JH, Zhen W, Wen BC. Long- lated metastases of either the pri- plaque. A week after surgery, 2 light- term effects in children treated with radio- mary choroidal melanoma or an un- gray lesions approximately 1 mm in therapy for head and neck rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 2000;48:1489- recognized systemic malignancy. size were seen at the root of the right 1495. When the eye was removed, we iris at the 7- to 8-o’clock and 10- 5. Raney RB, Anderson JR, Kollath J, et al. Late effects of therapy in 94 patients with localized rhab- found an occult ring melanoma of o’clock positions (Figure 1B). The domyosarcoma of the orbit: report from the In- the ciliary body with invasion of the lesions were observed for 4 months tergroup Rhabdomyosarcoma Study (IRS)–III, angle. but did not enlarge; an iris biopsy 1984-1991. Med Pediatr Oncol. 2000;34:413- 420. was performed and showed spindle 6. Merimsky O, Kollender Y, Issakov J, et al. Mul- Report of a Case. A 71-year-old melanoma cells. Further evalua- tiple primary malignancies in association with soft woman was referred for the evalu- tissue sarcomas. Cancer. 2001;91:1363-1371. tion found no evidence of malig- ation of a pigmented tumor in her nancy elsewhere, including the skin. right eye. An examination revealed The patient opted for removal of the a visual acuity of counting fingers at eye. A histopathologic examina- Unilateral Multifocal 3 ft OD and 20/40 OS. Positive find- tion revealed a largely necrotic Uveal Melanoma With ings included bilateral cataracts and (Ͼ95%) choroidal melanoma above Occult Ring Melanoma a 6-mm heart-shaped, pigmented the optic nerve (Figure 2A). No mi- choroidal tumor above the right op- totic figures were seen among the re- Unilateral multifocal uveal mela- tic disc (Figure 1A). A 3-mm flat, sidual spindle and epithelioid cells. noma is a neoplastic curiosity that pigmented nevus was present tem- A mixed cell–type melanoma had needs to be clinically distinguished poral to the left macula. A standard- encircled the ciliary body and fo- from metastatic carcinoma and me- ized A-scan of the right choroidal tu- cally invaded the angle (Figure 2B). tastases of cutaneous melanoma. We mor showed low internal reflectivity When 40 fields were viewed under describe a patient with a small pos- and a tumor height of 2.5 mm. A high-power magnification, 2 mi- terior choroidal melanoma who de- general medical evaluation and labo- totic figures were seen. Both tu- veloped 2 separate nonpigmented ratory studies showed no evidence mors were positive for the HMB-45 antigen. Results of serial sections confirmed that the 2 melanomas A B were not contiguous.

Comment. At least 16 cases of unilateral multifocal uveal melanoma have been reported in the literature.1,2 Our patient had no predisposing risks for uveal melanoma such as melanosis oculi or neurofi- bromatosis. She did not have bilateral diffuse uveal melanocytic tumors. The near-simultaneous Figure 1. A, A 6-mm pigmented tumor (arrows) is present above the right optic disc (arrowhead). recognition of both an anterior and The view of the fundus is hazy as a result of cataract. B, Two light-gray tumors (arrowheads) are barely posterior segment melanoma in the discernible in the angle of the right eye. same eye is highly unusual.3 The time sequence in which 2 discrete A B anterior segment tumors were de- tected in our patient raised the possibility of ocular metastasis of either the recently treated choroidal melanoma or an occult systemic malignancy. Prior to biopsy, the second possibility seemed more likely because the angle tumors were nonpigmented. The ring melanoma, which was clinically undetected because of minimal elevation, probably represents a primary uveal malignancy. The biological basis for multifocal uveal melanoma is unknown. Figure 2. A, The enucleated right eye reveals a predominately necrotic melanoma (arrow) adjacent to but not involving the optic nerve (hematoxylin-eosin; original magnification ϫ6). B, A coronal section several The possibility of occult ring mela- millimeters behind the limbus shows the ciliary body entirely replaced with a mixed cell–type melanoma noma needs to be considered when (hematoxylin-eosin; original magnification ϫ12). multiple angle tumors are found,

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 even in an eye harboring a discrete tion with a pterygium (Figure 1A). Case 2. A 66-year-old woman posterior melanoma. There was no epithelial defect, stro- was referred to us for a 1-month his- mal infiltration around the plaque, or tory of a foreign body sensation in her Mark E. Hammer, MD cellular reaction in the anterior cham- left eye. Initial slitlamp examination Tampa, Fla ber. Specimens were collected from showed a white, calcific-appearing Curtis E. Margo, MD, MPH the periphery of the plaque for smear plaque with an elevated and well- Lakeland, Fla and culture, and hourly administra- outlined border (Figure 2). The cor- tion of fortified antibiotic eyedrops nea was otherwise quiet with no cel- Corresponding author: Curtis E. was initiated. However, no resolu- lular reaction in the anterior chamber. Margo, MD, MPH, Department of tion of the corneal plaque was ob- The plaque was removed surgically Ophthalmology, Watson Clinic served for 1 week. Plaque removal and scraping for culture was per- LLP, 1600 Lakeland Hills Blvd, was tried and the lesion was easily re- formed from the underlying stro- Lakeland, FL 33805 (e-mail: cmargo moved, leaving an almost clear stromal bed. HAM was transplanted with @watsonclinic.com). mal bed underneath. Assuming a di- the basement membrane layer up to agnosis of a sterile corneal ulcer prevent a persistent epithelial de- 1. Dithmar S, Volcker HE, Grossniklaus HE. Mul- because of the quiet ocular findings fect. Corneal epithelium, initially tifocal intraocular malignant melanoma: report and negative culture report, the for- growing over the periphery of the of two cases and review of the literature. Oph- tified topical antibiotic regimen HAM, failed to cover the center of the thalmology. 1999;106:1345-1348. 2. Blumenthal EZ, Pe’er J. Multifocal choroidal ma- was changed to ofloxacin, 4 times HAM, which showed signs of disso- lignant melanoma: at least 3 melanomas in one daily, with hourly nonpreserved lution. At that time, pathologic ex- eye. Arch Ophthalmol. 1999;117:255-258. 3. Pe’er J, Bernstein-Lifshitz L. Case report: ante- artificial tears. An epithelial defect amination of the plaque disclosed rior and posterior uveal melanomas in one eye. at the plaque removal site persisted suspicious filamentous organisms Arch Ophthalmol. 1988;106:22-23. for 2 weeks, so we applied human embedded within severely degenera- amniotic membrane (HAM) and tive tissue, and the microbiology labo- removed the pterygium. However, ratory reported the growth of Micros- the epithelial defect slowly enlarged porum species. Treatment was begun Infectious Keratitis into the central cornea despite a lat- with 0.15% amphotericin B eye- Manifesting as a White eral tarsorrhaphy. A white plaque re- drops, and the HAM was covered Plaque on the Cornea appeared on the epithelial defect dur- slowly with epithelium, with no sign ing the next 3 months. Four months of recurrence at 3 months after dis- We experienced a cluster of 3 cases after her initial examination, we re- continuation of treatment. of culture-proved infectious kerati- peated removal of the corneal plaque Case 3. A 57-year-old man was tis that, although caused by different and microbiologic testing from the referred for a possible corneal ul- organisms, each had a white plaque stromal bed. The corneal plaque cer. He had complained of a gritty attached to the corneal surface with- showed a roughened surface that ap- sensation in his left eye for 3 weeks. out the typical findings associated peared calcific in nature (Figure 1B) He also had a white and apparently with an infectious corneal ulcer. and was easily detached. The cul- calcific plaque, which had a well- ture result disclosed Comamonas aci- demarcated and elevated margin Report of Cases. Case 1. A 68-year- dovorans with susceptibility to sev- (Figure 3A). A mild cellular reac- old woman visited our clinic com- eral antibiotics, including cefotaxime tion (1+) was seen in the anterior plaining of a foreign body sensation sodium, ceftriaxone sodium, cefta- chamber. Excisional biopsy of the and epiphora for 3 weeks in her right zidime, imipenem, and pefloxacin, plaque, scrapings from the stromal eye. She had no history of ocular dis- although the patient did not return bed for smear and culture, and trans- ease or trauma. On slitlamp exami- during the follow-up for treatment. plantation of HAM over the de- nation, a white plaque of gelatinous Three months later, she sought care nuded stroma were performed, fol- texture with sharply demarcated and for a corneal perforation at another lowed by initiation of treatment with elevated margins was seen on the na- clinic and underwent evisceration fortified antibiotics. One week later, sal paracentral cornea in conjunc- (Figure 1C). the HAM started to dissolve, reveal-

A B C

Figure 1. A, A white plaque of gelatinous texture with sharply demarcated and elevated margins is seen on the nasal paracentral cornea in conjunction with a pterygium. B, The corneal plaque, which slowly reappeared after the removal of the original plaque in part A, exhibits a roughened surface and an apparently calcific nature and was easily detached. C, Perforation is seen in the central cornea where the white plaque was attached in part B.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 ing a puslike fluid accumulation underneath. Natamycin eyedrops were added according to the biopsy result, which showed many filamentous fungal organisms within the plaque (Figure 3B). Acremonium species were cultured from the stromal bed. The corneal lesion improved gradually without any sequelae except for opacity that was limited to the HAM.

Comment. Although caused by different organisms, our 3 cases of infectious keratitis were characterized by the shared manifestations of a white corneal plaque, slow progression, and mild clinical inflam- matory features relative to most cases Figure 2. A white plaque, apparently calcific in nature, is seen with elevated and well-defined margins. of infectious keratitis. Entrapment Otherwise, the cornea appears to be quiet and the anterior chamber is clear. of less virulent microorganisms within the plaques, which were formed by an unknown mecha- A nism, might be the reason for the slow and mild clinical features. How- ever, corneal perforation is possible if the correct diagnosis and proper management are delayed as in case 1, where pathological examination of the plaque was not performed owing to our inexperience. We performed immediate HAM transplantation in cases 2 and 3 because of the problem of the persistent epithelial defect in case 1, where the initial negative microbiologic report influenced us not to be suspicious of an infection in cases 2 and 3. In retrospect, we do not think that HAM transplantation was es- sential to healing. In fact, the HAM might have acted to some extent as B a barrier against the penetration of antimicrobial eyedrops. The best management option would probably be an excisional biopsy of the plaque and the administration of antibiotics guided by an in vitro drug sensitivity test, without HAM transplantation. HAM could be used later if an epithelial defect persists after treatment of the infectious component. As for the cultured microorganisms in this report, C acidovorans is a ubiquitous gram-negative rod and is generally considered non- pathogenic. Keratitis caused by C acidovorans has been rarely reported, and no reported cases showed clini- Figure 3. A, A white and apparently calcific plaque shows a well-demarcated and elevated margin. B, The filamentous fungal organisms that were within the excised plaque (Gomori methenamine silver, cal features that were similar to our original magnification ϫ200). case 1.1,2 Microsporum, although one

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 of the most common causative or- Sekundo W. Keratitis due to the fungus Acre- the necrotic sclera was debrided and monium (Cephalosporium). Eye. 1994;8(pt ganisms for dermatomycoses, has 6):692-694. irrigated with gentamicin. A gram not been reported to cause infec- stain of the scleral nodule showed tious keratitis to the best of our gram-negative rods (Figure 2). The knowledge. Acremonium-caused culture report disclosed heavy keratitis is also rare compared with Infectious Scleritis After growth of Serratia marcescens that other fungal infections.3 Further Use of Immunomodulators was sensitive to gentamicin, amika- microbiologic evidence may be cin, ciprofloxacin, piperacillin so- needed to confirm the true role of Infectious scleritis, typically occur- dium, imipenem, ceftizoxime so- these organisms in corneal ulcers. ring in eyes having predisposing risk dium, and ceftazidime, but resistant We believe, however, that corneal factors, is vision-threatening. We to cefuroxime, ampicillin, and perforation, as in case 1, and a heal- present a case of infectious scleritis cephalothin sodium. Therapy with ing response to antifungal drops, after chemotherapy, which, to our topical and systemic gentamicin was as in cases 2 and 3, suggest the in- knowledge, has not been previ- continued, then tapered during the fectious nature whatever the actual ously reported as a risk factor. next 2 weeks until the lesion was re- causative organism might have solved (Figure 1B). No recurrence been. Report of a Case. A 58-year-old or visual impairment was found dur- In conclusion, these were all woman manifested symptoms of a ing the 1-year follow-up. cases of indolent corneal infections red, painful right eye for 1 day. Four A rheumatologic evaluation that manifested as white plaques on months previously, she had under- performed at presentation showed the cornea. It is important to per- gone right mastectomy for breast normal findings. The leukocyte form culture and histopathologic cancer and was receiving chemo- count was 6200/µL, with a de- studies on the plaque in addition to therapy with cyclophosphamide and creased percentage of polymor- the stromal bed for this kind of atypi- epidoxorubicin. She had com- phonuclear cells and lymphocytes cal infectious keratitis. pleted the fifth course of chemo- (polymorphonuclear cells, 48%; therapy 3 weeks before this visit. Her lymphocytes, 18%). The patient’s Beom-Jin Cho, MD medical history, including surgery leukocyte count had been decreas- Yong Beom Lee, MD and trauma, was otherwise unre- ing during 4 months of chemo- Seoul, South Korea markable. therapy. In particular, the percent- At presentation, slitlamp ex- age of polymorphonuclear cells had Corresponding author and reprints: amination showed conjunctival con- decreased from 77% to 48%. How- Beom-Jin Cho, MD, Department of gestion with a 2ϫ2-mm scleral nod- ever, there was no associated sys- Ophthalmology, College of Medi- ule surrounded by episcleral vessels temic infection. cine, University of Ulsan, Asan Medi- (Figure 1A). Other ocular find- cal Center, #388-1, Poongnap-dong, ings were unremarkable. Infec- Comment. Trauma and surgery are Songpa-gu, Seoul 138-040, South tious scleritis was suspected. She was important risk factors for infectious Korea. placed on a regimen of fortified topi- scleritis.1,2 Two cases of infectious cal cefazolin sodium (25 mg/mL) scleritis without history of trauma or 1. Stonecipher KG, Jensen HG, Kastl PR, Faulkner and gentamicin sulfate (14 mg/ surgery have been reported else- A, Rowsey JJ. Ocular infections associated with 3,4 3 Comamonas acidovorans. Am J Ophthalmol. 1991; mL) every hour and systemic gen- where. Maskin described a dia- 112:46-49. tamicin sulfate, (60 mg) every 8 betic patient with infectious scleri- 2. Brinser JH, Torczynski E. Unusual Pseudomo- hours. On the next day, we per- tis; the culture report was the same nas corneal ulcers. Am J Ophthalmol. 1977;84: 462-466. formed peritomy to verify the scleral as that from the patient’s foot ulcer. 3. Kennedy SM, Shankland GS, Lee WR, nodule. Cultures were obtained, and Maskin speculated it was probably

A B

Figure 1. A,A2ϫ2-mm scleral nodule (arrow) surrounded by engorged episcleral vessels. B, The abscess subsided after debridement and antibiotic treatment.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 cis-retinoic acid) is a vitamin A ana- logue that was first licensed in the United States in 1982 for the treatment of cystic acne. Use of isotretinoin during pregnancy is terato- genic and is associated with a constellation of fetal malformations collectively termed retinoic acid embryopathy.1 Retinoic acid embryopathy is characterized by craniofacial abnormalities in the form of hydrocephalus, microcephaly, a narrow, sloping forehead, hypertelorism, ear deformities, cleft palate, and micrognathia.1 Sys- temic anomalies include congenital heart defects and thymic malforma- tion.Reportedophthalmicfindingsare Figure 2. The gram stain from the scleral nodule showed gram-negative rods (arrowhead) microphthalmos,opticnervehypopla- (original magnification ϫ400). sia, and cortical blindness.2 We describe a child exposed to isotretinoin due to self-inoculation. Reynolds and of primary importance to prevent duringgestationwhosoughttreatment Alfonso4 reported infectious scleri- devastating consequences. for congenital restrictive ophthal- tis in a patient with acquired immu- moplegia and gustatory epiphora nodeficiency syndrome. Unfortu- Yih-Shiou Hwang, MD (crocodile tears syndrome). nately, a detailed history of the patient Yeong-Fong Chen, MD was not available. We found no Chi-Chun Lai, MD Report of a Case. An 11-week-old known risk factors of infectious scle- Henry Shen-Lih Chen, MD boy with numerous malformations ritis in our patient. The only pos- Ching-Hsi Hsiao, MD came to our unit with a history of sible clue was the patient’s immune Taipei, Taiwan poor visual tracking from birth. The status. Cyclophosphamide-related child’s mother had used isotreti- bone marrow suppression applies to noin (mean daily oral dosage, 53.3 Corresponding author and reprints: all elements of the bone marrow but mg) for acne during the first 9 weeks Ching-Hsi Hsiao, MD, Department of affects leukocytes to the greatest de- of her pregnancy. There was no Ophthalmology, Chang Gung Memo- gree.5 Such a condition may in- family history of parental consan- rial Hospital, No. 199, Tung Hwa crease the risk of infection before guinity or hereditary ocular or sys- North Road, Taipei 105, Taiwan, Re- suppression of neutrophil produc- temic disease. The infant was born public of China (e-mail: qq_hsiao tion is evident. Serious infection at term weighing 2.9 kg and was @yahoo.com). has been found to develop in 12% to found to have external and middle 32% of patients receiving high-dose ear malformations, patent ductus ar- cyclophosphamide.5 In addition, epi- 1. Riono WP, Hidayat AA, Rao NA. Scleritis: a clini- teriosus, patent foramen ovale, and copathologic study of 55 cases. Ophthalmology. doxorubicin also contributes to my- 1999;106:1328-1333. gastroesophageal reflux. At age 1 elosuppression. In our patient, che- 2. Smith JR, Chee SP. Nodular anterior scleritis as- month, he had a seizure. Electroen- motherapy might have suppressed sociated with ocular trauma. Singapore Med J. cephalography results were unre- 2001;42:180-181. the immune system, allowing subse- 3. Maskin SL. Infectious scleritis after a diabetic foot markable, and magnetic resonance quent development of infection. ulcer. Am J Ophthalmol. 1993;115:254-255. imaging of the orbits and brain re- 4. Reynolds MG, Alfonso E. Treatment of infec- However, we cannot identify whether tious scleritis and keratoscleritis. Am J Ophthal- vealed no malformations of the the infection source was exogenous mol. 1991;112:543-547. brainstem or cerebral structures; ex- or endogenous. 5. Buckner CD, Rudolph RH, Fefer A, et al. High- traocular muscles appeared normal dose cyclophosphamide therapy for malignant To our knowledge, this is the disease: toxicity, tumor response, and the ef- in size and configuration. Karyo- first report of infectious scleritis affects of stored autologous marrow. Cancer. 1972; type and fluorescence in situ hybrid- ter systemic immunosuppressive 29:357-365. ization analysis for chromosome 22 therapy. This case demonstrates that deletion demonstrated no abnor- microbial scleritis may imitate nodu- malities. lar scleritis, even though there may Congenital Restrictive The infant was hypotonic. Cra- be no history of trauma or surgery External Ophthalmoplegia niofacial abnormalities included a to implicate infection. The diagno- and Gustatory Epiphora prominent calvaria, a tall forehead, sis of infectious scleritis may be de- an oblique facial plane, microgna- Associated With Fetal layed and mistaken for an autoim- thia, anotia, and preauricular skin Isotretinoin Toxicity mune process. In patients at risk of tags (Figure). He had mild bilat- infections, such as our patient who Isotretinoin or Accutane (Hoff- eral blepharoptosis. Ocular motor was undergoing chemotherapy, it is man–La Roche Inc, Nutley, NJ; 13- examination revealed a striking limi-

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A C

Photographs of our patient at age 61⁄2 years. Craniofacial abnormalities characteristic of isotretinoin embryopathy are apparent, including a prominent calvaria, a tall forehead, an oblique facial plane, micrognathia (A), anotia, and preauricular skin tags (B and C).

tation in the amplitude and veloc- versional and vergence eye move- Concomitant gustatory epiphora ity of saccadic, pursuit, and ves- ments were unchanged. and ocular motility disturbances have tibulo-ocular reflex eye movements been reported with fetal thalido- in both the horizontal and vertical Comment. Our patient exhibits 2 mide exposure.5 The thalidomide ab- planes. Large-angle (30 prism diop- previously unreported ocular mani- normalities have been ascribed to a ters) alternating exotropia was noted festations of fetal isotretinoin ex- toxic insult to the ocular motor and with deficient convergence. Pupil- posure: congenital restrictive exter- facial brainstem nuclei before the fifth lary responses were normal. Cy- nal ophthalmoplegia and gustatory week of gestation. The findings in our cloplegic retinoscopy revealed sig- epiphora. The cause of the ophthal- patient suggest that exposure to nificant hyperopia (+5.00 diopters moplegia is not known, but it may isotretinoin during the early stages of OU). No funduscopic abnormali- represent a sporadic form of congen- fetal development can produce simi- ties were noted. Flash visually ital ocular fibrosis syndrome. Con- lar ocular motor abnormalities. evoked potential and photopic and genital ocular fibrosis syndrome is scotopic electroretinography re- a collection of nonprogressive, in- Medhat F. Guirgis, MD sponses were normal for the pa- herited motility disturbances char- Agnes M. F. Wong, MD, PhD tient’s age. Spectacles were pre- acterized by “stiff” fibrotic extraocu- Lawrence Tychsen, MD scribed to correct the hyperopia. lar muscles.3 It is unclear whether St Louis, Mo By 10 months of age, the pa- congenital ocular fibrosis syn- tient was noted to have epiphora drome represents a primary con- Corresponding author and reprints: when feeding (crocodile tear syn- genital myopathy or neuropathy. Lawrence Tychsen, MD, Room 2S- drome) and a lack of tear produc- Recent evidence suggests that con- 89, St Louis Children’s Hospital, One tion when crying (emotional genital ocular fibrosis syndrome Children’s Place, St Louis, MO 63110 alacrima). At 11 months of age, bi- may arise from a loss of neurons (e-mail: [email protected]). lateral lateral-rectus recessions were within brainstem ocular motor nu- performed to correct the exotropia. clei during embryologic develop- 1. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid 3 embryopathy. N Engl J Med. 1985;313:837-841. Forced duction testing during sur- ment. The neuronal loss second- 2. Fraunfelder FT, LaBraico JM, Meyer SM. Adverse gery revealed marked restriction to arily disrupts myogenesis, resulting ocular reactions possibly associated with isotreti- passive rotation in both horizontal in anomalous muscle develop- noin. Am J Ophthalmol. 1985;100:534-537. 3. Engle EC, Goumnerov BC, McKeown CA, et al. and vertical directions in each eye, ment. The presence of congenital Oculomotor nerve and muscle abnormalities in consistent with restrictive myopa- gustatory epiphora in our patient, congenital fibrosis of the extraocular muscles. Ann Neurol. 1997;41:314-325. thy. At age 6 years, he had a best- caused by maldevelopment of the 4. Ramsay J, Taylor T. Congenital crocodile tears: corrected visual acuity of 20/30 OU salivary and lacrimal nuclei within a key to the aetiology of Duane’s syndrome. Br J and an intermittent esotropia of 10 the pons and medulla, suggests a pri- Ophthalmol. 1980;64:518-522. 5. Miller MT, Stro¨mland K. Ocular motility in tha- prism diopters. The mild bilateral mary brainstem neuropathy as the lidomide embryopathy. J Pediatr Ophthalmol Stra- blepharoptosis and the limitation of cause of the ophthalmoplegia.4 bismus. 1991;28:47-54.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 revealed a medial orbital abscess. No A differential diagnosis of orbital Orbital Cellulitis and sinus disease was noted. cellulitis with abscess, idiopathic or- Abscess Secondary The patient was started on in- bitalinflammation,hematogenousdis- to Dacryocystitis travenous cefazolin and gentamicin semination, and malignancy was con- sulfate. She underwent an emergent sidered. Intravenous antibiotics were The symptoms of nasolacrimal duct orbitotomy with abscess drainage continued with minimal improve- obstruction include epiphora, con- through a medial Lynch incision. Co- ment. During the next several days, junctivitis, and mucoid discharge. pious amounts of necrotic purulent the patient’s medical condition dete- Dacryocystitis may develop when material were drained. A direct com- riorated due to gastrointestinal bleed- bacterial overgrowth occurs in the munication was noted between the ing and ascites. Once the patient was stagnant fluid of the lacrimal sac. posterior aspect of the lacrimal sac medically stable, a medial orbi- Whereas acute dacryocystitis is usu- and the intraconal space. The intra- totomy through a Lynch incision was ally characterized by tender presep- conal abscess was also evacuated. A performed. Upon dissection be- tal cellulitis, chronic dacryocystitis dacryocystorhinostomy was per- tween the medial and superior recti typically manifests as painless puru- formed. Cultures grew Staphylococ- muscles into the intraconal space, an lent reflux from the lacrimal sac. An- cus aureus. Postoperatively, the pa- abscess was encountered surround- tibiotic therapy is indicated for acute tient had resolution of the orbital ing the optic nerve. The abscess was infections, and dacryocystorhinos- inflammation and proptosis, but her noted to be extending from the area tomy is the definitive treatment. visual acuity remained no light per- of the lacrimal sac. Purulent mate- Although anterior extension ception OS. rial was drained, and a communica- into the preseptal soft tissues oc- Case 2. A 64-year-old woman tion with the abscess was identified. curs more often in acute dacryocys- was hospitalized with jaundice, an- Several dacryoliths were removed. An titis, orbital extension can occur, al- orexia, and hepatic failure second- osteotomy into the nasal cavity and though rarely, and result in orbital ary to chronic alcoholism. Two days a dacryocystorhinostomy with sili- cellulitis and abscess formation.1-9 after admission, swelling of the right cone stents were performed. Cul- Posterior extension into the orbit can upper and lower eyelids was noted. tures grew nonenterococcal group D result in devastating visual compro- She was afebrile but had a white streptococci, Streptococcus viridans, mise. We describe a series of 4 pa- blood cell count of 22.5ϫ103/µL and Streptococcus intermedius. Post- tients with orbital cellulitis and ab- with leukocytosis. Empiric intrave- operatively, the patient had resolu- scesses secondary to dacryocystitis nous vancomycin hydrochloride was tion of proptosis and improved ocu- (Table 1). started by the admitting service. lar motility, except for an adduction Ophthalmic consultation was ob- deficit. Her visual acuity remained Report of Cases. Case 1. A 38-year- tained. light perception OD. old woman had a history of epiphora Her visual acuity was light per- Case 3. A 62-year-old woman for many years but declined surgi- ception OD. An afferent pupillary sought care from her ophthalmolo- cal treatment. She had 1 previous defect was present. Marked right gist with a 5-day history of tearing episode of dacryocystitis that re- proptosis, diminished extraocular and swelling of the left upper and solved with systemic antibiotics. She motility, chemosis, and conjuncti- lower eyelids. Her ocular history in- sought care because of a 1-week his- val hyperemia were also noted. Di- cluded nasolacrimal obstructive tory of painful swelling and de- lated fundus examination showed symptoms for many years and prior creased vision in her left eye. right choroidal folds and retinal episodes of dacryocystitis. Oral On examination, her visual edema. A computed tomographic cephalexin monohydrate (250 mg, acuity was 20/20 OD and no light scan showed a large, irregular mass 4 times daily) was prescribed. Dur- perception OS. A left afferent pupil- in the medial and posterior orbit dis- ing the next 2 days, she developed lary defect was present. Her left globe placing the globe and optic nerve. proptosis and chemosis of the left eye was markedly proptotic, tense to ret- There was enlargement of the me- and was referred for consultation. ropulsion, and restricted in all fields dial rectus muscle and contrast en- Her visual acuity with correc- of gaze. Dilated funduscopic exami- hancement of the posterior sclera. tion was 20/20 OD and 20/60 OS. A nation revealed hyperemia of the left The bony orbit was intact, and the trace left afferent pupillary defect was disc. A computed tomographic scan sinuses were clear. noted. Marked chemosis and ery-

Table 1. Orbital Cellulitis and Abscesses Secondary to Dacryocystitis in 4 Patients

Patient No./ Location of Degree of Conjunctival Length of DCR Patent Age, y Orbital Abscess Proptosis Chemosis Motility Hyperemia Follow-up, mo at Last Visit 1/38 Extraconal Marked Yes Severely restricted 4+ 19 Yes 2/64 Intraconal Marked Yes Severely restricted 4+ 2 Yes 3/62 Intraconal Marked Yes Severely restricted 4+ 2 Yes 4/51 Intraconal Moderate No Restricted 2+ 6 Yes

*DCR indicates dacryocystorhinostomy.

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A, Coronal computed tomographic scan of a 51-year-old, otherwise healthy man shows dacryocystitis before orbital cellulitis and abscess formation. Note the proximity of the lacrimal sac to the intraconal space. B, Coronal computed tomographic scan shows progression to orbital abscess (arrow), indenting the globe.

thema were noted, and 13 mm of chemosis. Adduction was nearly full. medial orbital abscess (Figure, B). In- relative proptosis was measured. A Visual acuity measured 20/25 OS. A travenous trovafloxacin mesylate motility examination showed se- residual left afferent pupillary de- was initiated for improved anaero- verely restricted ductions of the left fect was present with slight pallor of bic coverage. When no clinical im- globe. Her intraocular pressure was the left optic nerve. provement was noted 24 hours later, 19 mm Hg OD and 46 mm Hg OS. Case 4. A 51-year-old, other- the patient underwent an endo- Dilated fundus examination showed wise healthy man sought care be- scopic dacryocystorhinostomy with slight hyperemia of the left nerve. The cause of a 2-day history of right- evacuation of copious purulent ma- patient was afebrile but had a white sided medial canthal swelling, terial from the lacrimal sac. Sili- blood cell count of 11.6ϫ103/µL with pain, redness, and tearing. He was cone stents were also placed. The re- leukocytosis. An orbital computed to- previously seen by his internist, sults of cultures were negative. A mographic scan showed a large me- who prescribed oral erythromycin lacrimal sac biopsy specimen showed dial orbital mass contiguous with the stearate. For several weeks before acute and chronic inflammation. lacrimal sac, suggestive of an ab- seeking care, he noted intermittent Follow-up at 1 week showed intact scess. The paranasal sinuses were epiphora and swelling that could vision, resolution of edema, full ocu- clear. The patient was hospitalized, be relieved with digital massage. lar motility, and no proptosis. His and intravenous cefazolin and gen- His medical history was unremark- stents were removed at 6 months, tamicin were initiated. Urgent me- able except for a penicillin allergy. and his dacryocystorhinostomy was dial orbitotomy through a Lynch in- On examination, his visual acu- patent. cision was performed. The lacrimal ity was 20/20 OU. Medial canthal sac and the superior aspect of the na- and lower-eyelid edema and ery- Comment. Patients with nasolacri- solacrimal duct were found to be thema were present. His motility was mal duct obstruction seek treat- grossly dilated and tense. The sac was full, and there was no proptosis. Ini- ment primarily to relieve symp- opened, and copious purulent mate- tial computed tomographic scan- toms of epiphora, irritation, and rial was removed and cultured. Three ning showed an enlarged lacrimal sac mucoid discharge. If obstruction large dark-gray dacryoliths were ex- and surrounding soft tissue inflam- progresses to acute dacryocystitis, tracted from the sac. Examination of mation (Figure, A). Intravenous pain and swelling of the lacrimal sac the sac revealed a fistulous commu- vancomycin and gentamicin were region occur, necessitating sys- nication extending from the sac into initiated. During the next 2 days, temic antibiotics and definitive the medial intraconal space. A dac- improvement was noted; however, surgical treatment. In chronic dacryocystorhinostomy was performed on the third day, when the patient ryocystitis, patients often obtain tem- with silicone stents. complained of increased pain, his porary relief of symptoms with ex- During the next several days, examination showed 3 mm of prop- ternal decompression of the lacrimal the patient showed gradual improve- tosis, increased resistance to retro- sac. If dacryocystitis is untreated, or- ment. Cultures grew S viridans, S in- pulsion, diminished extraocular bital extension has been reported.1-9 termedius, and Veillonella parvula. movements, and marked indura- These cases are summarized in Infectious disease consultation rec- tion of the medial canthal region. His Table 2. ommended 3 weeks of intravenous vision remained 20/20 OU, and no This study describes our se- cefazolin and 1 week of oral cepha- afferent pupillary defect was pres- ries of 4 patients who developed or- lexin. Follow-up at 8 weeks after the ent. A repeated computed tomo- bital cellulitis and orbital abscesses operation revealed complete reso- graphic scan showed marked or- arising from dacryocystitis. Of 4 pa- lution of the proptosis, edema, and bital soft tissue inflammation and a tients, 3 had intraconal spread of the

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Age of Final Previous Dacryoliths Sinus Source Patient Visual Acuity Dacryocystitis Present Bacterial Isolates Disease Ahrens-Palumbo and Ballen, 19821 60 y 20/20 Yes No Staphylococcus epidermidis Ethmoidal Allen et al, 19852 57 y 6/6 No . . . Eikenella corrodens and Ethmoidal Enterobacter aerogenes Campolattaro et al, 19973 3mo ... No ... Staphylococcus aureus No 3 y . . . Yes . . . Alpha streptococcus No 19y ... No ... S epidermidis No Kikkawa et al, 2002 (present study) 38 y NLP Yes Yes S aureus No 64 y NLP No Yes Nonenterococcal group, group D streptococci, No Streptococcus viridans, and S intermedius 62 y 20/25 Yes Yes S viridans, Staphylococcus intermedius, and No Veillonella parvula 51 y 20/20 Yes No None No Lawless and Martin, 19864 3 y . . . No, but probing ... Haemophilus influenza and S aureus Bilateral age1y maxillary Mauriello and Wasserman, 19965 84 y 20/70 No No S aureus Ethmoidal Molgat and Hurwitz, 19936 40 y 6/6 Yes Yes S viridans Ethmoidal and maxillary Ntountas et al, 19977 38 y 20/20 No Yes Streptococcus angiosus, Peptrostreptococcus, No and “anaerobic gram-negative rod” Warrak and Khoury, 19968 62 y . . . No No Morganella morganii No Weiss and Leib, 19939 17 y . . . No No S aureus No

*NLP indicates no light perception; ellipses, not available.

orbital abscess and culture-proven nel of communication can form In our series, 3 of 4 patients had bacterial infections; 3 patients also between the medial and inferior a prior history of dacryocystitis. In had prior episodes of dacryocysti- rectus muscles directly to the intra- fact, of the reported cases in Table tis. Each of these findings deserves conal space. Intraconal abscess for- 2, 6 (40%) of 15 had prior dacryo- further discussion. mation can lead to rapid vision loss, cystitis. In addition, 5 (33%) of 15 Most patients with dacryocys- necessitating urgent surgical inter- had dacryoliths, including 2 pa- titis develop preseptal cellulitis and vention. tients who did not have a prior his- not orbital extension. This has been Although intravenous antibi- tory of dacryocystitis but had dac- attributed to the orbital septum by its otics were initiated immediately in ryoliths found intraoperatively. We insertion on the posterior lacrimal all patients, surgical drainage is the believe that prior dacryocystitis is a crest, limiting spread to the orbit.5 definitive treatment. Surgical inter- risk factor for orbital extension. Dis- Several other barriers exist posteri- vention in all 4 cases consisted of tension of the lacrimal sac during orly, including the lacrimal fascia, the dacryocystorhinostomy with place- episodes of dacryocystitis can stretch posterior limb of the medial canthal ment of silicone stents and orbital the lacrimal sac walls and its poste- ligament, and deep heads of the pre- abscess drainage. Of 4 cases, 3 had rior barriers (posterior limb of the tarsal and preseptal orbicularis an external approach, and 1 case had medial canthal ligament, Horner muscles (Horner muscle). Because an endoscopic intranasal approach. muscle, and septum). These barri- the orbital septum and the medial All patients had a patent dacryocys- ers weaken from distension and canthal ligament insert on both the torhinostomy at the last follow-up cause breaches and rarefaction, in- anterior and posterior lacrimal crests, visit (range, 2-19 months). creasing the likelihood of posterior we postulate that the main barrier to The clinical bacteriological char- spread. posterior extension is the deep heads acteristics of dacryocystitis in adults Other causes of orbital celluli- of the preseptal and pretarsal orbi- have been studied previously.10 In our tis secondary to dacryocystitis have cularis muscles. Hence, the ana- series, 2 of 4 patients had polymicro- been postulated.1,2 In 1 case report, tomic barriers to prevent egress from bial infections, 1 patient had a single the authors speculated that postop- the lacrimal sac are greater posteri- organism, and 1 had no isolates. erative soft tissue swelling from orly than anteriorly. When examining the isolates from blepharoplasty might have contrib- Once the posterior barriers of our series and the previously re- uted to the obstruction of an al- the lacrimal sac have been breached, ported cases from Table 2, we find ready compromised lacrimal out- access to the intraconal space is es- that, in general, younger patients (Ͻ3 flow system.2 Other authors have sentially unimpeded, except for the years) tended to have single isolates, theorized that orbital involvement Tenon fascia and the intermuscular and older patients tended to have could have resulted from spread of septum. Because of the anterior and polymicrobial infections. These find- infection from the lacrimal sac to the inferior location of the nasolacrimal ings parallel those seen in orbital ab- ethmoid sinus through the lamina sac in relation to the globe, a chan- scesses secondary to sinus disease.11 papyracea, with subsequent exten-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 sion from the sinus to the orbit.1 lacrimal bypass operation should be- Campus Point Dr,La Jolla, CA 92093- None of our cases had any evi- warned of these potential conse- 0946 (e-mail: [email protected]). dence of sinus disease, and it is more quences. 1. Ahrens-Palumbo MJ, Ballen PH. Primary dac- likely that any sinus opacification ryocystitis causing orbital cellulitis. Ann Oph- seen is secondary to adjacent inflam- Don O. Kikkawa, MD thalmol. 1982;14:600-601. 2. Allen MV, Cohen KL, Grimson BS. Orbital cel- mation from the dacryocystitis La Jolla, Calif lulitis secondary to dacryocystitis following or unrelated sinus disease. Other blepharoplasty.AnnOphthalmol.1985;17:498-499. Grant W. Heinz, MD 3. Campolattaro BN, Lueder GT, Tycheson L. possible causes include hematog- Tucson, Ariz Spectrum of pediatric dacryocystitis: medical enous spread from other systemic and surgical management of 54 cases. J Pedi- sources and, in some cases, a pri- Ronald T. Martin, MD atr Ophthalmol Strabismus. 1997;34:143-153. mary orbital cellulitis that can ex- William N. Nunery, MD 4. Lawless M, Martin F. Orbital cellulitis and pre- Indianapolis, Ind septal cellulitis in childhood. AustNZJOph- tend into the lacrimal sac without thalmol. 1986;14:211-219. the dacryocystitis necessarily being Andrew S. Eiseman, MD 5. Mauriello JA, Wasserman BA. Acute dacryocystitis: an unusual cause of life-threatening or- causal. Washington, DC bital intraconal abscess with frozen globe. Oph- In summary, our series of or- thal Plast Reconstr Surg. 1996;12:294-295. 6. MolgatYM,HurwitzJJ.Orbitalabscessduetoacute bital cellulitis and abscess second- This study was supported in part by dacryocystitis.CanJOphthalmol.1993;28:181-183. ary to dacryocystitis has been pre- an unrestricted grant from Research 7. Ntountas I, Morschbacher R, Pratt D, Patel BC, sented. Orbital cellulitis and abscess to Prevent Blindness, Inc, New York, Anderson RL, McCann JD. An orbital abscess secondary to acute dacryocystitis. Ophthalmic can rapidly progress to an intra- NY. Surg Lasers. 1997;28:758-761. conal abscess and can cause severe vi- The views expressed in this ar- 8. Warrak E, Khoury P. Orbital abscess second- sual sequelae if untreated. Prompt rec- ticle are those of the authors and do ary to acute dacryocystitis. Can J Ophthalmol. 1996;31:201-202. ognition and appropriate surgical not reflect the official policy of the US 9. Weiss GH, Leib LM. Congenital dacryocysti- management of this condition are Army, the Department of Defense, or tis and retrobulbar abscess. J Pediatr Ophthal- mol Strabismus. 1993;30:271-272. necessary to prevent vision loss. Prior the US government. 10. Coden DJ, Hornblass A, Haas BD. Clinical bac- dacryocystitis is a risk factor for Corresponding author and re- teriology of dacryocystitis in adults. Ophthal developing orbital extension, and prints: Don O. Kikkawa, MD, Uni- Plast Reconstr Surg. 1993;9:125-131. 11. Harris GJ. Subperiosteal abscess of the orbit: age patients with prior episodes of dac- versity of California, San Diego, De- as a factor in the bacteriology and response to ryocystitis who elect not to have a partment of Ophthalmology, 9415 treatment. Ophthalmology. 1994;101:585-595.

Correction

Error in Reference. In the article titled “Goblet Cell Numbers and Epithelial Proliferation in the Conjunctiva of Patients With Dry Eye Syndrome Treated With Cyclosporine,” published in the March issue of the ARCHIVES (2002;120:330-337), on page 337, in the first reference, the editors of Principles and Practice of Ophthalmology: Clinical Practice are Daniel M. Albert and Frederick A. Jakobiec.

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