Bietti Crystalline Retinopathy and Juvenile Retinoschisis in a Family

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

Baltimore, Md, seeking a second OU. Preoperatively, her central cor- Corneal Ectasia After opinion after LASIK was done else- neal pachymetry readings were 511 Laser-Assisted In Situ where. Her chief complaint was µm OD and 482 µm OS, as ob- Keratomileusis that her vision had worsened since tained by a scanning slit measure- surgery and she could not function ment system (Orbscan Topogra- Laser-assisted in situ keratomileu- anymore with any form of visual phy; Bausch & Lomb, Inc, Rochester, sis (LASIK) has become the most aids. NY). She underwent full-correction common surgical option to correct Her ocular history was signifi- LASIK in both eyes. One month myopia. Certain preexisting condi- cant for keratoconus suspected by postoperatively, the patient’s best- tions are contraindications for 2 ophthalmologists but not by the corrected visual acuity was 20/40 OD last physician who recommended with −3.25+0.50ϫ125 and 20/50 OS LASIK, and they include unstable vi- ϫ sion, keratoconus, thin corneas, and performed bilateral simulta- with −2.25+0.75 85. pregnancy, and autoimmune dis- neous LASIK. Before LASIK, she When we first examined the pa- eases. A careful evaluation can help wore rigid gas-permeable contact tient, 5 months after the surgery, her select the good candidates and pre- lenses until she became intolerant best-corrected visual acuity was to those. 20/200 OD with −10.50+0.50ϫ90 dict which patients will have a ϫ guarded outcome. We describe the During the preoperative evalu- and 20/100 OS with −9.75+0.75 90. clinical and histologic features of a ation, an autorefractor revealed Her central corneal pachymetry read- patient who underwent penetrat- keratometry readings of 47.75 and ing was 365 µm OU by ultrasono- ing keratoplasty due to progres- 51.75 OD and 49.37 and 55.00 OS. graphic pachymetry. Corneal topog- sively worsening vision from cor- Her manifest refraction revealed a raphy revealed central steepening neal ectasia after LASIK. visual acuity of 20/25 OD with in both eyes (Humphrey Visual −11.25+3.75ϫ085 and 20/70 OS Instruments, San Leandro, Calif) Report of a Case. A 32-year-old with −13.00+3.75ϫ080. Her best- (Figure 1). Her keratometry read- woman came to the Refractive Sur- corrected visual acuity with rigid gas- ings, as indicated by the corneal gery Center, Wilmer Eye Institute, permeable contact lenses was 20/20 maps, reached 55 and 61 OD and 54

90 105 75

70.5 120 60 Power: 51.9 D 68.0 Radius: 6.50 mm 135 45

65.5 From Vertex 150 30 Distance: 0.00 mm 63.0 S-merid: 0° 165 15 60.5 From Pupil Distance: 0.17 mm 58.0 S-merid: 270° 180 0 55.5

53.0 Simulated Keratometer 195 345 50.5 61.50 D (5.49 mm) @98 56.37 D (5.99 mm) @8 48.0 210 330

Astigmatism: 5.13 D 45.5 225 315

43.0 CIM: 1.77 240 300 Shape Factor: 0.14 255 285 Diopters (D) 270

Figure 1. Corneal topography of the right eye after laser-assisted in situ keratomileusis, showing central steepening. S-merid indicates the distance from the vertex (large crosshair) and its location on the semimeridian; CIM, corneal irregularity measure.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Figure 2. Slitlamp appearance of the cornea, showing stromal thinning and Figure 3. Section of the corneal button showing the edge of the lamellar cut bulging after laser-assisted in situ keratomileusis, seen best just above the (lower right corner) and a paracentral thin area (periodic acid–Schiff, original lower pupillary margin. magnification ϫ3).

Figure 4. Discontinuity of the Bowman layer and a slanted area of mild Figure 5. Central area with a faint delineation (arrow) between the flap and scarring (arrow) at one margin of the corneal flap (periodic acid–Schiff, the remainder of the stroma (periodic acid–Schiff, original magnification original magnification ϫ100). ϫ160).

and 58 OS. No posterior corneal cur- tempted, but the patient did not be- The flap area has a slight increase in vature measurements were ob- lieve she could tolerate the lenses. cellularity compared with the retained. On slitlamp examination, she A diagnosis of corneal ectasia was mainder of the stroma. Centrally, the had well-centered LASIK flaps with made based on the progressive wors- cornea, including all layers, mea- nasal hinges in both eyes. The cor- ening of the cornea together with sured 317 µm in thickness, and the neal epithelium was dry centrally central thinning as measured by flap measured 81.5 µm. and stained with fluorescein. The pachymetry, and penetrating kera- Transmission electron micros- stroma appeared thin and bulging toplasty was recommended be- copy showed the discontinuity of the forward (Figure 2). The lamellar cause the cornea was too thin and Bowman layer (Figure 6) and a zone interface appeared clear in both eyes. dry to tolerate any other interven- of irregular collagen with a slight in- The rest of the anterior segment, in- tion. The patient underwent an un- creased number of fibrocytes in the cluding the anterior chambers, iri- complicated corneal transplanta- plane between the flap and the re- des, and lenses, appeared normal. In- tion (8.0-mm donor size to 7.5-mm mainder of the stroma (Figure 7). traocular pressures were 11 mm Hg recipient size), and corneal tissue There was no endothelial damage. OU by applanation tonometry. The was sent for histologic studies results of her dilated retinal exami- (Figure 3). Comment. This case represents an nation were unremarkable. Despite The light microscopy reveals example of corneal ectasia after punctal plugs and the hourly use of one margin of the corneal flap LASIK, for which the underlying risk preservative-free tears with lubri- with a discontinuity of the Bow- factors for ectasia appear to be a cating ointment at night, her visual man layer and a slanted area of mild combination of keratoconus, thin acuity continued to deteriorate. Cor- scarring (Figure 4). Looking at a preoperative central corneas, and neal topography revealed that the central area, there is a faint delinea- possibly a lamellar keratectomy. surface of the right eye was more ir- tion between the flap and the re- Several cases of corneal ectasia regular. A contact lens fit was at- mainder of the stroma (Figure 5). after LASIK have been reported,1-5

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Figure 6. One margin of the corneal flap, with discontinuity of the Bowman Figure 7. Central cornea with an area of irregularity of the collagen and an layer (arrow) and an area of scarring (asterisk) (original magnification increased number of fibrocytes (between arrows) in a plane between the ϫ2200). corneal flap and the remainder of the stroma (original magnification ϫ8800).

but only one report1 included patho- surgery, including lamellar or pen- logic findings. The histologic fea- etrating keratoplasty, should always Presumed Choroidal tures of our case echo previous light be included as part of the informed and Orbital Mastocytosis microscopic features. However, to consent. our knowledge, transmission elec- The pathologic features of cor- tron microscopic features have not neal ectasia include an interrup- Mastocytosis is a condition charac- been previously described. Even tion of the Bowman membrane with terized by the presence of excessive though the histopathologic changes mild anterior cellularity, a thinner numbers of tissue mast cells in dis- are consistent with the clinical find- stromal thickness, and no endothe- tinctive distributions, which pro- ings, it is still the physical proper- lial damage. duce symptoms related to mast cell ties, strength, and stability of the mediator release and the disruption thin cornea after LASIK that need to Nada S. Jabbur, MD of normal tissue function. To the best be studied to understand why some Walter J. Stark, MD of our knowledge, mastocytosis with patients have a guarded outcome. W. Richard Green, MD ocular and orbital involvement has Seitz et al6 studied the posterior cor- Baltimore, Md not been previously documented. We neal curvature changes after LASIK, describe a 42-year-old white man with and concluded that increased nega- biopsy-proven mastocytosis and mul- tive keratometric diopters and ob- Corresponding author: Walter J. tiple disseminated lesions who devel- late asphericity of the posterior cor- Stark, MD, The Wilmer Eye Institute oped a reduction in visual acuity to neal curvature pointed toward early at Greenspring Station, 10755 Falls counting fingers OS, an elevated cho- keratectasia after LASIK. Until a Rd, Suite 110, Baltimore, MD 21093. roidal mass in the macula, and bilat- better understanding of the biome- eral orbital tumors. chanical properties of the corneal 1. Geggel HS, Talley AR. Delayed onset keratectasia following laser in situ keratomileusis. J Cata- deformation is reached, certain gen- ract Refract Surg. 1999;25:582-586. Report of a Case. A 42-year-old non- eral guidelines should be followed. 2. McLeod SD, Kisla TA, Caro NC, et al. Iatro- Hispanic white man was diagnosed as These include performing central genic keratoconus: corneal ectasia following la- having mastocytosis in 1996 after a ser in situ keratomileusis for myopia. Arch Oph- corneal pachymetry and corneal thalmol. 2000;118:282-284. bone marrow biopsy. He had a 1-year topographic imaging in the pre- 3. Seiler T, Koufala K, Richter G. Iatrogenic kera- history of recurrent episodes of flush- operative evaluation of every poten- tectasia after laser in situ keratomileusis. J Re- ing, chest tightness, headache, and fract Surg. 1998;14:312-317. tial refractive surgery patient and 4. Seiler T, Quurke AW. Iatrogenic keratectasia af- fever and on examination was noted avoiding LASIK in patients whose ter LASIK in a case of forme fruste keratoconus. to have lymphadenopathy and hepa- J Cataract Refract Surg. 1998;24:1007-1009. final corneal stromal bed thickness 5. Koch D. The riddle of iatrogenic keratectasia. tosplenomegaly. No dermatologic is less than 250 µm or who appear J Cataract Refract Surg. 1999;25:453-454. lesions were present. to have keratoconus. Finally, cor- 6. Seitz B, Torres F, Langenbucher A, et al. Poste- He subsequently developed an rior corneal curvature changes after myopic la- neal deformation and ectasia with ser in situ keratomileusis. Ophthalmology. 2001; extramedullary mass lesion in tho- a possible need for more corneal 108:666-673. racic vertebrae 2 through 8, which

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 was compressing the spinal cord and was treated with excision and radiation therapy. A pathologic examination confirmed the lesion to con- sist of confluent mast cells. Six months later the patient developed urinary retention, and magnetic resonance imaging demonstrated a new mass lesion at sacral vertebrae 1 and 2. The second lesion was non- resectable and responded mini- mally to radiation therapy. In May 1999, the patient went to an outside ophthalmologist com- plaining of a 4-week history of vision loss in the left eye. According to the patient’s medical records, the examination results were remarkable for visual acuities of 20/20 OD, 20/40 OS, and a small serous retinal detachment involving the macula of the left eye. His visual acuity de- Figure 1. Ophthalmoscopic appearance of the left eye showing an elevated macular lesion with creased further from 20/60 OS in Au- pigmentary changes. gust 1999 to 20/400 OS in January 2000, and the serous detachment had enlarged with extension be- yond the vascular arcades. The patient first came to the National Eye Institute (Bethesda, Md) in April 2000. At that time, his visual acuities were 20/16 OD and counting fingers OS, with intraocular pressure readings of 15 mm Hg OD and 13 mm Hg OS. There was no proptosis according to Hertel ex- ophthalmometry. Extraocular movements were normal, and slitlamp examination results were normal in both eyes. A dilated retinal examination showed an approximately 200-µm pigment defect superior to the right fovea, an elevated macular lesion with pigmentary changes, and an inferior exudative retinal detachment in the left eye (Figure 1). The visual field was normal in the Figure 2. An ultrasonographic B-scan of the left eye (longitudinal scan through the macular area) right eye but showed a dense cen- showing an elevated subretinal mass (arrowhead). tral scotoma in the left (Humphrey Visual Field Analyzer; Zeiss Hum- the mass had a homogeneous inter- throughout (Figure 3). A computed phrey Systems, Dublin, Calif). An nal structure and was not calcified. tomographic scan of the chest, abdo- ultrasonographic B-scan showed An orbital T1-weighted postcon- men, and pelvis revealed multiple an elevated subretinal mass in the trastmagneticresonanceimagingscan pleural-based densities, a 1-cm low- macular area (Figure 2) and a shal- withfatsaturationshowedathickened, density lesion in the right lobe of the low serous retinal detachment infe- enhanced posterior pole in the left eye liver, splenomegaly, and retroperito- rior to this lesion. The mass was well corresponding to the sonographic le- neal adenopathy. A skeletal survey us- outlined, was located in the cho- sion.Anextraconalmasswascentered ing plain film showed diffuse mottling roid or subretinal space, and had a on the greater wing of the sphenoid of bony structures including the ribs, diameter of 9.6 mm and an eleva- bone and projected into the orbit, me- pelvis, and spine. Results of an upper tion of 3.5 mm. A standardized ul- dially displacing the lateral rectus. It gastrointestinal endoscopy and colo- trasonographic A-scan indicated that also projected into the middle cranial noscopy were negative. the lesion had moderately low acous- fossa as an epidural mass. The mar- Laboratory studies were no- tic reflectivity, which suggested that rowofthesphenoidbonewasreplaced table for mild pancytopenia, but no

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Findings from immunohistochemi- A cal staining for other hematologic neoplasms were negative. Results of a sternal marrow aspirate were abnormal, with 16% intact mast cells. Immunohistochemical staining of the resected paraspinal lesions was similarly consistent with mast cell tumor. Plasma tryptase concentra- tions greater than 20 ng/mL are associated with mastocytosis; the level in this patient was 293 ng/mL, sug- gesting an extremely high mast cell burden. The erythrocyte sedimen- tation rate was 35 mm/h. Results of

B serologies for human immunodefi- ciency virus, syphilis, and cytomega- lovirus were negative. The patient was treated with histamine1 (H1) and histamine2 (H2) blockers, aspirin, and oral cortico- steroids. He underwent a series of radiation treatments that resulted in resolution of the choroidal lesion and marked reduction in the bulk of the orbital lesions.

Comment. We describe a patient with a choroidal lesion, neurosensory reti- Figure 3. A, Axial T1-weighted postcontrast magnetic resonance imaging scan with fat saturation shows a thickened macula in the left eye (arrowhead). Expansive masses are present bilaterally in the sphenoid nal detachment, and orbital masses wings (arrows), both of which project into the middle cranial fossa as epidural masses. The mass on the emanating from the sphenoid bone. left projects into the orbit, displacing the lateral rectus medially. B, Coronal T1-weighted postcontrast The differential diagnoses for the cho- magnetic resonance imaging scan with fat saturation shows complete replacement of the sphenoid bone, roidal lesion would include a meta- with extension into the middle cranial fossa (arrows). static lesion, choroidal osteoma, amelanotic melanoma, heman- gioma, neurilemoma, leiomyoma, lymphoma, and retinal pigment epithelium hypertrophy or hyperplasia. The history of systemic mastocytosis with biopsy-proven mastocytomas from multiple sites and disseminated lesions involving bone and the reticuloendothelial system provided strong evidence that the intraocular and orbital masses were mastocytomas. Although fine-needle aspiration of the choroidal lesion or open biopsy of the orbital lesions might have been of additional value in con- firming the diagnosis,1 the patient instead opted for radiation therapy in light of the well-defined disseminated process and the increased risk of complications associated with submacular biopsy. A thorough sys- Figure 4. Trephine bone marrow biopsy specimen demonstrating diffuse involvement of the marrow space with mast cells (original magnification ϫ100, hematoxylin-eosin). Inset shows high-power view temic evaluation, including a com- (original magnification ϫ400). puted tomographic scan and gastrointestinal endoscopy showed no circulating mast cells were seen. A cells (Figure 4). Results of immu- evidence of a concurrent primary car- trephine biopsy at the iliac crest re- nohistochemical staining for the cinoma or lymphoma. vealed diffuse involvement of the mast cell markers tryptase and Mastocytosis is generally an in- marrow with sheets of fusiform mast surface CD117 (kit) were positive. dolent disease2 characterized by the

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 presence of an excessive number of target the kit pathway as well as bone man tissue mast cells, and a review of the literature. Virchows Arch A Pathol Anat Histo- tissue mast cells. The current classi- marrow transplantation. pathol. 1987;412:31-36. fication system divides the disease The ophthalmic literature in- 9. Mochizuki M, Kuwabara T, Chan CC, et al. An into 4 categories: category 1A, indo- cludes only 1 report of a mastocy- association between susceptibility to experimental autoimmune uveitis and choroidal mast cell lent cutaneous mastocytosis, is the toma, in which a 1-cm firm yellow numbers. J Immunol. 1984;133:1699-1701. most common type. Category 1B, in- nodule on the lower right lid that dolent systemic mastocytosis, is de- had been present since birth was ex- fined by mast cell infiltration of at cised from a 4-month-old boy. A his- least 1 organ system other than the topathologic diagnosis revealed this skin. Category 2 refers to mastocy- nodule to be a mastocytoma, and Bietti Crystalline tosis associated with a hematologic there was no reported recurrence Retinopathy and 8 disorder, namely, myelodysplastic within 8 months of follow-up. Juvenile Retinoschisis and myeloproliferative disorders. Ag- Our case suggests that masto- in a Family With cytosis may involve the choroid and gressive mastocytosis, category 3, is a Novel RS1 Mutation associated with lymphadenopathy, orbit. The patient had a particularly hepatosplenomegaly, and marked aggressive form of mastocytosis that Bietti crystalline retinopathy is a rare eosinophilia. Finally, category 4, mast diffusely involved both the bone mar- degenerative disease that features bi- cell leukemia, is marked by atypical row and reticuloendothelial system lateral retinal crystals, progressive at- mast cells in the marrow and periph- and formed solid extramedullary rophy of the retinal pigment epithe- eral blood.3 The course of disease in collections of mast cells. This may lium and choriocapillaris, and severe our patient may be best described as explain the involvement of the cho- visual loss. X-linked retinoschisis aggressive mastocytosis. roid, which normally contains resi- (XLRS) is a more common retinal The pathogenesis of mastocyto- dent mast cells and has characteris- disease characterized by cystic schi- 9 sis is believed to be related to kit, the tics similar to lymphoid tissue. sis at the fovea and variable periph- mast cell receptor for stem cell fac- eral retinoschisis. The gene respon- tor. Dysregulated kit or an excess of Howard F. Fine, MD sible for XLRS has been identified on its ligand could conceivably lead to Cem Akin, MD, PhD the X chromosome and designated abnormal mast cell proliferation and Peiman Hematti, MD RS1.1 We describe a family of Chi- the episodic release of preformed me- John Butman, MD, PhD nese origin in which a man, his diators, accounting for the signs and Rafael C. Caruso, MD daughter, and his grandson have symptoms of mastocytosis.4 Demon- Karl G. Csaky, MD, PhD novel mutations in the RS1 gene. stration that most adult-onset mas- Dean D. Metcalfe, MD Findings from examination of the tocytosis is associated with activat- Robert B. Nussenblatt, MD grandfather are characteristic of Bi- ing c-kit mutations is consistent with Michael R. Robinson, MD etti crystalline retinopathy, the this hypothesis.5,6 However, an ini- Bethesda, Md daughter is phenotypically normal, tial screen of the resected mastocy- and the grandson has classic XLRS. toma tissue in this patient failed to Corresponding author: Michael R. We believe that RS1 is a candidate demonstrate the presence of an acti- Robinson, MD, National Eye Insti- gene for some cases of Bietti crys- vating c-kit mutation. tute, National Institutes of Health, talline retinopathy. Therapy for mastocytosis is fo- Bldg 10/Room 10N112, 10 Center Dr, cused on blocking the effects of mast Bethesda, MD 20892-1863 (e-mail: Report of Cases. A 60-year-old Chi- cell mediators. H1 and H2 antago- [email protected]). nese man with poor vision in both nists and cromolyn sodium are ef- eyes since childhood was evalu- fective. Topical and systemic corti- 1. Shields JA, Shields CL, Ehya H, Eagle RC, De Pot- ated. Visual acuity was counting fin- ter P. Fine-needle aspiration biopsy of sus- costeroids may be efficacious in pected intraocular tumors. Ophthalmology. 1993; gers OD and 20/200 OS. There were selected advanced cases. Aspirin may 100:1677-1684. no corneal or conjunctival crystals. be used to ameliorate the adverse ef- 2. Horan RF, Austen KF. Systemic mastocytosis: ret- Fundus examination showed the rospective review of a decade’s clinical experi- fects of prostaglandin release, al- ence at the Brigham and Women’s Hospital. J In- presence of intraretinal crystals, though extreme caution must be ex- vest Dermatol. 1991;96:5S-13S. mostly concentrated in the poste- 3. Metcalfe DD. Classification and diagnosis of mas- Figure 1 ercised given the risk of precipitating tocytosis: current status. J Invest Dermatol. 1991; rior poles of both eyes ( ). secretory granule release. Triggers 96:2S-4S. There was atrophy of the retinal pig- such as insect bites and alcohol 4. Golkar L, Bernhard JD. Mastocytosis. Lancet. ment epithelium. The retinal ves- 1997;349:1379-1385. should be avoided; portable inject- 5. Nagata H, Worobec AS, Oh CK, et al. Identifica- sels were mildly attenuated and the able epinephrine is a prudent safe- tion of a point mutation in the catalytic domain optic nerves appeared normal. No guard to treat anaphylaxis.7 Cur- of the protooncogene c-kit in peripheral blood retinoschisis was present. Fluores- mononuclear cells of patients who have masto- rently there are no curative therapies cytosis with an associated hematologic disorder. cein angiography revealed patchy for disseminated mastocytosis. Ag- ProcNatlAcadSciUSA.1995;92:10560-10564. atrophy of the retinal pigment epi- 6. Bain BJ. Systemic mastocytosis and other mast gressive mastocytomas may be cell neoplasms. Br J Haematol. 1999;106:9-17. thelium and choriocapillaris. Elec- treated with excision and/or radia- 7. Metcalfe DD. The treatment of mastocytosis: an troretinogram responses were se- tion. Therapies under investigation overview. J Invest Dermatol. 1991;96:55S-56S. verely attenuated but retained some 8. Scheck O, Horny HP, Ruck P, et al. Solitary mas- at the National Institutes of Health tocytoma of the eyelid: a case report with spe- high-intensity white scotopic b- (Bethesda, Md) include agents that cial reference to the immunocytology of hu- wave amplitude and were not elec-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 A heterozygous for the same mutation, which substitutes arginine for cysteine at residue 223 (C223R)in the predicted protein.

Comment. The gene responsible for X-linked retinoschisis was recently identified and designated RS1.1 The gene consists of 6 exons and encodes a 224–amino acid protein. Exons 4 through 6 encode a highly conserved discoid domain believed to partici- pate in cell-to-cell adhesion. The Reti- noschisis Consortium recently reported 82 different RS1 mutations among 91% of 234 cases clinically diagnosed as having retinoschisis.2 An additional 12 novel mutations have recently been described, including that occurring in the grandson in this family.3 The vast majority of muta- B tions occur in exons 4 through 6 and those that eliminate or create a cysteine are common. It is possible that this is a co- incidental polymorphism rather than a disease-causing mutation. However, the evidence supports that this mutation resulted in retinoschisis in our patient. The child has the classic phenotype of XLRS, with no other abnormalities in the XLRS1 gene. The mutation occurs in an exon associated with numer- ous disease-causing mutations, and involves an amino acid substi- tution likely to alter the protein conformational structure in or near the crucial discoid domain. Figure 1. A, Color fundus photograph of the left eye of the proband. Intraretinal crystals are seen in the posterior pole. B, Fluorescein angiogram of the left eye of the proband demonstrates attenuation of the This mutation was not found in pigment epithelium and patchy atrophy of the choriocapillaris. 100 unrelated phenotypically normal patients whose X chromo- somes were sequenced.2 tronegative. The diagnosis of Bietti quadrant, including the macula. The Bietti crystalline retinopathy crystalline retinopathy was made. patient was reexamined at age 5 is a rare hereditary retinal degen- A 22-month-old boy (the son years. Visual acuity was 20/125 OD eration. The defining feature is the of the proband’s daughter) was seen and 1/150 OS. The electroretino- presence of crystals throughout the because of esotropia in the left eye. gram was markedly attenuated, with posterior retina. Vision loss ac- The child was the result of an un- an electronegative B wave in the companies progressive atrophy of complicated pregnancy and a full- high-intensity white scotopic re- the retinal pigment epithelium and term spontaneous vaginal delivery. sponse. Examination revealed par- choriocapillaris. The gene respon- Both parents were Chinese and had tial collapse of the large schisis cav- sible for Bietti crystalline retinopa- normal eye examination results. His ity in the right eye and enlargement thy has not been previously identi- only sibling was a reportedly nor- of inner layer holes in the left eye fied. Although generally believed mal half-brother (paternal). (Figure 2). to be autosomal recessive, the Examination revealed a large The RS1 gene was sequenced predominance of male cases has retinoschisis cavity in the right in- from the child, both parents, and led some authorities to suggest an ferotemporal quadrant, extending to both maternal grandparents. The X-linked inheritance.4,5 An auto- 1 disc diameter from the fovea. The grandfather and grandson were somal dominant pedigree with fovea displayed cystic schisis. In the hemizygous foraTtoCtransition phenotypic resemblance to Bietti left eye a large schisis cavity in- mutation at nucleotide 667 in exon crystalline retinopathy has also volved the entire inferotemporal 6 of the RS1 gene. The daughter was been reported.6 It seems likely that

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Topiramate (Topomax; Ortho- McNeil Pharmaceutical Inc, Raritan, NJ), an oral sulfamate, is used for the treatment of partial-onset seizures. We report the case of a patient with topiramate-induced acute bilateral myopia and angle-closure glaucoma with an echographic description of the pathogenic mechanism.

Report of a Case. A 43-year-old woman had blurred distance vision in both eyes, accompanied by a mild frontal headache. Her symptoms be- Figure 2. Color photograph of the left eye of the grandson (unaltered digital image). Note the prominent gan 1 day after starting topiramate, inferior schisis cavity with large inner-layer holes. progressed for 24 hours, and re- mained stable for the last 4 days be- Bietti crystalline retinopathy is a This study was supported by grant fore visiting the ophthalmologist. phenotypic description reflecting R01-EY10259 from the National In- Prior to the onset of symptoms, she more than one genotype. stitutes of Health, Bethesda, Md (Dr stated that she had excellent uncor- The pedigree in this report Sieving), the DiMattia and Sovel fami- rected distance vision and only used has 2 male members who carry a lies (Dr Sieving), and an unrestricted corrective lenses to read. She stopped novel mutation in the RS1 gene. grant from Research to Prevent Blind- her medication after 3 doses, at the The grandson has a phenotypic ex- ness Inc, New York, NY (Northwest- onset of symptoms. Initial exami- pression typical for XLRS and the ern University, Chicago). nation determined a visual acuity of phenotype exhibited by the grand- We wish to thank Kelagina- 20/20 OU with a 5-diopter (D) my- father is a crystalline retinal degen- mane T. Hiriyanna, PhD, Radha opic correction, narrow angles, and eration typical of Bietti crystalline Ayygagari, PhD, and Beverly M. an intraocular pressure (IOP) of 29 retinopathy. It is not clear why the Yashar MS, PhD, for discussions. mm Hg OD, and 30 mm Hg OS. Her 2 affected male members of the Corresponding author and re- medical history and review of sys- family, who share the same RS1 prints: David V. Weinberg, MD, 645 tems were unremarkable. She had no mutation, have such different phe- N Michigan Ave, Suite 440, Chicago, known previous drug allergies. Her notypic expressions. Perhaps some IL 60611 (e-mail: d-weinberg2 only other medication was parox- other, as yet unidentified, heritable @northwestern.edu). etine (Paxil; SmithKline Beecham or nonheritable factor influences Pharmaceuticals, Philadelphia, Pa). the expression of the gene. She was treated with 0.5% timolol 1. Sauer CG, Gehrig A, Warneke Wittstock R, et maleate in both eyes and referred for The findings in our pedigree al. Positional cloning of the gene associated with suggest that the C233R mutation X-linked juvenile retinoschisis. Nat Genet. 1997; further evaluation. has variable phenotypic expres- 17:164-170. The fifth day after discontinu- 2. The Retinoschisis Consortium. Functional im- ing topiramate, visual acuity was sion, including crystalline retinal plications of the spectrum of mutations found deposition and typical retinoschi- in 234 cases with X-linked juvenile retinoschi- 20/20 OU with a −4.50-D correc- sis. This or other mutations in the sis. Hum Mol Genet. 1998;7:1185-1192. tion. The pupils responded nor- 3. Hiriyanna KT, Bingham EL, Yashar BM, et al. RS1 gene may be responsible for Novel mutations in XLRS1 causing retinoschi- mally. The peripheral anterior cham- some cases of Bietti crystalline reti- sis, including first evidence of putative leader ber (AC) depth was estimated to be sequence change. Hum Mutat. 1999;14:423- less than 0.5 corneal thicknesses, and nopathy. 427. 4. Gass JDM. Heredodystrophic disorders affect- the central AC depth was 2 corneal ing the pigment epithelium and retina. In: Ste- thicknesses at the pupillary margin David V. Weinberg, MD reoscopic Atlas of Macular Diseases: Diagnosis and (Figure 1A). Iris bombe´ was not Chicago, Ill Treatment. 4th ed. St Louis, Mo: Mosby Year Book Inc; 1997:303-435. present, and IOP was 12 mm Hg OD Paul A. Sieving, MD, PhD 5. Chan WM, Pang CP, Leung ATS, Fan DSP, and 16 mm Hg OS. Gonioscopic ex- Eve L. Bingham, BA Cheng ACK, Lam DSC. Bietti crystalline retinopathy affecting all 3 male siblings in a family. amination of both eyes showed a 360° Ann Arbor, Mich Arch Ophthalmol. 2000;118:129-131. appositional closure (Figure 2A) Lee M. Jampol, MD 6. Richards BW, Brodstein DE, Nussbaum JJ, Fer- with opening on indentation. The encz JR, Maeda K, Weiss L. Autosomal domi- Marilyn B. Mets, MD nant crystalline dystrophy. Ophthalmology. 1991; optic nerve appeared normal, with Chicago 98:658-665. a cup-disc ratio of 0.3 in both eyes. -

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C D

Figure 1. Representative slitlamp photograph of the right eye demonstrating the following: A, a shallow anterior chamber; B, a deepened anterior chamber depth and gonioscopic view of the right eye; C, appositional closure of the anterior chamber angle; and D, open anterior chamber angle.

Ascan echography determined a cen- mides, was first described in 1938.1 without evidence of a systemic al- tral AC depth of 1.4 mm in both eyes Two previous occurrences of acute lergic response. As the mechanism and a distance of 15.6 mm from the myopia following use of topira- of angle closure does not involve pu- posterior aspect of the lens to the mate have been reported.2,3 The au- pillary block, peripheral iridec- macula. High-frequency B-scan (25 thors of both articles speculated that tomy and topical miotics are not use- MHz) revealed a narrow AC (Figure the mechanism was related to par- ful in the treatment of this type of 2A), forward displacement of the tial inhibition of carbonic anhy- secondary angle-closure glaucoma. lens, and swollen ciliary processes in drase. Although controversy exists Our patient improved after discon- both eyes (Figure 2C). regarding the exact mechanism of tinuing the topiramate. Topical timolol maleate, twice acute myopia and angle-closure daily in both eyes was continued for glaucoma after sulfonamide use, Douglas J. Rhee, MD 5 days. Twelve days after stopping most authors have attributed this to Marc J. Goldberg, MD topiramate, visual acuity was 20/15 ciliary body swelling.4 The 5D my- Richard K. Parrish, MD OU without correction, IOP was 10 opic refractive shift, sequential ul- Miami, Fla mm Hg OU, the AC depth was nor- trasound examinations, and slit- mal (Figure 1B), and the AC angles lamp photographs in this patient This article was supported by the Heed were open on gonioscopy (Figure document the ciliary body swelling Ophthalmic Foundation of Cleve- 1D). A-scan measurements showed and the associated forward migra- land, Ohio (Dr Rhee), and by an un- a central AC depth of 2.5 mm and a tion of the crystalline lens. restricted grant from Research to Pre- distance of 14.5 mm from the lens The pathophysiology of the cili- vent Blindness Inc, New York, NY. to the macula. Follow-up high- ary body swelling is unknown. Krieg The authors have no propri- frequency B-scan demonstrated and Schipper5 questioned an acute etary interest in any of the products deepening of the anterior chamber hypersensitivity reaction based on mentioned in this article. (Figure 2B, normal-sized ciliary pro- the observation that rechallenging Corresponding author: Richard cesses (Figure 2D), and a more pos- with the same medication failed to K. Parrish, MD, Bascom Palmer Eye teriorly positioned lens in both eyes. produce a second event. They specu- Institute, University of Miami Medi- late that drug-induced elevated pros- cal School, 900 NW 17th St, Miami, Comment. Acute myopia, a rare taglandins contribute to the forma- FL 33313 (e-mail: rparrish@med idiosyncratic reaction to sulfona- tion of edema within the ciliary body .miami).

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C D

Figure 2. Representative high-frequency B-mode ultrasound image of the right eye demonstrating: A, a shallow central anterior chamber (AC); and B, a deepened central AC. C, Swollen ciliary body process (arrow) and a narrow AC angle (asterisk). D, Normal-appearing ciliary body process (arrow) and a deep AC angle (asterisk). By comparing the corneal thickness, it is apparent that the images are taken at the same magnification.

1. Berns W. Proceedings of the Meeting of the Swed- contrast to early postoperative en- nation by a local ophthalmologist ish Ophthalmological Society, 3rd December, dophthalmitis, which results from revealed an “eye infection,” for 1938. Acta Ophthalmol. 1940;18:96-98. 2. Schear NJ, Rowan AJ, Wiener JA, Haug SJ, Min- intraocular inoculation of microor- which the patient received eye drops del JS. Drug-induced myopia: a transient side ganisms at the time of surgery.1 Late- (of an unknown type). When his effect of topiramate. Epilepsia. 1990;31:643. 3. Gubbay SS. The occurrence of drug-induced onset bleb-related infection occurs symptoms worsened, oral amoxicil- myopia as a transient side effect of topiramate more frequently following full- lin/clavulanic acid potassium was [letter]. Epilepisa. 1998;39:451. thickness procedures, adjunctive an- added to his regimen. The patient 4. Bovino JA, Marcus DF. The mechanism of transient myopia induced by sulfonamide therapy. tifibrosis chemotherapy, or when a denied any chronic diseases or im- Am J Ophthalmol. 1982;94:99-102. late-onset bleb leak is present.2 munodeficient states. His ocular his- 5. Krieg PH, Schipper I. Drug-induced ciliary body oedema: a new theory. Eye. 1996;10: The disease spectrum ranges tory included bilateral cataract ex- 121-126. from infection limited to the bleb to traction with posterior chamber frank endophthalmitis.3 We pre- intraocular lens insertion and bilat- sent a case of panophthalmitis and eral trabeculectomies, with adjunc- orbital abscess, which occurred as a tive 5-FU for primary open-angle late-onset complication of trabecu- glaucoma 7 years prior to presenta- Late-Onset Bleb-Related lectomy with adjunctive 5-fluoro- tion. There was no history of bleb Panophthalmitis With uracil (5-FU). leakage in the left eye, and the pa- Orbital Abscess Caused tient was not using topical antibiot- by Pseudomonas stutzeri Report of a Case. A 69-year-old ics as prophylaxis against bleb in- man had bilateral posterior cham- fection at the time of the initial Late-onset bleb-related endophthal- ber pseudophakia and a failed trab- infection. mitis is a potentially disastrous com- eculectomy in his right eye, and a Three weeks following the on- plication of trabeculectomy that may thin-walled, avascular conjunctival set of his initial symptoms, the pa- occur months to years after sur- filtering bleb in his left eye. He tient came to our institution for evalu- gery. The route of infection is be- developed pain, redness, and dis- ation. Examination of the right eye lieved to involve migration of bac- charge in his left eye while vaca- was unremarkable and revealed a vi- teria across the conjunctiva, in tioning in another country. Exami- sual acuity of 20/50, a flat superior

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S AC

Figure 1. The left eye is proptotic. A 1-cm retrobulbar abscess is present (arrowhead). Figure 2. Panophthalmitis involving the ciliary body, iris, choroid, and vitreous is present. S indicates sclera; C, cornea; AC, anterior chamber; I, iris; CB, ciliary body; and VA, bleb, and a deep and quiet anterior tures obtained at the time of enucle- vitreous abscess. chamber. The left eye was noted to ation revealed Pseudomonas stutzeri. have severe proptosis and absence of Blood cultures obtained at the time of pond water, sewage, and similar en- light perception. Extensive lid ecchy- admission were negative for organ- vironments. Most patients in whom mosis and edema were present. Eye isms. The patient was treated with in- the organism has been isolated have movements were severely restricted travenous vancomycin and ceftazi- been elderly and in poor health.4 Iso- in all directions. The conjunctiva dime for 4 days, and was discharged lation of the organism from eyes is ex- demonstrated extensive chemosis and home receiving oral amoxacillin/ tremely rare. We found only one case a superior filtering bleb with pro- clavulanate potassium, topical tobra- report in the ophthalmic literature, a nounced purulence. The cornea was mycin/dexamethasone, topical neo- case of delayed-onset endophthalmi- edematous and there was extensive mycin sulfate/polymyxin B sulfate, tis after cataract surgery, that men- fibrin and hypopyon in the anterior and dexamethasone ointment. tioned P stutzeri as the infecting or- chamber. The posterior chamber and ganism.5 Our patient was elderly, but the posterior segment could not be Comment. Late-onset bleb-related his general health status was not poor. visualized. endophthalmitis is a serious com- He had recently been abroad (in ur- The patient was hospitalized plication of filtering surgery. Previ- ban areas only) and it is unclear and treated with fortified cefazolin ously reported risk factors for the de- whether this contributed to the de- sodium and tobramycin sulfate velopment of this condition include velopment of his infection. drops, as well as intravenous van- inferior bleb location, blepharocon- The severe course of this case comycin hydrochloride and ceftazi- junctivitis, contact lens use, chronic reemphasizes the need for early de- dime. Computed tomography (CT) bleb leak, nasolacrimal duct obstruc- tection and rapid, appropriate in- scans of the orbits (Figure 1) re- tion, young age, male sex, use of ad- tervention based on the disease se- vealed proptosis of the left eye, with junctive antifibrosis agents, and the verity and offending organism. All significant periorbital inflamma- existence of a cystic, thin-walled patients with thin-walled filtering tory tissue as well as a 1-cm retro- bleb.3 Panophthalmitis occurs when blebs should be urged to seek im- bulbar abscess. There was also dif- the intraocular infection extends into mediate attention should symp- fuse infiltration of the retrobulbar fat, and involves the sclera. Our pa- toms of late-onset bleb-related in- and linear enhancement along the tient developed late-onset bleb- fection appear. optic nerve sheath. A diagnosis of in- related panophthalmitis with or- fectious panophthalmitis with orbital abscess—a complication rare Dan Lebowitz, MD bital abscess was made. enough that we could not find any Rabia Gu¨rses-O¨zden, MD The left eye was enucleated on similar case reports in the litera- Robert F. Rothman, MD the basis of the CT scan findings and ture. Presumably, the risk factors for Jeffrey M. Liebmann, MD the clinical scenario. This was com- development of late-onset panoph- Celso Tello, MD bined with drainage of the orbital ab- thalmitis are similar to those for Robert Ritch, MD scess. Histopathological examina- endophthalmitis, as the former rep- Valhalla, NY tion (Figure 2) revealed acute resents an untreated extraocular bacterial endophthalmitis with vitre- extension of the latter. The authors have no financial interest ous abscess, acute choroiditis, and Pseudomonas stutzeri, the caus- in any device or technique described in end-stage glaucoma, as well as optic ative organism in our case, is a non- this article. nerve, retinal, and choroidal atro- fermentative, Gram-negative bacte- Supported by the Oppenheimer phy with choroidal effusion. Cul- ria. The species is in manure, straw, Research Fund of the New York Glau-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 coma Research Institute, New York, complain of difficulty reading and rec- placed by a brown-green amor- NY. ognizing facial features. Symptoms re- phous smudge. Reprints: Robert Ritch, MD, Glau- lated to unilateral exudative AMD also Figure 3 demonstrates the ad- coma Service, Department of Ophthal- might include reduced binocular vi- verse effect of unilateral exudative mology, The New York Eye and Ear sual function and abnormal depth AMD on binocular visual function. Infirmary, 310 E 14th St, New York, perception. Although individuals When painting this figure, neither NY 10003 (e-mail: [email protected]). might not report reduced binocular eye was occluded. There clearly is a visual perception, many admit to clos- detrimental effect of her “bad” left 1. Wolner B, Liebmann JM, Sassani JW, Ritch R, Speaker M, Marmor M. Late bleb-related ening the “bad eye” to improve their eye on her ability to perceive fine de- dophthalmitis after trabeculectomy with adjunc- ability to see fine detail. tail. She is unable to suppress the ab- tive 5-fluorouracil. Ophthalmology. 1991;98: normal image from her left eye. As 1053-1060. 2. Greenfield DS, Sun˜ er IJ, Miller MP, et al. Report of a Case. A series of paint- a result, the painting is notable for Endophthalmitis after filtering surgery with ings by a Pennsylvania artist illus- loss of detail. Two central objects are mitomycin C. Arch Ophthalmol. 1996;114: 943-949. trates the effect of unilateral exu- identifiable, although it is difficult 3. Waheed S, Liebmann JM, Greenfield DS, et al. dative AMD on binocular visual to distinguish these objects as Recurrent bleb infections. Br J Ophthalmol. 1998; function. The artist is a 68-year-old peaches. The details of the leaves, 82:926-929. 4. Holmes B. Identification and distribution of Pseu- woman with a 3-year history of branches, and shadowing are lost. domonas stutzeri in clinical material. J Appl Bac- AMD characterized by drusen with teriol. 1986;60:401-411. mild retinal pigment epithelial al- Comment. Faubert and Overbury3 5. Jira´skova´ N, Rozsı´val P. Delayed-onset Pseudo- monas stutzeri endophthalmitis after uncompli- terations in the right eye and a fi- examined monocular and binocu- cated cataract surgery. J Cataract Refract Surg. brovascular macular scar in the left lar spatial contrast sensitivity in older 1998;24:866-867. eye (approximately 6 disc areas). people with and without AMD. They Her vision is 20/20 OD and 6/200 measured contrast sensitivity thresh- OS. Her symptoms included re- olds using spatial sine wave grat- duced vision with her left eye and ings. Contrast thresholds were cal- Effect of Unilateral the need to occlude her left eye to culated using Michelson contrast Exudative Age-Related perform tasks requiring fine visual ([Lmax−Lmin]/[Lmax+Lmin]), where Lmax Macular Degeneration acuity. Her symptoms were notice- and Lmin corresponded to the maxi- on Binocular able from the time of her initial vi- mum and minimum luminances in Visual Function sion loss and did not change sig- the image, respectively. In almost nificantly during the following 2 half of the population with AMD, Age-related macular degeneration years. sensitivity to spatial information, as (AMD) is the leading cause of vi- She performed a series of oil measured using spatial contrast sen- sion loss in people older than 65 paintings using monocular and bin- sitivity, was worse when both eyes years. Most cases of severe vision loss ocular vision. Figure 1 was painted were used together compared with are related to the development of with her left eye occluded. This when the stimuli were viewed with exudative AMD, which is character- painting is remarkable for vibrant only one eye. They use the term ized by the growth of abnormal ves- colors and fine detail. The peaches “binocular inhibition” to describe sels from the choroidal circulation. are well defined using bright col- this phenomenon and suggest that These abnormal vessels leak fluid ors; the leaves and branches are dis- for some patients with visual im- and blood into the macula. Eventu- tinct using appropriate shadowing. pairment related to AMD, one eye ally, a fibrotic macular scar can form. Figure 2 was painted with her right might be better than two. Symptoms of exudative AMD in- eye occluded. There is marked de- The effect of AMD on the vi- clude blurred vision, metamorphop- rangement of the image quality and sual perception of an artist has been sia, relative central scotoma, dyschro- loss of detail, with an inability to dis- examined previously.4 Terrence Bill- matopsia, photopsias, and formed tinguish the peaches, leaves, or ings, MD, a physician and trained hallucinations.1,2 Individuals often branches. The vibrant colors are re- artist, demonstrated the impact of

Figure 1. Oil painting done by a patient with Figure 2. Oil painting done by a patient with Figure 3. Oil painting done by a patient with age-related macular degeneration with the left age-related macular degeneration with the right age-related macular degeneration with both eye occluded. eye occluded. eyes open.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 AMD in a series of paired oil paint- tive degree of visual impairment can mology, Penn State University, PO Box ings using first the vision of both occur when visualizing objects with 850, Hershey, PA 17033 (e-mail: daq2 eyes and then the vision of his more both eyes simultaneously. The pos- @psu.edu). severely affected right eye alone. sibility of binocular inhibition 1. Fine AM, Elman MJ, Ebert JE, Prestia PA, Starr In contrast to the artist described should be considered when provid- JS, Fine SL. Earliest symptoms caused by neo- herein, the distortion and relative ing visual rehabilitative services for vascular membranes in the macula. Arch Oph- central scotoma of Dr Billings’ more individuals with unilateral vision loss thalmol. 1986;104:513-514. 2. Brown GC, Murphy RP. Visual symptoms asso- affected right eye had little impact related to AMD. ciated with choroidal neovascularization: pho- on his ability to paint with both eyes topsias and the Charles Bonnet syndrome. Arch together. Ophthalmol. 1992;110:1251-1256. David A. Quillen, MD 3. Faubert J, Overbury O. Binocular vision in older Exudative AMD can have a pro- Hershey, Pa people with adventitious visual impairment: found effect on monocular and bin- sometimes one eye is better than two. J Am Geri- atr Soc. 2000;48:375-380. ocular visual function. In some in- 4. Sperduto RD, Hagler WS, Ferris FL, Billings TE. dividuals with unilateral vision loss Corresponding author: David A. Senile macular degeneration: an artist’s view. related to exudative AMD, a rela- Quillen, MD, Department of Ophthal- JAMA. 1983;250:2506-2507.

Announcement

Ophthalmic Pathology Fellowship he American Ophthalmological Society–Knapp Fund and Research to T Prevent Blindness is offering a new 2-year postgraduate fellowship for training in ophthalmic pathology with an annual stipend of $52500. The first year of the proposed fellowship program will be spent in the study of diagnostic pathology in the initiation of experimental eye pathology laboratory research. The second year of fellowship training will include experimental pathology research combined with exclusive time in diagnostic pathology or time in a relevant clinical subspecialty. Applicants must be graduates of a medical school accredited by the American Medical Association, citizens of the United States, and have plans for an academic career. Deadline for submission of ap- plications: January 15, 2002, for fellowship starting in July 2002. Please direct all inquires and requests for application materials to Froncie A. Gutman, MD, AOS–Knapp Fund, Cleveland Clinic Foundation, 9500 Euclid Ave, Desk I-32, Cleveland, OH 44195; (216) 445-8145.

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