Juvenile Xanthogranuloma of the Limbus in an Adult

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

Juvenile xanthogranuloma (JXG) is a cutaneous granulomatous disease rarely seen in adults and has only been reported to occur at the limbus in very few cases. We describe a patient with an unusual cor- neal limbal mass and a skin rash, who was diagnosed histologically as having JXG. The clinical features and management of this rare entity are discussed.

Report of a Case. A 39-year-old man came to our department with a pain- Figure 1. Photograph showing typical orange-red maculopapular skin rash. less limbal mass on his right eye that had enlarged during 3 months. His visual acuity was 20/40 OU and on slitlamp examination, a yellowish, well-circumscribed, vascularized, round nodule was evident at the 6-o’clock position of the right limbus, measuring 6 mm in diameter. The visual axis was clear, and on gonioscopy, neither the trabecu- lar meshwork nor the iris was involved. Further ocular and orbital examination results were unremarkable. Systemic examination revealed an orange-red maculopapular rash involving the trunk, axillae, groin, and face (Figure 1). No associated lymphadenopathy, joint swelling, or oral ulceration were present. Exami- Figure 2. Photograph showing limbal lesion on the right eye. nation of cardiorespiratory and ab- dominal systems disclosed normal results. Complete blood cell count cell lesion with scattered lympho- findings, a diagnosis of adult-onset with differential white cell count, se- cytes and plasma cells. Occasional gi- JXG was made. rum lipid and urea levels, creatinine ant cells were also noted. Histopatho- We initially opted for con- estimation, plasma viscosity, liver logic examination of the skin lesion servative management since the function test results, and chest x- identified a well-circumscribed le- patient was reluctant to undergo ray film were all normal. Sarcoid- sion composed of histiocytic- surgery. However, 18 months fol- osis and tuberculosis were excluded looking cells with abundant, occa- lowing the initial examination, the le- on examination by a pulmonolo- sionally vacuolated cytoplasm, sion had grown to 9 mmϫ5.7 mm gist. Before a diagnosis could be spindle-shaped cells, foci of lympho- (Figure 2) and was causing some made, we performed biopsies of the cytes, and bands of collagen. Multi- discomfort. Surgical excision was car- ocular and skin lesions. nucleated cells were also found and ried out and the lesion was sent for The histopathologic report of these occasionally showed the char- histologic examination. This showed the limbal lesion showed early kera- acteristic features of a Touton giant a granulomatous lesion rich in Tou- tinization over a disorganized spindle cell. Based on the histopathologic ton-type giant cells, with occasional

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 976

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 fibrocytes and lack the eosinophilic infiltration. The other main differential diagnoses are dermoli- poma, dermoid, neurofibroma, and other xanthomas. Previously reported cases have been treated with surgical excision with or without lamellar kerato- plasty. Iris lesions, which are diffi- cult to treat surgically because of their vascularity, have been success- fully treated with topical and systemic steroids, radiotherapy, and in one case, low-dose methotrexate.10 In summary, to our knowledge, this is the first case report of skin involvement in an adult patient with limbal JXG. The skin lesions, when Figure 3. Histopathologic results showing the limbal lesion with multiple Touton giant cells present, appear to persist, whereas ϫ (hematoxylin-eosin; original magnification 20). in infants, they are usually self- limiting. Peribulbar lesions appear to foci of abundant xanthoid cells and Our case had a 5-year history of be slow-growing and painless. This di- areas of focally dense lymphoid in- cutaneous involvement before the on- agnosis should be made on histo- filtrates. These features are strongly set of the limbal mass. The cause for pathologic grounds and after exclu- suggestive of JXG (Figure 3). At the this delay is unknown but it has been sion of systemic granulomatous and last follow-up, 4 months after exci- suggested that a form of local irrita- histiocytic disorders. sion, there was no sign of recur- tion is the stimulus for the accumu- rence. Further follow-up was not pos- lation of histiocytes that character- Shabbir R. Mohamed, MRCOphth sible because the patient left the ize the lesion histopathologically. Non Matthews, FRCOphth country. However, there was nothing in our Antonio Calcagni, MD patient’s history to suggest that this Birmingham, England Comment. Juvenile xanthogranu- was case. The diagnosis was based on loma is a cutaneous granuloma- the clinical signs and symptoms and tous disease occurring primarily in the histopathologic appearance of bi- Corresponding author and reprints: infants younger than 12 months. It opsy specimens taken from the eye Shabbir R. Mohamed, MRCOphth, Bir- is rare in adults. The cutaneous le- and skin. The typical appearance is mingham Midland Eye Centre, West- sions are orange-red macules or pap- a mixture of foamy and epithelioid ern Road, Birmingham B18 7QH, ules arising predominantly on the histiocytes with a scattering of lym- England (e-mail: shabbir@doctor face, neck, and upper trunk. They phocytes, eosinophils, and occa- .com). resolve spontaneously within 1 to 5 sional plasma cells. The classic Tou- 1. Zimmerman LE. Ocular lesions of juvenile xan- years. Ocular complications occur in ton giant cell, with its wreath of thogranuloma. Am J Ophthalmol. 1965;60:1011- 1035 approximately 10% of patients. Iris nuclei, is often seen, especially in ma- 2. Shields CL, Shields JA, Buchanon HW. Solitary lesions are the most common and ture lesions. orbital involvement with juvenile xantho- sometimes cause spontaneous hy- Juvenile xanthogranuloma runs granuloma. Arch Ophthalmol. 1990;108:1587- 1589 phema and secondary glaucoma. In a benign course and therefore must 3. Sonoda T, Hashimoto H, Enjoji M. Juvenile xan- the series by Zimmerman,1 eyelid le- be differentiated from the more se- thogranuloma. Cancer. 1985;56:2280-2286 sions were the next highest in fre- rious group of histiocytic disor- 4. Harvey P, Lee JA, Goepel JR. Isolated xanthogranuloma of the limbus in an adult. Br J Oph- quency, with epibulbar lesions being ders—namely, the Langerhans cell thalmol. 1994;78:657-659 comparatively rare. Orbital lesions histiocytoses, also known as histio- 5. Collum LMT, Mullaney J. Adult limbal xanthogranuloma. Br J Ophthalmol. 1984;68:360-363. have also been reported infre- cytosis X. Typically, JXG lesions are 6. Yanoff M, Perry HD. Juvenile xanthogranu- 2 quently. Solitary tumors seem to be distinguished by the lack of stain- loma of the corneoscleral limbus. Arch Oph- more common in adult- and adoles- ing for S100 protein. However, in a thalmol. 1995;113:915-917 3 7. Wang JJ, Edward DP, Tu E. Xanthogranuloma cent-onset disease. recent series, 6 of 100 cases were of the corneoscleral limbus in an adult. Can To our knowledge, there have positive for monoclonal markers of J Ophthalmol. 2001;36:275-277 been 4 reported cases of JXG oc- S100 protein.8 Juvenile xanthogranu- 8. Kraus MD, Haley JC, Ruiz R, et al. “Juvenile” 4-7 xanthogranuloma: an immunophenotypic study curring at the limbus in an adult. loma lesions also show positivity for with a reappraisal of histogenesis. Am J Der- None of these cases had coexistent macrophage markers, such as CD68 matopathol. 2001;23:104-111. 9 9. Zelger B, Cerio R, Orchard G, Wilson-Jones E. skin lesions. All were treated by and HAM56 but lack Birbeck gran- Juvenile and adult xanthogranuloma: a histo- surgical excision and no recur- ules on electron microscopy. Fi- logical and immunohistochemical compari- rences were reported; the longest brous histiocytomas can appear his- son. Am J Surg Pathol. 1994;18:126-135. 10. Parmley VC, George DP, Fannin LA. Juvenile follow-up, however, was only 2 tologically similar to JXG but xanthogranuloma of the iris in an adult. Arch years. typically have a storiform pattern of Ophthalmol. 1998;116:377-379

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 977

Figure 1. A, A 5-year-old boy developed eyelid swelling and proptosis of the left eye. B, Axial computed tomography reveals a left orbital mass eroding the frontal bone with extension into the temporal fossa. C, Histopathologic examination showed admixture of histiocytes with nuclear folds, eosinophils, and multinucleated giant cells (hematoxylin-eosin, original magnification ϫ250). out palpable mass. Computed tomography (CT) showed an orbital mass with a heterogeneous internal structure in the lateral wall of the left orbit and temporal fossa, with erosion of the frontal and zygo- matic bones (Figure 1B). Incisional biopsy findings revealed a dark brown mass consistent with degenerated blood. Histopathologic examination showed clotted blood that contained eosinophils, histiocytes, and small multinucleated giant cells (Figure 1C). These findings suggested the diagnosis of either giant cell reparative granuloma or Langer- hans cell histiocytosis. The bone defect closed spontaneously without treatment in 8 months. In June 1990, 18 months after initial examination, the boy devel- Figure 2. Axial computed tomography demonstrated a similar mass in the superolateral aspect oped painful, nonerythematous swell- of the right orbit with destruction of the frontal bone into the brain and temporal fossa. The left ing of his right upper eyelid. The CT orbit showed a healed lesion and bone defect. findings disclosed a similar lesion in the superolateral aspect of the right volvement, and a computerized lit- orbit with destruction of frontal bone Bilateral Sequential erature search using Medline dis- and extension into the brain and tem- Orbital Involvement by closed no other examples. We herein poral fossa. The mass contained den- Eosinophilic Granuloma report a case of eosinophilic granu- sities consistent with fragments of loma that exhibited sequential bi- bone. The previously affected left or- Langerhans cell histiocytosis is an lateral orbital involvement. bit appeared normal (Figure 2). In- uncommon, multisystem disease cisional biopsy of the right orbital with a clinical spectrum that in- Report of a Case. In November mass was performed, and dark black cludes benign unifocal disease (eo- 1988, a 5-year-old otherwise healthy tissue consistent with degenerated sinophilic granuloma), chronic boy was referred to us for evalua- blood was observed intraopera- multifocal disease (Hand-Schu¨ ller- tion of left eyelid swelling and pro- tively. Histopathologic examination Christian disease), and acute or sub- ptosis that had developed over 1 showed hemorrhagic tissue with small acute fatal disseminated disease (Let- month (Figure 1A). He had been multinucleated giant cells, large his- terer-Siwe disease).1 It accounts for diagnosed elsewhere as having al- tiocytes with folded nuclei, eosino- 1% to 7% of biopsied orbital tu- lergic eyelid edema, and he had been phils, and fibrosis. The histiocytic cells mors.2 Eosinophilic granuloma is the treated with topical corticosteroids showed intense positive immunore- most common variant of Langer- with no response. There was a his- activity for S-100 protein, support- hans cell histiocytosis, with approxi- tory of head trauma 3 months ear- ing the diagnosis of eosinophilic mately 20% of cases affecting the or- lier that caused bilateral eyelid ec- granuloma in the right orbit. After 6 bital area.2 When it occurs in the chymoses, and spontaneous healing months’ follow-up, the second le- orbit, it is usually unilateral and lo- occurred. sion healed spontaneously without calized. We are unaware of a previ- Ocular examination disclosed further therapy. At 93 months’ follow- ously reported case of eosinophilic visual acuity of 20/20 OU. There was up, the patient remains healthy with- granuloma with bilateral orbital in- 5 mm of left axial proptosis without systemic problems.

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 978

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Comment. Eosinophilic granu- instead of Langerhans cell histiocy- associated with a bad prognosis.4 In loma is a rare disease that is classi- tosis and classified it further into uni- our case, none of these factors were fied as a variant of Langerhans cell focal and multifocal eosinophilic present. histiocytosis. It is generally diag- granuloma. In a survey of 238 cases nosed in children or young adults of eosinophilic granuloma from the Hakan Demirci, MD and shows a predilection for males.1 general pathology laboratory in a Carol L. Shields, MD In the orbit, it typically manifests as cancer center, multifocal eosino- Jerry A. Shields, MD a painful, tender, erythematous philic granuloma was found in 85 Ralph C. Eagle, Jr, MD swelling near the superolateral part cases (36%) at the time of diagno- Philadelphia, Pa of the orbit anteriorly. In more pos- sis.3 Of these cases, 63% involved teriorly located tumors, eyelid swell- only bones (n=53), 24% involved This study was supported in part by ing or proptosis can be the first sign. both bone and soft tissue (n=20), the Paul Kayser International Award Computed tomography is the most and 14% involved only soft tissue of Merit in Retina Research, Hous- helpful diagnostic test and shows an (n=12). The involved bone in- ton, Tex (Dr J. Shields), Macula Foun- irregular, serrated osteolytic lesion cluded skull (52%), femur (29%), dation, New York, NY (Dr C. Shields), with sclerotic margins. Histopatho- and rib (22%). Soft tissue involve- the Noel T. and Sara L. Simmonds En- logic evaluation displays a prolifera- ment included skin (14%), lymph dowment for Ophthalmic Pathology, tion of large histiocytic cells with node (13%), and lung (11%). An- Wills Eye Hospital (Dr Eagle), and folded nuclei consistent with Langer- other review of 348 cases treated in the Eye Tumor Research Foundation, hans cells with interspersed eosin- multiple pediatric hematology/ Philadelphia, Pa (Dr C. Shields). ophils and small multinucleated gi- oncology departments revealed that Corresponding author: Carol L. ant cells. The histiocytic cells show isolated bone lesions were mostly Shields, MD, Oncology Service, Wills a positive immunoreactivity for unifocal or bifocal in 39% of cases Eye Hospital, 900 Walnut St, Phila- S-100 protein, CD1 (OKT6) anti- and multifocal in 19% of cases.4 Dif- delphia, PA 19107. gen, and ␣-1 antichymotrypsin. Elec- ferent from unifocal eosinophilic 1. Shields JA, Shields CL. Histiocytic tumors and tron microscopy demonstrates in- granuloma, multifocal eosino- pseudotumors. In: Shields JA, Shields CL. Atlas tracytoplasmic Birbeck granules philic granuloma usually has bimo- of Orbital Tumors. Philadelphia, Pa: Lippincott corroborating the diagnosis of dal distribution and one peak be- Williams & Wilkins; 1999:154-164. 1 2. Henderson JW, Farrow GM. Orbital Tumors. 2nd Langerhans cell histiocytosis. In the tween the ages of 0 to 10 years and ed. New York, NY: Brian C Decker (Thieme- orbit, the differential diagnosis in the other between the ages of 20 to Stratton); 1980:580-584. 3. Lieberman PH, Jones CR, Steinman RM, et al. children includes dermoid cyst, lac- 30 years. Bilateral sequential or- Langerhans cell (eosinophilic) granulomatosis: rimal gland tumor, primary bone tu- bital involvement, as seen in our a clinicopathologic study encompassing 50 years. mors such as osteosarcoma, aneu- case, is highly unusual, if not unique. Am J Surg Pathol. 1996;20:519-555. 4. The French Langerhans’ Cell Histiocytosis Study rysmal bone cyst, ossifying fibroma, The treatment of eosinophilic Group. A multicentre retrospective survey of fibrous dysplasia, and metastatic tu- granuloma may include surgical cu- Langerhans’ cell histiocytosis: 348 cases ob- mors, such as neuroblastoma and rettage, low dose irradiation, admin- served between 1983 and 1993. Arch Dis Child. 1996;75:17-24. Ewing sarcoma. istration of cytotoxic agents, sys- 5. Wirtschafter JD, Nesbit M, Anderson P, In the orbit, in contrast to eo- temic corticosteroids, or intralesional McClain K. Intralesional methylprednisolone 5 for Langerhans’ cell histiocytosis of the orbit sinophilic granuloma, dermoid cyst corticosteroids. In some cases, ini- and cranium. J Pediatr Ophthalmol Strabismus. is a round to ovoid lesion with a well- tial biopsy followed solely by obser- 1987;24:195-197. defined, enhancing thin wall and vation is curative, leading to sponta- 6. Glover AT, Grove AS. Eosinophilic granuloma of the orbit with spontaneous healing. Ophthal- nonenhancing contents on CT neous resolution of the inflammatory mology. 1987;94:1008-1012. evaluation. Epithelial tumors of the mass as occurred in our case.6 The lacrimal gland (except adenoid cys- systemic prognosis of patients with tic carcinoma) rarely affect young unifocal eosinophilic granuloma and children and generally cause bone multifocal eosinophilic granuloma Hereditary X-Linked fossa formation rather than a large limited to bone is excellent.3 In a re- Juvenile Retinoschisis: bone defect that reflects an epicen- view of 348 cases treated in pediat- A Review of the Role ter of the lesion in the bone. Pri- ric hematology/oncology depart- of Mu¨ller Cells mary bone tumors do not exhibit the ments, the survival rate was 96% to characteristic lytic lesion with scle- 100% at 7 years in patients with eo- Hereditary X-linked retinoschisis rotic margin of eosinophilic granu- sinophilic granuloma limited to (RS) is the most common cause of loma on CT scan. Metastatic or- bone.4 However, in some cases, lo- juvenile macular degeneration in bital tumors show the irregularly cal recurrence of the lesion is ob- males1,2 and may lead to vitreoreti- shaped bony defects, usually occur- served between 6 and 18 months.3 In nal degeneration characterized by ring late in the course of neuroblas- our case, there has been no recur- cystic spoke-wheel maculopathy, pe- toma or Ewing sarcoma, and sys- rence or progression to dissemi- ripheral retinoschisis, alterations temic evaluation almost invariably nated disease after 8 years. The mul- of the vitreous body, and a reduced reveals the primary tumor. tivariate prognostic analysis in 348 b wave on the electroretinogram. Its In a recent study, Lieberman et cases showed that organ involve- prevalence ranges from 1:5000 to al3 suggested using the term Langer- ment, age younger than 1 year, and 1:25000.3,4 The condition is usu- hans cell (eosinophilic) granuloma failure responding to therapy were ally bilateral and affects males only.

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 979

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 respectively; incubation, 10 min). Prior to incubation with vimentin and neurofilaments, slides were pretreated for 15 minutes in citrate buffer (microwave); prior to fibronectin incubation, slides were pretreated with pronase for 10 minutes. The RS1 antibody was provided by one of us (B.H.F.W.) and is identical to the RS1 antibody described in Molday et al.18 Raising the RS1 antibody and the specificity have been described pre- ∗ viously.18 In short, the amino pep- tide LSSTEDEGEDPWYQKAC, corresponding to aa22-39 of the human RS1 precursor protein,20 was conju- Figure 1. The family pedigree reveals an X-linked mode of inheritance with several affected males. Open square indicates male; shaded square, male with juvenile retinoschisis; shaded square with slash, male gated to keyhole limpet hemocyanin with juvenile retinoschisis who died; open circle, female; circle with dot, carrier female; and asterisk, the and used to immunize New Zealand index patient. White rabbits. For immunolabeling, a 1:1000 dilution of rabbit serum was Males with juvenile RS usually seek eral authors postulated that juve- used. Prior to incubation, slides were treatment because of diminished vi- nile RS arises from a basic inher- pretreated for 10 minutes in citrate sion at school age, followed by pro- ited defect in probably the innermost buffer (microwave). A formalin- gressive visual deterioration later in portion of the cytoplasm of Mu¨ ller fixed paraffin-embedded eye with a life. Peripheral retinoschisis is found cells.7,10,11 Current molecular ge- healthy human retina was used as a in 50% of patients and may be lim- netic and immunohistochemical control. ited to the inferior temporal quad- findings contradict the theory of a Material was sampled from the rant. Breaking of the inner schisis primary defect in the Mu¨ ller cells18 formalin-fixed retina and embed- layer may lead to unsupported reti- and suggest an abnormality that in- ded in epoxy resin after dehydra- nal vessels in the vitreous cavity, teracts with a Mu¨ller cell receptor or tion with grading acetone. Semi- called a “congenital vascular veil.”5 components of the extracellular ma- thin sections (1 µm) for light There have been few reports on the trix.19 Based on immunohistochemi- microscopy were made with a glass histopathologic characteristics of cal analysis with a RS1-specific an- knife and stained with toluidine blue RS.6-11 The principal feature in all tibody applied to the enucleated eye (1% weight-volume ratio). Ultra- these cases was a large schisis cav- of a relatively young patient with RS, thin sections (70-80 nm) were cut ity originating from the nerve fiber we support the theory that photo- with a diamond knife and mounted layer (NFL). Several theories con- receptors appear to be the cells pri- on unfilmed 300-mesh copper grids. cerning the pathogenesis of RS have marily involved in the pathologic After staining for 30 minutes with been postulated. First, findings on characteristics of RS. uranyl acetate and 2 minutes with fluorescein angiography led to a vas- lead citrate, the ultrathin sections cular theory of RS development12 be- Patient, Materials, and Methods. At were examined with a Zeiss EM 902 cause of delayed development of the age 5 months, our patient was diag- transmission electron microscope retinal and choroidal vasculature in nosed as having X-linked juvenile RS. (Carl Zeiss, Oberkochen, Ger- which the retina outgrows its blood At age 19 years, his right eye was many) with an acceleration voltage supply infratemporally. Vascular enucleated. The enucleated eye was of 80 kV. changes might play a role in the evo- fixed in 4% formaldehyde solution in Our patient was also enrolled lution of the schisis,13 and RS may a 0.1M phosphate buffer. After hori- in a large study by the Retinoschi- be complicated by neovascular glau- zontal sectioning, the eye was em- sis Consortium21 on screening for coma.14 Second, Schepens15 be- bedded in paraffin. Sections (5-µm) mutations of the gene involved in RS lieved that the primary abnormal- were incubated with polyclonal an- (RS1). ity was vitreous traction on the inner tibody glial fibrillary acid protein retinal surface caused by inad- (DAKO, Glostrup, Denmark) (dilu- Results. The family pedigree re- equate growth or shrinkage of the tion, 1:1200; incubation, 30 min at vealed an X-linked mode of RS inher- cortical vitreous. The histologic room temperature; peroxidase- itance with several males affected characteristics of RS in a male in- antiperoxidase method). The mono- (Figure 1). In our patient, pursuit fant with congenital retinal detach- clonal antibodies vimentin (Bio- movements, a convergent strabis- ment and splitting in the inner retina Genex, San Ramon, Calif), and mus of his right eye, and remnants of but no schisis16 and in 2 male in- fibronectin (DAKO) and neuro- persistent pupillary membranes fants with congenital hereditary RS17 filaments (Sanbio, Uden, the Neth- were recorded on early examina- supported the theory of a vitreoreti- erlands) were applied using the tion. At age 5 years, a cataract devel- nal developmental anomaly. Third, avidin-biotin complex method oped in his right eye. Visual acuity was based on pathological findings, sev- (dilution, 1:3200, 1:1200, and 1:300, light perception OD and 20/200

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 980

D E F ∗ ∗

G H I

J K L

Figure 2. Cataract and large iris nodules in the right eye (A). Funduscopy of the left eye (B) of a patient with juvenile retinoschisis shows delicate retinal cysts. In the enucleated eye, a depigmented area is noted macroscopically in the posterior pole (C) with some vascular veils extending anteriorly. Microscopically, the cysts originated from schisis in the nerve fiber layer in the inferotemporal part of the retina (asterisks) (D). The underlying retina and the nasal retina were detached (arrows), and the retina was folded at the base of the schisis cavities (hematoxylin-eosin, original magnification ϫ1.7). In the nasal-posterior part of the retina (E), there is splitting in the inner and outer plexiform layers (arrows) (hematoxylin-eosin, original magnification ϫ100). In the central retina (F) multiple PAS (periodic acid–Schiff)–positive globules are present in all retinal layers (original magnification ϫ400). In the anterior segment (G), occlusion of the pupil is present. The lens shows a hypermature cataract with posterior synechiae and rupture of the anterior lens capsule with a reactive inflammatory infiltrate (hematoxylin-eosin, original magnification ϫ25). Glial fibrillary acid protein stains strongly positive throughout the retina (H) (original magnification ϫ400). The nerve fiber layer (I) stains strongly positive with S100 (original magnification ϫ250). A healthy human retina (J) with strong RS1 antibody immunostaining in the inner segments of the photoreceptors, strong membranous staining in the outer nuclear layer, moderate immunostaining in the inner nuclear layer and the plexiform layers, and negative staining in the ganglion cell layer and the nerve fiber layer (original magnification ϫ250). The retinoschisis-affected eye with negative RS1 antibody staining in the atrophic central retina (K) and markedly reduced staining in the relatively well-preserved peripheral retina (L) (original magnification ϫ250).

OS. At age 8 years, his right eye matous uveitis with large iris nod- and initially responded to topical ste- showed a mature cataract with pos- ules occurred in the right eye from roids and cycloplegia. Laboratory terior synechiae. Recurrent granulo- age 18 years onward (Figure 2A) testing did not reveal a cause for the

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 981

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 uveitis. The patient was treated with clusion of the pupil, and iris bombe´ was found in exon 4 containing part 200 mg hydroxychloroquine sulfate were present. The lens showed a hy- of the conserved discoidin domain per day. Electroretinography and vi- permature cataract with posterior of the RS1 gene.20 sual evoked potential were almost synechiae and rupture of the ante- nonrecordable in the right eye. At age rior lens capsule (Figure 2G). A re- Comment. The histological find- 19 years, iris neovascularization de- active mixed inflammatory infil- ings in our patient are characteris- veloped in the right eye with second- trate was present, with histiocytes tic of juvenile RS with an unusual ary glaucoma; it was treated with ac- and giant cells within the lens cap- complication of phacoantigenic en- etazolamide and local therapy. sule. Foamy cells surrounded the dophthalmitis, which explains the Eventually, the right eye was enucle- lens and were present in the ante- clinical findings of granulomatous ated. The visual acuity of the left eye rior chamber. Granulomas were anterior uveitis. Immunostaining was counting fingers at the most re- noted along the pigment epithe- with the RS1-specific antibody18 was cent examination (Figure 2B). lium of the iris and ciliary body and markedly reduced in the RS- The eye was fixed in formalin focally at the retinal pigment epi- affected eye. The healthy human and transported to the pathology de- thelium, with associated uveitis. retina stained strongly positive in the partment. Macroscopically, occlu- On immunohistochemical ex- inner segments of the photorecep- sion of the pupil, a mature cataract, amination, glial fibrillary acid pro- tors and the outer nuclear layer, and posterior synechiae were noted tein (Figure 2H) and vimentin stained moderately positive throughout the in the anterior segment. In the pos- strongly positive throughout the inner nuclear layer and the plexi- terior pole, a depigmented area was retina and the inner and outer layer form layers, and negative in the in- found, with some vascular veils ex- of the schisis cavities. The NFL (Fig- ner retina. This is consistent with tending anteriorly (Figure 2C). The ure 2I) and the inner and outer lay- findings for the same antibody ap- retina was partly detached, with deli- ers of the schisis cavities stained plied in mouse and monkey retinas cate cysts inferiorly in the eye. On strongly positive with S100. The roof and a normal human retina.18 Simi- microscopic examination, the cysts of the schisis cavity and the NFL larly, a retina-specific polyclonal an- were seen to have originated from stained focally positive with neuro- tibody, designated retinoschisin, has schisis in the NFL in the inferotem- filaments. The PAS-positive glob- been described in mouse and hu- poral part of the retina and were cov- ules stained strongly positive with fi- man retinas.19 Although messenger ered by a glial membrane. The un- bronectin. In the healthy human RNA of the causative RS1 gene was derlying retina and the nasal retina retina, immunostaining with the RS1 detected only in the photoreceptor were detached (Figure 2D). There antibody revealed intense staining of layer, the protein product of the gene was marked splitting in the NFL of the inner segments of the photore- (retinoschisin) was present both in the nasal retina along the plane of ceptors, strong membranous stain- the photoreceptors and within the the ganglion cell layer and detach- ing in the outer nuclear layer, mod- inner portions of the peripheral hu- ment of the inner limiting mem- erate staining in the inner nuclear man retina, and there was patchy im- brane (ILM). Alcian blue/hyaluroni- layer and the plexiform layers, and munoreactivity in the inner and dase staining was negative. The negative staining in the ganglion cell outer nuclear layers at the macula. retina was folded at the base of the layer and the NFL (Figure 2J). The By genetic linkage analysis, RS schisis cavities with marked hyalin- RS-affected eye showed negative stain- was first mapped to the distal re- ization of intraretinal vessels and de- ing in the atrophic central retina (Fig- gion of Xp, and subsequent refine- generative calcification. In the nasal- ure 2K) and markedly reduced stain- ment eventually localized the RS posterior part of the retina, there was ing in the relatively well-preserved gene in Xp22.2.22 Sauer et al20 iden- splitting in the inner and outer plexi- peripheral retina (Figure 2L). tified a candidate gene for RS, des- form layers (Figure 2E). In the de- On electron microscopic ex- ignated RS1 (alias XRLS1). The RS1 pigmented posterior pole, the reti- amination, splitting had occurred in gene has 6 exons and encodes a 224 nal pigment epithelium showed the NFL in the semithin sections. In- amino acid protein, which con- proliferative and degenerative traretinal globules were present in tains a highly conserved discoidin changes with atrophy of the photo- the inner nuclear layer and the in- domain. The RS1 mRNA encodes a receptors and the outer nuclear layer. ner part of the outer plexiform layer secretable adhesion protein.20,23 Its In the pupil-optic block, the retina and were composed of basement role is implicated in cell-cell adhe- was partly detached without obvi- membrane–like material in the ul- sion and phospholipid binding, in- ous schisis cavities. The inner retina trathin sections (Figure 3A). A glial dicating that RS1 is important in cell showed splitting in the NFL and de- membrane was present at the vit- adhesion processes during retinal detachment of the ILM. In the central real side of the ILM. The retinal sur- velopment.20,21 It was postulated that retina, multiple PAS (periodic acid- face of the ILM was attached to foot- the protein product RS1 is ex- Schiff)–positive globules were pres- plates of degenerated Mu¨ ller cells. pressed and assembled in photore- ent in all retinal layers, sometimes The plasma membrane of some ceptors of the outer retina and bi- with lumens (Figure 2F). In the Mu¨ ller cells was focally deficient polar cells of the inner retina as a macular area, degenerative changes with intraretinal deposits of inter- disulfide-linked oligomeric protein were found in the outer plexiform mediate filaments (Figure 3B). complex.18,19 Recently, it has been and nuclear layers. In the anterior In our patient and his family, demonstrated in vitro that retinos- segment iris, neovascularization, oc- the missense mutation Arg102Trp chisin is selectively taken up and

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 982

Figure 3. Electron microscopic examination shows intraretinal globules composed of basement membrane–like material (A). The plasma membrane of some Mu¨ller cells was focally deficient with intraretinal deposits of intermediate filaments (B) (original magnification ϫ7000).

transported by Mu¨ ller cells into the inner retina, eventually leading to the schisis cavities.10,11 In our pa- inner retina in a direction-specific schisis formation. The basement tient, the immunohistochemical manner.24 Juvenile RS may there- membrane of the Mu¨ ller cells forms (glial fibrillary acid protein, S100, fore be caused by abnormalities in part of the ILM. The Mu¨ ller cell is and neurofilament) and electron mi- the secreted photoreceptor protein the principal glial cell of the retina croscopic findings (presence of de- at some distance from the site of RS and is in intimate contact with the generative Mu¨ ller cells and depos- pathologic characteristics.19 Dis- inner segments of the photorecep- its of intermediate filaments) are coidin domains are present in ex- tors and the cells of the middle reti- consistent with earlier findings. tracellular or transmembrane pro- nal layers, surrounding large areas However, glial fibrillary acid pro- teins in cell adhesion or cell-cell of retinal vessels. The dysfunc- tein and S100 positivity were not re- interactions.25 The interaction of RS1 tional protein or abnormalities in the stricted to the retina adjacent to the protein with a Mu¨ller cell surface re- interaction of the protein with a schisis.10,11 These differences may be ceptor or the extracellular matrix Mu¨ ller cell receptor or extracellu- explained by the age at the time of would be in keeping with its dis- lar matrix may therefore be ex- enucleation (age, 19 years vs 55, 53, coidin domain.19 pected to affect the middle and in- and 83 years10,11); our case prob- We found no expression of RS1 ner retinal layers and to produce ably represents an earlier stage of the protein in the central atrophic retina structural defects in the ILM and the disease. We support the hypothesis and markedly reduced staining in the NFL. This could account for the that the basement membrane–like relatively well-preserved periph- schisis, which was present not only material and filaments that accumu- eral retina in the RS-affected eye. in the inner retinal layers but also na- late extracellularly within the atro- This is consistent with a recent study sal-posteriorly in the inner and outer phic central retina may be caused by showing reduced antibody staining plexiform layers. The cone-shaped abnormalities in the interaction of in chimera mice with a targeted RS1 zone of Mu¨ ller cells in the central the (defective) RS protein and a knockout.26 The reduced staining in and inner part of the fovea centralis Mu¨ ller cell receptor or extracellu- the human RS-affected eye may be plays an important role in the struc- lar matrix.19 explained by the missense DNA mu- tural integrity of the macula, and de- In summary, earlier stud- tation found in our patient, which fective cell-cell interaction may ies18,19 have established through im- may have resulted in a dysfunc- explain the characteristic foveo- munohistochemical analysis the cel- tional protein with a reduced half- macular schisis, later replaced by lular distribution localization of RS life and defective cellular adhesive atrophic changes.27 Similarly, Mu¨ller protein in mammalian and healthy function. Many missense and pro- cells may also be involved in the ex- human retinas. The photorecep- tein-truncated mutations of the caus- tracellular deposits of amorphous tors and bipolar cells appeared to be ative RS1 gene have now been iden- PAS-positive dots in the retina and, the cell types primarily involved in tified and are thought to be possibly, walls of small vessels. The maintaining the integrity of the cen- inactivating.19 Such a defective ad- PAS-positive deposits were noted in tral and peripheral retina, secreting hesive protein may still be trans- all retinal layers in the atrophic cen- a cell adhesion protein taken up and ported by the Mu¨ ller cells into the tral retina and were not restricted to transported by Mu¨ ller cells into the

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 983

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 inner retina.18,19 In our study of an and leakage in X-linked (juvenile) retinoschi- mon.1 Hemangiomas of the eye are sis. Br J Ophthalmol. 1979;63:368-373. RS-affected human eye, a mutation 14. Ando A, Takahashi K, Sho K, Matsushima M, most often associated with poste- of the RS1 gene appears to give rise Okamura A, Uyama M. Histopathological find- rior segment structures. We could to a dysfunctional adhesive pro- ings of X-linked retinoschisis with neovascu- find no previously described asso- lar glaucoma. Graefes Arch Clin Exp Ophthal- tein, resulting in defective cellular mol. 2000;238:1-7. ciation between vascular tumors of retinal adhesion that eventually leads 15. Schepens CL. Congenital retinoschisis. Klin the iris and CNS in adults. Most of Oczna. 1988;90:127-132. to schisis formation. 16. Laatikainen L, Tarkkanen A, Saksela T. Heredi- the modern reports of iris vascular 2,3 tary X-linked retinoschisis and bilateral congen- tumors occur in isolation. There Cornelia M. Mooy, MD, PhD ital retinal detachment. Retina. 1987;7:24-27. is one case of diffuse congenital hem- 17. Kawano K, Tanaka K, Murakami F, Ohba N. Dordrecht, the Netherlands Congenital hereditary retinoschisis: evolution angiomatosis with a unilateral iris L. Ingeborgh van den Born, MD at the initial stages. Graefes Arch Clin Exp Oph- cavernous hemangioma; however, thalmol. 1981;217:315-323. Seerp Baarsma, MD 18. Molday LL, Hicks D, Sauer CG, Weber BH, this syndrome appears to be uni- 4 Dion A. Paridaens, MD Molday RS. Expression of X-linked retinoschi- formly fatal by age 1 year. Rotterdam, the Netherlands sis protein RS1 in photoreceptors and bipolar cells. Invest Ophthalmol Vis Sci. 2001;42:816- Thea Kraaijenbrink, MSc 825. Report of a Case. A 48-year-old white Arthur Bergen, PhD 19. Grayson C, Reid SN, Ellis JA, et al. Retinoschi- woman was referred for evaluation af- sin, the X-linked retinoschisis protein, is a se- ter her local ophthalmologist noted Amsterdam, the Netherlands creted photoreceptor protein and is expressed an unusual iris mass in her right eye. Bernhard H. F. Weber, PhD and released by Weri-Rb 1 cells. Hum Mol Gen. 2000;9:1873-1879. The patient’s medical history was sig- Wu¨rzburg, Germany 20. Sauer CG, Gehrig A, Warneke-Wittstock R, et al. Positional cloning of the gene associated with nificant for schizophrenia for which X-linked juvenile retinoschisis. Nat Genet. 1997; she had been treated with thiorida- This study was presented in part at the 17:164-170. zine hydrochloride for many years. annual meeting of the Verhoeff- 21. Retinoschisis Consortium. Functional impli- She was diagnosed with multiple cav- Zimmerman Society, Portland, Ore, cations of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis ernous hemangiomas of the brain and April 24, 1999. (XRLS). Hum Mol Genet. 1998;7:1185-1192. brainstem 7 years earlier after a sei- Corresponding author and re- 22. Arden GB, Gorin MB, Polkinghome PJ, Jay M, Bird AC. Detection of the carrier state of X- zurelike episode prompted brain im- prints: Cornelia M. Mooy, MD, PhD, linked retinoschisis. Am J Ophthalmol. 1988; aging (Figure 1). The brain lesions Pathology Laboratory Dordrecht, Jkvr 105:590-595. have since been followed with serial Van den Santheuvelweg 2A, 3317NL 23. Reid SN, Akhmedov NB, Piriev NI, Kozak CA, Danciger M, Farber DB. The mouse X-linked MRI studies and found to be stable. Dordrecht, the Netherlands (e-mail: juvenile retinoschisis cDNA: expression in pho- Examinations by her neurosurgeon [email protected]). toreceptors. Gene. 1999;227:257-266. 24. Reid SN, Farber DB. Transport of a photore- showed no neurologic deficit. Re- 1. Deutman AF. Vitreoretinal dystrophies. In: Krill ceptor-secreted protein, retinoschisin, by Mu¨ller cent laboratory studies revealed nor- A, Archer DB, eds. Hereditary Retinal and Cho- cells [ARVO abstract]. Invest Ophthalmol Vis Sci. mal liver and kidney function. Her roidal Diseases. New York, NY: Harper & Row; 2001;42(suppl):S654. 1977:1043-1108. 25. Baumgartner S, Hofmann K, Chiquet- other medications were lorazepam, 2. Forsius H, Krause U, Helve J, et al. Visual acu- Ehrismann R, Bucher P. The discoidin family carisoprodol, and famotadine. Her ity in 183 cases of X-chromosomal retinoschi- revisited: new members from prokaryotes and ocular history is significant for myo- sis. Can J Ophthalmol. 1973;8:385-393. a homology based fold prediction. Protein Sci. 3. George ND, Yates JR, Moore AT. X-linked reti- 1998;7:1626-1631. pia with astigmatism. noschisis. Br J Ophthalmol. 1995;79:697-702. 26. Hiriyanna KT, Takada Y, Kondo M, Bingham On examination, we found her 4. George ND, Yates JR, Moore AT. Clinical fea- EL, Sieving PA. X-linked retinoschisis: RS1 func- best-corrected visual acuity was 20/25 tures in affected males with X-linked retinos- tional genomics and physiological dysfunc- chisis. Arch Ophthalmol. 1996;114:274-280. tion [ARVO abstract]. Invest Ophthalmol Vis Sci. OU. The right inferior iris had a lobu- 5. Mann I, Macrae A. Congenital vascular veils in 2001;42(suppl):S647. lated blood-filled mass that appeared the vitreous. Br J Ophthalmol.1938;22:1-10. 27. Gass JD. Mu¨ ller cell cone, an overlooked part 6. Zimmerman LE, Naumann G. The pathology of the anatomy of the fovea centralis: hypoth- to be vascular in nature and did not of retinoschisis. In: McPherson A, ed. New and esis concerning its role in the pathogenesis of extend into the angle on gonioscopy Controversial Aspects of Retinal Detachment. New macular hole and foveomacular schisis. Arch (Figure 2). Anterior segment echog- York, NY: Harper & Row; 1968:400-423. Ophthalmol. 1999;117:821-823. 7. Yanoff M, Rahn EK, Zimmerman LE. Histopa- raphyshowedthislesiontobe2.1mm thology of juvenile retinoschisis. Arch Ophthal- thick with an irregular internal struc- mol. 1968;79:49-53. ture and entirely contained within the 8. Manschot WA. Pathology of hereditary condi- Presumed Iris Hemangioma tions related to retinal detachment. Ophthal- iris. Iris angiography did not detect mologica. 1971;162:223-234. Associated With Multiple flow through the lesion. Golden 9. Manschot WA. Pathology of hereditary juve- Central Nervous System nile retinoschisis. Arch Ophthalmol. 1972;88: brown deposits in the subepithelial 131-138. Cavernous Hemangiomas layers and superficial stroma of her 10. Condon GP, Brownstein S, Wang NS, Kearns cornea and anterior stellate golden AF, Ewing CC. Congenital hereditary (juvenile X-linked) retinoschisis: histopathologic and We present the unique case of a pa- brown deposits in her lenses were ultrastructural findings in 3 eyes. Arch Oph- tient with a vascular iris lesion con- thought to be secondary side effects thalmol. 1986;104:576-583. sistent with a cavernous heman- ofherthioridazineregimen.Herfundi 11. Kirsch LS, Brownstein S, de Wolff-Rouendaal D. A histopathological, ultrastructural, and im- gioma and central nervous system were normal. She had no cutaneous munohistochemical study of congenital heredi- (CNS) cavernous hemangiomas vascular lesions. tary retinoschisis. Can J Ophthalmol. 1996;31: 301-310. demonstrated by magnetic reso- 12. Ewing CC, Cullen AP. Fluorescein angiogra- nance imaging (MRI). Clinical re- Comment. We describe a patient phy in X-chromosomal maculopathy with reti- ports of iris vascular tumors are rare with a vascular iris lesion and CNS noschisis (juvenile hereditary retinoschisis). Can J Ophthalmol. 1972;7:19-28. and cases with histopathologic ab- cavernous hemangiomas that may 13. Green JL, Jampol LM. Vascular opacification normalities are even more uncom- represent a single disease process. Al-

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 984

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 rophages.1 The liberation of TNF-␣ A B is thought to stimulate the inflammatory process by binding to cell surface receptors. Infliximab is a chi- meric antibody of the IgG class, which binds TNF-␣, inhibiting its activity.2 The Food and Drug Ad- ministration has approved infliximab, as an intravenous infusion, for the treatment of rheumatoid arthritis and Crohn disease.3 Cytokine-targeted therapy in patients with rheumatoid arthritis has been increasing and has generally been reported to be safe, although headache and respiratory congestion may occur. Review of the Figure 1. Magnetic resonance imaging of multiple cavernous hemangiomas of the brain and brainstem. package insert for infliximab lists A, Multiple hyperintense lesions with TI-weighted imaging; B, corresponding larger hypointense areas “neurologic events” as possible ad- consistent with hemosiderin deposition with gradient echo imaging. verse affects and adds that “Inflix- imab and other agents that inhibit normalities. We propose that this TNF have been associated in rare clinical syndrome may represent a cases with exacerbation of clinical new type of disseminated hamar- symptoms and/or radiographic evi- toma distinctly different from other dence of de-myelinating disease.”4 phakomatoses. Inhibition of TNF-␣ has also been studied in multiple sclerosis Scott A. Larson, MD (MS), in which high TNF-␣ levels Thomas A. Oetting, MD, MS have been noted in MS plaques and Iowa City, Iowa mononuclear cells of patients with 5 The authors have no proprietary or fi- demyelinating disease. In animal ␣ nancial interest in any products men- models of MS, the infusion of TNF- tioned herein. is associated with worsening symp- 6 Corresponding author: Thomas toms. However, a randomized, con- Figure 2. Inferior iris vascular tumor not A. Oetting, MD, MS, UIHC, Deptart- trolled study of lenercept, another ␣ involving the angle, right eye. ment of Ophthalmology and Visual TNF- inhibitor that also inhibits the Sciences, 200 Hawkins Dr, Iowa City, cytokine lymphotoxin, found no 7 though we have no histopathologic IA 52242-1091 (e-mail: thomas- benefit in patients with MS. Fur- findings from her iris lesion, its clini- [email protected]). thermore, patients treated with len- cal appearance seems consistent with ercept had a significant increase in past reports of histologically proven 1. Ferry AP. Hemangiomas of the iris and ciliary the rate of relapses and a trend to- 3 body: do they exist? a search for a histologi- iris cavernous hemanigomas. Her cally proved case. Int Ophthalmol Clin. 1972;12: ward more severe relapses. CNS lesions have the MRI charac- 177-194. One report of an exacerbation teristic of benign cavernous heman- 2. Prost M. Cavernous hemangioma of the iris. Oph- of preexisting demyelinating dis- 5,6 thalmologica. 1987;195:183-187. giomas : no mass effect, hyperin- 3. Lam S. Iris cavernous hemangioma in a patient ease in 2 patients with rapidly pro- tensity on T1 weighting (Figure 1A), with recurrent hyphema. Can J Ophthalmol. 1993; gressive MS has suggested a pos- 28:36-39. and significant T2 shortening cre- 4. Naidoff MA, Kenyon KR, Green RW. Iris he- sible link between infliximab and 8 ating a larger black halo represent- mangioma and abnormal retinal vasculature in demyelination. In these 2 patients, ing hemosiderin deposition most no- a case of diffuse congenital hemangiomatosis. TNF-␣ infusion was associated with Am J Ophthalmol. 1971;72:633-644. table on gradient echo (Figure 1B). 5. Gomori JM, Grossman RI, Goldberg HI, Hack- increased disease activity on mag- In addition, the MRI lesions have not ney DO, Zimmerman RA, Bilaniuk LT. Occult netic resonance imaging (MRI). The changed for the past 7 years. Mul- cerebral vascular malformations: high field MR number of lesions observed with imaging. Radiology. 1986:158:707-713. tiple CNS hemangiomas raise the 6. Osborn AG. Intracranial vascular malforma- contrast-enhanced MRI remitted and possibility of an inherited condi- tions. In: Diagnostic Neurology. St Louis, Mo: then increased again after rechal- tion; however, the patient had no Mosby-Year Book Inc; 1994:284-328. lenge with the TNF-␣ inhibitor. knowledge of this problem in her To our knowledge, there have family. been no reports of optic neuritis as- To our knowledge, the associa- Retrobulbar Optic Neuritis sociated with infliximab. We de- tion between CNS and iris heman- Associated With Infliximab scribe a 55-year-old woman with giomas has not been previously de- rheumatoid arthritis who devel- scribed. Furthermore, this patient Tumor necrosis factor (TNF) ␣ is a oped retrobulbar optic neuritis of the did not have any retinal vascular ab- cytokine derived chiefly from mac- left eye after the infusion of inflix-

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 985

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 A ing treatment, her vision slowly improved to 20/30 OS, and her visual field deficit resolved.

Comment. The patient’s clinical course was consistent with retrobulbar optic neuritis. Although optic ° 30 neuritis associated with central nervous system demyelination is well known to occur after age 50 years, most cases occur between the ages of 20 and 50 years.8 In a study of the incidence of monosymptomatic optic neuritis in Stockholm, Sweden, only 1 (0.7%) of 147 patients was aged 55 B years or older.9 Hence, our patient’s age of 55 years is somewhat atypical for an initial episode of demyelinating optic neuritis. Although the relationship between the onset of visual symptoms 30° and the infusion of infliximab may have been coincidental, this association is similar to that seen in the prior report of the exacerbation of rapidly progressive MS in 2 patients treated with this TNF-␣ inhibitor.10 In both patients, an increase in the number of gadolinium-enhancing lesions on Figure 1. Findings from automated perimetry (Humphrey 24-2 threshold program [Zeiss Humphrey Systems, Dublin, Calif] shows gray scale [right] and pattern deviation [left]) of the right eye (A) are MRI was noted between 3 and 10 normal. The left eye (B) shows a superior altitudinal defect. days after the initial infusion. A second infusion, given 2 weeks after the imab. Although the optic neuritis improvement in the stiffness in her first dose, caused a second, smaller may have been coincidental to the hands within weeks of beginning the spike of lesions on MRI, which de- use of infliximab, we believe that this infliximab. She was also taking con- creased over the ensuing 3 weeks. In case report should heighten aware- jugated estrogens (Premarin; Wyeth addition, the number of lympho- ness of a possible link between loss Pharmaceuticals, St David’s, Pa) and cytes and the IgG index in the cere- of vision from demyelination and folic acid. There was no family his- brospinal fluid, both indicative of MS TNF-␣ inhibition. tory of demyelinating disease. activity, increased after the initial in- Best-corrected visual acuity was fusion. The authors speculated that Report of a Case. A 55-year-old 20/25 OD and 20/50 OS. She iden- the inability of infliximab to pen- woman with a 2-year history of rheu- tified 14 of 14 Ishihara pseudoiso- etrate the blood-brain barrier, as matoid arthritis chiefly affecting the chromatic color plates with the right documented by the failure to detect hands sought treatment with a 5-day eye and 6 of 14 with the left eye, and the cytokine in the cerebrospinal history of decreased vision in the left she had a left relative afferent pu- fluid, may have rendered the TNF-␣ eye accompanied by pain with eye pillary defect. Findings from auto- inhibitor ineffective. movement. She had no paresthesia, mated perimetry were normal in the A randomized, placebo- weakness, or bowel and bladder dys- right eye and showed a superior al- controlled study of 168 patients with function and no history of neuro- titudinal visual field defect in the left MS (excluding patients with rap- logic disease. She had initially been eye (Figure 1). Her optic discs were idly progressive MS) treated with treated with methotrexate (one 12-mg healthy. Gadolinium-enhanced MRI lenercept, another TNF-␣ antago- subcutaneous injection per week) for of the brain and orbits revealed mild nist, found an increase in the fre- 1 year; however, because of persis- enhancement of the orbital portion quency of exacerbations and a trend tent stiffness of the hands, inflix- of the left optic nerve (Figure 2). toward more severe exacerbations imab was added. Initially, she re- There were no other lesions consis- when compared with the placebo.7 ceived 240 mg (3 mg/kg) of infliximab tent with demyelination within the The increased rate of exacerbations every 2 weeks for 3 doses, followed brain. was noted both 24 and 48 weeks af- by an infusion of the same dose ev- She was treated with1gofin- ter the onset of treatment. In addi- ery 8 weeks, for a total of 9 infusions. travenous methylprednisolone per tion, there was a statistically signifi- Her loss of vision and pain with eye day for 3 days, followed by a taper- cant dose-dependent decrease in the movement began 3 days after her last ing dose of oral prednisone over the time to first exacerbation in pa- infusion of infliximab. She reported next 10 days. Three weeks after seek- tients treated with lenercept.

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 986

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 ported in association with tumor necrosis fac- A tor alpha antagonism. Arthritis Rheum. 2001; 44:1977-1983. 2. Kremer JM. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med. 2001;134:695-706. 3. Elliot MJ, Ravinder NM, Feldmann M, et al. Randomised double-blind comparison of chi- meric monoclonal antibody to tumor necrosis factor alpha (cA2) vs placebo in rheumatoid arthritis. Lancet. 1994;344:1105-1110. 4. Remicade (infliximab) [package insert]. Mal- vern, Pa: Centocor Inc; 2001. 5. Killestein J, Kalkers NF, Meilof JF, Barkhof F, van Lier RAW, Polman CH. TNF alpha pro- duction by CD4+ T cells predicts long-term increase in lesion load on MRI in MS. Neurol- ogy. 2001;57:1129-1131. 6. Probert L, Akassoglou K, Pasparakis M, Kont- georgos G, Kollias G. Spontaneous inflammatory demyelinating disease in transgenic mice showing central nervous system-specific expression of tumor necrosis factor alpha. Proc NatlAcadSciUSA. 1995;92:11294-11298. 7. The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/ MRI Analysis Group. TNF neutralization in MS. B Neurology. 1999;53:457-465. 8. Rodriguez M, Siva A, Cross SA, O’Brien PC, Kurland LT. Optic neuritis: a population- based study in Olmsted County, Minnesota. Neurology. 1995;45:244-250. 9. Jin Y-P, de Pedro-Cuesta J, Soderstrom M, Staw- iarz L, Link H. Incidence of optic neuritis in Stockholm, Sweden, 1990-1995, I: age, sex, birth, and ethnic-group related patterns. J Neu- rol Sci. 1998;159:107-114. 10. van Oosten BW, Barkhof F, Truyen L, et al. In- creased MRI activity and immune activation in 2 multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology. 1996;47:1531-1534. 11. Fernandez-Arquero M, Arroyo R, Rubio A, et al. Primary association of a TNF gene polymor- phism with susceptibility to multiple sclerosis. Neurology. 1999;53:1361-1363. 12. Selmaj KW. Tumour necrosis factor and anti- tumour necrosis factor approach to inflammatory demyelinating diseases of the central ner- Figure 2. Axial (A) and coronal (B) T1-weighted magnetic resonance imaging with contrast shows vous system. Ann Rheum Dis. 2000;59(suppl 1): enhancement of the retrobulbar portion of the left optic nerve. i94-i102.

Other explanations have been antagonism and demyelination, es- ␣ proposed attempting to link TNF- pecially in light of the increasing use Central Retinal Vein inhibition and an increased risk of this cytokine inhibitor. Occlusion in Bird-Shot of demyelination. Robinson et al1 Retinochoroidopathy have suggested that TNF-␣ antago- Rod Foroozan, MD nists may directly alter the im- Lawrence M. Buono, MD Visual loss in bird-shot retinocho- mune response, increasing autoim- Robert C. Sergott, MD roidopathy is caused by cystoid mune activity and enhancing Peter J. Savino, MD macular edema, optic neuropathy and demyelination. Other investigators Philadelphia, Pa atrophy, vitreous opacities, epireti- have noted a possible link between nal membranes, and subretinal neo- MS susceptibility and polymor- The authors have no proprietary inter- vascularization. We describe a pa- phism of the promoter region of the tient with this syndrome whose visual ␣ 11 est in any of the products described in TNF- gene sequence, and some loss was caused by a central retinal have suggested a role for an alter- this article. Dr Foroozan has a fellowship vein occlusion. This may occur as a ation in adhesion molecule expres- rare vascular complication of bird- 12 from the Heed Ophthalmic Founda- sion. shot retinochoroidopathy. Although this patient’s retro- tion, Cleveland, Ohio. bulbar optic neuritis may have been Corresponding author and re- Report of a Case. A 62-year-old coincidental to the infusion of inf- prints: Robert C. Sergott, MD, Neuro- woman was evaluated for a 2-day his- liximab, we believe that this case re- Ophthalmology Service, Wills Eye Hos- tory of blurred vision and floaters in port underscores both the clinical pital, 900 Walnut St, Philadelphia, PA both eyes. Her ocular history was awareness of the possible associa- 19107. unremarkable, and her medical tion and the need for further study 1. Robinson WH, Genovese MC, Moreland LW. history was notable for systemic hy- of the possible link between TNF-␣ Demyelinating and neurologic events re- pertension. Blood pressure was well

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 987

Figure 1. Fundus photography (A, right eye; B, left eye) on initial ocular examination showing disc edema and vascular sheathing predominantly in the right eye in association with a depigmented cream-colored area in the nasal area of the fundus.

Figure 2. Fluorescein fundus angiography of the right eye on initial ocular Figure 3. Late-phase fluorescein angiogram (at 690 seconds, right eye), examination. Late-phase fluorescein angiogram showing marked diffuse obtained 2 years and 4 months after onset of the disease, showing leakage of fluorescein and disc edema. numerous retinal hemorrhages, tortuosity of retinal veins, diffuse leakage of fluorescein, and marked disc edema.

controlled during treatment. On ini- 20/20 OU. Peripheral retinal peri- Comment. Diffuse and bilateral reti- tial ocular examination, visual acuity phlebitis and disc edema decreased. nal vasculitis, particularly along the was 20/25 OU. Slitlamp examina- After 4 months, the patient ex- major retinal vessels, and retinal vas- tion findings revealed no evidence of perienced a recurrence of uveitis. Disc cular leakage are frequent in bird- anterior chamber inflammation in ei- edema and periphlebitis were exac- shot retinochoroidopathy. Vascu- ther eye. Intraocular pressure was 14 erbated, and central retinal vein oc- lopathy leads to cystoid macular mm Hg OU. Fundus examination re- clusion developed (Figure 3). Vi- edema and papilloedema.1,2 sults revealed bilateral mild vitre- sual acuity decreased to 20/100 OD. Vascular occlusion is known to itis, retinal periphlebitis, and disc Afferent pupillary defect was pres- occur in the presence of vasculitis edema in association with depig- ent. No etiologic factor, except very (up to 5% of branch vein occlusion mented cream-colored spots lo- mild systemic hypertension, was is owing to vasculitis),3 and vascu- cated predominantly in the nasal area found during the follow-up evalua- lar occlusion has been described in of the fundus (Figure 1). These find- tion. A regimen of 60 mg daily of systemic disease associated with vas- ings in association with the pres- prednisone was administered, with no culitis.4-6 However, cross-referenc- ence of HLA-A29 led to the diagno- amelioration in the right eye. Capil- ing “central retinal vein occlusion” sis of birdshot retinochoroidopathy. lary closure occurred. A panretinal la- and “bird-shot retinochoroidopa- Fluorescein angiography demon- ser photocoagulation was per- thy” on the MEDLINE database strated diffuse retinal vasculitis with formed. Despite this treatment, brings up no items. A 1988 study by disc edema (Figure 2). As no vi- preretinal and prepapillary neovas- Priem and Oosterhuis2 of 102 pa- sual loss occurred, the patient re- cularization occurred 4 years after the tients with bird-shot retinochoroido- ceived no treatment and was put un- onset of the vein occlusion. When last pathy reports such an association: 1 der medical control. Spontaneous seen, 6 years after the first examina- central retinal vein occlusion and 2 remission was noted 2 years after on- tion, visual acuity was reduced in the branch retinal vein occlusions. The set, and visual acuity improved to right eye to hand motions. authors note that this incidence is

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 988

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 higher than that found in a healthy Dumonde DC. A point prevalence study of 150 Five days later, the patient re- patients with idiopathic retinal vasculitis, 1: di- population of the same age. agnostic value of ophthalmological features. Br porteddecreasedvisionintherighteye Two hypotheses may be ad- J Ophthalmol. 1989;73:714-721. and right-sided hearing loss. Visual vanced concerning central retinal vein 5. Ohara K, Okubo A, Sasaki H, Kamata K. Branch acuity was 20/40 OD and 20/50 OS. retinal vein occlusion in a child with ocular sar- occlusionassociatedwithbirdshotreti- coidosis. Am J Ophthalmol. 1995;119:806-807. Dilated fundus examination revealed nochoroidopathy. The obstruction of 6. Snyers B, Lambert M, Hardy JP. Retinal and cho- focal areas of peripheral retinitis in the roidal vaso-occlusive disease in systemic lupus asmallperipheralretinalvenuleiswell erythematosus associated with antiphospho- right eye and stable retinitis in the left documented in vasculitis. Although lipid antibodies. Retina. 1990;10:255-260. eye. Intravitreal ganciclovir sodium lesscommon,largerretinalvesselsmay (2000 µg/0.05 mL) and foscarnet so- also become inflamed and subse- dium (1200 µg/0.05 mL) were admin- quently occluded, as occurred in our isteredintherighteye3timesperweek reported clinical case. Furthermore, Necrotizing Herpetic for a total of 5 injections. Audiogra- in bird-shot retinochoroidopathy, Retinopathy Associated phy demonstrated bilateral hearing pathological features include granu- With Ramsay Hunt loss, and magnetic resonance imaging lomatous inflammation in the retina Syndrome revealed neuritis in bilateral cranial around and under retinal veins and in nerveVIII.Onserialdilatedfundusex- the underlying choroid.1 Ramsay Hunt syndrome is a herpes aminations, the confluent retinitis did Priem and Oosterhuis have de- zoster infection of cranial nerve VII, not break through the laser demarca- veloped another hypothesis: pa- causing facial paralysis, and may also tion in the right eye, and the focal le- tients with bird-shot retinochoroid- involve cranial nerves VIII, IX, V, X, sions did not become confluent in the opathy have a high incidence of and VI, in order of decreasing fre- left eye. After 2 weeks of intravenous cardiovascular disease (systemic hy- quency.1 Necrotizing herpetic reti- and intravitreal therapy, the retinitis pertension, coronary artery dis- nopathy refers to the spectrum of washealedinbotheyesandvisualacu- ease, strokes). Central retinal vein disease encompassing acute retinal ity stabilized at 20/50 OD and 20/100 occlusion would then be one of the necrosis and progressive outer reti- OS. Two months later, after discon- manifestations of cardiovascular nal necrosis, and consists of periph- tinuing systemic medication against risk.2 The risk for this patient of de- eral necrotizing retinitis, vitritis, and medical advice, the patient developed veloping vein occlusion was in- retinal arteritis caused by a herpes recurrent necrotizing herpetic reti- creased by the association of disc virus.2 To our knowledge, we de- nopathy with retinal detachments in edema and absence of an optic cup, scribe the first case of bilateral nec- both eyes. After intravenous and in- which is known to be a risk factor rotizing herpetic retinopathy in an travitreal antiviral therapy and retinal for nonarteritic optic neuropathy. immunosuppressed patient with detachmentrepairwithvitrectomyand In conclusion, we believe that Ramsay Hunt syndrome. silicone oil tamponade in both eyes, as observed in our clinical case, cen- visual acuity was 20/70 OD and 20/40 tral retinal vein occlusion may oc- Report of a Case. A 38-year-old OS. Nine months after initial exami- cur as a rare vascular complication woman with acquired immunode- nation, visual acuity was stable at 20/ of bird-shot retinochoroidopathy. ficiency syndrome (CD4 cell count 300 OD and 20/80 OS, with bilateral 2 months prior was 214/µL) had ve- posterior subcapsular cataracts. Franck Fajnkuchen, MD sicular lesions in the distribution of Ce´line Giraud, MD left cranial nerve V3, left-sided hear- Comment. In 1907, Ramsay Hunt de- Damien Gatinel, MD ing loss, left facial weakness, and described facial nerve palsy associated Gilles Chaine, MD creased vision in the left eye. Vi- with ipsilateral hearing loss and ve- Bobigny, France sual acuity with pinhole was 20/25 sicular lesions on the pinna or in the OD and 20/30 OS. Slitlamp exami- auditory canal.1 Facial weakness with None of the authors has any finan- nation revealed anterior vitreous associated vesicles establishes the di- cial interest in the subject matter dis- cells in the left eye. Results of diagnosis of Ramsay Hunt syndrome.3 cussed in this article. lated fundus examination of the right The benefit of systemic steroids is Corresponding author and re- eye were unremarkable and in the equivocal; intravenous acyclovir so- prints: Gilles Chaine, MD, Service left eye revealed focal and conflu- dium is indicated in patients with im- d’Ophtalmologie, Hoˆpital Avicenne, ent retinitis inferiorly and tempo- munosuppression or encephalitis.3 125 route de Stalingrad, 93009 Bo- rally. Necrotizing herpetic retinopa- Most patients regain function of cra- bigny, CEDEX, France (e-mail: thy in the left eye was diagnosed, the nial nerves VII and VIII.3 To our [email protected]). retinitis was demarcated with laser knowledge, 1 case of necrotizing her- treatment, and intravenous ganci- petic retinopathy associated with 1. Le Hoang P, Ryan S. Birdshot retinochoroid- clovir and foscarnet were initiated. Ramsay Hunt syndrome has been re- opathy. In: Pepose JS, Holland GN, Wilhelmus 4 KR, eds. Ocular Infection and Immunity. St Louis, Intravitreal ganciclovir sodium ported. In contrast to our case, the Mo: Mosby–Year Book Inc; 1996:570-578. (2000 µg/0.05 mL) and foscarnet so- previously described patient was im- 2. Priem HA, Oosterhuis JA. Birdshot chorioreti- nopathy: clinical characteristics and evolution. dium (1200 µg/0.05 mL) were ad- munocompetent and developed uni- Br J Ophthalmol. 1988;72:646-659. ministered in the left eye 3 times per lateral necrotizing herpetic retinopa 3. Lang GE, Spraul CW. Risk factors for retinal oc- week for a total of 7 injections. Au- thy. Systemic ganciclovir and foscar- clusive diseases. Klin Monatsbl Augenheilkd. 1997; 211:217-226. diography demonstrated left-sided net were administered to our patient 4. Graham EM, Stanford MR, Sanders MD, Kasp E, neuronal hearing loss. because it has been reported that,

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 989

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 among patients with acquired immu- splenic enlargement at the time of 30%. There was no lymphadenopa- nodeficiency syndrome who de- diagnosis, consistent with stage 0 thy or splenomegaly. These findings velop necrotizing herpetic retinopa- CLL. He did not require treatment. suggested that the orbital recur- thy, combination therapy with At initial examination, his vi- rence of the CLL was not associated intravenous ganciclovir and foscar- sual acuity was 20/30 OU. The ex- with systemic recurrence. He re- net is associated with better visual out- amination findings were notable for mained unchanged at last follow-up comes than treatment with intrave- normal pupils, severely limited duc- 14 months after initial examination nous acyclovir or intravenous tions in all directions in both eyes, and had no evidence of recurrence, foscarnet alone.5 Ophthalmologists and bilateral ptosis (Figure 1). Le- either within the orbit or systemi- should monitor the fundus for reti- vator function was 2 mm OU. Pal- cally. nitis in any patient with Ramsay Hunt pation revealed marked resistance to syndrome and decreased vision. retropulsion in both eyes. Comment. Chronic lymphocytic leu- Computed tomography dem- kemia is the most common type of Alan M. Verm, MD onstrated enlargement of all extra- leukemia in the United States. It is Ingrid U. Scott, MD, MPH ocular muscles in both eyes, with usually B cell in origin and is char- Janet L. Davis, MD mild enlargement of the lacrimal acterized by the proliferation of lym- Miami, Fla glands and soft tissues of both up- phocytes that accumulate within the per and lower eyelids (Figure 2). blood, bone marrow, lymph nodes, This research was supported in part The patient underwent ante- and extranodal tissues. Patients are by Research to Prevent Blindness Inc, rior orbitotomy with biopsy speci- typically older than 50 years, and the New York, NY. mens obtained from the anterior or- disease is more common in men. Corresponding author: Janet L. bital fat. Histologic examination Leukemia, in general, has been Davis, MD, Bascom Palmer Eye In- revealed a dense infiltrate of small reported in tissues throughout the stitute, 900 NW 17th St, Miami, FL lymphocytes that stained positive for eye, as well as in the orbit and ad- 33136 (e-mail: [email protected] IgD kappa, CD5, CD19, CD20, and nexal structures. Clinically, these .miami.edu). CD23, consistent with B-cell CLL. structures are more involved in acute These marker studies were identi- leukemias, with retinal findings most 1. Aviel A, Marshak G. Ramsay Hunt syndrome: a cranial polyneuropathy. Am J Otolaryngol. 1982; cal to the pattern observed at the frequently observed. Acute leuke- 3:61-66. time of initial diagnosis of CLL. mia is well known for its ability to 2. Guex-Crosier Y, Rochat C, Herbort CP. Necro- He was treated with local ra- manifest within the orbit as a granu- tizing herpetic retinopathies: a spectrum of herpes-virus induced diseases determined by the im- diation to both orbits consisting of locytic sarcoma, or chloroma, usu- mune state of the host. Ocul Immunol Inflamm. 200 rad (200 cGy) per fraction over ally in children. 1997;5:259-265. 10 fractions. This resulted in com- Autopsystudieshaveshownocu- 3. Birinyi F. Facial weakness and rash. Acad Emerg Med. 1996;3:1153-1155. plete resolution of his ptosis and res- lar and periocular involvement of 4. Yeo JH, Pepose JS, Stewart JA, Sternberg P, Liss toration of normal motility in both chronicleukemiain75%ofpatients.1,2 RA. Acute retinal necrosis syndrome following herpes zoster dermatitis. Ophthalmology. 1986; eyes at 1 month after initiating treat- Clinically, CLL may be observed in 3 93:1418-1422. ment (Figure 3). A computed to- structures throughout the eye. Sev- 5. Moorthy RS, Weinberg DV, Teich SA, et al. Man- mography scan obtained 3 months eral manifestations of CLL have been agement of varicella zoster virus retinitis in AIDS. Br J Ophthalmol. 1997;81:189-194. after beginning radiation treatment reported in and around the orbit, demonstrated reduction in the size including infiltration of the lacrimal of the extraocular muscles. sac resulting in epiphora and dacryo- When the diagnosis of orbital cystitis,4-6 lacrimal gland swelling,7 Chronic Lymphocytic CLL was made, he was referred to his sicca syndrome (without lacrimal Leukemia of the Orbit hematologist/oncologist for sys- gland enlargement),8 optic nerve in- temic evaluation. Blood work re- filtration,9 proptosis,10,11 ophthal- Report of a Case. A 78-year-old man sults revealed a white blood cell count moplegia,10,11 ptosis,11 andorbitalapex was referred to our clinic for evalu- of 8.3ϫ103/µL and hematocrit of syndrome.11 ation of bilateral ptosis that developed over the previous 2 months. His ocular history was remarkable for cataract extraction and intraocular lens implantation in both eyes 1 year prior to initial examination. His medical history was significant for chronic lymphocytic leukemia (CLL) diagnosed 7 years earlier during a laboratory workup for anemia (hematocrit, 22.1%) and lympho- cytosis (white blood cell count, 150ϫ103/µL), which was detected on results of routine blood work. There was no lymphadenopathy or Figure 1. External appearance at initial examination demonstrating profound ptosis OU.

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 990

Figure 2. Computed tomography scans in the coronal (A) and axial (B) planes demonstrating enlargement of the extraocular muscles in both eyes.

Oculoplastics, Orbit, and Cosmetic Surgery, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114. (e-mail: eye_plastics@meei .harvard.edu).

1. Allen RA, Straatsma BR. Ocular involvement in leukemia and allied disorders. Arch Ophthal- mol. 1961;66:490-508. 2. Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv Ophthalmol. 1983; 27:211-232. 3. Newman NM, Smith ME, Gay AJ. An unusual case of leukemia involving the eye: a clinico- pathological study. Surv Ophthalmol. 1972;16: 316-321. Figure 3. External appearance 1 month after completing radiation treatment, demonstrating improved 4. Stokes WH. Dacryocystitis in lymphatic leu- upper eyelid position in both eyes. kemia. Arch Ophthalmol. 1938;20:85-87. 5. Benger RS, Frueh BR. Lacrimal drainage ob- The patient in this report differs dence of systemic disease activity at struction from lacrimal sac infiltration by lymphocytic neoplasia. Am J Ophthalmol. 1986; from previous reports of CLL involv- the time of diagnosis and, in fact, his 101:242-245. ing the orbit in several ways. First, pre- blood cell counts at the time of diag- 6. Munro S, Brownstein S, Jordan DR, McLeish W. viously reported manifestations of or- nosis of his orbital CLL were at their Nasolacrimal obstruction in two patients with chronic lymphocytic leukemia. Can J Ophthal- bital CLL infiltration include a diffuse best since his initial CLL diagnosis. mol. 1994;29:137-140. orbital mass10 and unilateral extraocu- To our knowledge, there have been 7. McNally L, Jakobiec FA, Knowles DM. Clini- 11 cal, morphologic, immunophenotypic and mo- lar muscle enlargement. Radio- no reports of periocular or orbital lecular genetic analysis of bilateral ocular ad- graphically, our patient had findings manifestation of CLL in the setting of nexal lymphoid neoplasms in 17 patients. Am suggestive of thyroid-associated orbi- systemic remission. While second- J Ophthalmol. 1987;103:555-568. 8. Gumpel JM. Chronic lymphatic leukaemia pre- topathy, namely, enlargement of the ary lymphopoietic tumors have been senting as Sjogren’s syndrome. Proc R Soc Med. extraocularmusclesbilaterally.Weare reported in association with CLL 1972;65:877-878. unaware of this manifestation of CLL (Richter syndrome),12-14 the identi- 9. Currie JN, Lessell S, Lessell IM, Weiss JS, Al- bert DM, Benson EM. Optic neuropathy in having been reported previously. cal tumor markers in specimens from chronic lymphocytic leukemia. Arch Ophthal- Clinically,hisneartotalophthalmople- the orbit and from initial diagnosis mol. 1988;106:654-660. 10. Skinnider LF, Romanchuk KG. Orbital involve- gia and ptosis suggested a disease en- suggest that the orbital manifesta- ment in chronic lymphocytic leukemia. Can tity other than thyroid-associated or- tion was part of the same disease pro- J Ophthalmol. 1984;19:142-144. bitopathy. However, the radiographic cess. This observation suggests that 11. Rubin PAD, Harris N. Case records of the Mas- sachusetts General Hospital: case 4-1993. New findings shown here suggest that CLL the possibility of local orbital recur- Engl J Med. 1993;328:266-275. should be included in the differential rence should be considered despite a 12. Richter MN. Generalized reticular cell sarcoma diagnosis of bilateral extraocular seemingly indolent disease course. of lymph modes associated with lymphatic leukemia. Am J Pathol. 1928;4:285-299. muscle enlargement. 13. Trump DL, Mann RB, Phelps R, Roberts H, Con- Second, CLL seen within the or- Mark P. Hatton, MD ley CL. Richter’s syndrome: diffuse histiocytic lymphoma in patients with chronic bit has been described as the initial Peter A. D. Rubin, MD lymphocytic leukemia. Am J Med. 1980;68:539- manifestation of the disease or occur- Boston, Mass 548. ring in patients with active and, in 14. Hattenauer MG, Pach JM. Ocular lymphoma in a patient with chronic lymphocytic leuke- some cases, worsening systemic dis- Corresponding author and reprints: mia. Am J Ophthalmol. 1996;122:266- ease.4-6,9,10 Our patient had no evi- Peter A. D. Rubin, MD, Department of 268.

(REPRINTED) ARCH OPHTHALMOL / VOL 120, JULY 2002 WWW.ARCHOPHTHALMOL.COM 991

©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 necrosis is a retinal infection. In the mouse system, 2. Miller AE. Selective decline in cellular immune response to varicella-zoster in the BALB/c mice that receive an anterior chamber injection elderly. Neurology. 1980;30:582-587. 3. Liesegang TJ. Biology molecular aspects of herpes simplex and varicella-zoster of an antigen acquire an unusual systematic immune virus infections. Ophthalmology. 1992;99:781-799. response, termed “anterior chamber–associated immune 4. Thygeson P, Hogan S, Kimura S. The uvea: observation on uveitis associated deviation” (ACAID).19,20 In this system, impaired anti- with viral disease. Trans Am Ophthalmol Soc. 1957;55:333-352. gen-specific DH coexists with high serum titers of an- 5. Kaufman HE, Kanai A, Ellison ED. Herpetic iritis: demonstration of virus in the anterior chamber by fluorescent antibody techniques and electron microscopy. tigen-specific antibodies. The results presented in this Am J Ophthalmol. 1971;71:465-469. article serve to support our hypothesis that anterior 6. Saiki RK, Scharf S, Faloona F, et al. Enzymatic amplification of b-globin se- chamber–associated immune deviation may be the quences and restriction site analysis for diagnosis of sickle cell anemia. Sci- immunologic mechanism that is triggered in the eyes of ence. 1985;230:1350-1354. some patients undergoing idiopathic reactivation of VZV 7. Usui M, Usui N, Goto H, Minoda H, Rai T. Polymerase chain reaction for diagnosis of herpetic intraocular inflammation. Ocul Immunol Inflamm. 1993;1:105- in the trigeminal ganglion. For reasons yet to be 112. revealed, zosteriform spread of antigenic VZV particles 8. Kamiya H, Ihara T, Hattori A, et al. Diagnostic skin reaction with varicella antigen to the anterior chamber leads to suppression of virus- and its clinical application at occurrence of varicella patients in an institution for specific T cells that mediate DH, and by so doing, rob handicapped children. J Infect Dis. 1977;136:784-788. + 9. Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis, I: anterior the eye of the protection afforded by these CD4 T cells. uveitis. Am J Ophthalmol. 1959;47:155-170. Acute viral infection of sensitive intraocular tissues rang- 10. Wormack LW, Liesegang TJ. Complications of herpes zoster ophthalmicus. Arch ing from iris to retina is the inevitable consequence. If Ophthalmol. 1983;101:42-45. we could understand how to abort anterior chamber– 11. Doggart JH. Herpes zoster ophthalmicus. Br J Ophthalmol. 1933;17:513-524. associated immune deviation in this situation, intraocu- 12. Ross JVM. Herpes zoster ophthalmicus sine eruption. Arch Ophthalmol. 1949; 42:808-812. lar complications of ophthalmic herpes zoster might be 13. Lewis GW. Zoster sine herpete. Br Med J. 1958;2:418-421. eliminated from clinical ophthalmology. 14. Sakai J, Usui N, Usui M, et al. Detection of varicella-zoster virus DNA by the polymerase chain reaction in 4 uveitis patients. J Eye (Atarashii Ganka). 1992;9:447- Submitted for publication October 2, 2001; final revision re- 452. 15. Stavrou P, Mitchell SM, Fox JD, et al. Detection of varicella-zoster virus DNA in ceived April 24, 2002; accepted May 16, 2002. ocular samples from patients with uveitis but no cutaneous eruption. Eye. 1994; Corresponding author: Takeshi Kezuka, MD, PhD, De- 8:684-687. partment of Ophthalmology, Hachioji Medical Center, Tokyo 16. Yamamoto S, Tada R, Shimomura Y, et al. Detecting varicella-zoster virus DNA Medical University, 1163, Tate-machi, Hachioji-city, Tokyo, in iridocyclitis using polymerase chain reaction: a case of zoster sine herpete. 193-8639, Japan (e-mail: [email protected]). Arch Ophthalmol. 1995;113:1358-1359. 17. Kashiwase M, Sakai J, Usui M. Uveitis associated with zoster sine herpete. Diagnosis and clinical findings. J Jpn Ophthalmol Soc. 2000;104:97-102. REFERENCE 18. Tanaka Y, Harino S, Danjo S, et al. Skin test with varicella-zoster virus antigen for ophthalmic herpes zoster. Am J Ophthalmol. 1984;98:7-10. 19. Streilein JW. Ocular immune privilege and the Faustian dilemma: the proctor lec- 1. Kezuka T, Sakai J, Usui N, et al. Evidence for antigen-specific immune deviation ture. Invest Ophthalmol Vis Sci. 1996;37:1940-1950. in patients with acute retinal necrosis. Arch Ophthalmol. 2001;119:1044-1049. 20. Streilein JW. Regulation of ocular immune responses. Eye. 1997;11:171-175.

Correction

Error in Text. In the Clinicopathologic Report titled “Retrobulbar Optic Neuritis Associated With Inflix- imab,” published in the July issue of the ARCHIVES (2002;120:985-987), an error occurred on page 985. In the right-hand column, the fourth paragraph beginning “One report of an exacerbation of preexisting demyelinating disease...” should be omitted.

(REPRINTED) ARCH OPHTHALMOL / VOL 120, SEP 2002 WWW.ARCHOPHTHALMOL.COM 1188