Exercise-Induced Vasospastic Amaurosis Fugax

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

lomata acuminata. While receiving flamed fibrovascular cores Conjunctival Papillomas highly active antiretroviral therapy (Figure 2). Nucleated keratino- Caused by Human (HAART), including indinavir sul- cytes from the paraffin-embedded Papillomavirus Type 33 fate, nevirapine, and combivir, he has specimen were microdissected un- had no new opportunistic infections der direct visualization. After protein- Conjunctival papillomas are associ- and his CD4+ cell count has in- ase K digestion, DNA sequences for ated with human papillomavirus creased above 200/mm3. He sought HPV genotypes 16, 18, and 33 were (HPV) infection. In children, the le- ophthalmic care because of occa- amplified with a kit (PCR Human sions are typically manifestations of sional bleeding from the conjuncti- Papillomavirus Detection Kit; Pan an infection acquired during deliv- val lesions. An initial ocular exami- Vera, Madison, Wis) and transblot- ery.1 In adults, conjunctival papillo- nation revealed bilateral inferior ted for Southern blot hybridization. mas are most likely venereal and are palpebral conjunctival papillomas that Briefly, the common sense primer for often associated with anogenital le- were excised from the right eye. The HPV types 16, 18, and 33 was 5Ј- sions.2 Papillomas due to HPV more results of a histopathologic examina- AAGGGCGTAACCGAAATC- frequently progress to malignancy in tion showed conjunctival papillo- GGT-3Ј and the antisense primers of patients with the human immuno- mas without atypia. The results of an each HPV strain were as follows: 5Ј- deficiency virus (HIV) infection.3 Hu- immunohistochemistry test for HPV GTTTGCAGCTCTGTGCATA-3Ј for man papillomavirus types 6, 11, 16, types 6, 11, 16, 18, 31, and 33 was HPV 16, 5Ј-GTGTTCAGTTCCGT- and 18 have been identified in be- negative. The conjunctival lesions re- GCACA-3Ј for HPV 18, and 5Ј- nign and malignant conjunctival le- curred, and he was referred to the Na- GTCTCCAATGCTTGGCACA-3Ј for sions using various antigen and DNA tional Eye Institute, Bethesda, Md. HPV 33. The hybridization probes detection techniques.2 For the first The results of our examination were were 5Ј-CATTTTATGCAC- time, to our knowledge, we report the unremarkable, except for the pres- CAAAAGAGAACTGCAATG-3Ј for finding of HPV type 33 in conjunc- ence of 1.2- to 1.5-mm nodular le- HPV 16, 5Ј-TGAGAAACACACCA- tival papillomas excised from an HIV- sions on the right upper and lower CAATACTATGGCGCGC-3Ј for positive patient. palpebral conjunctiva and large, con- HPV 18, and 5Ј-CATTTTGCAG- fluent, verrucous lesions involving the TAAGGTACTGCACGACTATG-3Ј Report of a Case. A 34-year-old HIV- left upper and lower palpebral con- for HPV 33. The polymerase chain re- positive man complained of bilateral junctiva (Figure 1). A left palpe- action was performed for each HPV conjunctival lesions of 4 years’ dura- bral conjunctival excisional biopsy strain under the following condition. Ten years earlier, he was diag- was performed. A histopathologic ex- tions: 94° for 30 seconds to denature nosed as having HIV after develop- amination of the biopsy specimen re- the primers, 55° for 2 minutes for ing pneumocystis pneumonia, a vealed papillary fronds of acanthotic primer annealing, and 72° for 2 min- Mycobacterium avium-intracellulare squamous epithelium without atypia utes for primer extension. The reac- infection, and perianal HPV condy- and koilocytic changes overlying in- tion was repeated for 35 cycles, con-

Figure 1. Diffuse left lower palpebral conjunctival papillomas. Figure 2. Photomicrograph showing multiple papillary fronds of acanthotic conjunctival epithelium without atypia or koilocytic changes overlying fibrovascular cores infiltrated by subacute inflammatory cells (arrow) (hematoxylin-eosin, original magnification ϫ400).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 cluding with a final extension at 72° for 10 minutes. The results demonstrated HPV type 33 DNA sequences in the epithelium of the conjunctival Case papillomas (Figure 3). Postopera- tively, the patient was unavailable for follow-up.

Comment. Human papillomavirus is Positive an oncogenic double-stranded DNA Control papovavirus that infects keratino- cytes and causes benign and malig-

nant hyperproliferative squamous 12 3 epithelial tumors. With approximately 100 subtypes identified, HPV Figure 3. Southern blot detection of amplified DNA polymerase chain reaction products for human is now the most common sexually papillomavirus (HPV) types 16, 18, and 33 from the epithelia microdissected from the conjunctival papillomas. Lane 1 indicates HPV type 16; lane 2, HPV type 18; and lane 3, HPV type 33. transmitted disease. Human papillomavirus is the cause of verrucae (skin warts), condylomata acuminata (ve- cently HPV type 33 has been asso- fections on the risk of ocular neo- nereal or genital warts), and muco- ciated with breast cancer in Chi- plasia. We report for the first time, cutaneous papillomas, which repre- nese and Japanese patients.9 to our knowledge, the presence of sent 7% to 12% of all conjunctival Infection with HIV increases the HPV type 33 in conjunctival papil- lesions.1,4 Most commonly associ- risk for HPV-associated malignancy lomas. Although the conjunctival ated with benign anogenital lesions and may be a cofactor linking HPV papillomas in our patient were be- and respiratory papillomas, HPV infection and neoplasia.5 The immu- nign, we suspect that the coinci- types 6 and 11 are classified as low- nodeficiency secondary to HIV may dence of the HIV infection and the risk subtypes because they rarely facilitate the oncogenic effects of oncogenic HPV type 33 places the progress to invasive cancer. Human HPV by altering the host susceptibil- patient at an increased risk for re- papillomavirus types 16 and 18 are ity to HPV infection and impairing current and persistent conjunctival considered high risk because they are immune tumor surveillance. A di- papillomas and a conjunctival ma- associated with epithelial dysplasia rect molecular interaction between lignancy. Further follow-up is and squamous cell carcinomas, par- HIV and HPV could also promote needed to determine if HAART will ticularly in the uterine cervix and anal the development of cancer. Re- ameliorate or potentiate the pa- canal. Human papillomavirus types cently, it has been shown that the tient’s risk of ocular disease. 31, 33, 35, 45, 51, 52, and 56 have HIV-1 tat protein potentiates the ex- an intermediate risk of malig- pression of HPV oncoproteins.5 Ronald R. Buggage, MD nancy.5 The effect of HAART in HIV- Janine A. Smith, MD Conjunctival HPV infection infected patients with HPV disease Defen Shen, PhD may be established during delivery is unclear. Heard and coworkers10 at- Chi-Chao Chan, MD through an infected birth canal, by tributed the reduced prevalence of Bethesda, Md sexual contact, or by autoinocula- cervical HPV lesions in HIV- tion. Human papillomavirus anti- positive women treated with HAART + Corresponding author and reprints: Dr gens are reported in 5% to 45% of to their increased CD4 cell count. Buggage, National Eye Institute, Na- conjunctival papillomas, with HPV Similarly, anal HPV lesions were tional Institutes of Health, 10 Center Dr, types 6 and 11 most commonly more likely to regress in HIV- + Bldg 10, Room 10N112, Bethesda, MD found in papillomas from children positive men with higher CD4 cell 20892-1857 (e-mail: BuggageR@intra and HPV types 16 and 18 more fre- counts who were receiving HAART. .nei.nih.gov). quently associated with dysplasia Other studies5 involving HIV- and carcinoma in older patients. positive men with anal HPV lesions 1. McDonnell PJ, McDonnell JM, Kessis T, et al. Detection of human papillomavirus type 6/11 Normal conjunctiva has also been who were receiving HAART, how- DNA in conjunctival papillomas by in situ hy- 2,6 shown to harbor HPV antigens. ever, suggest that anal HPV does not bridization with radioactive probes. Hum Pathol. Human papillomavirus type 33 regress and that the improved sur- 1987;18:1115-1119. 2. Miller DM, Brodell RT, Levine MR. The conjunc- is an uncommon genotype found in vival from HAART may paradoxi- tival wart: report of a case and review of treat- benign, dysplastic, and malignant le- cally cause an increased risk of anal mentoptions.OphthalmicSurg.1994;25:545-548. sions. In a study7 defining the dis- cancer. 3. Waddell KM, Lewallen S, Lucas SB, et al. Car- cinoma of the conjunctiva and HIV infection tribution of HPV genotypes in male An increased incidence of con- in Uganda and Malawi. Br J Ophthalmol. 1996; genital lesions, it was detected in junctival malignancy in Africa has 80:503-508. 4. Cotran RS, Kumar N, Collins T. Neoplasia: Rob- only 1 (0.6%) of 175 specimens. Se- been attributed to the combination bins Pathologic Basis of Disease. Philadelphia, Pa: ropositivity to HPV type 33 in- of HIV-induced immunosuppres- WB Saunders Co; 1999:311-312, 1048-1051. creased with age in a study8 of east- sion, HPV infection, and UV light ex- 5. Palefsyk JM. Anal squamous intraepithelial le- 3 sions in human immunodeficiency virus– ern European women. Primarily posure. This finding supports the positive men and women. Semin Oncol. 2000; found in anogenital lesions, re- combined effect of HIV and HPV in- 27:471-479.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 6. Naghasfar Z, McDonnell PJ, McDonnell JM, et al. Genital tract papillomavirus type 6 in recurrent conjunctival papilloma. Arch Ophthal- mol. 1986;104:1814-1815. 7. Grce M, Husnjak K, Skerlev M, Lipozencic J, Pavelic K. Detection and typing of human pap- illomaviruses by means of polymerase chain reaction and fragment length polymorphism in male genital lesions. Anticancer Res. 2000;20: 2097-2102. 8. Tachezy R, Hamsikova E, Hajek T, et al. Hu- man papillomavirus genotype spectrum in Czech women: correlation of HPV DNA presence with antibodies against HPV-16, 18, 33 virus-like particles. J Med Virol. 1999;58:378- 386. 9. Yu Y, Morimoto T, Sasa M, et al. HPV 33 DNA in premalignant and malignant breast lesions Figure 1. Right eye at time of initial appearance: in Chinese and Japanese populations. Antican- tiny keratic precipitates are seen, and the pupil is Figure 3. High-frequency (20-MHz) ultrasound cer Res. 1999;19:5057-5061. slightly oval. 10. Heard I, Schmitz V, Costagliola D, et al. Early of the right eye, revealing a ciliary body mass. regression of cervical lesions in HIV- Rule indicates millimeters. seropositive women receiving highly active antiretroviral therapy. AIDS. 1998;12:1459- 1464.

Bilateral Iridociliary T-Cell Lymphoma

Intraocular lymphoma is generally of the B-cell type, commonly affecting the posterior segment of the eye, and in most cases is associated with central nervous system (CNS) lymphoma.1 Primary involvement of the Figure 2. Left eye at time of initial appearance: anterior uvea is very rare.2-4 T-cell iris white mass and bulging at the 6-o’clock position. Engorgement of the iris vessels, lymphoma is not commonly seen in hypopyon, and a distorted pupil are seen. the eye. We describe a patient with Figure 4. High-frequency (20-MHz) ultrasound non-Hodgkin lymphoma (NHL) of ent, and the lens was clear. An ex- of the left eye, showing a bigger ciliary body the T-cell type affecting primarily the amination of the left eye showed a mass pushing the iris forward. The anterior chamber angle was closed in inferior quadrants. iris and ciliary body of both eyes as hyperemic bulbar and perilimbal Rule indicates millimeters. the first manifestation of the sys- conjunctiva, white keratic precipi- temic disease. tates, and cells (+4) and flare (+2) in the anterior chamber with a 2-mm whereas the posterior pole was un- Report of a Case. A 31-year-old man hypopyon. The iris was bulging and remarkable (B-scan, 10 MHz). An an- came to our clinic with left anterior was infiltrated by a whitish mass at terior chamber tap from the left eye uveitis of 4 weeks’ duration that was the 6-o-clock position (Figure 2). was performed twice, but microbio- unresponsive to topical steroids. Marked engorgement of the iris ves- logic and cytologic evaluations were During the previous weeks, he had sels was present. The pupil was se- noncontributory. Findings from the noticed a progressive worsening of verely distorted (pulled upward) and uveitis workup, including a com- his vision with mild ocular discom- mid-dilated. The lens was clear. No plete blood cell count, erythrocyte fort in his left eye. No pain or red- cells were present in the vitreous, sedimentation rate, antinuclear an- ness was present. His history was and the posterior segment was nor- tibody test, VDRL test, purified pro- remarkable for oral drug abuse (3,4- mal in both eyes. tein derivative (tuberculin) test, hu- methylene dioxymethamphet- The combination of iris distor- man immunodeficiency virus test, amine [Ecstasy]) and lysergic acid tion and infiltration with painless se- and chest x-ray films, were within diethylamide. He denied intrave- vere intraocular inflammation raised normal limits. Because of com- nous drug administration. On ex- the possibility of a tumor masquer- plaints of paresthesia in both legs, amination, his visual acuity was ading as anterior uveitis. Investiga- the patient underwent a neurologic 20/20 OD and 20/60 OS. Intraocu- tions included an ultrasound exami- examination, computed tomogra- lar pressure readings were 10 mm Hg nation (high resolution, 20 MHz) of phy of the brain, and lumbar punc- and 17 mm Hg, respectively. A bio- the eyes that revealed a ciliary body ture, which all yielded normal re- microscopic examination of the right mass pushing the iris forward. This sults. eye demonstrated tiny white ke- occurred in both eyes but was more Within a few days, the ocular ratic precipitates and cells (+1) and pronounced in the left eye (Figure 3 disease progressed rapidly in both flare (+1) in the anterior chamber and Figure 4). Bilaterally, the an- eyes. Iris and anterior chamber angle (Figure 1). No synechiae were pres- terior choroid was thickened, infiltration increased, leading to an

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Figure 7. Left eye appearance after the first course of treatment with cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone. After an initial good response, regrowth of the iris lesion was noticed. tumor were diagnostic for peripheral large T-cell lymphoma. An additional systemic workup, including a bone marrow examination, Figure 5. Sheets of atypical large lymphoid cells are seen (hematoxylin-eosin stain, original magnification total body computed tomography, ϫ 40). and brain magnetic resonance imaging, disclosed no systemic involvement. The patient was treated with systemic chemotherapy consisting of cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone. Signs of uveitis re- gressed rapidly in both eyes with melting of the iris mass lesion. How- ever, a recurrence was noted in the left eye 2 weeks later. A new well- defined iris mass was seen in addition to a recurrence of the pseudo- hypopyon and increased intraocular pressure (Figure 7). A newly ap- pearing dense vitreous infiltration was noted. Central nervous system involvement was ruled out with brain magnetic resonance imaging. A more aggressive second course of chemotherapy was started Figure 6. The atypical lymphoid cells stain positively with the immunohistochemical stain CD3 5 (pan-T-cell marker, original magnification ϫ 40). following the Magrath protocol. A high dose of intravenous methotrexate and leucovorin calcium was increased intraocular pressure read- specimen from the nodule in the added. Methotrexate was adminis- ing of 28 mm Hg OS. In view of the iris was composed of diffuse sheets tered intrathecally as well as intra- lack of response to topical steroids, of large atypical lymphoid cells vitreally (400 µg/0.1 mL injected a diagnostic biopsy of the left eye was (Figure 5). Apoptotic bodies and twice weekly, 7 times).6 The sec- performed. During the procedure, mitotic figures were seen. The ond course of chemotherapy in- the iris was noted to be massively in- specimen underwent immunohis- duced a rapid response. The white filtrated and extremely fragile. Be- tochemical staining; the atypical lesion resorbed completely, and the hind the iris, a white plaque of cells cells stained with leukocyte com- patient remained stable during 9 was seen on the lens surface with lo- mon antigen and CD3 (pan-T-cell months of follow-up (Figure 8). calized lens opacity behind it. marker) (Figure 6) but did not The vitreous became free of cells af- A few iris pieces were excised, stain with CD20, CD79-␣, CD30, ter 7 injections of intravitreal metho- fixed in formalin, and embedded in terminal deoxynucleotidyl transfer- trexate. The ciliary body mass and paraffin. All fluid washed from the ase, myeloperoxidase, neuron- choroidal infiltration had totally dis- anterior chamber during the proce- specific antigen, or HMB-45. The appeared at a repeated echographic dure was collected and underwent morphologic appearance together examination 4 months after the on- a cytologic evaluation. The biopsy with the immunophenotype of the set of disease. Visual acuity im-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 proved to 20/20 OD and 20/40 OS large B-cell lymphoma, but only one but in more advanced stages they may and remained stable. Eight months of them had clinical iris infiltration overlap considerably.10 after the diagnosis of ocular lym- and appears in our table. One of the Ocular signs and symptoms of phoma, skin lesions were noticed reported cases was described as B- lymphoma may occur before the on- and lymphomatous cells were found cell lymphoma, 2 of them were re- set of systemic or CNS manifesta- in the biopsy specimen. ferred to as reticulum cell sarcoma tions. In NHL of the CNS, the pres- with no specification of cell type, and ence of vitreous cells masquerading Comment. We present an unusual 3 were considered T-cell lym- as vitritis is the most common ocu- manifestation of bilateral iridocili- phoma. All of the patients with T- lar finding, followed by an anterior ary T-cell lymphoma masquerad- cell lymphoma, including ours, had uveitis–like picture and subretinal ing as steroid-resistant uveitis in an systemic lymphomatous involve- yellow infiltrates. At the time of in- otherwise healthy young patient. ment (with only 1 case of additional traocular appearance, CNS involve- Similar iris lymphoma cases have infiltration of the CNS), and all but ment is seen in 60% of patients. been described in 6 patients, all of one showed an early anterior seg- Diagnosis of ocular lymphoma whom showed systemic involvement involvement.1 withCNSinvolvementrequiresasam- 1-3,7-9 ment of the disease. In 3 of these Intraocular lymphoma may in- plingofthevitreousorsubretinalspace patients, primary iris infiltration was volve the uveal tract, retina, vitreous, and identification of malignant lym- 3,7,8 noticed clinically ; these patients or optic nerve head. Typically affect- phocytic cells. With the use of immu- were affected by systemic NHL (bone ing older people, intraocular lym- nohistochemical stains, the type of marrow and lymph node–visceral phoma has also been described in lymphoma can easily be defined. Al- lymphoma). The other 3 reported youngpatients.8 Bilateralinvolvement thoughprimaryintraocularlymphoma cases exhibited a late iris involve- isseeninabout80%ofcases.Although cells have been identified by histo- ment, with a delay of more than a severaltypesofintraocularlymphoma pathologic diagnosis in the iris, cili- year between the initial appearance have been recognized, large cell lym- ary body, and optic nerve in a few pa- of nonspecific uveitis and the sub- phoma is the most common one. In- tients, lymphoma in these sites has sequent clinical iris infiltration. In traocularlymphomaisgenerallyofthe rarely been observed clinically.2 these cases, the lymphoma in- B-cell type, similar to NHL elsewhere The mechanism allowing uveal 1,2,9 volved the CNS as well as the eye. inthebody,whereasT-celllymphoma invasion by lymphoma cells re- The Table summarizes the is quite rare.1 mains unknown. Hematogenous clinical findings of the 6 cases of in- Malignant lymphoma is usu- spread should be considered. Pre- traocular NHL with clinical iris in- ally a systemic disease affecting mul- vious histopathologic reports dem- volvement previously reported in the tiple organs. Occasionally, intraocu- onstrate a perivascular distribution literature, in comparison with our lar involvement may be the initial of malignant cells in the iris,11 sup- 2 case. Velez et al reported 2 cases of manifestation of the systemic dis- porting this possibility. Velez et al2 ease. Two different forms of NHL can have proposed that long-standing ag- affect the eye: the CNS type and the gressive tumors of the posterior seg- systemic (lymph node–visceral) form. ment break through the Bruch mem- Intraocular lymphoma affecting brane and invade the choroid, thus only the eye is rare. The intraocular gaining access to the anterior uveal involvementcanbedividedinto2gen- structures. eral types of disease. The first is vit- In our patient, the iris, ciliary reoretinal lymphoma and is the most body, and anterior choroid were ini- common form; it is found in associa- tially the only sites of lymphoma- tion with CNS lymphoma, which is tous involvement. The vitreous of the usually of the B-cell type.1 The second left eye was infiltrated during a sec- is uveal lymphoma, which is associ- ond exacerbation of the disease. Our Figure 8. Left eye 6 months after chemotherapy. Complete regression of the iris lesion with ated with visceral or nodal involve- case is a rare, T-cell NHL with an af- residual scarring and posterior synechiae ment. In the early stages the disease finity for the anterior uvea and a later are seen. may assume one of these 2 variations, infiltration of the skin during chemo-

Anterior Uveal Lymphoma: Review of the Literature*

Source No. of Cases Clinical Iris Involvement Vitreous Cells Cell Type CNS or Systemic Lymphoma Jensen et al3 1 Primary No T-cell Bone marrow Raju and Green9 1 Delayed (7 y later) Yes RCS CNS Cooper and Riker8 1 Primary No RCS Lymph node–visceral Velez et al2 1 Delayed (2 y later) Yes B-cell CNS Goldey et al7 1 Primary No T-cell Visceral Coupland et al1 1 Delayed Not mentioned T-cell Visceral and delayed CNS Our report 1 Primary Yes (delayed) T-cell Skin

*CNS indicates central nervous system; RCS, reticulum cell sarcoma.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 therapy, showing the aggressive na- mass. Following removal of the mass tion location in the iris stroma (Figure ture of the patient’s disease. by iridocyclochoroidectomy and lo- 1). B-scan ultrasonography showed a calized vitrectomy, it proved histo- pedunculated mass that had me- Claudia Yahalom, MD pathologically to be a malignant me- dium to high echogenicity, arose from Yossi Cohen, MD dulloepithelioma with cytoplas- the ciliary body, and measured 9 mm Edward Averbukh, MD mic melanin pigment. Five months in diameter and 7 mm in thickness. Irene Anteby, MD later, tumor recurrence necessitated The left eye had a visual acuity of Gail Amir, MB, ChB enucleation. Although ciliary body 20/20 and was entirely normal. Jacob Pe’er, MD medulloepithelioma is usually an Our clinical differential diagno- Jerusalem, Israel amelanotic, fleshy mass with an in- sis included neoplasm of the ciliary tralesional cystic component, it can body pigment epithelium, medullo- Corresponding author and reprints: occur as a pigmented solid tumor that epithelioma, melanocytoma, and Jacob Pe’er, MD, Department of Oph- may resemble a melanoma or a neo- melanoma. The parents were of- thalmology, Hadassah University plasm of the pigment epithelium. fered the options of enucleation, fine- Hospital, PO Box 12000, Jerusalem Intraocular medulloepithe- needle aspiration biopsy, or local re- 91120, Israel (e-mail: [email protected] lioma is a well-known but uncom- section. They elected to have the .ac.il). mon pediatric neoplasm that usu- tumor removed by local resection. A ally occurs in the ciliary body.1-4 This partial lamellar iridocyclochoroidec- 1. Coupland SE, Foss HD, Assaf C, et al. T-cell and embryonic tumor is believed to arise tomy and localized vitrectomy were T/natural killer-cell lymphomas involving ocu- 7 lar and ocular adnexal tissues: a clinicopatho- from the primitive medullary epithe- performed and it appeared that the logic, immunohistochemical, and molecular lium that composes the anterior lip entire mass was removed intact along study of seven cases. Ophthalmology. 1999;106: of the optic cup.5 It usually occurs on with fragments of lens to which the 2109-2120. 2. Velez G, de Smet MD, Whitcup SM, Robinson the ciliary body of a young child as a tumor was adherent. Moderate bleed- M, Nussenblatt RB, Chan CC. Iris involve- fleshy gray or pink mass, often with ing from the cyclitic membrane oc- ment in primary intraocular lymphoma: re- curred during tumor removal. port of two cases and review of the literature. clinically evident cysts. Although Surv Ophthalmol. 2000;44:518-526. small amounts of pigment occasion- In September 1997, the patient 3. Jensen OA, Johansen S, Kiss K. Intraocular T- ally can be observed pathologically in was found to have a tractional retinal cell lymphoma mimicking a ring melanoma: first manifestation of systemic disease: report the cytoplasm of medulloepithe- detachment in the affected eye and of a case and survey of the literature. Graefes lioma cells, such pigmentation is not underwent a pars plana vitrectomy, Arch Clin Exp Ophthalmol. 1994;232:148-152. observed clinically.4 A pigmented me- lensectomy, and scleral buckling pro- 4. Goeminne JC, Brouillard A, Jaumain P, et al. Bilateral granulomatous panuveitis as initial pre- dulloepithelioma in the central ner- cedure with successful retinal reat- sentation of diffuse systemic T-cell lym- vous system has been reported,6 but tachment. At the time of that surgery, phoma. Ophthalmologica. 1999;213:323-325. however, a light tan mass was ob- 5. Advani S, Pai S, Adde M, et al. Preliminary re- we are unaware of a clinically pig- port of an intensified, short duration chemo- mented medulloepithelioma of the served just superior to the area of the therapy protocol for the treatment of pediatric ciliary body. We report a clinico- original tumor (Figure 2). The pa- non-Hodgkin’s lymphoma in India. Ann On- col. 1997;8:893-897. pathologic correlation of a malig- tient was referred to the Oncology Ser- 6. Fishburne BC, Wilson DJ, Rosenbaum JT, Neu- nant medulloepithelioma of the cili- vice and enucleation was performed. welt EA. Intravitreal methotrexate as an ad- ary body that was intensely pigmented There is no local recurrence or me- junctive treatment of intraocular lymphoma. Arch Ophthalmol. 1997;115:1152-1156. clinically and histopathologically. tastasis 3 years postenucleation. 7. Goldey SH, Stern GA, Oblon DJ, Mendenhall NP, Smith LJ, Duque RE. Immunophenotypic characterization of an unusual T-cell lym- Report of a Case. In July 1997, a Pathologic Findings. On gross ex- phoma presenting as anterior uveitis. Arch Oph- 3-year-old white girl with a normal amination, the original tumor re- thalmol. 1989;107:1349-1353. birth and medical history was noted moved by iridocyclochoroidectomy 8. Cooper EL, Riker JL. Malignant lymphoma of ϫ ϫ the uveal tract. Am J Ophthalmol. 1951;34:1153- to have intermittent exotropia and a measured 11 8 6 mm. Micro- 1158. white pupillary reflex in her right eye. scopically it consisted of a scleral base, 9. Raju VK, Green W. Reticulum cell sarcoma of Examination revealed a ciliary body a pigmented superficial portion, and the uvea. Ann Ophthalmol. 1982;14:555-560. 10. Shields JA, Shields CL. Intraocular Tumors: A mass and the patient was referred to a nonpigmented deeper portion Text and Atlas. Philadelphia, Pa: WB Saunders the Oncology Service at Wills Eye (Figure 3). The area that appeared Co; 1992. 11. Vogel MH, Font RL, Zimmerman LE, Levine Hospital. The right eye had a visual pigmented grossly was composed mi- RA. Reticulum cell sarcoma of the retina and acuity of light perception and an in- croscopically of cords and tubules of uvea: report of six cases and review of the lit- traocular pressure of 21 mm Hg. well-polarized epithelium that was erature. Am J Ophthalmol. 1968;66:205-215. There was a deeply pigmented mass partially pigmented (Figure 3). The in the ciliary body inferotemporally. area was surrounded by a fib- A membrane of dense fibrovascular rous matrix containing spindle cells. Pigmented tissue emanated from the area of the Single, intensely pigmented cells, Medulloepithelioma tumor and surrounded the equato- probably melanophages, were ad- of the Ciliary Body rial region of the lens (Figure 1). A mixed with the neuroepithelial tu- moderately dense nuclear and poste- bules (Figure 4). Corresponding to A 3-year-old girl developed leukoco- rior subcapsular cataract precluded a the less pigmented peripheral area ria in her right eye and was found to clear view of the fundus. A coinci- seen grossly were spindle cells and tu- have a fibrovascular cyclitic mem- dental irregular iris nevus was pre- bules of nonpigmented epithelium set brane and a pigmented ciliary body sent from the 9- to 10-o’clock posi- in a matrix of mucopolysaccharide

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Figure 1. A pigmented ciliary body mass and vascularized cyclitic membrane Figure 4. Most of the pigmented portion of the tumor comprisesf cords and is present in the ciliary body inferotemporally. There is an irregular iris nevus tubules of neuroepithelial cords and tubules that contain cytoplasmic superior to the lesion. pigment. Note the rosettelike formation (hematoxylin-eosin, original magnification ϫ50).

Figure 2. Standard slitlamp photograph through dilated pupil showing Figure 5. Pool of lucent material surrounding a tubule of polarized recurrence of the tumor which appears as a dome-shaped, light tan mass neuroepithelium in the nonpigmented area of the tumor (hematoxylin-eosin, in the ciliary body. original magnification ϫ100).

Figure 3. Histopathologic features of the resected tumor are the pigmented Figure 6. Colloidal iron stain discloses large amounts of neuroepithelial tubules in the superficial area of the tumor (top right) and the mucopolysaccharide surrounding the neuroepithelial elements (colloidal iron, nonpigmented sarcomatoid area (bottom left) (hematoxylin-eosin, original original magnification ϫ100). magnification ϫ50).

(Figure 5) that stained positive for muscle or cartilage was identified in mor cells were present very close to colloidal iron (Figure 6) and that the available sections. The tumor in- one of the surgical margins. The fi- was partially sensitive to hyaluroni- corporated and encompassed the nal diagnosis was pigmented medul- dase digestion. The pigment showed equatorial portion of fragmented lens loepithelioma. It was classified as ma- positive staining with the Fontana- tissue. The stroma of the pars plana lignant on the basis of cytologic Masson stain, confirming that it was was infiltrated by pigmented tumor features, mitotic activity, and focal in- melanin. Areas of the tumor con- cells. A few mitotic figures were pres- vasion of the ciliary body stroma. tained a sarcomatoid arrangement of ent and the nuclei appeared pleo- Histopathologic study of the the cells, but no convincing skeletal morphic and hyperchromatic. Tu- enucleated eye revealed the ex-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 pected changes following removal of of clinically pigmented medulloepi- Our case exemplifies the diffi- a ciliary body tumor and subse- theliomaoftheciliarybody.Itoccurred culties encountered in local resec- quent vitrectomy and retinal detach- in an 18-year-old African woman who tion of a ciliary body medulloepithe- ment surgery. The most noteworthy had a black epibulbar mass and expul- lioma. Local surgical removal of this histopathologic finding was a nod- sive hemorrhage.8 Hence, the appear- tumor is frequently complicated by ule in the ciliary body area immedi- ance of that ciliary body medulloep- extensive bleeding from the fibrovas- ately superior to the area of prior tu- thelioma was quite different from the cular neoplastic cyclitic membrane. mor resection. Most of the nodule one seen in our case. Although most Recurrence is frequent because the tu- consisted of a florid proliferation of medulloepitheliomas lack pigment mor often grows as a thin sheet on the spindle-shaped fibroblasts that ap- clinically, a few melanin granules are surface of ocular structures, which peared to be organizing areas of de- sometimes observed microscopically may be inapparent at the time of lo- generated blood. The base of the nod- in ciliary body medulloepitheliomas.4 cal tumor removal.4,15 Neoplastic cells ule was composed of cords, bands, Our case showed findings con- can be left behind in the cyclitic mem- and islands of pigmented cells that re- sistent with other reported malignant brane and enucleation often be- sembled those seen in the previ- medulloepitheliomas, except that the comes necessary because of residual ously resected pigmented medullo- cytoplasm of many of the neuroecto- or recurrent tumor.4 Iridocyclec- epithelioma. No heteroplastic dermal cells contained pigment. We tomy can be successful only for rela- elements were identified. The main do not believe that the tumor arose tively small tumors that are not asso- diagnosis was recurrent or residual from the pigment epithelium because ciated with an extensive neoplastic pigmented medulloepithelioma. pigment epithelial tumors do not pro- cyclitic membrane. Interestingly, this duce hyaluronic acid, which was pre- tendency for recurrence contrasts to Comment. Intraocular medulloepi- sent in our patient’s tumor. Concern- acquired adenomas of the nonpig- thelioma is a rare embryonic neo- ing the origin of the melanin pigment mented and pigmented epithelium of plasm that usually is diagnosed in the in our case, it is known that pigmen- the ciliary body, which can often be first decade of life as a ciliary body tation can be present in other tumors completely removed by iridocyclec- mass.1-4 It can be classified as benign of neuroectodermal origin, including tomy.16 In summary, we report the or malignant and as teratoid or non- ependymoma, cerebellar medullo- clinical and histopathologic features teratoid.5 Histopathologic criteria for blastoma,schwannoma,meningioma, of a malignant medulloepithelioma of malignancy include the presence of and pigmented neuroectodermal tu- the ciliary body that was clinically and undifferentiated areas that resemble mor of infancy.6 Melanin pigment is histopathologically pigmented. This retinoblastoma or sarcoma and local also a transient feature in the fetal pi- unique variation of a rare neoplasm invasiveness. Metastasis is very rare neal gland and is sometimes present should be included in the differen- and usually occurs in cases with ex- in pinealoblastomas.6 Therefore, it is tial diagnosis of pigmented lesions of traocular extension. In 2 reported se- not surprising that melanin pigmen- the ciliary body. ries the tumor was classified as ma- tation may also occur in intraocular lignant in 66%1 and 90%.4 The medulloepithelioma, which is also a Jerry A. Shields, MD nonteratoid medulloepithelioma is a neoplasm of neuroectodermal deriva- Ralph C. Eagle, Jr, MD pure neoplastic proliferation of cells tion. Carol L. Shields, MD that resembles the medullary epithe- The differential diagnosis of a Arun D. Singh, MD lium without heteroplastic ele- pigmented medulloepithelioma in- Philadelphia, Pa ments, whereas the teratoid variant cludes ciliary body melanoma, neo- Johane Robitaille, MD contains heteroplastic elements like plasm of the pigment epithelium of Halifax, Nova Scotia hyaline cartilage, rhabdomyoblasts, the ciliary body, melanocytoma, and striated muscle, and neural tissue re- iridociliary cyst. Ciliary body mela- This study was by supported the Eye sembling brain. The tumor in our pa- noma can occur in children9,10 and can Tumor Research Foundation, Phila- tient was a malignant teratoid medul- appear very similar to the tumor in delphia, Pa (Drs C. L. Shields and loepithelioma. our case. However, the cyclitic mem- J. A. Shields), the Award of Merit in Clinically, ciliary body medullo- brane seen in our patient would be Retina Research, Houston Tex (Dr J. epithelioma is usually a fleshy pink le- unexpected with a ciliary body mela- A. Shields), the Macula Foundation, sion. Large cystic spaces that contain noma. Adenoma of the pigment epi- New York, NY (Dr C. L. Shields), and vitreouslike material may be present. thelium of the ciliary body occurs the Noel T. and Sara L. Simmonds Often there is a fibrovascular cyclitic mostly in adult patients,11 but it can Endowment for Ophthalmic Pathol- membrane containing cords of tumor occasionally occur in children.12 The ogy, Wills Eye Hospital, Philadel- cells.4 The medulloepithelioma in our adenoma of the ciliary body pig- phia (Dr Eagle). patient was unusual in that it was ment epithelium reported in a child This study was presented at the deeply pigmented clinically and his- by Campochiaro and associates12 was combined meeting of the Armed Forces topathologically and lacked a cystic remarkably similar to our case in that Institute of Pathology Ophthalmic component.Apigmentedmedulloepi- it was a pigmented mass associated Alumni Society, Theobald Society, and thelioma of the central nervous sys- with a cyclitic membrane. Iridocili- Hogan Society, Washington, DC, April tem has been reported as a tumor in ary cysts can appear pigmented, but 20, 2001. the fourth ventricle in a 9-year-old they do not produce a cyclitic mem- A. K. Samad, MD, and Edward boy.6 We are aware of one other case brane and secondary cataract.13,14 J. Doherty, OD, assisted in the care of

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 the patient. Lorenz E. Zimmerman, 13. Shields JA. Primary cysts of the iris. Trans Am intraocular and systemic antibiotics, Ophthalmol Soc. 1981;79:771-809. MD, and Ian W. McLean, MD, re- 14. Lois N, Shields CL, Shields JA, Mercado G. Pri- and for which a diagnostic subretinal viewed the histopathologic sections and mary cysts of the iris pigment epithelium: biopsy was performed. concurred with the diagnosis. cinical features and natural course in 234 patients. Ophthalmology. 1998;105:1879-1885. Reprints not available from the Report of a Case. A 69-year old man 15. Singh A, Singh AD, Shields CL, Shields JA. Iris was admitted to our hospital with authors. neovascularization in children as a manifestation of underlying medulloepithelioma. JPe- pleuritic chest pain, chronic fa- 1. Broughton WL, Zimmerman LE. A clinico- diatr Ophthalmol Strabismus. In press. tigue, weight loss, and a left upper pathologic study of 56 cases of intraocular me- 16. Shields JA, Eagle RC Jr, Shields CL, De Potter. dulloepithelioma. Am J Ophthalmol. 1978;85: Acquired neoplasms of the nonpigmented cili- lobe lung mass on computed tomog- 407-418. ary epithelium (adenoma and adenocarcinoma). raphy, which was judged to be a ma- 2. Shields JA, Shields CL. Tumors of the nonpig- Ophthalmology. 1996;103:2007-2016. lignant or infectious process. The pa- mented ciliary epithelium. In: Shields JA, Shields CL, eds. Intraocular Tumors: A Text and Atlas. tient had glomerulonephritis with Philadelphia, Pa: WB Saunders Co; 1992:465- renal failure and had received oral 481. prednisone for 16 months. Ocular 3. Shields JA, Shields CL. Tumors of the nonpig- Endogenous Nocardia mented ciliary epithelium. In: Shields JA, Shields history was unremarkable. CL, eds. Atlas of Intraocular Tumors. Philadel- asteroides Endophthalmitis During admission, the patient re- phia, Pa: Lippincott, Williams & Wilkins; 1999: 310-321. ported having 2 days of floaters in the 4. Shields JA, Eagle RC Jr, Shields CL, De Potter ocardia asteroides, a Gram- right eye. No pain or photophobia was P. Congenital neoplasms of the nonpig- positive, aerobic, soil- present. Examination disclosed vi- mented ciliary epithelium (medulloepi- borne bacterium, is a cause sual acuity of 20/30 OD and 20/20 OS. thelioma). Ophthalmology. 1996;103:1998- N 2006. of opportunistic infections in im- Pupils, visual fields to count fingers, 5. Zimmerman LE. The remarkable polymor- munocompromised patients, par- color-plate test results, and tensions phism of tumors of the ciliary epithelium: The Norman McAlister Lecture, Part 1. Trans Aust ticularly those with lymphoreticu- were normal. Slitlamp examination Coll Ophthalmol. 1970;2114-2125. lar neoplasms, long-term pulmonary disclosed mild cataracts in both eyes. 6. Sharma MC, Mahapatra AK, Gaikwad S, Jain AK, Sarkar C. Pigmented medulloepithe- disorders, and long-term steroid use. Ophthalmoscopy of the right eye dis- lioma: report of a case and review of the litera- The organism is usually inhaled and closed 2+ vitritis and an elevated mass ture. Child Nerv Sys. 1998;14:74-78. may cause localized or dissemi- 3 disc diameters in size inferotempo- 7. Shields JA, Shields CL, Shah P, Sivalingam V. Par- tial lamellar sclerouvectomy for ciliary body and nated infections. A predilection for ral to the fovea within the vascular ar- choroidal tumors. Ophthalmology. 1991;98:971- its spread to the brain and soft tis- cades (Figure 1). The lesion was yel- 983. sues has been noted. Suppurative ne- lowish with hemorrhages on the 8. Pe’er J, Hidayat AA. Malignant teratoid medulloepithelioma manifesting as a black epibul- crosis and abscess formation is the surface. The disc was unremarkable. bar mass with expulsive hemorrhage. Arch Oph- pathologic hallmark. Nocardia is dis- Ophthalmoscopy findings of the left thalmol. 1984;102:1523-1527. 9. Shields CL, Shields JA, Milite J, De Potter P, Sab- tinguished by beaded, branching, eye were unremarkable. bagh R, Menduke H. Uveal melanoma in teen- filamentous growth in purulent exu- The following day, visual acu- agers and children: a report of 40 cases. Oph- date and tissue sections. ity declined to 20/100 OD and 2+ an- thalmology. 1991;98:1662-1666. 10. Singh AD, Shields CL, Shields JA, Sato T. Uveal Ocular involvement by Nocardia terior chamber cell and 3+ vitritis were melanoma in young patients. Arch Ophthal- is very rare, with approximately 30 present. Vitreous tap was performed mol. 2000;118:918-923. cases of intraocular nocardial infec- and samples were sent for bacterial 11. Shields JA, Shields CL, Gunduz K, Eagle RC Jr. 1-4 Adenomas of the ciliary body pigment epithe- tion reported in the literature. Op- and fungal cultures and mycobacte- lium: The 1998 Albert Ruedemann, Sr, Memo- timal therapeutic regimens are not es- rial stains. A tuberculin skin test was rial Lecture, Part 1. Arch Ophthalmol. 1999;117: 592-597. tablished. Only 2 reports detail expe- performed. Serologic tests for her- 5 12. Campochiaro PA, Gonzalez-Fernandez F, New- riences with intravitreal antibiotics. pes simplex and varicella zoster vi- man SA, Conway BP, Feldman PS. Ciliary body We report our experience with a case ruses, cytomegalovirus, and syphilis adenoma in a 10-year-old girl who had a rhab- domyosarcoma.ArchOphthalmol.1992;110:681- of endogenous N asteroides endoph- were performed. The patient was 683. thalmitis treated with vitrectomy and treated with 5 µg of intravitreal am-

A B

Figure 1. A, Ophthalmic appearance of the optic nerve head and subretinal abscess in the temporal area of the macula. B, Yellowish appearance of the subretinal abscess with overlying retinal hemorrhages. Moderate vitritis was present.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Figure 2. Axial magnetic resonance imaging scan of the brain disclosed a 4-mm-diameter ring-enhancing lesion (arrow) of the left A temporal lobe that was judged to be an abscess. Moderate enhancement of the sclera of the right globe with associated minimal enhancement of periorbital tissues was present.

photerocin B and intravenous am- B photerocin B for presumptive fungal endophthalmitis. The oral prednisone was tapered. The patient was observed for 1 week, with no improvement. Bron- choscopic and transthoracic needle biopsies of the lung lesion were at- tempted but histopathologic test results disclosed inflammation only, with no tumor or organisms present. A wedge resection of the lung lesion was subsequently performed. One week after initial intravitreal injection, visual acuity had declined to hand motions OD. A relative afferent papillary defect was present in the right eye. The ocular lesion now appeared to involved C much of the macula and optic disc, Figure 3. Ultrastructural appearance of septated filamentous organisms that measured 1.1 µm in although it was difficult to view be- diameter in the subretinal biopsy (A, original magnification ϫ8100; B, ϫ15000; C, ϫ60000). cause of dense vitritis. All cultures and serologic test results were nega- of the procedure followed by fluid- noted on transmission electron mi- tive at this time. A second intravit- gas exchange. croscopy of the subretinal biopsy. real injection of 5 µg of amphotero- Eleven days after initial ocular Postoperatively, no view of the cin B was administered. presentation, examination of the posterior segment was possible. Pars plana vitrectomy with reti- lung specimen disclosed filamen- Echography performed 1 week after nal and subretinal biopsy were per- tous organisms. Thirteen days after surgery disclosed an extensive shal- formed 10 days after the initial ocu- presentation, the culture of the lung low retinal detachment with enlarge- lar examination. Intraoperatively, a tissue was positive for N asteroides ment of the lesion. Surgical repair was large yellowish mass was present in- (ie, at 8 days of growth). The pa- considered but was not performed ferotemporally and extended to tient began taking oral trimetho- due to the patient’s anesthesia risk. within 1 disc diameter of the fovea. prim-sulfamethoxazole. Based on A 4-mm-diameter ring-enhanc- Subretinal fluid was present through- sensitivity data, the eye was in- ing lesion of the left temporal lobe out the macula. Neuroretinitis was jected intravitreally with 25 µg of was noted on a brain magnetic reso- present and extended from the optic imipenem and 200 µg of amikacin nance imaging scan, which was disc along the superior and inferior (doses were adjusted downward to considered to be a small abscess temporal arcades. During biopsy, the account for the 50% air bubble in the (Figure 2). The lesion remained subretinal tissue was noted to be ex- vitreous). Cultures of the vitrec- stable during treatment. The patient tremely firm in consistency. Intravit- tomy specimen became positive at was discharged 3 weeks after admis- real vancomycin (1 mg) and ceftazi- 4 days of growth and organisms con- sion due to improvement in his sys- dime (2 mg) were injected at the end sistent with Nocardia species were temic condition. Long-term oral tri-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 limited for imipenem,7,8 it displays comparable efficacy to intravitreal vancomycin in experimental Bacil- lus cereus endophthalmitis,9 and to amikacin in experimental Pseudo- monas aeruginosa endophthalmitis.10 We chose to administer intravitreal imipenem in light of these data, known nocardial sensitivity and synergy data, and the patient’s deteriorating ocular condition. A course of intravenous ceftriaxone was also added for the above reasons. Despite these measures, A B phthisis ensued in our patient. Sulfonamides remain the anti- Figure 4. Filamentous organisms in the lung biopsy specimen (A and B, Gomori methanamine silver; original magnification ϫ1000). biotic of choice for Nocardia elsewhere in the body. Trimethoprim- sulfamethoxazole is the preferred formulation by most clinicians de- methoprim-sulfamethoxazole was Comment. Endogenous N asteroi- spite increased myelotoxicity with prescribed. A 2-week course of out- des endophthalmitis is associated with this combination. In vitro synergis- patient intravenous therapy with dismal outcomes, with many eyes tic activity has been demonstrated ceftriaxone sodium was adminis- progressing to blindness despite treat- against most isolates.11 The vari- tered for the ocular infection. Six ment. The primary site of infection able and chronic course of nocar- months after the onset of the condi- is most often in the lung. Patients may diosis necessitates long treatment tion, the results of a repeated mag- have features of anterior or poste- durations (6-12 months). Alterna- netic resonance image scan of the rior uveitis. Symptoms include float- tive regimens are largely based on in brain disclosed resolution of the tem- ers, decreased vision, pain, and pho- vitro susceptibilities and efficacy in poral lobe lesion. However, the pa- tophobia. Chorioretinitis with animal models, and include amika- tient’s visual acuity deteriorated to no subretinal abscess formation is the cin and imipenem12 and other com- light perception, the eye became hallmark of endogenous nocardial binations.13,14 phthisical, and it was enucleated 7 endophthalmitis.6 Exudative retinal months after the onset of the ocular detachment may occur. Typically, or- Eugene W. M. Ng, MD condition. ganisms are located under the reti- Ingrid E. Zimmer-Galler, MD Histopathologic examination renal pigment epithelium or in the sub- W. Richard Green, MD sults of the vitreous specimens dis- retinal space and may proliferate Baltimore, Md closed an intense polymorpho- along the Bruch membrane.6 nuclear leukocyte infiltrate. Light and Nocardia infections may be dif- Supported in part by the FA Hadley electron microscopic evaluation of ficult to diagnose. Organisms can be Travelling Scholarship, the Univer- the retinal biopsy disclosed fibrin- identified on Gram, acid-fast, and sity of Western Australia, Perth, Aus- ous material and a dense infiltrate of Gomori methenamine silver stains. tralia, and the Independent Order of polymorphonuclear leukocytes and Nocardia organisms grow readily on Odd Fellows, Winston-Salem, NC. mononuclear inflammatory cells. No most nonselective media and typi- Corresponding author: W. organisms were identified. Electron cal colonies are usually seen after 3 Richard Green, MD, Eye Pathology microscopic study of the subretinal to 5 days. Cultures and smears are Laboratory, The Johns Hopkins Hos- biopsy disclosed numerous filamen- positive in only one third of cases. pital, Maumenee 427, 600 N Wolfe St, tous, septated organisms that mea- Retinal and subretinal biopsies were Baltimore, MD 21287. sured 1.1 µm in diameter (Figure 3). performed in this case because of di- 1. Lakosha H, Pavlin CJ, Lipton J. Subretinal ab- Histopathologic examination of the agnostic uncertainty. Electron mi- scess due to Nocardia farcinica infection. Retina. lung biopsy specimen revealed bron- croscopic examination of the sub- 2000;20:269-274. chopneumonia with occasional clus- retinal biopsy was successful in 2. Knouse MC, Lorber B. Early diagnosis of No- cardia asteroides endophthalmitis by retinal bi- ters of filamentous organisms with demonstrating organisms. opsy: case report and review. Rev Infect Dis. the silver stain (Figure 4). Exami- The treatment of ocular nocar- 1990;12:393-398. nation of the enucleated eye dis- dial infection has been met with lim- 3. Price NC, Frith PA, Awdry PN. Intraocular nocardiosis: a further case and review. Int Oph- closed iris neovascularization, cy- ited success, although favorable out- thalmol. 1989;13:177-180. clitic membrane, detachment of the comes are common for infections at 4. Bullock JD. Endogenous ocular nocardiosis: a clinical and experimental study. Trans Am Oph- retina with extensive subretinal pro- nonocular sites. The role of vitrec- thalmol Soc. 1983;81:451-531. liferation, a serosanguinous ciliocho- tomy in nocardial endophthalmitis 5. Davitt B, Gehrs K, Bowers T. Endogenous No- roidal effusion, rare foci of lympho- is uncertain. We injected amikacin cardia endophthalmitis. Retina. 1998;18:71-73. 6. Jampol LM, Strauch BS, Albert DM. Intraocu- cytes in the choroid, and no microbial and imipenem intravitreally in our lar nocardiosis. Am J Ophthalmol. 1973;76:568- organisms. patient. Although toxicity data are 573.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 7. Finlay KR, Chow AW. Ocular toxicity and phar- locations.1 Primitive neuroectoder- macokinetics of intravitreal N-formimidoyl thienamycin. In: Abstracts of the 23rd Inter- mal tissue has long been known to be science Conference on Antimicrobial Agents and associated with teratomatous tissue in Chemotherapy. Washington, DC: American So- both intracranial2 and ovarian sites.3,4 ciety of Microbiologists; 1983;117. 8. Smith MA, D’Aversa G, Sable M, Farbowitz M, One report found a neuroblastoma Sorenson J, Green WR. Retinal toxicity of in- within a testicular teratoma.5 travitreal sparfloxacin, ofloxacin, and imipenem in a rabbit model. J Toxicol-Cutaneous Primary congenital teratomas of Ocul Toxicol. 1999;18:65-73. the orbit are uncommon and rarely 9. Alfaro DV III, Hudson SJ, Offele JJ, et al. Ex- malignant. Four prior reports de- perimental posttraumatic Bacillus cereus endophthalmitis in a swine model: efficacy of in- scribe malignant orbital terato- travitreal ciprofloxacin, vancomycin, and mas.6-9 One case was primarily an in- imipenem. Retina. 1996;16:317-323. 10. Alfaro DV III, Hudson SJ, Kasowski EJ, et al. tracranial teratoma involving the 6 Experimental pseudomonal posttraumatic en- optic nerve. Another report had no Figure 1. Axial computed tomography scan dophthalmitis in a swine model: treatment with description of the nature of the ma- at age 6 months showing marked proptosis ceftazidime, amikacin, and imipenem. Retina. 7 secondary to a partially septated intraconal 1997;17:139-145. lignant cells. Garden and McMa- 8 mass with calcifications. Note that the orbital 11. Smego RA Jr, Moeller MB, Gallis HA. Trimeth- nis described a case in which the rim is expanded and thinned without osseous oprim-sulfamethoxazole therapy for Nocardia malignant cell population ap- destruction. infections. Arch Int Med. 1983;143:711-718. 12. Threlkeld SC, Hooper DC. Update on manage- peared 3 years after the excision of ment of patients with Nocardia infection. Curr a benign orbital teratoma and con- vealed increased hyperopia with a re- Clin Top Infect Dis. 1997;17:1-23. ϫ 13. Menendez R, Cordero PJ, Santos M, et al. Pul- sisted of cells believed to be a ma- fraction of +4.00 +1.50 90 OD and monary infection with Nocardia species: a re- lignant germ cell tumor. An orbital +14.00 +3.00ϫ85 OS. The right fun- port of 10 cases and review. Eur Respir J. 1997; teratoma with neuroblastic and rhab- dus was unremarkable, while the left 10:1542-1546. 14. Gombert ME, Aulicino TM. Synergism of imi- domyoblastic elements has also been showed chronic papilledema charac- penem and amikacin in combination with other documented.9 We report a case of or- terized by a pale halo of edema around antibiotics against Nocardia asteroides. Antimi- bital teratoma with malignant neu- the disc. An orbital computed tomog- crob Agents Chemother. 1983;24:810-811. roblastomatous features. raphy scan showed a septated intraconal mass with calcifications that had Report of a Case Clinical History. increased in size from the previous Neuroblastoma Within The patient was the product of an un- magnetic resonance imaging find- a Congenital Orbital complicated pregnancy and was born ings, and had extended into the lac- Teratoma at full term via normal abdominal de- rimal fossa (Figure 1). The orbital livery. She was initially seen at age 5 rim was expanded and thinned, but Congenital orbital teratomas are weeks for the evaluation of congen- there was no osseous destruction. The rarely malignant. In fact, a total of ital and increasing proptosis of her left orbital tumor was excised by a left lat- 4 prior reports exist in the litera- eye. At that time, grossly she had 4 to eral orbitotomy. ture describing malignant orbital 5mmofproptosisofthateye,andthere teratomas, and only 2 of these de- waspositiveresistancetoretropulsion. Histopathology. The specimen con- scribe the nature of the malignant Pupils were 3 mm and sluggish bilat- sisted of 3 pieces of tissue, the larg- cells. We report a case of a congen- erally, without a relative afferent de- est measuring 30ϫ19ϫ9 mm. The ital orbital teratoma containing foci fect. The anterior chamber was quiet specimen was bisected, and exami- of neuroblastomatous elements con- andofmoderatedepth.Biomicroscopy nation revealed areas of a serosalike firmed by immunohistochemical and fundoscopy were unremarkable. surface. In addition, there was one techniques. Given that the tumor Cycloplegic retinoscopy revealed a re- cystic area filled with gelatinous ma- was noninvasive and no systemic in- fraction of +3.50 +.50ϫ80 OD and terial and hair. Another area was firm volvement was discovered, no fur- +5.50+1.50ϫ90OS.Amagneticreso- and gray, suggestive of cartilage. ther treatment was undertaken. Two nance imaging scan showed a diffuse Microscopic examination re- years following the operation, the pa- mass that enhanced with contrast in vealed a complex cystic structure tient remained free of tumor in the the left orbit. An orbital ultrasound re- lined partially by pseudostratified orbit and at other sites. A review of vealed cystic cavities with fluid levels ciliated columnar epithelium and the literature concludes that simi- present within the orbit. Lymphan- partially by keratinized stratified lar cases should be handled by com- gioma was believed to be the most squamous epithelium. There were plete excision, and further therapy likely diagnosis, and the mass was ob- adnexal structures in the portion of should be based on the pathologi- served. the wall lined by the squamous epi- cal findings of the individual case. By 6 months of age, the patient thelium. The cyst was filled with ke- Teratomas are generally benign had progressive proptosis of her left ratinous debris. Adjacent to the cyst congenital growths, which by defini- eye. The extraocular movements re- was a well-circumscribed cartilagi- tion consist of derivatives from each mained intact, but the left eye was un- nous structure. In addition, there of the 3 germ-cell layers. They are able to fix. External examination of was mature central nervous system most commonly found in the go- the left eye revealed a palpable mass tissue present. In one focal area as- nads, but they may develop ectopi- in the inferolateral orbit. No relative sociated with the central nervous cally in cervical, mediastinal, sacro- afferent pupillary defect was pres- system tissue, there was a focus coccygeal, intracranial, and orbital ent. Cycloplegic retinoscopy re- (measuring 5ϫ4 mm) of undiffer-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 tient. Some authorities feel that the presence of immature cellular components should not be taken as evidence of malignancy.4 However, the prognosis of central nervous system teratomas is worse for the immature teratoma than for the mature teratoma, and dissemination of tumor cells systemically and in cerebrospi- nal fluid has been documented in immature intracranial teratomas.2 Mayberger et al,4 in a report on a benign cystic teratoma of the ovary with neuroblastomatous change, sug- gested that if the teratoma is noninvasive, without metastasis, then removal alone is adequate. This sugges- tion relies on the theory that the primitive neuroectodermal tissue Figure 2. Close proximity of mature nervous tissue with immature neuroblastic tissue in the teratoma within the teratoma is derived from ϫ (hematoxylin-eosin, original magnification 200). ectodermal germ cells and not from matureneuraltissue,whichdeveloped into undifferentiated tissue. However, a separate study warned that the cli- nicianmustbeawarethatonoccasion, primaryneuroectodermaltumorsarise ectopically in the ovary, along with teratomatous tissue.3 These latter tumors are known to metastasize, with the risk increasing as the degree of dif- ferentiation of the neuroectodermal tissue decreases. The same study sug- gested that tumors with endodermal and mesodermal features along with primitiveneuroectodermaltissuemay beclassifiedandtreatedasbenigntera- tomas, while those with massive, confluent growth of neuroectodermal tissue and little of the other 2 germ layers may be primary malignant tumors. Ulbright et al5 argue that treat- Figure 3. Area of neuroblastoma, demonstrating undifferentiated small, round cells with high ment should be individualized de- nuclear-cytoplasmic ratios, moderately condensed chromatin, and occasional nucleoli (hematoxylin-eosin, original magnification ϫ200). pending on the type of non–germ cell tumor involved, speculating that some forms of non–germ cell ma- entiated, small, round cells with noreactivitywithneuron-specificeno- lignancies (specifically leiomyosar- modest amounts of eosinophilic cy- lase (Figure 4) and synaptophysin. coma, nephroblastoma, neuroblas- toplasm (Figures 2 and 3). The The pattern of reactivity was consis- toma, and giant cell tumor), when chromatin of the cells was moder- tent with neuroblastoma, and would found within teratomas, may not ately condensed, and there were oc- be unlikely in any of the morphologic affect the prognosis.5 As a result, they casional small nucleoli. There was differentialsinthiscase,whichinclude argue that such tumors should be 1 mitosis in 20 high-power fields. leukemic infiltrates, Ewing sarcoma, called “non-germ cell malignancy in There were no rosettes present. primitiveneuroectodermaltumor,and teratoma” and advocate treatment of Paraffin-embeddedsectionswere Wilms tumor. the growth as a benign teratoma with stained using an immunoperoxidase complete resection. The results of technique.Thesmall,undifferentiated Comment. The intriguing aspect of their study further indicate that the cells displayed negative immunoreac- this case was the presence of imma- role of chemotherapy is question- tivity with keratin, CD99 (product of ture cells consistent with neuroblas- able in such tumors. MIC2 gene, positive in glioblastoma, toma in an otherwise typical orbital The management of this case ependymoma, Ewing sarcoma, and teratoma. The presence of these cells was discussed at the Pediatric Tu- acute lymphoblastic leukemia), and raised interesting questions in the mor Board. Based on the above con- vimentin. There was positive immu- subsequent management of the pa- siderations, this tumor was classi-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 N-acetylcysteine. The more recent use of nerve growth factor,1 amniotic membrane transplantation,2-4 and scleral lens2 has been reported. Non- surgical therapeutic options have limited effect, and surgical procedures such as lamellar or penetrating keratoplasty become necessary to pre- serve the anatomic integrity of the globe. Vision-threatening procedures (Gunderson flap, tarsorrha- phy, evisceration, or enucleation) may also become necessary. Recently, growth factors,1,5-8 neuropeptides,5-8 andfibronectin6 have promoted epithelial wound healing. Topical substance P (SP) and insulinlike growth factor 1 (IGF-1) circum- vented surgical intervention in this Figure 4. Neuron-specific enolase stain of the immature cells within the teratoma. Positive (brown) case. staining is consistent with a diagnosis of neuroblastoma (original magnification ϫ400). Report of a Case. A 79-year-old monocular woman with a persistent epi- fied as an immature teratoma con- neural elements (neuroblastomatous change) in benign cystic teratoma: malignant or not? Ob- thelial defect following penetrating taining neuroblastomatous ele- stet Gynecol. 1969;33:114-117. keratoplasty in the left eye visited the ments. The tumor had been com- 5. Ulbright TM, Loehrer PJ, Roth LM, Einhorn LH, University of Wisconsin (Madison) pletely excised, and no other treat- Williams SD, Clark SA. The development of non- germ cell malignancies within germ cell tu- Cornea Service for consultation. ment was undertaken. The child has mors. Cancer. 1984;54:1824-1833. Her medical history was signifi- been followed up for 2 years and has 6. Samii M, Ramina R, Koch G, Reusche E. Malig- cant for Fuchs endothelial dystrophy, nant teratoma of the optic nerve: case report. Neu- no evidence of recurrent orbital tu- rosurgery. 1985;5:696-700. cataracts, and primary repair of a trau- mor or neuroblastoma at other sites. 7. Saradarian AV. Malignant teratoma of the or- matic ruptured globe with subsequent In conclusion, orbital terato- bit: six and one half years’ observation. Arch Oph- thalmol. 1947;37:253. evisceration of the right eye. In her mas may rarely contain non–germ 8. Garden JW, McManis JC. Congenital orbital- pseudophakic left eye, penetrating cell malignancies. The initial clini- intracranial teratoma with subsequent malig- keratoplasty was performed. A small cal management of these cases nancy: case report. Br J Ophthalmol. 1986;70: 110-113. suture tract leak and a small epithe- should be complete excision. Deci- 9. Soares EJC, Lopes K da S, Andrade J de S, Fa- lial defect associated with a trace graft sions regarding adjunctive chemo- leiro LC, Alves JCR. Orbital malignant tera- override were present on the first day toma: a case report. Orbit. 1983;2:235-242. therapy or radiation therapy should followingsurgery.Thesuturetractleak be based on the pathologic findings healed quickly. for the individual case. The defect persisted despite dis- David J. Wilson, MD Substance P, Insulinlike continuing polymyxin B sulfate, add- Roger A. Dailey, MD Growth Factor 1, and ing erythromycin, and reducing the John L. Wobig, MD Surface Healing frequency of 1% prednisolone. Four Portland, Ore postoperative months of artificial Jason W. Dimmig, BA Impaired adhesion, migration, and/or tears, pressure patching, bandage Burlington, Vt mitosis can compromise corneal contact lens, autologous serum com- epithelial healing. Persistent epithe- bined with artificial tears, and an- Corresponding author and reprints: lial defects can progress to ulcer- terior stromal micropuncture were David J. Wilson, MD, 3375 SW Ter- ation, perforation, or endophthalmi- ineffective at healing the defect. williger Blvd, Casey Eye Institute, tis. Currently, our options are limited The defect and the threat of Portland, OR 97201-4197 (e-mail: to methods that address the under- complications persisted. At consul- [email protected]). lying cause of the epithelial defect. In tation, her pinhole visual acuity was 1. Henderson JW, Campbell RJ, Farrow GM, Gar- addition to addressing exposure kera- 20/80 OS; medications included rity JA. Orbital Tumors. 3rd ed. New York, NY: topathy, mechanical irritation to the erythromycin and 0.2% brimonidine Raven Press; 1994:61-64. eye, and systemic diseases, clini- tartrate for ocular hypertension. The 2. McLendon RE, Tien RD. Tumors and tumor- like lesions of mal-developmental origin. In: Big- cians supplement the tear film, mini- anesthetic epithelial defect mea- ner DD, McLendon RE, Bruner JM, eds. Russell mize the mechanical aspects of de- sured 1.0ϫ2.0 mm (Figure 1). The and Rubenstein’s Pathology of Tumors of the Ner- vous System. Vol 2. 6th ed. London, England: Ar- layed wound healing, and use sutures were intact. Graft override nold; 1998:315-323. collagenolytic enzyme inhibitors. Spe- still occurred adjacent to the epithe- 3. Kleinman GM, Young RH, Scully RE. Primary cific therapy includes preservative- lial defect. neuroectodermal tumors of the ovary: a report of 25 cases. Am J Surg Pathol. 1993;17:764-778. free artificial tears, pressure patch- This elderly monocular woman 4. Mayberger HW, Carlson AS, Lim S. Immature ing, bandage contact lens, and was offered an option of vision-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Comment. Our armamentarium for corneal epithelial wound healing is limited. The trigeminal nerve and the neuropeptide it releases, SP, con- tribute to the maintenance of healthy corneal epithelium. Substance P has been shown to be synergistic with IGF-1 in the promotion of cellular processes conducive to wound healing.5 Three reported cases describe the complete resurfacing of persistent epithelial defects in human cor- neas in response to SP used synergis- tically with IGF-1.6-8 Our patient responded to this therapy and did not require surgical intervention, suggesting a therapeutic advantage of this combined therapy. Our case, collec- Figure 1. Epithelial defect adjacent to region of graft override. tively with those cited, demon- strates the need for prospective clinical trials to declare the clinical value of this treatment modality in prevent- ing the devastating consequences of nonhealing epithelial defects.

Catherine H. Lee, MD Amanda L. Whiteman, DVM Christopher J. Murphy, DVM, PhD Neal P. Barney, MD Madison, Wis Peter B. Taylor, MD Fond du Lac, Wis Ted W. Reid, PhD Lubbock, Tex

This study was supported by an un- restricted grant from Research to Pre- vent Blindness Inc (New York, NY), Figure 2. Intact epithelium after treatment with topical substance P and insulinlike growth factor 1. Fine and grants EY1252601 and superficial punctate staining and a whorl pattern lie in the previously defective area. EY10841-04 from the National Insti- tutes of Health, Bethesda, Md. Corresponding author and re- threatening surgical procedures or persistent trophic effect after 2 hours prints: Neal P. Barney, MD, Depart- topical SP with IGF-1. The patient un- of cellular contact with SP. ment of Ophthalmology and Visual Sci- derstood the investigational and com- Complete healing occurred ences, University of Wisconsin, 2870 University Ave, Suite 206, Madison, WI passionate-use nature of SP and IGF- within 1 week (Figure 2). Symp- 1. Informed consent was obtained. tomatic itching was mild and 53705 (e-mail: npbarney@facstaff Sterile SP (250 µg/mL) and temporary. Her epithelium re- .wisc.edu). IGF-1 (1.0 µg /mL) were prepared, mained intact during a 2-week taper 1. Lambiase A, Bonini S, Caprioglio G, Aloe L. Topi- dispensed, refrigerated, and dis- of SP and IGF-1 administration. Poly- cal treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. 1998; carded after 1 week. One drop of myxin B and both SP and IGF-1 338:1174-1180. each compound was administered were discontinued at the end of the 2. Rosenthal P, Cotter JM, Baum J. Treatment of every 15 minutes for 2 hours each second and third weeks of treat- persistent corneal epithelial defect with extended wear of a fluid-ventilated gas- morning and night for the first week. ment, respectively. Her epithelium re- permeable scleral contact lens. Am J Ophthal- Polymyxin B and brimonidine were mained intact on follow-up exami- mol. 2000;130:33-41. 3. Tsubota K, Satake Y, Ohyama M, et al. Surgical continued. This treatment fre- nation at 3 weeks after discontinu- reconstruction of the ocular surface in ad- quency was chosen on the basis of ing therapy, and it has remained vanced cicatricial pemphigoid and Stevens- in vitro data (Christopher J. Mur- healed without epithelial break- Johnson syndrome. Am J Ophthalmol. 1996;122: 38-52. phy, DVM, PhD oral communica- down throughout the ensuing 8 4. Lee S, Tseng SCG. Amniotic membrane trans- tion, January 2001), suggesting a months. plantation for persistent epithelial defects with

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 ulceration. Am J Ophthalmol. 1997;123:303- enlarged capillary cavities without grams of the same eye showed a pe- 312. 5. Nishida T, Nakamura M, Ofuji K, Reid T, Man- intervening brain parenchyma. ripheral retinal vascular lesion, char- nis M, Murphy CJ. Synergistic effects of SP with Clinical symptoms include sei- acteristic of a cavernous angioma ILGF-1 on corneal epithelial cell migration. J Cell zures, hemorrhage, and focal neu- (Figure 1A and B). The lesion had Physiol. 1996;169:159-166. 6. Morishige N, Komatsubara T, Chikama T, rological deficits. Their prevalence first been observed when the patient Nishida T. Direct observation of corneal nerve is close to 0.5% in the general popu- was11yearsold.Therightfunduswas fibres in neurotrophic keratopathy by confocal biomicroscopy. Lancet. 1999;354:1613-1614. lation. Familial forms are increas- normal. Her visual acuity between 7. Chikama T, Fukuda K, Morishige N, Nishida T. ingly recognized. Three CCM loci episodes of keratitis was 20/20 OU. Treatment of neurotrophic keratopathy with sub- were mapped to chromosomes 7q There was no other eye abnormality. stance-P-derived peptide (FGLM) and insulinlike growth factor I [letter]. Lancet. 1998;351: (CCM1), 7p (CCM2), and 3q From 1995 to 1999, we did not ob- 1783-1784. (CCM3). KRIT1, a protein of un- serve any change of the retinal cav- 8. Brown S, Lamberts D, Reid T, Nishida T, Mur- known function, was recently iden- ernoma.Resultsofdermatologicaland phy CJ. Neurotrophic and anhidrotic keratopathy treated with substance P and insulinlike tified as the mutated protein in fami- neurological examinations were nor- growth factor-1. Arch Ophthalmol. 1997;115: lies with the CCM1 gene.1 mal. Brain magnetic resonance imag- 926-927. Cavernomas have been observed ing showed 4 cavernomas (Figure in other organs such as the retina. We 1C). Five relatives of the patient were report what is to our knowledge the also known to have cerebral caverno- A Novel KRIT1/CCM1 first observation of a KRIT1 mutation mas. We could not perform ophthal- Truncating Mutation in a patient with retinal and cerebral mological examinations on these sub- in a Patient With Cerebral cavernous angiomas. jects because they live in another and Retinal Cavernous country. Angiomas Report of a Case. A 34-year-old wom- Sequencing of exon 10 of the an was followed up for recurrent KRIT1 gene in our patient revealed Cerebral cavernous malformations herpetic keratitis of the left eye. A fun- a heterozygous insertion of cyto- (CCM) are defined by abnormally dus examination and retinal angio- sine after nucleotide 1374 that

A C

Figure 1. A, Fundus examination of the left eye showing a localized peripheral cluster of saccular whitish to dark red aneurysms of various sizes. B, The same lesion was observed using fluorescein angiography. The adjacent vessels were normal, and there was no sign of leakage. C, Magnetic resonance imaging (1.5 T; T2- weighted imaging axial sequences) showing a cerebral cavernoma close to the right ventricle (white arrow), seen as a mixed hypointense and hyperintense signal.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 these lesions are underlaid by a com- MT C A T C C C C T G T G T A mon mechanism and that KRIT1 WT C A T C C C T G T G T A T plays an important role in cutaneous, retinal, and cerebral vascular development.

Sophie Laberge-Le Couteulx, MD Antoine P. Bre´zin, MD Bertrand Fontaine, MD, PhD Elisabeth Tournier-Lasserve, MD MT Pierre Labauge, MD Paris, France

Dr Laberge-Le Couteulx received a fel- lowship from the Fondation pour la Re- cherche Me´dicale. Dr Labauge ben- efited from a poste d’accueil INSERM and was supported by the Colle`ge des Enseignants de Neurologie. This work was supported by INSERM and the Ministe`redel’Enseignement Su- pe´rieur et de la Recherche. Corresponding author: Pierre La- bauge, MD, Faculte´ de Me´decine Lari- boisie`re, Laboratoire de Ge´ne´tique des Maladies Vasculaires, 10 Avenue de WT Verdun, EPI 99-21, 75010 Paris, Ce- dex, France (e-mail: labauge@hotmail .com).

1. Laberge-Le Couteulx S, Jung HH, Labauge P, et Figure 2. Chromatograms of mutated (MT) DNA of the patient and wild-type (WT) DNA of a healthy al. Truncating mutations in CCM1, encoding control. The arrow indicates the site of the mutation. KRIT1, cause hereditary cavernous angiomas. Nat Genet. 1999;23:189-193. 2. Messmer E, Laqua H, Wessing A, Spitznas M, Weidle E. Nine cases of cavernous heman- gioma of the retina. Am J Ophthalmol. 1983;95: caused a frameshift leading to a pre- brain as well as the cosegregation of 383-390. 3. Dobyns WB, Michels VV, Goover RV, et al. Fa- mature stop codon (Figure 2), and both types of lesions strongly sug- milial cavernous malformations of the central therefore a truncated protein. This gest that the occurrence of these 2 nervous system and retina. Ann Neurol. 1987;6: mutation was not detected in a panel conditions is not coincidental. In- 578-583. 4. Sarraf D, Payne AM, Kitchen ND, Sehmi KS, of 50 healthy controls. The DNA se- terestingly, the mutation observed in Downes SM, Bird AC. Familial cavernous he- quence of the complete gene was de- our patient is similar in nature to mangioma: an expanding ocular spectrum. Arch termined, and no other mutation was those observed in families with Ophthalmol. 2000;118:969-973. 5. Eerola I, Plate KH, Spiegel R, Boon LM, Mul- found. CCM; namely, mutations leading to liken JB, Vikkula M. KRIT1 is mutated in hyper- a truncation of the C-terminal part keratotic cutaneous capillary-venous malforma- 1 tion associated with cerebral capillary Comment. Retinal cavernomas are of KRIT1. Because the insertion of malformation. Hum Mol Genet. 2000;9:1351- rare and usually asymptomatic. The a cytosine at nucleotide 1374 has not 1355. largest series reported so far consists previously been reported, we can of 9 cases.2 Most reports are of spo- not exclude the possibility that this radic retinal cavernomas with no as- mutation is associated specifically sociated neurological disease. The oc- with the occurrence of both retinal Retinal Alterations currence of retinal and familial brain and cerebral lesions. In this article, in Acquired Partial cavernomas has seldom been de- we show for the first time that a mu- Lipodystrophy: scribed.3,4 In the absence of a system- tation in KRIT1, a gene known to ex- A Case Report atic fundus examination, retinal cav- ist in most families who have CCM ernomas could be undiagnosed in pa- with isolated brain cavernomas, is Acquired partial lipodystrophy tients with brain cavernomas. In rare present in a patient with both reti- (PLD) is an uncommon disorder of cases such as that described in this renal and brain cavernomas. Another unknown cause, usually affecting port, the diagnosis of retinal caver- mutation in the KRIT1 gene was re- women, characterized by the loss of nomas can lead to the detection of cently found in one family charac- subcutaneous adipose tissue of the asymptomatic cerebral cavernomas. terized by the cosegregation of cu- upper half of the body, including the The vascular nature of the le- taneous and brain cavernomas.5 face. Persistent low C3 serum lev- sions observed in the retina and These results strongly suggest that els and normal serum levels of C1q,

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 C4, and C2, the early reacting components of the classic pathway, are frequently found in these patients. The presence in the patient’s serum of the C3 nephritic factor, an immunoglobulin G antibody that stabilizes the alternative C3 convertase, suggests C3 activation via the alternative pathway.1 These comple- mentary abnormalities may occur without renal disease. Ocular complications of PLD have been described only in case reports. They are characterized by the presence of yellow, drusen-like lesions at the posterior pole and are always associated with type II mesangiocapillary glomerulonephritis.2-4

Report of a Case. A 38-year-old white woman with a 10-year history of progressive facial wasting was referred 36 months earlier to the out- patient service of clinical immunology for symptoms of arthralgia, myalgia, and morning stiffness, un- successfully treated with nonsteroi- dal antiinflammatory drugs. Results of physical examination showed the characteristic appearance of PLD localized to the face (Figure 1) with skin hyperpigmentation, normal muscular tone, and trophism. There was no evidence of arthritis or signs of visceral involvement. Laboratory examination results showed normal erythrocyte sedimentation rate, white and red blood cell counts, levels of blood glu- cose (Ͻ100 mg/dL [Ͻ5.6 mmol/ Figure 1. Photograph of the patient showing facial wasting and cutaneous hyperpigmentation, with no L]), blood urea nitrogen (30-46 involvement of the shoulders. mg/dL [10.7-16.4 mmol/L]), and serum creatinine (Ͻ1.10 mg/dL [Ͻ97.2 µmol/L]), creatinine clear- no signs of renal disease, either clini- were round, discrete with defined ance rate (80-110 mL/min [1.3-1.8 cal or serological, were observed borders (some were confluent), and mL/s]), and urinalysis results. Nor- throughout the 3 years of follow- of different sizes, the larger located mal plasma levels were found for up, a renal biopsy was not per- at the posterior pole. The drusen- muscle enzymes, thyroid hor- formed. Despite 1- year treatment like lesions were more numerous mones, adrenocorticotropic hor- with hydroxychloroquine, no sig- in the nasal quadrants of the retina mone, and cortisol. All of these re- nificant changes in joint symptoms but larger in the temporal areas. sults remained normal after a 31⁄2- were reported by the patient. Fluorescein angiography results year follow-up examination. The A routine ophthalmic exami- demonstrated that all of the lesions patient tested negative for anti- nation was carried out 11 months af- had early hyperfluorescence, which nuclear autoantibodies and posi- ter hydroxychloroquine treatment. remained unchanged throughout tive for rheumatoid factor (serum Visual acuity was 20/20 OU, the an- the examination, showing the char- level, 40-160 IU/mL). Serum terior segment and lachrymal secre- acteristics of small hard drusen. The complement components showed tion did not show any pathological central fovea revealed normal pig- very low levels of C3 (3.0-4.5 mg/dL change, and the intraocular pres- mentation (Figure 2). [normal value, 80-170 mg/dL]) and sure was normal. The fundus ex- Color vision was normal. Vi- normal levels of C1q, C4, and fac- amination revealed a large number sual field examination showed de- tor B. The assay for alternative C3 of drusen-like lesions at the poste- creased central sensitivity in both nephritic factor was positive. Since rior pole and midperiphery that eyes, with an enhancement of the

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Figure 2. Fluorescein angiography showing the distribution of the numerous hyperfluorescent drusen-like spots, more numerous in the nasal quadrants of the retina but larger in the temporal areas. The central foveae show normal pigmentation.

blind spot. Electroretinogram re- and a basement membrane struc- 4. Trabucchi G, Sannace C, Introini U, Brancato R. Partial lipodystophy with associated fundus ab- sults and visual evoked potentials ture. Under this aspect, the role of normalities: an optical coherence tomography were normal, while the electro- highly permeable vessels in the patho- study. Br J Ophthalmol. 1998;82:326. oculogram results revealed a pathogenesis of such lesions could be hy- 5. Wilson CB, Yamamoto T, Ward DM. Renal diseases. In: Stites DP, Stobo JD, Wells YV, eds. Ba- logical result in both eyes, with an pothesized. Eye involvement is rare sic and Clinical Immunology. New York, NY: Arden index of 120. This situation in PLD and has always been found in Appleton & Lange; 1987:495-515. remained unchanged at a 25-month patients with renal impairment. follow-up. The case we reported is, to our A study was also carried out on knowledge, the first with ocular in- her living relatives: 2 daughters, her volvement in PLD without impair- Exercise-Induced sister, her brother, and his 3 sons. ment of renal function. Whether the Vasospastic Amaurosis None of them showed signs of the dis- nephritic factor plays a direct role in Fugax ease or complement abnormalities. the pathogenesis of retinal lesions is not conclusive since an ocular ex- Amaurosis fugax is characterized by Comment. Partial lipodystrophy is amination of normal subjects with a sudden, monocular, painless, tem- a rare disease characterized by an in- serum nephritic factor has not been porary visual loss due to a hypoper- volvement of the subcutaneous fat reported to our knowledge. fusion of retinal circulation. Some of tissue. A high percentage (65%- Although the retinal lesions do the more frequent causes include ath- 70%) of patients with PLD have low not seem to be site-threatening, an eromatous disease of the internal ca- serum levels of C3 and normal se- ophthalmic examination should be rotidorophthalmicartery,vasospasm, rum levels of C1q, C4, C2, and B fac- performed in patients with PLD, even optic neuropathies, giant cell arteri- tor. These findings indicate the ac- in the absence of renal function im- tis, angle-closure glaucoma, increased tivation of the complement cascade pairment, to have a complete clinical intracranialpressure,orbitalcompres- through the alternative pathway, due picture. sive disease, a steal phenomenon, and to the presence in the serum of the blood hyperviscosity or hypercoagu- Pasquale Aragona, MD, PhD nephritic factor, an immunoglobu- lability.1 Vasospasm may account for Paolina Quattrocchi, MD lin G antibody that stabilizes the al- many cases of unknown cause.1-4 Am- Costantino J. Trombetta, MD ternative C3 convertase, with con- aurosis fugax due to exercise-induced Edoardo Ferlazzo, MD sequent continuous consumption of vasospasm has been described only Rosaria Spinella, MD C3. This immunoglobulin G was once,in1989byImesandHoyt.3 They Domenica Bonanno, MD found to be associated with a mem- described 6 healthy young adults who Messina, Italy branoproliferative nephritis, known experiencedvisuallossprecipitatedby as type II mesangiocapillary glo- Corresponding author and reprints: exercise. Three of them had monoc- merulonephritis. This association is Pasquale Aragona, MD, PhD, Viale ular visual loss. not constant; in fact, it was de- Boccetta 70, I-98122 Messina, Italy Exercise-induced visual distur- scribed that patients with PLD who (e-mail: [email protected]). bances not due to a hypoperfusion of were positive for nephritic factor did retinal circulation include pigmen- not develop nephropathy; on the 1. Sisson JPG, West RJ, Fallows J, et al. The comple- tary glaucoma attacks, which may be ment abnormalities of lipodystrophy. N Engl 5 other hand, the nephritic factor was J Med. 1976;294:461:465. painless, Uhthoff symptom after op- also found, although rarely, in the 2. Davis TM, Holdright DR, Schulemberg WE, tic neuritis,6 and unformed halluci- 5 Turner RC, Joplin GF. Retinal pigment epithe- serum of subjects in good health. lial change and partial lipodystrophy. Postgrad nations secondary to occipital lobe tu- 7 Retinal and renal lesions de- Med J. 1988;64:871-874. mors. We describe 3 more patients velop at the interface between con- 3. O’BrienC,Duvall-YoungJ,BrownM,ShortC,Bone with exercise-induced monocular M. Electrophysiology of type II mesangiocapillary volute microvessels, such as those of glomerulonephritis with associated fundus abnor- transient visual loss, probably caused the choriocapillaris and glomerulus, malities. Br J Ophtalmol. 1993;77:778-780. by vasospasm.

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Ophthalmoscopic image of the right eye of the patient from case 1 during an asymptomatic period (A) and during an attack provoked by climbing stairs (B and C). B, A pale optic disc, a more distinct fovea, and a narrowing of all branches of the retinal arteries and veins, obtained 1 minute 54 seconds after the acute visual loss. C, Normal diameter of all retinal vessels, obtained 2 minutes 15 seconds after the acute visual loss and 10 seconds after the return of vision in the right eye.

Report of Cases. Case 1. For 5 years, central retinal artery. We never ob- attack showed a reproducible mild a 65-year-old man experienced recur- served a relative afferent pupillary de- constriction of the visual field in his rent exercise-induced transient mon- fect during an attack. Treatment with right eye. The left eye was always ocular blindness. Visual symptoms aspirin or nifedipine had no effect. asymptomatic.Arepeatedintakeofni- consisted of a rapid progressive visual Case 2. A 40-year-old physician fedipine resulted in the successful pre- field constriction in his right eye. If the saw us because of a single attack of a vention of visual symptoms and a nor- patient did not stop exercising, com- hemianopic temporal scotoma in the mal right automated perimetry find- plete monocular blindness would oc- lefteyethathadoccurredduringheavy ing after exercise. He had a history of cur.Theeventslastedfrom30seconds physical activity. The episode lasted thrombosis of the left superficial fem- to 3 hours. They regularly appeared about 30 minutes. By covering 1 eye, oral artery. At the time of the exami- during heavy sport activities such as he noticed that the defect was truly nations, the patient was not taking any jogging or biking. During the 5 years, monocular. He had a history of mi- medication. He had been smoking in- the frequency and strength of the at- graineandhadexperiencedheadaches termittently since he was a young tacks continuously decreased. The pa- or stomachaches several times after adult. He had no history of migraine. tient was in excellent health, had par- heavy bodybuilding. He had under- The same blood work-up as in case 1 ticipated in sports regularly since his gone a work-up by internal medicine wasperformed,andresultswerefound youth, and had no coronary risk fac- specialistsforthestomachaches,which to be normal. Stress electrocardio- tors. He had no history of migraine. werediagnosedtobeofvasospasticori- graphic findings were normal. Results He underwent an extensive work-up gin. Treatment with aspirin before of transcranial and transorbital Dop- thatincludedaneuro-ophthalmologic sportsparticipationreducedthedegree plerandduplexultrasonographywere examination (with a gonioscopy), of the symptoms. Results of a neuro- normal except for a slight hypoplas- computerized visual field testing, ophthalmologic examination and ki- ticrightvertebralartery.Furtherwork- visual-evokedpotentials,ageneraland netic perimetry were completely nor- up was refused by the patient. cardiovascular clinical examination, mal. Because of the patient’s history of echocardiography,Holtermonitoring, chronicexercise-inducedmigraineand Comment. Vasospasm is a recog- magnetic resonance angiography, and stomachache, the ocular symptoms nized cause of amaurosis fugax1,3 and transcranial and transorbital Doppler were considered by exclusion also to also occurs in elderly patients.2 As- and duplex ultrasonography. The re- be caused by vasospasm, and no fur- sociated conditions include mi- sults were normal. Blood evaluation ther examinations were carried out. graine, cluster headache, temporal included a complete blood cell count, Case 3. For 14 years, a 45-year- arteritis, polyarteritis nodosa, and bloodchemicalanalyses,bloodcoagu- old man experienced an exercise- eosinophilic vasculitis. lation studies, and tests for thyroid induced transient “graying out”in his Our 3 patients had exercise- function, erythrocyte sedimentation right eye lasting from 30 seconds to induced monocular attacks, prob- rate, antinuclear antibodies, cryo- 15 minutes. Covering 1 eye confirmed ably caused primarily by vasospasm. globulins, syphilis, Lyme disease, and that the symptoms were monocular. They illustrate the variety of tran- anticardiolipinantibodies.Becausethe Resultsofaneuro-ophthalmologicex- sient monocular visual symptoms and patient was regularly able to provoke amination, including a gonioscopy, findings that occur with exercise. Our such episodes by climbing stairs, we were normal. Because this patient too first patient experienced rapid pro- had the opportunity to examine the was able to provoke such episodes by gressive visual field constriction. If ex- patient several times during an attack. climbing stairs, we were able to exam- ercising was not stopped, complete We could use fundus photography to ine him several times during an attack. monocular blindness would occur. observe and document the occlusion We did not see any fundus abnormali- Anophthalmoscopy revealed a tran- of the right central retinal artery ties, possibly because stopping exer- sient central artery occlusion (Figure). (Figure).ADopplerultrasonographic cise resulted in a rapid recovery of vi- Our second patient noticed a hemi- study during an attack showed a tran- sual acuity. However, immediate re- anopic temporal scotoma in his left sient stopping of blood flow in the peated automated perimetry after an eye. The third patient described the

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 visual loss as “graying out.”Comput- cium channel blocker nifedipine was Corresponding author and reprints: erized perimetry performed immedi- able to reduce the severity of the at- Daniel S. Mojon, MD, Department of ately after an attack revealed an tacks. Our second patient was able to Neuro-Ophthalmology and Strabis- ipsilateral mild peripheral visual field reduce the stomachaches by taking as- mus, Kantonsspital, 9007 St Gallen, constriction. In contrast to the 6 cases pirin before performing sports. Be- Switzerland (e-mail: daniel.mojon described by Imes and Hoyt,3 one of cause he had had only 1 attack in- @kssg.ch). ourpatientswithexercise-inducedva- volving the visual system and was 1. Newman NJ. Cerebrovascular disease. In: Miller sospasm had a late onset at age 60 comfortable with aspirin intake, cal- NR, Newman NJ, eds. Walsh & Hoyt’s Clinical years. Therefore, we conclude that va- cium channel blockers were not tried. Neuro-Ophthalmology. Vol 3. 5th ed. Baltimore, sospasm may also occur in elderly pa- In our third patient, nifedipine could Md: Williams & Wilkins; 1998:3420-3426. 2. Burger SK, Saul RF, Selhorst JB, Thurston SE. tients with a recent onset of exercise- successfully prevent attacks. Transient monocular blindness caused by vaso- induced amaurosis fugax. To our knowledge, this is the spasm. N Engl J Med. 1991;325:870-873. 3. Imes RK, Hoyt WF. Exercise-induced transient Vasospastic amaurosis fugax is first report showing that the cal- visual events in young healthy adults. J Clin Neuro- presumed to be caused by a vaso- cium channel blocker nifedipine may ophthalmol. 1989;9:178-180. spasm or reduced arterial flow.2,4 Va- be effective in certain patients with 4. Winterkorn JM, Kupersmith MJ, Wirtschafter JD, Forman S. Brief report: treatment of vasospas- sospasms could be caused by a ves- exercise-induced vasospastic amau- tic amaurosis fugax with calcium-channel block- sel hypersensitivity to certain vaso- rosis fugax. ers. N Engl J Med. 1993;329:396-398. constrictors released during physi- 5. Campbell DG, Schertzer RM. Pigmentary glaucoma. In: Ritch R, Shields MB, Krupin T, eds. cal exercise or by an inappropriate Andrea Jehn, MD The Glaucomas. 2nd ed. St Louis, Mo: Mosby- high release of such mediators (eg, Barbara Frank Dettwiler, MD Year Book Inc; 1996:975-991. Johannes Fleischhauer, MD 6. Beck RW. Optic neuritis. In: Miller NR, New- catecholamines, endothelin-1, or neu- man NJ, eds. Walsh & Hoyt’s Clinical Neuro- 4 ropeptide Y). Winterkorn et al re- Matthias Sturzenegger, MD Ophthalmology. Vol 1. 5th ed. Baltimore, Md: Wil- ported a successful treatment with cal- Bern, Switzerland liams & Wilkins; 1998;599-662. 7. Lessell S, Kylstra J. Exercise-induced visual hal- cium channel blockers. In our first Daniel S. Mojon, MD lucinations, a symptom of occipital lobe tu- patient, neither aspirin nor the cal- St Gallen, Switzerland mors. J Clin Neuroophthalmol. 1988;8:81-83.

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