Retinitis Pigmentosa Associated with Ectopia Lentis

CLINICOPATHOLOGIC REPORTS, CASE REPORTS, AND SMALL CASE SERIES

SECTION EDITOR: W. RICHARD GREEN, MD

tion of the oil progressing through the In January 2001, glaucoma sur- Silicone Oil Egressing tube and histopathologic analysis of gery was needed to control elevated Through an Inferiorly the orbital tissue surrounding the ex- intraocular pressure (IOP). The eye Implanted Ahmed Valve truded silicone oil. was aphakic and had total traumatic aniridia. An Ahmed valve was im- Silicone oil use as an adjunct to com- Report of a Case. A 69-year-old white planted inferonasally in an attempt plicated vitreoretinal surgery is be- man lost his left eye to trauma at age to avoid the silicone oil bubble coming more frequent. Refractory 12 years. In September 2000, blunt (Figure 1 and Figure 2). The pa- glaucoma in these patients is com- trauma resulted in a lacerated eye- tient’s IOP responded well initially mon. Isolated reports have men- brow, scleral rupture, uveal prolapse, but rose subsequently to 30 mm Hg. tioned the possibility of silicone oil extrusion of his crystalline lens, reti- A bubble of silicone oil was wrap- migrating and/or obstructing the nal detachment, and suprachoroidal ping the tip of the tube (Figure 3). tube in the anterior chamber of Mol- hemorrhage in his right eye. A limited Silicone oil could be seen migrating teno implants (IOP, Costa Mesa, anterior chamber washout was per- through the Ahmed tube (Figure 4 Calif).1,2 This report describes a case formed at the time of the primary re- and Figure 5) and the bleb over the of intraocular silicone oil egressing pair. Ten days later, he underwent implant progressively enlarged and through an Ahmed implant (New pars plana vitrectomy, silicone oil in- appeared encapsulated during the World Medical, Rancho Cucamonga, jection, and a scleral buckle. A pars next few months. A glistening mate- Calif), impairing the functioning of plana vitrectomy revision with endo- rial was noted in cystic spaces over- the tube and requiring replacement laser,membranestripping,andsilicone lying the Ahmed implant under the of the implant plus oil removal. We oilreinjectionwereperformed1month conjunctiva. An inferior ectropion present photographic documenta- laterforarecurrentretinaldetachment. that progressed gradually was also

Figure 1. Slitlamp photograph showing the Ahmed tube inferonasally short Figure 2. Retroillumination photograph showing a patent Ahmed tube. after implantation. Notice total traumatic aniridia and superotemporal paralimbal scleral wound with interrupted sutures.

Figure 3. Slitlamp photograph showing “candle wax” appearance of the Figure 4. Retroillumination photograph showing a level of silicone oil silicone oil wrapped around the tip of the Ahmed tube. (arrow) inside the Ahmed tube.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 5. Retroillumination photograph taken on a different day shows a Figure 6. Histopathologic examination of orbital tissue excised during different level of silicone oil (arrow) inside the Ahmed tube. removal of valve shows empty vacuoles consistent with silicone oil and larger deposit of oil surrounded by epithelioid histiocytes and foreign body giant cells (hematoxylin-eosin, original magnification ϫ200).

noted. The volume of the silicone the migration of the silicone oil It seems that a “unicameral” eye bubble in the vitreous cavity de- through the Ahmed implant. The in- with silicone oil, particularly with sig- creased from an estimated 85% fill to flammatory reaction observed in the nificant iris defects, is a poor candi- an estimated 50% fill. Ectropion re- periocular tissues, apparently caused date for successful IOP control with pair was necessary in June 2001. by the silicone oil, has been docu- a seton in a 1-stage procedure. In our Owing to persistently elevated mented before.1,2 This contrasts with case, the inferior location of the im- IOP measurements, transcorneal re- no observed clinical reaction in in- plant did not prevent silicone oil moval of the silicone oil combined traocular tissues, although histo- movement out of the eye with sec- with replacement of the Ahmed im- pathologically foreign-body granu- ondary impairment of IOP control. plant was performed. Multiple sili- lomas have been documented in Silicone oil removal needs to be con- cone oil–filled conjunctival cysts intraocular tissues. sidered prior to implantation of a se- were found surrounding the Ahmed The silicone oil did impair the ton in such cases. If silicone oil re- plate. A tissue sample was taken in- drainage of aqueous through the im- moval is not an option, diode laser ferotemporally from a thick cap- plant as evidenced by the elevated cyclophotocoagulation is another al- sule surrounding the Ahmed im- IOPs. Encapsulation of the bleb might ternative for IOP control. plant. Histopathologic analysis of the also have contributed to the obstruc- tissue surrounding the plate dem- tion of the implant. The photographs Jose Morales, MD onstrated fibroconnective tissue with (Figures 3 and 4), showing oil at dif- Michel Shami, MD numerous small vacuoles. Surround- ferent levels of the tube, demonstrate Geert Craenen, MD ing this tissue were numerous for- the progression of the silicone oil Thom F. Wentlandt, CRA eign-body giant cells and histio- through the tube of the Ahmed im- Lubbock, Tex cytes (Figure 6). plant. We believe that aphakia with total aniridia resulted in an anatomic Corresponding author: Jose Morales, Comment. To our knowledge, this situation (a truly unicameral eye) that MD, Texas Tech University Health Sci- is one of the first documented cases favored the anterior migration of the ences Center, Department of Ophthal- of silicone oil exiting the eye through silicone oil when the patient inadvert- mologyandVisualSciences,3601Fourth an Ahmed implant. Review of the lit- ently assumed a supine position. This St, STOP 7217, Lubbock, TX 79430- erature yielded 2 previous reports, was probably favored by the well- 7217(e-mail:[email protected]). both involving Molteno implants in known physical attraction of the sili- aphakic patients1,2 and 1 recent re- conetubetowardthesiliconeoil.Once 1. Hyung SM. Min JP. Subconjunctival silicone oil 3 drainage through the Molteno implant. KorJOph- port involving an Ahmed implant. an oil bubble made it to the entrance thalmol. 1998;12:73-75. Minckler4 describes adhesion of the ofthetube,thecombinedeffectofcap- 2. Senn P, Buchi ER, Daicher B, Schipper I. Bubbles silicone oil to the anterior chamber illary action with elevated IOP may in the bleb: troubles in the bleb? molteno implant and intraocular tamponade with silicone portion of the drainage tube, resem- have facilitated the migration of the oil in an aphakic patient. Ophthalmic Surg. 1991; bling candle wax, without lumen ob- oil to the subconjunctival space. The 26:379-382. 3. Nazemi PP, Chong LP, Varma R, Burnstine MA. struction. He recommends placing patient’s IOP has been under control Migration of intraocular silicone oil into the sub- the tube in an inferior location to since replacement of the Ahmed im- conjunctival space and orbit through an Ahmed minimize the chance of oil-tube ob- plant and removal of the silicone oil. glaucoma valve. Am J Ophthalmol. 2001;132: 929-931. struction. In our case, the inferior lo- His last corrected visual acuity was 20/ 4. Minckler D. Silicone oil glaucoma: cases in con- cation of the tube did not prevent 50 OD. troversy. J Glaucoma. 2001;10:51-54.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 olol administered daily. The pa- utes, and then washed in Tris- Lens Dislocation tient’s grandfather, cousin, and buffered saline. The sections were in Marfan Syndrome: mother also had Marfan syndrome. incubated with a 1:5 dilution of pre- Potential Role of Matrix Her mother developed bilateral lens immune serum from the secondary Metalloproteinases in subluxation and glaucoma. A sys- host species. Tissue sections were in- temic examination revealed arachno- cubated with 1:100 goat primary poly- Fibrillin Degradation dactyly and a high arched palate. clonal antifibrillin antibody (Santa Ophthalmologic examination re- Cruz Biotechnology, Santa Cruz, Marfan syndrome is an autosomal vealed a best-corrected visual acuity Calif) and 1:100 mouse primary dominant disorder with pleiotro- of 20/220 OD and 20/120 OS. The monoclonal anti-MMP–1, anti- pic manifestations that involve the right eye had an intraocular pres- MMP–2, anti-MMP–3, anti-MMP–9 ocular, cardiovascular, and skeletal sure of 19 mm Hg; and the left eye, (ICN Pharmaceuticals, Costa Mesa, systems. Marfan syndrome re- 18 mm Hg. Goldmann visual fields Calif), 1:100 TIMP-1, TIMP-2 (ICN), mains primarily a clinical diagno- were normal. Slitlamp examination and 1:100 TIMP-3 (Calbiochem, San sis with a frequency of 2 to 3 indi- confirmed bilateral superonasal lens Diego, Calif) overnight at 4°C. The viduals per 10000. Patients with this subluxation that was worse in the sections were then washed in 0.05M disorder may have a variety of ocu- right eye than in the left (Figure). Tris-buffered saline (pH, 7.6) before lar complaints, most commonly, The fundus was normal, with cup- the addition of a biotinylated rabbit subluxation of the lens, which oc- disc ratios of 0.2 for each eye. The antigoat secondary antibody (for curs in more than 60% of patients.1 ocular examination was otherwise fibrillin) and biotinylated goat anti- Several studies have identified the normal. Because of the advanced zo- mouse secondary antibody (for MMPs FBN1 fibrillin gene located on chro- nular dialysis, bilateral intracapsular and TIMPs). The antibodies di- mosome 15 as defective in this syn- lens extractions were performed with rected against human antigens dis- 2 ␣ drome. a cryoprobe and without -chymo- play no cross-reactivity and are all IG1 Matrix metalloproteinases trypsin. The lenses were so mobile subclass antibodies. Sections were (MMPs) are proteolytic enzymes that they were expressed from the eye again washed, incubated for 1 hour important in physiological and by injecting viscoelastic inferiorly and with horseradish peroxidase– pathological remodeling, the activ- posteriorly (in front of the vitreous conjugated streptavidin (Dako, ity of which is stringently controlled face), and scleral fixated posterior Carpinteria, Calif), and the immuno- by a family of natural antagonists, chamber intraocular lenses were su- reactivity was revealed by adding the tissue inhibitors of MMPs tured into position with standard 3-amino-9-ethylcarbazole (Sigma, (TIMPs). Both MMPs and TIMPs techniques. Sydney, Australia). Control reac- are present in the aqueous humor in Both crystalline lenses from the tions were included, incubating sec- normal and inflamed eyes,3 result- patient were immediately formalin tions with an isotype antibody and ing in their interaction with the lens fixed. Lenses from corneal donor omitting the primary antibody or add- zonules. postmortem eyes (n=8) were enucle- ing preimmune serum. Sections were We describe a patient with ated 4 to 8 hours after the time of counterstained with hematoxylin, Marfan syndrome lens subluxation death and were also immediately viewed by light microscopy, and pho- associated with positive MMP ex- fixed in formalin. The 10 lenses were tographed with Spot Version 2.2 for pression and no TIMP immunoreac- paraffin embedded, and 4-µm sec- Windows (Diagnostic Instruments tivity within the lens zonule. To our tions were placed on slides coated Inc, Sterling Heights, Mich). knowledge, this is the first report of with 3-amino propyltriethoxy trieth- Macroscopically, both the MMP staining associated with lens oxysilane (TES) for immunohisto- Marfan lenses appeared normal. Mi- zonules in a patient with Marfan syn- chemical analysis using a panel of croscopically, both Marfan lens cap- drome. Understanding the role these monoclonal antibodies directed sules appeared thickened, with the proteases play may lead to the devel- against MMP-1, MMP-2, MMP-3, germinative zone smaller than that opment of novel therapies to MMP-9, and TIMP-1, TIMP-2, and of the normal lens. Immunohisto- reduce the progressive nature of TIMP-3. Matrix metalloproteinases chemical analysis revealed specific Marfan syndrome lens subluxation. seem to be stable for as long as 24 localization of MMP-1 (Figure, A), hours in harvested ocular tissue.4 MMP-3 (Figure, C), and MMP-9 Report of a Case. A 43-year-old Sections were deparaffinized in (Figure, D) in the Marfan lens zon- woman diagnosed with Marfan xylene, rehydrated through decreas- ules, with relatively little or no syndrome in 1980 was referred to ing graded ethanol, followed by two MMP-2 (data not shown) and no the Ophthalmology Clinic at Prince 5-minute washes in 0.05mM of Tris- TIMP-1, TIMP-2, or TIMP-3 immu- of Wales Hospital (Sydney, Austra- buffered saline (10ϫ stock Tris- noreactivity (Figure, L-N). In con- lia) in 1999. The patient described de- buffered saline contains 0.25M Tris trast, no MMP-1 or MMP-3 stain- terioration of her vision occurring base, 0.25M Tris-hydrochloride, and ing was observed in the zonules of throughout a 9-month period. Her 8.5% sodium chloride, with a pH of normal lenses (Figure, E and F) but medical history included mitral val- 7.6). Antigen retrieval method was TIMP-1, TIMP-2, and TIMP-3 were vuloplasty in 1997, paroxysmal atrial not necessary. Endogenous peroxi- detected in the zonules of the nor- fibrillation, scoliosis, and hyperten- dase was quenched with 3% hydro- mal lenses (Figure, H-J). On all lens sion controlled with 50 mg of aten- gen peroxide/methanol for 5 min- sections, more than 1 zonular site

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B D

E F H I J

K L M N

Immunohistochemistry of normal and Marfan syndrome lenses revealed positive immunoreactivity for matrix metalloproteinases (MMP)–1, MMP-3, and MMP-9 (A, C, and D) on Marfan lens zonules, with no tissue inhibitors of MMPs (TIMP)–1, TIMP-2, or TIMP-3 (L-N) immunoreactivity. The arrows indicate the zonule. When the primary antibody was omitted, no immunoreactivity could be detected in the Marfan lens (B) or the normal lens (G). In contrast, no MMP-1 (E) or MMP-3 (F) staining was observed in the zonule of normal lenses, but TIMP-1, TIMP-2, and TIMP-3 (H-J) was detected (original magnification ϫ125). A fibrillin monoclonal antibody was included to identify the lens zonule in the Marfan lens (K) (original magnification ϫ250).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 contained MMP or TIMP activity. A changes may account for the in- fibrillin monoclonal antibody was increased incidence of ocular disease Histopathological Changes cluded to identify the lens zonule in observed in older patients with Following Photodynamic the Marfan lens (Figure, K). Sec- Marfan syndrome. Therapy in Human Eyes tions incubated with isotype con- If the proposed hypothesis re- trol antibodies demonstrated no re- garding the role of MMPs in Marfan- activity in either the Marfan (Figure, associated lens subluxation is cor- To identify histopathological changes B) or normal lenses (Figure, G). rect, then the development of matrix induced by photodynamic therapy metalloproteinase inhibitors may be (PDT), 2 human eyes received PDT Comment. This is the first case re- of potential therapeutic value in the usingverteporfin1weekbeforeenucle- port, to our knowledge, describing treatment of progressive lens sub- ation for large malignant melanoma. zonule-associated staining of MMPs luxation and other complications of Twolightdoses,50and100J/cm2,were in Marfan syndrome lens subluxa- Marfan syndrome.10 applied to unaffected chorioretinal tion. We hypothesize that the prod- areas and the optic disc using the uct of the defective FBN1 gene in Nitin H. Sachdev, MBChB standard procedure recommended Marfan syndrome is more prone to Nick Di Girolamo, PhD for patients with age-related macular degradation by MMPs as compared Peter J. McCluskey, FRACO, FRACS degeneration (ARMD). with normal fibrillin. It is also pos- Angela V. Jennings, MBBS Characteristic hypofluores- sible that dysregulation of MMPs Roger McGuinness, FRACO, FRACS cence following PDT was docu- and TIMPs results in the progres- Denis Wakefield, FRCPA mented angiographically 1 week sive destruction of lens zonules and MinasT.Coroneo,FRACO,FRACS,MD later. The enucleated globes were subsequent lens subluxation. Sydney, Australia processed for standard light and elec- The lens zonule consists of a se- tron microscopy. ries of fibers composed of microfi- The PDT-treated areas revealed The authors have no proprietary in- brils that are 8 to 12 nm in diameter. uniform occlusion of the choriocap- terests in any of the products or com- The fibrils consist largely of a cysteine- illary layer. Vascular endothelial cells panies mentioned in this article. rich microfibrillar component of the were swollen, detached from the base- Corresponding author: Minas T. fibrillin elastin system. In other tis- ment membrane, and showed rup- Coroneo, FRACO, FRACS, MD, sues, fibrillin provides a template for ture and fragmentation to complete Department of Ophthalmology, elastin deposition.5 Genetic linkage degeneration. Capillary lumina were Prince of Wales Hospital, University between the fibrillin gene and the filled with cell debris, fibrin, and of New South Wales, Randwick, Syd- Marfan phenotype has been estab- thrombocytes. Remaining intact en- ney, Australia (e-mail: m.coroneo lished, and the gene mapped to the dothelial cells seemed to generate @unsw.edu.au). same chromosomal position as the novel vascular channels by recanali- 6 disease locus. Understanding of the 1. Maumenee IH. The eye in the Marfan syn- zation of the obliterated lumen. The functions of the fibrillin-containing drome. Trans Am Ophthalmol Soc. 1981;79:684- overlying retinal pigment epithe- 733. microfibrils is still incomplete, and 2. Sarfarazi M, Tsipouras P, Del Mastro R, et al. lium (RPE) showed no significant al- correspondingly, no comprehensive A linkage map of 10 loci flanking the Marfan teration. Photoreceptors and optic theory of the pathogenesis of Marfan syndrome locus on 15q: results of an Interna- nerve exposed to verteporfin and 100 tional Consortium study. J Med Genet. 1992; 2 syndrome has emerged to date. 29:75-80. J/cm of light were structurally unre- Both fibrillin molecules and 3. Di Girolamo N, Verma MJ, McCluskey PJ, et markable. al. Increased matrix metalloproteinases in the fibrillin-rich microfibrils are suscep- aqueous humor of patients and experimental Photodynamic therapy in- tible to degradation by serine pro- animals with uveitis. Curr Eye Res. 1996;15: duces at a dosage used clinically in teases, and amino acid substitu- 1060-1068. the treatment of ARMD a selective 4. Kamei M, Hollyfield JG. TIMP-3 in Bruch’s tions (as found in Marfan syndrome) membrane: changes during aging and in age- destruction of vascular endothelial change the fragmentation pat- related macular degeneration. Invest Ophthal- cells within the choriocapillary layer. terns.7 Fibrillin degradation prod- mol Vis Sci. 1999;40:2367-2375. Recanalization of the physiological 5. Robinson PN, Godfrey M. The molecular ge- ucts generated by MMP activity pro- netics of Marfan syndrome and related micro- choroid is observed as early as 1 vide conclusive evidence that these fibrillopathies. J Med Genet. 2000;37:9-25. week following PDT. Neural struc- 6. Maslen CL, Glanville RW. The molecular ba- enzymes cause specific changes to sis of Marfan syndrome. DNA Cell Biol. 1993; tures, photoreceptors, and RPE re- 7 assembled microfibrils. As most of 12:561-572. mained intact. the mutations in fibrillin-1 are found 7. Ashworth JL, Murphy G, Rock MJ, et al. Fibril- The therapeutic benefit of PDT lin degradation by matrix metalloproteinases: within epidermal growth factor– implications for connective tissue remodel- using verteporfin in the treatment of like motifs and are predicted to dis- ling. Biochem J. 1999;340(pt 1):171-181. predominantly classic choroidal neo- rupt calcium binding, it has been 8. Reinhardt DP, Ono RN, Sakai LY. Calcium sta- vascularization (CNV) has intro- bilizes fibrillin-1 against proteolytic degrada- suggested that these mutations ren- tion. J Biol Chem. 1997;272:1231-1236. duced a novel strategy into the man- der fibrillin-1 more susceptible to 9. Hanssen E, Franc S, Garrone R. Fibrillin-rich agement of exudative ARMD. A 8 microfibrils: structural modifications during proteolytic cleavage. Previous in- ageing in normal human zonule. J Submicrosc prospective, randomized, double- 1 vestigators have demonstrated struc- Cytol Pathol. 1998;30:365-369. masked clinical trial demonstrated tural modifications in fibrillin-rich 10. Boyle JR, McDermott E, Crowther M, et al. Doxy- that verteporfin PDT reduces the risk cycline inhibits elastin degradation and reduces microfibrils during aging of human metalloproteinase activity in a model of aneu- of severe visual loss, preserves con- ciliary zonules.9 These age-related rysmal disease. J Vasc Surg. 1998;27:354-361. trast sensitivity, and may even im-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 prove visual acuity in a subgroup of consistent with choroidal nonper- horizontally, and it reached 12 mm patients. The results of the Treat- fusion.7 in height. Localized exudative reti- ment of Age-Related Macular De- To identify the structural ef- nal detachments were associated generation With Photodynamic fects induced by PDT, intact reti- with the malignancies. Both eyes Therapy Study Group provided the nal, RPE, and choroidal layers of hu- showed mild age-related degenera- rationale for the recent approval of man eyes that were scheduled for tive changes of the macular area with the method by the health authori- enucleation were exposed to verte- some scattered drusen. ties. Meanwhile, thousands of pa- porfin therapy. Light and electron Photodynamic Therapy. Photo- tients with neovascular ARMD re- microscopic evaluation was per- dynamic therapy using verteporfin ceived PDT following the guidelines formed, with particular emphasis on was applied 7 days before the sched- of the Treatment of Age-Related photoreceptor, RPE, and choriocap- uled enucleation. Retinochoroidal ar- Macular Degeneration With Photo- illary alterations. eas without involvement by the tu- dynamic Therapy trial. mor or the accompanying serous The characteristic features ob- Patients and Methods. The study detachment were selected by oph- served in patients undergoing PDT protocol was compiled using the Dec- thalmoscopy and angiography. The seem to be well characterized: clini- laration of Helsinki, and approved by procedure was performed according cal exudation of serous fluid, blood, the institutional ethics committee. In- to the approved treatment recom- and lipids is halted; and retinal edema formed consent was obtained from mendations for patients with ARMD. resolves.2 By angiography, cessation each patient, specifically indicating Verteporfin was administered intra- of leakage from classic CNV is docu- the scientific nature of the photody- venously by infusion of 6 mg of drug mented,3 which usually recurs and re- namic procedure with no therapeu- per square meter of body surface area quires repeated treatment applica- tic relevance in respect to the under- over 10 minutes. Photoactivation was tions to achieve long-term absence of lying malignancy. started 5 minutes after the comple- exudative activity.4 However, de- Patients. Two eyes of 2 pa- tion of the administration, with light spite thorough clinical and angio- tients received PDT. Both organs at a wavelength of 689 nm delivered graphic evaluation, the knowledge of were scheduled for enucleation be- by a diode laser and a laser-link slit- the photodynamic effects on hu- cause of malignant melanoma of the lamp (Coherent Inc, Palo Alto, Calif). man ocular structures is limited and uvea too large for conservative man- Two areas per eye were treated sub- mostly based on observation of the agement. Tumors were located an- sequently, a first one with a total light secondary phenomena induced by teriorly so that the posterior pole was dose of 50 J/cm2 followed by a sec- PDT than a revelation of primary accessible ophthalmoscopically and ond one with application of a light mechanisms. for photosensibilization. Patient 1 dose of 100 J/cm2, both at an irradi- A histopathological evalua- was a 72-year-old man who had a ance constant of 600 mW/cm2. Ex- tion from animal studies has de- large tumor reaching the ciliary body posures are shown schematically in tected changes within the physi- in the supranasal quadrant, with a Figure 1A and B. In eye 1, the 100- ological choroid and the RPE and tumor base of 35 mm radially and J/cm2 spot had a diameter of 5000 µm laser-induced CNV.5,6 In patients, 36 mm at the equator and a height and was positioned superiorly to the PDT-associated findings seem to be of 12 mm. Patient 2, an 85-year-old optic nerve, including the disc (Fig- contradictory: retinal function is woman, was seen with a prominent ure 1A). The 50-J/cm2 spot with a di- maintained or improved, while ho- tumor mass located superiorly at the ameter of 3000 µm was directed onto mogeneous choroidal hypofluores- 12-o’clock position. The tumor size the retina below the optic nerve head. cence seen angiographically may be was 24 mm vertically and 23 mm In eye 2, the area receiving 50 J/cm2 was located central to the temporal inferior vascular arcade, while the 100- J/cm2 spot was placed below the vascular arcade (Figure 1B). Clinical Documentation. Visual

A acuity was examined before, 1 day af- D ter, and 1 week after PDT, and was B unchanged, with 20/400 in patient 1 B I A and 20/100 in patient 2. No addi-

C C tional field defects were described by D the patients. Ophthalmoscopically, no change in the clinical appearance of the retina, the RPE, or the choroid was noted; treated areas were indistin- A B II guishable from the surrounding retina. Fluorescein angiography (FA) Figure 1. Eye 1 (A) and eye 2 (B) showing the location of the tumor (A), the associated retinal and indocyanine green angiography 2 2 detachment (B), and the laser spots exposed to 50 J/cm (C) and 100 J/cm (D) of light. Treatment spots (ICGA) were performed to localize were placed on areas without involvement of the tumor or detachment. Globe 1 was bisected vertically through the laser spots. Globe 2 was first bisected horizontally, followed by a vertical section adjacent to and quantify the vascular effects be- laser spot D. fore and 1 week after PDT.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Histopathological Evaluation. In patient 2, the central spot Choroidal vascular changes Immediately after surgical removal, that illuminated with 50 J/cm2 of seen in globe 2 were identical to find- the globes were fixed in a combina- light showed absence of the chorio- ings observed in globe 1. An occlu- tion of 4% paraformaldehyde and 1% capillary background fluorescence sion of capillaries of the choroid was glutaraldehyde in a 0.1M phosphate but maintenance of the vascular pat- seen only in PDT-exposed areas buffer for 5 days and processed for tern of medium- and larger-caliber (Figure 3A). Endothelial cells were routine paraffin embedding. A mac- vessels without any reduction in swollen, detached from the base- roscopic examination and transillu- fluorescent demarcation of these ves- ment membrane, and partially rup- mination were performed, and the tu- sels during early ICGA (Figure 2C). tured. Large-caliber vessels ap- mor dimensions were measured. The area that had received 100 J/cm2 peared to be regular and perfused. Angiographic images were used to lo- of light demonstrated choriocapil- However, the RPE and the Bruch cate PDT-treated areas before dissec- lary loss combined with a marked membrane were unchanged. Un- tion of the posterior pole. Globe 1 was decrease in the overall density of treated areas showed vascular chan- bisected along the laser spots and pro- choroidal vessels. Late-phase ICGA nels with intact endothelial lining cessed for light and transmission elec- showed the persistence of hypofluo- (Figure 3B). tron microscopy. Globe 2 was reem- rescence in both areas, with exuda- Electron Microscopy. Photody- bedded from paraffin into epoxy resin tion from the margins and the re- namic therapy–treated areas showed for electron microscopy. maining patent vessels within the occlusion and degenerative changes For light microscopy, 8-µm- lesions (Figure 2D). of the choriocapillaris (Figures 4A, thick paraffin sections were stained Light Microscopy. In globe 1, B, and D, 5A-F, and 6B-D) com- with hematoxylin-eosin and peri- PDT-treated areas were identified su- pared with untreated areas with wide odic acid–Schiff. For electron micros- perior and inferior to the optic nerve. open lumina, several rows of loosely copy, tissue specimens containing Complete occlusion of the chorio- organized erythrocytes, and intact fe- the choroid and retina of the PDT- capillary vascular lumina was noted nestrated endothelia of the capillar- treated areas and untreated control ar- in these areas. Vascular channels ies (Figures 4C and E, 5G, and 6A). eas were postfixed in 2% buffered os- were blocked by swollen endothe- Vascular alterations in the treated ar- mium tetroxide and embedded in lial cells that enclosed red blood cells eas comprised swelling of endothe- epoxy resin (Epon) according to the and fibrin. In some segments, the lu- lial cells and a few pericytes leading standard method. Semithin sections men was completely obliterated, to narrowed, compressed, capillary (1 µm) were stained with toluidine while others demonstrated a re- lumina with densely packed de- blue O; ultrathin sections (0.2 µm) sidual small opening. Occlusion was formed erythrocytes immured be- were stained with uranyl acetate– seen throughout the dimensions of tween the endothelial lining (Fig- lead citrate and examined with an the treatment spot and reached a ures 4D and 6B). Alterations further electron microscope (LEO 906E; depth of approximately 150 µm be- comprised endothelial shrinkage, Zeiss, Oberkochen, Germany). low the Bruch membrane. Small ruptures, fragmentations, and the de- deeper vessels were also clogged, tachment of cells from their base- Results. Angiography. By FA, light- while larger choroidal vessels showed ment membrane up to complete de- exposed areas revealed homogeneous open lumina with intact, not degeneration of the endothelial lining, hypofluorescence characteristic for formed, erythrocytes. Areas adja- leaving denuded vascular basement PDT, with no difference in fluorescent to the photosensitized spot ex- membranes (Figures 5A and B and cence intensity between the 2 differ- hibited a regular choroidal vascular 6C). Finally, complete occlusion of ent light doses. Indocyanine green an- structure with open capillary chan- capillary lumina by fibrin, platelets, giography provided a more detailed nels and larger choroidal vessels. and cellular debris derived from en- image of the choroidal vasculature Intact choroidal sections taken dothelial cells, macrophages, and and the extent of vaso-occlusion. In from control areas appeared less granulocytes was frequently ob- patient 1, the image taken 1 week af- condensed and thicker than PDT- served (Figures 4A and B and 5C and ter PDT was partially obscured by the treated sections. Retinal pigment D). Erythrocytes in the affected cap- bullousserousdetachmentassociated epithelial cells were attached and illaries were often degenerative, ap- with the tumor located in the nasal showed only minor age-related pearing as ghost cells. Granulocytes periphery. However, a round hypo- changes, with vacuolization in the accumulated in the lumina of af- fluorescent area with a sharp demar- treatment zone and in control ar- fected capillaries and macrophages cation during early ICGA was docu- eas. Photoreceptors were artifi- seemed to gather in the periphery of mented in the 50- and the 100-J/cm2 cially detached in some areas, but did degenerated vessels. Extravasation spot (Figure 2A). Retinal perfusion not show any structural changes. of erythrocytes and migration of in- was not compromised with the Capillaries of the optic nerve head flammatory cells into the extracellu- higher-dose treatment, including were open and lined with intact en- lar space could often be observed the optic nerve. In late ICGA, hypo- dothelial cells. Neural structures, (Figure 5B). In case of advanced en- fluorescence was still present, with such as ganglion cells and axons, dothelial degeneration, the original scattered areas of leakage from larger showed no evidence of structural vessel outline was occasionally de- choroidal vessels (Figure 2B). No alteration, histologic signs related lineated by erythrocyte configura- pathologic exudation was seen from to ischemia, or infiltration of the tions or by electron-dense blood- the vasculature of the optic nerve. nerve. plasma accumulations (Figure 6C

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C D

Figure 2. Eye 1. Early (A) and late (B) phases of indocyanine green angiography (ICGA), with demarcation of the 2 spots exposed to 100 J/cm2 superiorly, including the optic nerve, and 50 J/cm2 inferiorly. The increasing serous detachment originating from the tumor partially covers the nasal aspect of the image. The arrows indicate the borders of choroidal hypofluorescence. Eye 2. Early (C) and late (D) phases of ICGA, with hypofluorescent areas treated with 50 J/cm2 of light central and 100 J/cm2 of light peripheral to the vascular arcade.

and D). Remaining intact endo- the optic nerve head consistently ap- with 100 J/cm2 and, therefore, rep- thelial cells appeared to reorganize peared intact after exposure to 100 resent rather extensive vacuoliza- into smaller capillaries within the J/cm2 of light. tion of the RPE cytoplasm and sepa- degenerated original vessel outline, The RPE appeared mostly in- ration from the Bruch membrane. forming a novel vascular lumen tact over large areas and showed Figure 6, depicting patient 2, is not (Figure 6D). focal vacuolar degeneration in the quite representative because of re- Degenerative changes of deeper 100-J/cm2 treated areas only; partly, embedding from paraffin and a (outer) choroidal vessels with ex- bullous separation of individual pig- rather poor preservation of the ul- travasation of red blood cells was ob- ment epithelial cells from the Bruch trastructure. However, slight alter- served in the 100-J/cm2, but not in the membrane could be observed. The ations of RPE cells, such as intra- 50-J/cm2, treated spots, where those overlying photoreceptor layer ap- cellular vacuolization indicative of vessels appeared essentially nor- peared intact in all PDT-treated ar- intracellular edema, were also evi- mal with wide open lumina (Fig- eas (Figure 5F). Figures 4A and D dent in the areas treated with 50 ures 4A and B and 5E). Capillaries of and 5C, D, and E show areas treated J/cm2 (Figure 7). Retinal pigment

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 epithelial cells appeared otherwise normal with regard to their plasma membrane, cytoplasmic organ- elles, nuclei, and melanin granules. The retinal capillaries appeared generally normal in areas 2 treated with either 50 or 100 J/cm A (Figure 8).

Comment. Photodynamic treatments using verteporfin with the procedure recommended for patients with neovascular ARMD were performed in human eyes. The treatment effect was controlled by angiographic imaging, and the areas of B interest were identified and sub- Figure 3. Light microscopy of a choroidal section of eye 2 following photodynamic therapy. A, The sequently evaluated by light and superficial portion of the choroid appears condensed, with obliterated vascular lumina within the capillary electron microscopic histologic fea- layer (arrow), while large vessels remain patent. B, Choriocapillary vessels and deeper vessels of an tures, with the aim to qualify struc- untreated area are open (arrow) and contain red blood cells (original magnification ϫ450). tural changes induced by PDT. The primary effect of PDT seems tures. Clots consisted of densely Based on the homogeneity and the in- to be damage of the choriocapillary packed red blood cells, thrombo- tensity of hypofluorescence in an an- endothelium, as indicated by swell- cytes, and fibrin. Macrophages were giographic modality using a low ing, fragmentation, detachment from found, consistent with an inflamma- wavelength, like FA, masking of the its basement membrane, and degen- tory stimulus. None of the described underlying fluorescence was sus- eration; however, recanalization of mechanisms is selective for neovas- pected (eg, by hemoglobin or an al- occluded choriocapillaries seems to cular endothelial cells. Hence, inten- tered RPE).16 The fact that hypofluo- occur within a short interval. Signifi- sive damage to physiological vascu- rescence covers precisely the area of cant alterations of the RPE and the lar structures should be expected. the treatment spot and resolves slowly neural retina do not occur. In animal studies, the only during the following weeks suggests Vascular endothelial damage is source of histologic features to date, transient choroidal nonperfusion the major hallmark of photody- closure of choriocapillaris following rather than masking—which was sub- namic tissue effects and results from verteporfin therapy, was proved by stantiated with correlation of angio- the direct interaction of a singlet of light and electron microscopy.5,6 A di- graphic and histopathological fea- oxygen with the lipids of endothe- rect dose-response relationship was tures. The consistency of histologic lial cytoplasmic membranes.8 Addi- found with capillary occlusion at results and ICGA imaging is striking tional intracellular photo-oxidation lower doses, while higher light doses because by ICGA, choriocapillary causes a rearrangement of the cyto- invariably led to alteration of larger shutdown was seen in the 50-J/cm2 skeleton, with shrinkage of the en- choroidal vessels and RPE.5 The pho- treated spot (Figure 3A) and disap- dothelial cells and exposure of the tothrombotic efficacy of verteporfin pearance of larger vessels occurred in basement membrane, an intensive clearly depends on the drug and light the 100-J/cm2 treated spot (which was thrombogenic stimulus.9 Activated dose applied, with larger-caliber ves- supported by the respective extent of platelets release vasoactive media- sels occluded at an increasing dos- vascular obliteration in histopatho- tors (eg, thromboxane, tumor necro- age.11 Accordingly, occlusive effects logical features). Indocyanine green sis factor ␣, and histamine).8 Blood were also found in deeper layers and angiography may, therefore, be rec- flow stasis is the result of endothe- in vessels with larger lumina in areas ommended as a useful clinical tool for lial swelling, erythrocyte sludging, exposed to 100 J/cm2 of light in hu- documentation of photodynamic vas- platelet adhesion, vasoconstriction, man eyes. Occlusive choroidal ef- cular effects.7,17,18 and increased vascular permeabil- fects are not specific for verteporfin How is obvious choriocapillary ity. The release of cytokines, such as or liposomal preparations, but have occlusion compatible with mainte- interleukin 1␤, interleukin 2, and also been described with various other nance of visual function? Histologic tumor necrosis factor ␣, from at- compounds with hydrophilic or features reveal structural integrity of tracted macrophages further facili- amphiphilic character, such as overlying photoreceptors after an in- tates vessel closure.10 The mechanis- purlytin, lutetium texaphyrin, ATX- terval of hypothetical hypoxia for as tic sequelae of these phototoxic S10 (Na), and mono-L-aspartyl long as 1 week. Microperimetry, a 12-15 effects were seen histologically (Fig- chlorin e6. sensitive test of photoreceptor func- ures 5 and 6): vascular endothelial Intensive controversy was raised tion, demonstrates improvement of membranes were discontinuous, and by the characteristic hypofluores- retinal sensitivity within the treated cells were fragmented. Cellular swell- cence seen regularly after PDT. Hy- CNV area in 80% of eyes at 4 weeks.18 ing and detachment from the base- pofluorescence is most pronounced The oxygen supply provided by ment membrane were common fea- in FA performed 1 week after PDT. patent large vessels might guarantee

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RPE EX

RPE

A C

RPE RPE

D E

Figure 4. Light microscopic appearance (1-µm semithin sections) of the choroid and the retina of patients 1 (A-C) and 2 (D and E) (toluidine blue O). A, The retina and choroid in the area treated with 100-J/cm2 spots, showing complete obstruction of the choriocapillaris (arrows) and a slightly vacuolated retinal pigment epithelium (RPE). The deeper choroidal vessels and the overlying photoreceptor layer (PR) appear normal (original magnification ϫ350). B, The choroid in the area treated with 50-J/cm2 spots, showing occlusion of the choriocapillaris (arrows), open deeper vessels, and a rather normal RPE (original magnification ϫ620). There are minor changes in the RPE (ie, rounding up of the apices is the result of retinal detachment). C, The choroid in an untreated area showing choriocapillaries (arrows) with wide-open lumina and a normal-appearing RPE; retinal detachment and accumulation of subretinal exudate (EX) occurred secondary to tumor development (original magnification ϫ670). D, The choroid in the photodynamic therapy–treated area showing occlusion of the choriocapillaris (arrows) due to swelling of endothelial cells and open deeper vessels (original magnification ϫ630). E, The choroid in an untreated area with an intact choriocapillaris (arrows) and a normal-appearing RPE (original magnification ϫ630).

photoreceptor survival. A more con- following days and reaches its maxi- reduction in photoreceptor func- vincing argument is the observation mal intensity after 3 days to 1 week.19 tion, however, defined as a transient that progression of occlusion is ex- Apparently, photoreceptors and RPE visual disturbance, was reported tremely slow. Short-term follow-up by are better capable of tolerating a pro- by 18% of the PDT-treated patients in ICGA demonstrated that choroidal longed reduction in oxygen supply the Treatment of Age-Related Mac- perfusion is not compromised at all than an immediate choroidal throm- ular Degeneration With Photody- for several hours after PDT. Choroid- bosis, which is usually associated with namic Therapy trial.1 Although the al darkening only occurs during the significant visual loss.20,21 A relative progression of the disease was halted

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EN A B

∗ ∗ RPE

BM RPE ∗ ∗

E FI

C D

RPE ∗

∗ ∗

BM RPE

E F G

See legend on next page.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 5. Electron microscopic appearance of the choroid and the retina of patient 1 in areas treated with 50 J/cm2 (A and B) and 100 J/cm2 (C-F) of light and in untreated areas (G). A, A choriocapillary showing rupture and fragmentation of endothelial cells (ENs) and detachment from their basement membrane (arrows); deformed erythrocytes fill the vessel lumen. B, A choriocapillary with advanced degeneration of ENs, leaving a denuded basement membrane (arrows) and extravasation of erythrocytes. C, A choriocapillary completely obstructed by cell debris, erythrocytes (E), and fibrin (FI); the asterisk indicates large vacuoles that are present in the overlying retinal pigment epithelium (RPE). D, Occlusion of the choriocapillaris and vacuolar degeneration (asterisks) of the RPE. E, The choroid, showing degenerative changes of the choriocapillaries (arrows), vacuolar changes of the RPE (asterisks), and intact deeper vessels. F, Intact photoreceptor cells overlying an area with occluded choriocapillaries. G, An intact choriocapillary and RPE in an adjacent untreated area. BM indicates Bruch membrane; bar, 3 µm (A and B) and 5 µm (C-G).

RPE

RPE BD

EN E

A B

RPE

RPE BD

C D

Figure 6. Electron microscopic appearance of the choriocapillaris and retinal pigment epithelium (RPE) of patient 2 in untreated areas (A) and photodynamic therapy–treated areas (B-D). The ultrastructural preservation is suboptimal due to reembedding from paraffin. A, A normal-appearing choriocapillary and RPE in an untreated central area. B, A choriocapillary with a compressed lumen and an immured erythrocyte (E) due to swelling of endothelial cells (ENs); the overlying RPE shows slight vacuolar degeneration. C, Extensive degeneration of vascular ENs. The arrows indicate the original capillary lumen. D, The remaining ENs appear to reorganize into smaller capillaries within the degenerated original capillary outline (arrows). BD indicates basal laminar deposits; bar, 5 µm (all parts).

successfully, patients lost a mean of 2 ization is illustrated histologically by logical features of the CNV com- lines of visual acuity during follow-up, the formation of novel lumina within plex as well. Cessation of leakage which might reflect a residual chorio- previously occluded channels. Elec- from classic CNV is the prominent capillary alteration.1 tron microscopy in experimental angiographic feature in clinical Recanalization was found in models showed duplication of vas- PDT.1-4 Typically, CNV nets are still multiple areas of the primarily oc- cular basement membranes indica- delineated in early FA during follow- cluded choriocapillary. Slow pro- tive of recanalization.22 An intralu- up, but become progressively si- gression of photothrombosis over 1 minal reorganization would lead to lent with resolution of leakage ac- week in concordance with increas- a reduplication of the vascular wall, tivity. Histopathological features ing recanalization during the same potentially with restoration of the reveal a possible mechanism of bar- interval might be a competing vascular barrier. Recanalization pro- rier stabilization in those with treated mechanism and in summary re- cesses might play an important role CNV with recanalization. Persis- duce the extent of ischemia. Recanal- in the observed change in the bio- tent CNV without extravasation

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Figure 7. Electron microscopic appearance of the retinal pigment epithelium Figure 8. Electron microscopic appearance of a retinal capillary of patient 1 of patient 1 in the area treated with 50 J/cm2 of light. The cells show slight in the area treated with 50 J/cm2 of light. The vascular endothelial cells (ENs) intracellular vacuolization (asterisk), but appear rather normal and attached show no obvious alterations. PE indicates pericyte; bar, 3 µm. to the Bruch membrane (BM); the underlying choriocapillary shows rupture and fragmentation of its endothelial lining (EN). The bar indicates 5 µm.

would not further compromise reti- sels and neural structures, including clude choroidal perfusion as a factor nal integrity. Such an involutional photoreceptors and the optic nerve, for retreatment indication. stabilization is the therapeutic ra- remained intact even if exposed to a tionale of various interventions, such light dose twice as high as conven- Ursula Schmidt-Erfurth, MD as radiotherapy, antiangiogenesis, tionally used. Moderate RPE changes Horst Laqua, MD and transpupillary thermotherapy, could be found. Increased vacuoliza- Luebeck, Germany which do not eradicate CNV but de- tion was documented, which was par- Ursula Schlo¨tzer-Schrehard, MD crease the exudative activity.23-25 tially within normal age-related lim- Arne Viestenz, MD Spontaneously regressed CNV his- its, at 50 J/cm2 in our patients, who Gottfried O. H. Naumann, MD tologically exhibits persistent neo- primarily had age-related macular Erlangen, Germany vascular channels, however, with changes. Whether this damage was a lack of exudation due to a restored direct consequence of the PDT effect barrier function either due to RPE or developed secondarily due to cho- The Wellman Laboratories of Photo- or endothelial reproliferation.26 riocapillary occlusion for as long as medicine, Massachusetts General Hos- Recanalization is most likely an 1 week is difficult to analyze. Deter- pital, Boston, and Dr Schmidt-Erfurth important mechanism of CNV recur- mining the histologic features imme- are holders of a patent on the use of rence, particularly because recur- diately or shortly after photosensiti- verteporfin and have a proprietary in- rent “growth” and enlargement of zation is obviously not an option terest under the guidelines of Harvard CNV occurs at a faster rate than de considering the risk of widespread Medical School, Boston. novo occurrence of CNV.4 Choroi- phototoxic damage during the surgi- Corresponding author: Ursula dal ischemia induced by PDT might cal procedure at a time of high sen- Schmidt-Erfurth, MD, Department of stimulate growth factor expression sitizer retention. Retinal pigment epi- Ophthalmology, University Eye Hos- (eg, vascular endothelial growth fac- thelial cells also demonstrate a high pital Luebeck, Ratzeburger Allee tor), which is recognized as a major regenerative potential following struc- 160, D-23538 Luebeck, Germany stimulator of CNV.27,28 Repair of cho- tural damage.30,31 (e-mail: uschmidterfurth@ophtha roidal damage might be a challenge The histopathological findings .mu-luebeck.de). in elderly eyes because choroidal of this study identify important 1. Treatment of Age-Related Macular Degenera- density and integrity were compro- mechanisms of PDT in human eyes. tion With Photodynamic Therapy (TAP) Study mised with age.29 A combination The extent of vaso-occlusion with Group. Photodynamic therapy of subfoveal cho- therapy of PDT with antiangiogenic concomitant thrombosis of a nor- roidal neovascularization in age-related macular degeneration with verteporfin: one-year re- agents might, therefore, be promis- mal choriocapillaris is documented, sults of 2 randomized clinical trials—TAP ing in respect to CNV recurrence but as are active repair mechanisms. In fu- report. Arch Ophthalmol. 1999;117:1329- 1345. problematic in respect to choroidal ture clinical applications of PDT, the 2. Schmidt-Erfurth U, Miller J, Sickenberg M. Pho- regeneration. application of a low light dose should todynamic therapy of subfoveal choroidal neo- Although verteporfin PDT of be considered to allow for appropri- vascularization: clinical and angiographic ex- amples. Graefes Arch Clin Exp Ophthalmol. 1998; CNV does not spare the physiologi- ate choroidal regeneration in be- 236:365-374. cal choroidal capillaries, retinal ves- tween treatment intervals and to in- 3. Miller JW, Schmidt-Erfurth U, Sickenberg M,

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 et al. Photodynamic therapy with verteporfin therapy: ICG-angiographic and microperimet- hand motions OD; the left eye had for choroidal neovascularization caused by age- ric findings. Arch Ophthalmol. 2000;118:580- related macular degeneration: results of a single 582. been enucleated. She gave a history treatment in a phase 1 and 2 study. Arch Oph- 22. Husain D, Kramer M, Kenney AG, et al. Ef- of bilateral sporadic retinoblastoma thalmol. 1999;117:1161-1173. fects of photodynamic therapy using vertepor- diagnosed at age 12 months and man- 4. Schmidt-Erfurth U, Miller JW, Sickenberg M, fin on experimental choroidal neovasculariza- et al. Photodynamic therapy with verteporfin tion and normal retina and choroid up to 7 aged initially with chemotherapy and for choroidal neovascularization caused by age- weeks after treatment. Invest Ophthalmol Vis Sci. cryotherapy to the right eye and related macular degeneration: results of retreat- 1999;40:2322-2331. enucleation of the left eye. One year ments in a phase 1 and 2 study. Arch Ophthal- 23. Finger PT, Chakravarthy U, Augsburger JJ. Ra- mol. 1999;117:1177-1187. diotherapy and the treatment of age-related later, 2 tumor recurrences were de- 5. Schmidt-Erfurth U, Hasan T, Gragoudas E, Mi- macular degeneration: external beam radia- tected at the site of previous cryo- chaud N, Flotte TJ, Birngruber R. Vascular tar- tion therapy is effective in the treatment of age- geting in photodynamic occlusion of subretinal related macular degeneration. Arch Ophthal- therapy scars superiorly and infero- vessels. Ophthalmology. 1994;101:1953-1961. mol. 1998;116:1507-1511. nasally, measuring 1.5ϫ1.5ϫ1.0 6. Kramer M, Miller JW, Michaud N, et al. Lyso- 24. Fung WE. Interferon alpha 2a for treatment of mm and 12.0ϫ10.5ϫ8.0 mm, re- somal benzoporphyrin derivative verteporfin in age-related macular degeneration. Am J Oph- photodynamic therapy: selective treatment of thalmol. 1991;112:349-350. spectively. The inferonasal mass dis- choroidal neovascularization in monkeys. Oph- 25. Reichel E, Berrocal A, Ip M, et al. Transpupil- played vitreous seeds and the eye was thalmology. 1996;103:427-438. lary thermotherapy of occult subfoveal choroid- classified as Reese-Ellsworth group 7. Schmidt-Erfurth U, Michels S, Hager A, al neovascularization in patients with age- Laqua H. ICG-angiographic analysis of the related macular degeneration. Ophthalmology. Vb. External beam radiotherapy us- photodynamic mechanism in the photody- 1999;106:1908-1914. ing 3500 rad was delivered through namic treatment of choroidal neovasculariza- 26. Miller H, Miller B, Ryan SJ. The role of retinal tion. Invest Ophthalmol Vis Sci. 1998;39(suppl): pigment epithelium in the involution of sub- an anterior portal. A cataract was sub- S242. retinal neovascularization. Invest Ophthalmol Vis sequently removed. During the fol- 8. Finger VH. Vascular effects of photodynamic Sci. 1986;27:1644-1652. lowing 24 years, the tumors were fol- therapy. J Clin Laser Med Surg. 1996;14:323- 27. McLeod DS, Lutty GA. High-resolution histologic 328. analysis of the human choroidal vasculature. In- lowed-up elsewhere and remained 9. Henderson BW, Dougherty TJ. How does pho- vest Ophthalmol Vis Sci. 1994;35:3799-3811. regressed. Examination under an- todynamic therapy work? Photochem Photo- 28. Kvanta A, Algvere B, Berghin L, Seregard S. Sub- esthesia with complete funduscopy biol. 1992;55:145-157. foveal fibrovascular membranes in age-related 10. Gollnick SO, Liu X, Owczarczak B, Musser DA, macular degeneration express vascular endo- was performed for 9 consecutive Henderson BW. Altered expression of inter- thelial growth factor. Invest Ophthalmol Vis Sci. years and office evaluation for the leukin 6 and interleukin 10 as a result of pho- 1996;37:1929-1934. todynamic therapy in vivo. Cancer Res. 1997; 29. Kwak N, Okamoto N, Wood J, Campochiaro subsequent 15 years. Radiation com- 57:3904-3909. P. VEGF is major stimulator in model of cho- plications of maculopathy, dry eye, 11. Lange N, Ballini JP, Waguieres G, van den Bergh roidal neovascularization. Invest Ophthalmol Vis and corneal opacification com- H. A new drug-screening procedure for pho- Sci. 2000;41:3158-3164. tosensitizing agents used in photodynamic 30. Heriot WJ, Machemer R. Pigment epithelial re- bined with photophobia afforded a therapy for CNV. Invest Ophthalmol Vis Sci. pair. Graefes Arch Clin Exp Ophthalmol. 1992; poor view of the fundus during those 2001;42:38-46. 230:91-109. 15 years. 12. Obana A, Gohto Y, Kanas M, Nakajima S, Kan- 31. Roider J, Michaud N, Flotte TJ, Birngruber R. eda K, Miki T. Selective photodynamic effects Response of the retinal pigment epithelium to At the most recent examina- of the new photosensitizer ATX-S10 (Na) on selective photocoagulation. Arch Ophthalmol. tion, there was a hyphema and vit- choroidal neovascularization in monkeys. 1992;110:1786-1792. Arch Ophthalmol. 2000;118:650-658. reous hemorrhage that precluded a 13. Blumenkranz MS, Woodburn KW, Qing F, Ver- view of the fundus. The patient was dooner S, Kessel D, Miller R. Lutetium tex- referred to the Ocular Oncology Ser- aphyrin (LU-Tex): a potential new agent for ocular fundus angiography and photody- vice at Wills Eye Hospital (Philadel- namic therapy. Am J Ophthalmol. 2000;129: phia, Pa) for further management. 353-362. Mushroom-Shaped Results of ocular ultrasound re- 14. Mori K, Yoneya S, Ohta M, et al. Angiographic Choroidal Recurrence and histologic effects of fundus photody- vealed a mushroom-shaped fundus namic therapy with a hydrophilic sensitizer of Retinoblastoma mass measuring 15.0 mm in base (mono-L-aspartyl chlorin e6). Ophthalmology. 25 Years After Therapy 1999;106:1384-1391. and 10.3 mm in thickness. There was 15. Thomas EL, Rosen R, Murphy R, et al. Purly- a slight suggestion of calcification in tin (SnET2)-photodynamic therapy produces An important method of conserva- the tumor but no acoustic shadow- closure of subfoveal choroidal neovascularization in humans. Invest Ophthalmol Vis Sci. 1998; tive therapy for retinoblastoma during in the orbit (Figure 1). Vascu- 39(suppl):S242. ing the past 50 years has been ex- lar pulsations were absent. Vitre- 16. Flower RW, Snyder WJ. Expanded hypothesis ternal beam radiotherapy. In general, ous echoes suggestive of blood were on the mechanism of photodynamic therapy action on choroidal neovascularization. Retina. this modality offers favorable tu- noted. Based on these findings, the 1999;19:365-369. mor control, but subsequent moni- differential diagnosis included late- 17. Schmidt-ErfurthU,MichelsS,BarbazettoI,Laqua H. Photodynamic effects on choroidal neovas- toring for local recurrence and ap- onset recurrence of retinoblastoma cularization and physiological choroid. Invest plication of salvage therapy have or choroidal melanoma. Ophthalmol Vis Sci. 2002;43:830-841. been emphasized. Several authors The right eye was enucleated. 18. Schmidt-Erfurth U. Indocyanine green angiography and retinal sensitivity after photody- have observed that recurrence is usu- Gross pathology revealed a mush- namic therapy of subfoveal choroidal neovascu- ally detected within 1 year of room-shaped amelanotic choroidal larization. Semin Ophthalmol. 1999;14:35-44. therapy.1,2 We report late-onset cho- tumor (Figure 2). Histopathologic 19. Michels S, Schmidt-Erfurth U. Early vascular changes induced by photodynamic therapy us- roidal recurrence of retinoblas- examination results confirmed that ing verteporfin. Invest Ophthalmol Vis Sci. 2001; toma 25 years following therapy. the tumor was a poorly differenti- 42(suppl):S304. 20. Aug LP, Yap EY, Fam HB. Bilateral choroidal ated, mitotically active retinoblas- infarction in a patient with antiphospholipid Report of a Case. A 25-year-old Latin toma forming a massive tumor in the syndrome: a case report. Clin Exp Ophthalmol. American woman noticed sudden, ciliary body and peripheral choroid 2000;28:326-328. 21. Hoerauf H, Schmidt-Erfurth U. Combined cho- painless visual loss in her only eye (Figure 2). The tumor cells grew in roidal and retinal ischemia during interferon on awakening. Visual acuity was a confluent fashion without necro-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 sis. The cells had scant cytoplasm stable regression is achieved in 29% and subsequent cobalt plaque radio- and showed intense positive immu- to 66% of eyes.1,2 therapy and xenon photocoagulation. noreactivity for neuron-specific Tumor recurrence following ex- Recurrence was discovered 10 years enolase and were negative for S100 ternal beam radiotherapy generally is afteranintervalofstablefindings.Oth- protein, consistent with retinoblas- detected within 1 year of treatment2,5 ers have recognized late recurrence at toma. A few calcific foci from a pre- and 96% occurs within 2 years follow- 4.5 and 9 years.5,7 vious scar were noted near the base ingtreatment.1 Inananalysisof65eyes An alternative possiblity to tu- of the recurrence. There was tumor treated with external beam radio- mor recurrence in our case could be invasion of the anterior chamber. therapy,allretinoblastomarecurrences new tumor formation in a patient Chemoprophylaxis for metastatic dis- were found within 2.75 years of treat- with germinal mutation of the reti- ease was provided using vincristine, ment.1 Tumor recurrence was more noblastoma gene. In most in- etoposide, and carboplatin for 6 likely in slightly older children (1.8 stances, new tumors in bilateral cases months. years in the recurrence group vs 0.9 occur within 1 to 2 years from ini- yearsinthenonrecurrencegroup)and tial diagnosis.8 Late-onset new tu- Comment. Whole-eye radio- in those with larger tumors (16 mm mors after 5 years of follow-up in bi- therapy for retinoblastoma offers tu- in the recurrence group vs 8.9 mm in lateral retinoblastoma have been mor control in 41% to 74% of cases.1-4 the nonrecurrence group). observed at 8 years9 and 12 years.10 When radiotherapy is combined with Recurrenceofretinoblastomabe- Another possibility for the patho- focal salvage treatments (cryo- yond 4 years following radiotherapy genesis of this tumor is that it rep- therapy, laser photocoagulation, and is extremely rare. Ytteborg and Arne- resents a radiation-induced second plaque radiotherapy), tumor con- sen6 observed one case of late-onset cancer.11 It seems highly improb- trol improves to 80%.2 However, tu- recurrence12yearsafterradiotherapy. able to have retinoblastoma as a mor control decreases with more ad- The patient had shown initial poor tu- second cancer after treatment of re- vanced retinoblastoma, such as mor control for 2 years following 2 tinoblastoma. In our case, it is most Reese-Ellsworth group V, where courses of external beam radiotherapy likely that choroidal recurrence of retinoblastoma developed after 25 years. Another interesting facet of this case was the configuration of the recurrence as a mushroom-shaped choroidal mass, suggestive of melanoma with a rupture through the Bruch membrane.12 The mushroom configuration has rarely been found with nonmelanoma tumors, such as choroidal metastasis13,14 and choroidal hemangioma,15 that have broken through the Bruch membrane. To our knowledge, this is the first report of choroidal invasion from retinoblastoma assuming this configuration. However, we have seen another case of retinoblastoma histopathologi- cally that had massive choroidal invasion and had ruptured through the Bruch membrane, assuming a mush- Figure 1. B-scan ocular ultrasound of an eye with no fundus view owing to hyphema and vitreous hemorrhage. Note the echogenic mushroom-shaped fundus mass in the peripheral choroid and ciliary room configuration. Because of the ul- body region. trasound findings, melanoma was a

A B C

Figure 2. Pathologic examination revealed an amelanotic mushroom-shaped choroidal mass. A, Gross pathologic appearance of the retina and retinal pigment epithelium lining the inner surface of the choroidal mass. B, The choroidal mass is noted with overlying retinal tissue (hematoxylin-eosin, original magnification ϫ10). C, Poorly differentiated retinoblastoma is shown (hematoxylin-eosin, original magnification ϫ200).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 diagnostic consideration since cho- 8. Salmonsen P, Ellsworth RM, Kitchin FD. The An Ahmed (New World Medi- occurrence of new retinoblastomas after treat- roidal melanoma has been reported ment. Ophthalmology. 1965;86:837-843. cal Inc, Cucamonga, Calif) tube in association with both unilateral and 9. Stallard HB. The conservative treatment of reti- shunt with a Tutoplast (Tutogen bilateral retinoblastoma.11,16 noblastoma. Trans Ophthalmol Soc UK. 1962; Medical Inc, Clifton, NJ) patch graft 82:473-534. In summary, we report a remark- 10. Skeggs D, Williams J. The treatment of ad- was implanted superotemporally ablecaseofchoroidalrecurrenceofreti- vanced retinoblastoma by means of external ir- without complication, and the tube radiation combined with chemotherapy. Clin noblastoma25yearsafterradiotherapy, Radiol. 1966;17:169-172. was placed into the anterior cham- that assumed a mushroom shape, 11. Wong FL, Boice JD, Abramson DH, et al. Can- ber. The IOP postoperatively was simulating a choroidal melanoma. We cer incidence after retinoblastoma: radiation consistently lower than 21 mm Hg. dose and sarcoma risk. JAMA. 1997;278:1262- advise that patients with retinoblas- 1267. However, there was gradually in- toma maintain regular monitoring of 12. Shields JA, Shields CL. Ultrasonography of Pos- creasing proptosis, and by 2 months the affected eye(s) throughout their terior Uveal Melanoma: Atlas of Intraocular Tu- mor. Philadelphia, Pa. Lippincott Williams & postoperatively, he had developed 6 lifetimes. If difficulty in visualization Wilkins; 1999:109. mm of proptosis, with marked dis- developsowingtomediaopacityorpa- 13. Shields CL, Shields JA, Gross N, et al. Survey placement of the right globe inferi- of 520 uveal metastases. Ophthalmology. 1997; tient cooperation, then regular ocular 104:1265-1276. orly. There was significant limita- ultrasonographyandexaminationwith 14. Ward SD, Byrne BJ, Kincaid MC, Mann ES. Ul- tion of elevation, restriction of sedation are warranted. trasonographic evidence of a mushroom- abduction, and exposure keratitis of shaped choroidal metastasis. Am J Ophthal- mol. 2000;130:681-682. the right eye. The patient and his Carol L. Shields, MD 15. Spraul CW, Kim D, Fineberg E, Grossniklaus parents were notably unhappy with Michelle R. Piccone, MD HE. Mushroom-shaped choroidal hemangioma. Am J Ophthalmol. 1996;122:434-436. the cosmetic result. Magnetic reso- Jerry A. Shields, MD 16. Singh AD, Shields CL, Shields JA, Sternberg P. Oc- nance imaging results revealed a Ralph C. Eagle, Jr, MD currence of retinoblastoma and uveal melanoma large, focal collection of fluid su- Philadelphia, Pa in the same patient. Retina. 2000;20:305-306. perolaterally to the globe. The tube Michael Singer, MD shunt could be identified within the San Antonio, Tex fluid collection (Figure). The diagnosis was proptosis caused by the Cosmetically Significant cyst surrounding the Ahmed tube This research was supported by the Proptosis Following a Tube shunt. Eye Tumor Research Foundation, Shunt Procedure It was elected to follow up the Philadelphia, Pa (Dr C. L. Shields), patient conservatively. The expo- the Paul Kayser International Award A 16-year-old boy was hit in the right sure keratitis was treated with in- of Merit in Retina Research, Houston eye with a paint ball, resulting in a tensive lubrication and it gradually Tex (Dr J. A. Shields), and the Noel dislocated lens, prolapsed iris, and cleared. The IOP remained be- T. and Sara L. Simmonds Endow- a vitreous hemorrhage. He had a len- tween 12 and 15 mm Hg. There was ment for Ophthalmic Pathology, sectomy, vitrectomy, and complete no symptomatic diplopia, presum- Wills Eye Hospital, Philadelphia (Dr iridectomy. Subsequent visual acu- ably because of the poor vision in the Eagle). ity was hand movements OD and a right eye. After 6 weeks of follow- Corresponding author and re- right afferent pupillary defect with up, the proptosis had decreased to prints: Carol L. Shields, MD, Ocular no identifiable anterior segment a 1-mm difference between the 2 Oncology Service, Wills Eye Hospi- structures.The visual acuity in was globes and there continued to be tal, 900 Walnut St, Philadelphia, PA 20/20 OS. One month following mild limitation of elevation of the 19107. surgery, the patient developed el- right eye. One year later, the eye re- 1. Abramson DH, Servodidio CA, De Lillo AR, et evated intraocular pressure (IOP) mained slightly proptosed and in- al. Recurrence of unilateral retinoblastoma fol- ranging between 40 and 50 mm Hg. feriorly displaced, but the cosmetic lowing radiation therapy. Ophthalmol Genet. 1994;15:107-113. The patient was referred for man- defect was considered tolerable by 2. Toma NMG, Hungerford JL, Plowman PN, et agement of his glaucoma. the patient and his parents. al. External beam radiotherapy for retinoblastoma, II: lens sparing technique. Br J Ophthal- mol. 1995;79:112-117. Report of a Case. When we first saw Comment. To our knowledge, this 3. Schipper J. Retinoblastoma: A Medical and Ex- the patient, the optic disc of the right is the first reported case of propto- perimental Study [thesis]. the Netherlands: State University of Utrecht; 1980. eye had a cup-disc ratio of 0.6. In sis following implantation of a drain- 4. Foote RL, Garretson BR, Schomberg PJ, et al. Ex- contrast, the left optic disc had al- age device. Oculomotility prob- ternal beam irradiation for retinoblastoma: pat- most no cup. It was believed that lems secondary to tube shunts are terns of failure and dose-response analysis. Int J Radiat Oncol Biol Physics. 1989;16:823-30. marked glaucoma damage had al- known complications of Ahmed, 5. Messmer EP, Sauerwein W, Heinrich T, et al. ready occurred. Visual acuity was too Krupin (Hood Laboratories, St Pem- New and recurrent tumor foci following local poor to permit a meaningful visual broke, Mass), Baerveldt (Pharma- treatment as well as external beam radiation in eyes of patients with hereditary retinoblas- field examination. It was believed cia & Upjohn, Bridgewater, NJ), and toma. Graefes Arch Ophthalmol. 1990;228:426- that surgery was necessary to con- Molteno (OP Inc, Costa Mesa, Calif) 431. 1-5 6. Ytteborg J, Arnesen K. Later recurrence of reti- trol the IOP, and because of the ex- drainage implants. There has been noblastoma. Acta Ophthalmol. 1972;50:367- tensive scarring caused by the pre- 1 reported case of extraocular muscle 374. vious surgery and the absence of restriction with the Ahmed tube 7. Paterson MW, Charteris AA. Retinoblastoma: report of 19 patient treated with radiotherapy. vitreous, a tube shunt procedure was shunt. The tube shunt was placed su- Br J Ophthalmol. 1965;49:347-358. considered appropriate. peronasally and resulted in an ac-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Paradoxical Intraocular Pressure Elevation After Combined Therapy With Latanoprost and Bimatoprost

Latanoprost is a prostaglandin F2a analogue prodrug that is used in the management of ocular hypertension and glaucoma. Latanoprost is widely prescribed and has displayed ocular hypotensive efficacy greater than that exhibited by timolol maleate in controlled compara- tive studies.1-4 The effect on intraocular pressure (IOP) seems to be caused by increased uveoscleral out- Magnetic resonance imaging shows the tube shunt within a collection of fluid superolaterally to the globe. flow.5,6 Bimatoprost is a new ocular compound that appears to mimic the quired pseudo-Brown syndrome on plication of drainage devices, em- prostamides. Prostamides are the the first postoperative day. phasizing the need for an appropriate most recently described members of Oculomotility disturbances may discussion with the patient prior to the fatty-acid amide family and are result from several factors. First, when surgery. It also reports, to our knowl- potent ocular hypotensive agents. Bi- an implant placed under the rectus edge, the first case of proptosis fol- matoprost also has been shown to muscles is responsible for produc- lowing the placement of an Ahmed have superior hypotensive efficacy ing diplopia, the limitation of move- tube shunt. Finally, it suggests that compared with timolol.7,8 Bimato- ment is in the direction of the im- a period of observation may be use- prost seems to work by enhancing plant, eg, a superotemporal quadrant ful before embarking on surgical cor- pressure-independent aqueous out- implant produces a hypotropia that rection for motility disturbances fol- flow, presumably corresponding to increases in upgaze, an esotropia that lowing implantation of drainage uveoscleral outflow and conven- increases in abduction, or a combi- devices. tional outflow through the trabec- nation of both. This is thought to be ular meshwork. Bimatoprost has also related to a posterior fixation effect in- Helen V. Danesh-Meyer, MD, FRACO been noted to increase aqueous produced by scarring between the muscle Auckland, New Zealand duction.9 belly and the sclera. Scarring poste- George L. Spaeth, MD We have recently noted 3 pa- rior to the widest portion of the im- Marlan Maus, MD tients who have demonstrated plant will weaken the function of the Philadelphia, Pa marked paradoxical IOP elevation af- muscle in its field of action. Second, ter adding bimatoprost to the treat- a large bleb produced by aqueous ex- Corresponding author: Helen V. ment regimen of an eye already being pansion of the capsule that forms Danesh-Meyer, MD, FRACO, Depart- treated with latanoprost, and we pre- around the reservoir may result in a ment of Ophthalmology, University of sent those cases. crowding-effect that limits the move- Auckland, Auckland, New Zealand (e- ment of the eye and in mechanical dis- mail: [email protected]). Report of Cases. Case 1. A 61-year- placement of muscles.3 The most old African American man had been common factor that results in oculo- diagnosed as having open-angle motility disturbances is the large size 1. Topouzis F, Coleman AL, Choplin N, et al. Fol- glaucoma 6 months previously. low-up of the original cohort with the Ahmed of the implant and its location or ex- glaucoma valve implant. Am J Ophthalmol. 1999; When he was first evaluated by one tension under a muscle belly. Many 128:198-204. of us (L.W.H.) a month after his di- patients with motility disturbance sec- 2. Huang MC, Netland PA, Coleman AL, et al. In- agnosis, he was noted to have a termediate-term clinical experience with the ondary to drainage device place- Ahmed glaucoma valve implant. Am J Ophthal- Goldmann applanation IOP of 22 ment require surgical intervention to mol. 1999;127:27-33. mm Hg OD and 19 mm Hg OS. He correct the misalignment. In our case, 3. Ball SF, Ellis GS, Harrington RG, et al. Brown’s had been using timolol 0.5% in both superior oblique tendon syndrome after Baerveldt the proptosis and motility distur- glaucoma implant [letter]. Arch Ophthalmol. eyes twice daily until discontinu- bance appeared 2 months after the 1992;110:1368. ing this medication 1 week before 4. Coats DK, Paysse EA, Orenga-Nania S. Ac- placement of the Ahmed device and quired pseudo-Brown’s syndrome immediately the visit. For compliance reasons and resolved partially 6 weeks following following Ahmed valve glaucoma implant. Oph- as a trial in 1 eye, he began apply- the initial visit. thalmic Surg Lasers. 1999;30:396-397. ing timolol maleate ophthalmic 5. Christmann LM, Wilson ME. Motility distur- This case highlights the motil- bances after Molteno implants. J Pediatr Oph- gel-forming solution (Timoptic XE; ity disturbance that may be a com- thalmol Strabismus. 1992;29:44-48. Merck & Co, Inc, West Point, Pa)

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 0.5% in the right eye once daily in chloride was replaced with bimato- however, many patients eventually the morning. A horseshoe retinal tear prost once daily in the morning in the require more than 1 medication.11 Re- was incidentally found in the right left eye. At the next follow-up visit cent studies12,13 have shown the im- eye, and the patient underwent pro- in 2 weeks, the IOP was 7 mm Hg OD portance of lowering the IOP in the phylactic laser treatment of the tear and 35 mm Hg OS. Bimatoprost was management of glaucoma, perhaps to at the same visit. discontinued, with resumption of lower levels than were thought nec- At follow-up 3 weeks later, the dorzolamide hydrochloride– essary in the past. With the develop- IOP was 24 mm Hg OD and 21 mm timolol maleate ophthalmic solu- ment of newer glaucoma medica- Hg OS. Because he required a lower tion twice daily with the patient ap- tions and combinations thereof, lower target IOP, timolol maleate ophthal- plying nasolacrimal duct occlusion. target IOPs are more readily achieved. mic gel-forming solution was re- At the follow-up visit 2 weeks later, Because many patients with glau- placed with latanoprost in the right the IOP was 6 mm Hg OD and 13 coma require combination therapy, eye once daily in the evening. Two mm Hg OS. The IOP was measured the combination of the 2 powerful hy- months following his initial visit, the in the late morning or early after- potensive agents latanoprost and bi- IOP was 25 mm Hg OD and 15 noon at each visit and was measured matoprost may become a popular mm Hg OS, and bimatoprost was by the same person (L.W.H.) each treatment option. In addition, latano- added to the treatment regimen in time. The patient reported compli- prost and bimatoprost offer conve- the right eye once daily in the morn- ance with the medical regimen at nient once daily dosing. ing. At follow-up 5 weeks later, the each visit. Latanoprost and bimatoprost IOP was 48 mm Hg OD and 21 Case 3. A 62-year-old white seem to work by increasing uveo- mm Hg OS. Bimatoprost was dis- woman was diagnosed as having scleral outflow, so combining 2 drugs continued, and the IOP 1 week later acute-angle closure in the left eye in that facilitate outflow may not be the (following use of latanoprost alone 1974 and underwent surgical pe- most optimal approach, although in the right eye) was 33 mm Hg OD ripheral iridectomy. She had laser these 2 agents presumably work on and 20 mm Hg OS. The patient re- peripheral iridotomy performed on different receptors. Woodward et al14 ported compliance with therapy at the right eye in 1982. She had been showed that bimatoprost has no every follow-up visit, and the ante- using treatment drops for glauco- significant affinity for prostaglandin rior segment remained stable. The main both eyes since the 1970s, with receptors or for several other recep- IOP was measured in the early to late some recent difficulty in control- tors in a feline iris sphincter prepa- afternoon at each visit and by the ling the IOP in the left eye. During ration. This finding, albeit in a fe- same person (L.W.H.) each time. the past year, the IOP had re- line model, supports the concept that Case 2. A 70-year-old white mained in the midteens in the right the target receptor for bimatoprost is man was diagnosed as having pig- eye, but had ranged between 16 and pharmacologically unique. mentary glaucoma, more severe in 23 mm Hg OS. By May 2001, the IOP It is also known that the use of the right eye than in the left, in 1988. was 13 mm Hg OD and 19 mm Hg latanoprost twice daily is less effec- He had undergone trabeculectomy OS using 1 drop of latanoprost daily tive than once daily application,15-18 in the right eye and had received an in both eyes in the evening and 1 and an early study7 also shows that Ahmed valve implantation in the left drop of brimonidine tartrate twice bimatoprost twice daily is less effec- eye in February 2000. Medications daily in the left eye. One drop of bi- tive than bimatoprost once daily. In in the right eye had been discontin- matoprost in the left eye every a study of 40 healthy volunteers who ued since the trabeculectomy. How- evening was added to the regimen. received latanoprost once daily in one ever, the condition of the left eye re- Four weeks later, the IOP was 42 eye and twice daily in the fellow eye, quired that glaucoma medications be mm Hg OS, although the patient had Linden and Alm18 showed that once resumed. By March 2001, the IOP discontinued the bimatoprost 4 days daily dosing resulted in a signifi- was 10 mm Hg OU, with the pa- before this visit because of irrita- cantly lower IOP compared with tient applying latanoprost once daily tion and redness of the left eye. The twice daily dosing on day 15, but not in the evening in the left eye and a IOP in the right eye was 16 mm Hg on day 2. They believed that a twice combination of dorzolamide hydro- at that visit. Timolol maleate oph- daily regimen of latanoprost leads to chloride and timolol maleate ophthalmic gel-forming solution 0.5% desensitization at the level of the FP- thalmic solution (Cosopt; Merck & once daily in the morning in the left receptor. In monkeys, treatment with Co, Inc) twice daily in the left eye, eye was added to the current regi- large dosages of prostaglandin F2a for with a stable anterior segment in men of latanoprost and bri- 4 to 8 days induces loss of extracel- both eyes. At follow-up in May 2001, monidine, and 3 days later the IOP lular material between the ciliary the dorzolamide hydrochloride– was 15 mm Hg OU. muscle bundles.19,20 In their 6-month timolol maleate ophthalmic solu- comparison of the effects of bimato- tion was replaced with dorzola- Comment. Glaucoma is a chronic, prost vs timolol, Sherwood et al7 re- mide hydrochloride twice daily, as progressive disease characterized by ported a 33% reduction of IOP from the patient was noted to have bra- visual field loss and optic nerve dam- baseline with bimatoprost once daily, dycardia. He continued using la- age, often in the presence of el- compared with a 26% reduction with tanoprost in the left eye. The IOP at evated IOP.10 Patients with glau- bimatoprost twice daily. They specu- that visit measured 8 mm Hg OD and coma are usually treated initially with lated that twice daily dosing of bi- 20 mm Hg OS. Dorzolamide hydro- monotherapy to reduce their IOP; matoprost may give concentrations

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 that are past the peak of the dose- been demonstrated (Achim Krauss, 3-month clinical trial. Ophthalmology. 2001; 108:1023-1032. response curve, resulting in reduced PhD, oral communication, March 24, 9. Brubaker RF, Schoff EO, Nau CB, et al. Effects efficacy. Commercially available la- 2001), so bimatoprost was applied in of AGN 192024, a new ocular hypotensive tanoprost and bimatoprost are near the morning in 2 of the 3 patients for agent, on aqueous dynamics. Am J Ophthal- mol. 2001;131:19-24. the top of their dose-response curves, convenience. 10. Shields MB. Textbook of Glaucoma. 3rd ed. so using them together results in ex- In summary, latanoprost and Baltimore, Md: Williams & Wilkins; 1992:172- 188. cessive dosages (Carl Camras, MD, bimatoprost are powerful ocular hy- 11. Everitt D, Avorn J. Systemic effects of medica- written communication, March 12, potensive lipids that have shown ef- tions used to treat glaucoma. Ann Intern Med. 2001). Brubaker et al9 demonstrated ficacy superior to that of timolol in 1990;112:120-125. 12. AGIS Investigators. The Advanced Glaucoma that bimatoprost also causes an in- controlled clinical trials. Using these Intervention Study (AGIS), 7: the relationship crease in aqueous production. Per- 2 medications together may lead to between control of intraocular pressure and vi- marked IOP elevation in some pa- sual field deterioration. Am J Ophthalmol. 2000; haps the increased aqueous flow in 130:429-440. the face of compromised conven- tients, and close surveillance is ad- 13. Collaborative Normal-Tension Glaucoma Study tional outflow is the reason for the vised whenever combined therapy is Group. Comparison of glaucomatous progression between untreated patients with normal- elevated IOP. Interestingly, the com- prescribed. Further study is indi- tension glaucoma and patients with therapeu- bination of latanoprost and unopros- cated to determine more clearly tically reduced intraocular pressures. Am tone isopropyl, another hypotensive which patients might be at risk for J Ophthalmol. 1998;126:487-497. 14. Woodward DF, Krauss AH, Chen J, et al. The lipid, has been reported to have an ad- this paradoxical reaction. pharmacology of bimatoprost (Bimatoprost). ditive pressure-lowering effect on di- Surv Ophthalmol. 2001;45(suppl 4):S337- 21 Leon W. Herndon, MD S345. urnal curve characteristics. 15. Alm A, Villumsen J, Tornquist P, et al. Intra- Each of our patients demon- Sanjay G. Asrani, MD ocular pressure-reducing effect of PhXA41 in strated marked IOP elevation within Gayle H. Williams, MD, PhD patients with increased eye pressure: a one- month study. Ophthalmology. 1993;100:1312- 2 to 5 weeks after adding bimato- Pratap Challa, MD 1317. prost to the treatment regimen of an Paul P. Lee, MD 16. Nagasubramanian S, Sheth GP, Hitchings RA, eye being treated with latanoprost. Durham, NC et al. Intraocular pressure-reducing effect of PhXA41 in ocular hypertension: comparison of There are possible mitigating fac- dose regimens. Ophthalmology. 1993;100:1305- tors other than the combination 1311. therapy that could have contributed Corresponding author: Leon W. Hern- 17. Alm A, Widengard I, Kjellgren D, et al. Latano- don, MD, Duke University Eye Cen- prost administered once daily caused a main- to the pressure rises in our patients. tained reduction of intraocular pressure in glau- Although each patient claimed com- ter, PO Box 3802, Durham, NC 27710 coma patients treated concomitantly with (e-mail: [email protected]). timolol. Br J Ophthalmol. 1995;79:12-16. pliance with medical therapy, missed 18. Linden C, Alm A. Latanoprost twice daily is less doses of the eyedrops could have led 1. Alm A, Stjernschantz J, for the Scandinavian La- effective than once daily: indication of recep- to rebound elevation in IOP. In case tanoprost Study Group. Effects on intraocular tor subsensitivity? Curr Eye Res. 1998;17:567- pressure and side effects of 0.005% latano- 572. 2, the patient had a diagnosis of pig- prost applied once daily, evening or morning: 19. Lutjen-Drecoll E, Tamm E. Morphological study mentary glaucoma. Wide swings of a comparison with timolol. Ophthalmology. of the anterior segment of cynomolgus mon- IOP have been demonstrated with 1995;102:1743-1752. key eyes following treatment with prostaglan- 2. Camras CB, the United States Latanoprost Study din F2␣. Exp Eye Res. 1988;47:761-769. secondary glaucomas, such as pig- Group. Comparison of latanoprost and timo- 20. Tamm E, Rittig M, Lutjen-Drecoll E. Elek- mentary and pseudoexfoliative glau- lol in patients with ocular hypertension and tronenmikroskopische und immunhistoche- coma, although this possibility would glaucoma: a six-month, masked, multicenter mische untersuchungen zur augendrucksenk- trial in the United States. Ophthalmology. 1996; enden wirkung von prostaglandin F2␣ [in be unlikely in this patient, as there 103:138-147. German]. Fortschr Ophthalmol. 1990;87:623- was no evidence of active pigment 3. Watson P, Stjernschantz J, the Latanoprost Study 629. Group. A six-month, randomized, double- 21. Stewart WC, Sharpe ED, Stewart JA, et al. Ad- dispersion. In case 3, the patient had masked study comparing latanoprost with timo- ditive efficacy of unoprostone isopropyl 0.12% a diagnosis of combined mecha- lol in open-angle glaucoma and ocular hyper- to latanoprost 0.005%. Am J Ophthalmol. 2001; nism glaucoma after peripheral iri- tention. Ophthalmology. 1996;103:126-137. 131:339-344. 4. Mishima HK, Masuda K, Kitazawa Y, et al. A dectomy. Certainly, variability of IOP comparison of latanoprost and timolol in pri- control is notorious in this setting; mary open-angle glaucoma and ocular hyper- however, this patient had under- tension. Arch Ophthalmol. 1996;114:929-932. 5. Alm A, Villumsen J. PhXA34, a new potent ocu- Orbital Cellulitis as a Late gone iridectomy many years previ- lar hypotensive drug: a study on dose-response ously, and gonioscopic findings were relationship and on aqueous humor dynamics in Complication of Glaucoma healthy volunteers. Arch Ophthalmol. 1991;109: Shunt Implantation unchanged. Although this patient had 1564-1568. discontinued bimatoprost 4 days be- 6. Ziai N, Dolan JW, Kacere RD, Brubaker RF. The fore the follow-up visit, she had used effects on aqueous dynamics of PhXA41, a new Orbital cellulitis is a rare complica- prostaglandin F2␣ analogue, after topical appli- the medication for 3 weeks before dis- cation in normal and ocular hypertensive hu- tion of glaucoma tube shunt implan- continuing it, so it is likely that there man eyes. Arch Ophthalmol. 1993;111:1351- tation. We describe a patient who de- was a lingering effect of the bimato- 1358. veloped orbital cellulitis 15 months 7. Sherwood M, Brandt J, for the Bimatoprost prost. The effect on diurnal IOP of la- Study Groups 1 and 2. Six-month comparison after placement of a Baerveldt tube tanoprost applied once daily in the of bimatoprost once-daily and twice-daily with shunt (Pharmacia Corporation, Pea- timolol twice-daily in patients with elevated in- evening has been shown to be supe- traocular pressure. Surv Ophthalmol. 2001;45 pack, NJ). The proximal portion of rior to that of latanoprost applied (suppl 4):S361-S368. the Baerveldt tube shunt had eroded once daily in the morning.1 The IOP- 8. Brandt JD, VanDenburgh AM, Chen K, for the through the conjunctiva, presum- Bimatoprost Study Group. Comparison of lowering advantage of applying bi- once- or twice-daily bimatoprost with twice- ably serving as a portal of entry for matoprost in the evening has not daily timolol in patients with elevated IOP: a microorganisms. The cellulitis was

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 mide, timolol maleate, dorzolamide hydrochloride, and brimonidine tartrate. The patient had an extensive medical and ocular history. She had hypertension, gout, and hypothyroid- ism and had undergone aortic valve replacement and bilateral knee re- placements. In the right eye, she had undergone multiple penetrating kera- toplasties for Fuchs endothelial dystrophy and graft failure. She also had placement of a Baerveldt tube shunt (350 mm2 ) for chronic angle- closure glaucoma. In the left eye, she had undergone penetrating kerato- plasty with cataract extraction and intraocular lens implantation. Three years later, she underwent implantation of a Baerveldt tube shunt (350 mm2) for chronic angle-closure glaucoma. Four months following inser- tion of the glaucoma tube shunt, she Figure 1. Computed tomographic scan of the orbits with contrast (axial section) demonstrates preseptal underwent repeated penetrating kera- soft tissue swelling surrounding and extending from the region of the left Baerveldt tube shunt (long toplasty, anterior synechialysis, and arrow). Infiltration of the orbital fat is also apparent (short arrow). Of note is that Baerveldt tube shunts shunt revision for iris incarceration of are impregnated with barium and therefore are radio-opaque. the tube. Subsequently, she required surgical drainage of peripheral choroidal effusions and scleral patch graft reinforcement for tube erosion through the conjunctiva 11 months prior to initial examination. She was afebrile at clinical examination. Visual acuity was light perception in the right eye and hand motions temporally in the left eye (her visual acuity was 20/400 OS 1 year previously). The intraocular pressures were 19 mm Hg OD and 12 mm Hg OS. She had a right relative afferent pupillary defect with 50% light desaturation. Ocular duc- tions were full in the right eye. In the left eye she had severe limitation of motility in all directions. There was swelling, erythema, tenderness, and warmth of the left upper eyelid, and the globe was inferiorly displaced. The left conjunctiva also had diffuse hyperemia and was chemotic. On computed tomography of the Figure 2. Computed tomographic scan of the orbits with contrast (coronal section) demonstrates inferior orbits, preseptal soft tissue swell- displacement of the globe, as well as inflammation around the levator–superior rectus complex (arrow). ing was extended from the region of the glaucoma tube shunt, with successfully treated with intrave- sion in her left eye. According to the some infiltration of the intraconal nous antibiotics and subsequent re- referring ophthalmologist, the left in- fat (Figure 1 and Figure 2). Bio- moval of the glaucoma tube shunt. traocular pressure had become el- microscopic and fundus examina- evated to the 40–mm Hg range and tion findings did not reveal any Report of a Case. A 78-year-old Af- vision had worsened from count- evidence of endophthalmitis or rican American woman was seen ing fingers to no light perception panophthalmitis. with a 3-day history of left eye pain, over the preceding 3 days. She had The patient was admitted and eyelid swelling, and decreased vi- been treated with oral acetazola- started receiving intravenous ampi-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 junctiva allowed entry of microorganisms into the subconjunctival space and secondarily into the orbit. Given the lengthy duration between the scleral reinforcement surgery and the development of cellulitis, it is unlikely that residual buried epithelium from the reinforcement surgery could have caused the delayed glaucoma tube shunt exposure. Ex- posure of glaucoma tube shunts may be managed successfully with anterior surgical revision5 and/or pars plana vitrectomy and repositioning the tube into the vitreous cavity.6 However, in the setting of active orbital cellulitis, immediate treatment with intravenous antibiotics is necessary. Subsequent removal of the Figure 3. Anterior segment biomicroscopy reveals erosion of the Baerveldt tube through the conjunctiva glaucoma tube shunt implant may be (arrow). required for complete resolution of the infection. cillin sodium/sulbactam sodium. 1 month following a stage 1 Mol- Adrian M. Lavin˜a, MD The ocular motility and eyelid teno shunt procedure.1 The tube had Jeffrey L. Creasy, MD swelling improved dramatically been tucked under the conjunctiva Nashville, Tenn within 24 hours. Intravenous meth- and was found to have slipped out, ylprednisolone sodium succinate presumably creating a portal of en- James C. Tsai, MD (Solu-Medrol; Pharmacia Corpora- try for infection. The patient was New York, NY tion) was then added. Following treated with systemic antibiotics and This work was supported in part by several more days of intravenous required removal of the shunt. In con- the Homer McK Rees Scholar Award antibiotics, the left conjunctival hy- trast, our case involved a functional (Dr Tsai) and an unrestricted grant peremia became localized to the su- glaucoma tube shunt of over 1 year’s from Research to Prevent Blindness perotemporal quadrant region. duration that eroded through the con- Inc, New York, NY. There was conjunctival erosion and junctiva. The differential diagnosis The authors have no propri- exposure of the proximal portion of also included an orbital inflamma- etary interest in any of the products the Baerveldt tube with negative tory syndrome. Indeed, myositis has mentioned. Seidel test results (Figure 3). The been reported to be associated with Corresponding author and re- bleb over the tube shunt appeared Baerveldt tube shunt surgery.2 This prints: James C. Tsai, MD, Harkness convex (indicative of a functional case occurred in a patient with a his- Eye Institute, 635 W 165th St, New shunt implant). tory of ocular myositis before glau- York, NY 10032 (e-mail: jct2002 Given the persistent ocular coma tube shunt surgery. However, @columbia.edu). pain and redness, the glaucoma our patient’s rapidly progressive tube shunt was surgically removed. course, her dramatic improvement 1. Karr DJ, Weinberger E, Mills RP. An unusual case No growth was observed from any with intravenous antibiotics, and the of cellulitis associated with a Molteno implant in a 1-year-old child. J Pediatr Ophthalmol Stra- of the bacterial cultures. The pa- computed tomographic scan find- bis. 1990;27:107-110. tient’s ocular symptoms resolved ings in the left orbit are consistent 2. Kean OT, Alward WLM, Kardon RH. Myositis associated with a Baerveldt glaucoma implant. and her visual acuity improved to with an infectious process. Am J Ophthalmol. 1999;128:375-376. counting fingers range. Moreover, Orbital cellulitis has occurred 3. Kanski JJ, Gregor Z. Retinal Detachment: A Co- the left intraocular pressure re- in patients with other periocular im- lour Manual of Diagnosis and Treatment. 2nd ed. 3 Oxford, England: Butterworth-Heinman Ltd; mained stable with antiglaucoma plants, including scleral buckles. In- 1994:128-129. medication. fections with scleral buckles have 4. Smiddy WE, Miller D, Flynn HW. Scleral buckle usually been associated with expo- removal following retinal reattachment surgery: clinical and microbiologic aspects. Oph- Comment. Orbital cellulitis is a rare sure of the implant or explant. The thalmic Surg. 1993;24:440-445. complication of glaucoma tube shunt treatment of these infections al- 5. Tsai JC, Grajewski AL, Parrish RK II. Surgical revision of glaucoma shunt implants. Ophthal- implantation. To our knowledge, most invariably requires removal of mic Surg Lasers. 1999;30:41-46. this is the first case of orbital cellu- the element, as well as treatment 6. Joos K, Lavin˜ a AM, Agarwal A, Tawansy K. litis reported in a patient with a with antibiotics.4 Successful repositioning of glaucoma shunt implants after pars plana vitrectomy for ante- functioning tube shunt. A case of or- We believe that exposure of the rior segment complications. Ophthalmology. bital cellulitis was reported in a child Baerveldt tube through the con- 2001;108:279-284.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Report of Cases. Case 1. A 42-year- associated with ectopia lentis was Retinitis Pigmentosa old Japanese woman was brought in detected bilaterally. The lens Associated With for a consultation in 1999 because was dislocated inferiorly and Ectopia Lentis her mother noticed that the pa- showed mild opacities in both eyes tient’s visual acuity was gradually de- (Figure 1). creasing. She was born under as- Results of fundus examination Retinitis pigmentosa (RP) is charac- phyxial conditions after an 8-month showed macular degeneration terized by night blindness, visual field pregnancy. She began walking at age associated with pigmentary retinal loss, and reduced or extinguished 7 years, talking at age 10 years, and degeneration in the pericentral electroretinogram results. Retinitis began menses at age 17 years. Mi- region in both eyes. The retinal pigmentosa may be associated with a crocephaly was pointed out at age 5 arteries were attenuated and the wide variety of ocular and systemic years. She did not have a history of optic disc was somewhat pale disorders. Ectopia lentis, a disloca- convulsions or ocular trauma, and (Figure 2). Fluorescein angiogra- tion of the crystalline lens, may cause could speak and understand only a phy showed hyperfluorescence of visual disturbances depending on the few words. She was 140.8 cm tall, the posterior lesions associated type and degree of dislocation and weighed 53.6 kg, had an arm span with a hypofluorescence in the may be associated with a variety of of 135 cm, and a head circumfer- peripapillary region bilaterally ocular and systemic abnormalities. ence of 48 cm (less than the third (Figure 2). When associated with systemic dis- percentile). No other systemic dis- The amplitudes of the a-waves orders, ectopia lentis may be an im- orders were observed. on the results of dark-adapted stan- portant diagnostic sign.1 An associa- Her visual acuity was 20/470 dard electroretinograms were se- tion between RP and ectopia lentis has OD and 20/710 OS using Teller verely reduced and the b-waves were rarely been reported. We describe 2 acuity cards but nystagmus was extinguished. The rod-isolated re- siblings exhibiting RP and ectopia len- not observed. Slitlamp biomicros- sponses were extinguished while the tis with an autosomal recessive in- copy revealed normal corneas and cone-isolated responses were mark- heritance pattern. anterior chambers but iridodonesis edly reduced (Figure 3).

A B

C D

Figure 1. Slitlamp photographs showing dislocation of the lens inferiorly in the right (A) and left (B) eyes of case 1. In case 2, the lens in the right (C) and left (D) eyes were dislocated superiorly and nasally, respectively.

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Figure 2. A and C, Fundus photographs of the left eye showing pigmentary retinal degeneration in the pericentral region and macular degeneration. B and D, Fluorescein angiograms showing diffuse hyperfluorescence of the posterior lesions. A and B, case 1. C and D, case 2.

Scotopic Blue Standard Flash Photopic Red at age 5 years. However, he had no history of convulsions or ocular R R R trauma. He could speak and under- Normal stand only a few words and had L L L been our patient since 1990 be- µ 100 µV 100 µV 100 V cause his mother noticed that he had 20 ms 20 ms 10 ms impaired visual acuity and night blindness. The initial visual acuity was 20/ R R R 200 OU using Teller acuity cards. Slit- lamp examination showed ectopia Case 1 L L lentis in the right eye. Fundus exami- L nation results disclosed macular degeneration associated with pigmentary retinal degeneration bilaterally. R Neuronal ceroid lipofuscinosis was R R suspected because of both pigmen- Case 2 L tary retinal degeneration and mental L L retardation; however, there were neither vacuolated lymphocytes nor Figure 3. Electroretinograms (ERGs) of cases 1 and 2. The standard and cone-isolated responses were inclusion bodies specific for the dis- severely reduced while the rod-isolated responses were nonrecordable in case 1. All ERGs of case 2 were ease. Results of computed tomography nonrecordable. and magnetic resonance imaging showed microcephaly but no abnor- Case 2. The 37-year-old brother pregnancy. He began to walk at age mality in the brain. of case 1 was also born under as- 2 years and abnormal electroen- In 1999, he was 159.5 cm tall, phyxial conditions after a full-term cephalogram results were detected weighed 56.0 kg, had an arm span

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Funduscopic Appearance Family Member/Age, y Refraction Visual Acuity Lens in Both Eyes in Both Eyes Other Abnormalities Patient 1/42 −4.50, −4.25 A180 OD 20/470 OD Subluxated Retinitis pigmentosa Microcephaly, mental retardation −7.75, −5.00 A20 OS 20/710 OS Patient 2/37 −5.25, −1.50 A90 OD 20/630 OD Subluxated Retinitis pigmentosa Microcephaly, mental retardation −3.00, −3.50 A10 OS 20/630 OS Father/68 +1.25, −3.00 A90 OD 20/25 OD Cataract Normal . . . +1.25, −3.00 A90 OS 20/25 OS Mother/72 +2.5 OD 20/25 OD Cataract Normal . . . +2.0 OS 20/32 OS

*Ellipses indicate not applicable.

of 145 cm, and a head circumfer- Weil-Marchesani syndrome, hyper- chorioretinal disorders associated ence of 49 cm (less than the third lysinemia, and sulfite oxidase defi- with ectopia lentis may be a new percentile). His visual acuity was 20/ ciency because both patients had nei- clinical entity although subclinical 630 OU using Teller acuity cards. He ther the characteristic skeletal features and genotypic classification will be was exotropic but nystagmus was nor the abnormal amino acid levels necessary. not observed. Slitlamp biomicros- in the plasma and/or urine. Further- copy revealed that the corneas and more, Refsum syndrome, in which Hajime Sato, MD, PhD anterior chambers were normal but both RP and ectopia lentis can be Yuko Wada, MD, PhD iridodonesis associated with ecto- present, was excluded because of the Toshiaki Abe, MD, PhD pia lentis was observed in both eyes. absence of peripheral neuropathy and Miyuki Kawamura, MD The lens in the right eye was dislo- the normal plasma levels of phy- Ryosuke Wakusawa, MD cated upward while that in the left tanic acid. Serologic testing ruled out Makoto Tamai, MD, PhD eye was dislocated nasally (Figure 1). lues. Chromosomal study revealed Sendai, Japan The lenses had mild opacities. Fun- normal karyotype in both patients, dus examination and fluorescein an- and they had no sign of hyperexten- Corresponding author and reprints: giography results disclosed a simi- sibility of the joints and skin, poly- Hajime Sato, MD, PhD, Department of lar appearance to those of his sister dactyly, and cardiovascular disor- Ophthalmology, Tohoku University (Figure 2). All electroretinograms ders. None of the syndromes or eye School of Medicine, 1-1 Seiryo-machi, were nonrecordable (Figure 3). diseases in the literature matched the Aoba-ku, Sendai 980-8574, Japan signs and symptoms of our patients. (e-mail: [email protected]). Comment. Our 2 patients are mem- Although microcephaly with 1. Nelson LB, Maumenee IH. Ectopia lentis. Surv bers of a Japanese family with RP, ec- chorioretinopathy has been found as Ophthalmol. 1982;27:142-160. topia lentis, microcephaly, and men- a hereditary disorder (OMIM [on- 2. Simon NP. Long-term neurodevelopmental out- tal retardation with no history of line mendelian inheritance in man] come of asphyxiated newborns. Clin Perinatol. 1999;26:767-778. consanguinity (Table). They had 251270), the mental retardation and 3. Guillaumat L, Lemaitre M. Myopie forte, reti- twin brothers who died soon after microcephaly observed in our pa- nite pigmentaire, luxation congenitale des deux birth for unknown reasons. Results tients may have resulted from the cristallins chez une jeune fille issue d’un mar- riage consaguin: probleme pathogenique. Bull Soc of ocular examination of the parents asphyxial condition because peri- Ophthalmol Fr. 1948;3:90-92. exhibited only cataractous lenses that natal asphyxia associated with hy- 4. Noble KG, Bass S, Sherman J. Ectopia lentis, chorioretinal dystrophy and myopia. Doc Ophthal- were considered to be caused by age- poxic-ischemic brain injury is an mol. 1993;83:97-102. related changes and the lenses were important cause of neurodevelop- 5. Simonelli F, Crecchio GD, Testa F, et al. Reti- not dislocated. They had no com- mental impairments, such as motor nal degeneration associated with ectopia lentis. plaints of night blindness although disabilities, visual and/or hearing im- Ophthalmic Genet. 1999;20:121-126. the patients’ father had congenital pairments, and cognitive and learn- dyschromatopsia. There was no ex- ing disabilities.2 The degree of visual posure to toxic substances or infec- impairment depends on the extent tious organisms during pregnancy. of damage of the optic radiations Pigmentary Retinopathy We conclude that some of the disor- and/or visual cortex. Associated With ders associated with our patients were To the best of our knowledge, Intravitreal Fomivirsen congenital and were inherited in an only 3 cases of hereditary chorio- autosomal recessive fashion. retinal disorders associated with Cytomegalovirus (CMV) retinitis is From a review1 of the ocular ectopia lentis have been reported.3-5 the leading cause of visual loss in pa- findings and systemic disorders as- Although these patients also showed tients with acquired immunode- sociated with patients with ectopia autosomal recessive inheritance, they ficiency syndrome (AIDS). Treat- lentis, we were able to exclude the had dense or posterior subcapsular ment modalities include intravenous most common syndromes, such as cataracts. Our patients showed mild ganciclovir sodium, cidofovir, or Marfan syndrome, homocystinuria, nuclear and cortical cataracts. Thus, foscarnet sodium; oral ganciclovir or

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Figure 1. Case 1. A, Left fundus composite photograph of active cytomegalovirus (CMV) in the macula prior to fomivirsen sodium injection. No peripheral photographs were taken. B, New pigmentary changes in the 360° midperipheral retina. The CMV retinitis in the macula is inactive.

valganciclovir hydrochloride; intra- administered every other week; RPE tions were given. Six months vitreal (IV) injections of ganciclo- stippling was diagnosed after weekly following the initial IV injection, vir, cidofovir, or foscarnet; and gan- injections of 165 µg for 3 weeks. We findings from examination of ciclovir implants. Foscarnet, report 2 additional cases of periph- the left eye revealed new pigmen- ganciclovir, and cidofovir selec- eral pigmentary changes accompa- tary changes in the 360° midpe- tively inhibit viral DNA polymer- nied by electroretinogram (ERG) ab- ripheral retina previously unaf- ase. Fomivirsen sodium (Vit- normalities following IV injection of fected by CMV retinitis (Figure ravene, ISIS 2922; ISIS Pharmaceu- fomivirsen. 1B). The ERG revealed an absent ticals, Carlsbad, Calif) is the latest rod response, 40% reduction in addition to the armamentarium of Report of a Case. Case 1. A 34- year- cone amplitude, and normal im- local CMV retinitis treatment op- old African American man with plicit times (Figure 2). Visual tions. A phosphorothioate oligo- AIDS had failed HAART. His CD4 field testing was not performed nucleotide administered intravit- cell count was 20 cells/µL. The pa- because the patient was too debili- really, fomivirsen inhibits CMV tient had human immunodefi- tated. No cataract was found at a replication through an antisense ciency virus (HIV) retinopathy in the follow-up examination 3 months mechanism, binding to viral mes- right eye and CMV retinitis in zones after the last injection. senger RNA and blocking its tran- 1 and 2 of the left eye in May 2000 Case 2. A 41-year-old white scription.1,2 The Food and Drug Ad- (Figure 1A). The fovea was in- man had AIDS and a CD4 cell count ministration approved fomivirsen in volved and vision had decreased to below 50 cells/µL. He was also fail- August 1998 as highly active anti- 20/400 OS. Cytomegalovirus retini- ing HAART, and his left eye CMV retroviral therapy (HAART) began tis was initially treated with intra- retinitis was controlled with a gan- to dramatically decrease the inci- venous ganciclovir followed by IV ciclovir implant. The right eye had dence of CMV retinitis.3 fomivirsen. Fomivirsen was used HIV retinopathy and lattice degen- Clinical experience with IV owing to a shortage of ganciclovir. eration in the superior and inferior fomivirsen is limited. Reported ad- The patient received a 2-dose induc- periphery at initial examination verse effects with the approved dos- tion regimen consisting of 330 µg (Figure 3A). Cytomegalovirus age include transient and revers- of IV fomivirsen sodium injections retinitis involving zone 3 of the ible inflammation in the anterior every other week. His retinitis pro- superotemporal quadrant devel- chamber (19%), increase in intra- gressed when he failed to return for oped in the right eye at 4 months’ ocular pressure (19%), vitreitis follow-up during the next 7 weeks. follow-up in January 2001. The (11%), and uveitis (5%). Cataract The induction regimen was re- right eye received one 330-µg IV (9%) has also been reported.2 Iso- peated when the patient returned. He fomivirsen sodium injection while lated case reports describe foveal reti- then received a maintenance dose of he awaited surgery for an IV ganci- nal pigment epithelial (RPE) stip- 330 µg 1 month after the second in- clovir implant. There was no ocular pling with reversible bull’s-eye duction, totaling 5 injections of fo- hypertension or inflammation in maculopathy,4 peripheral RPE stip- mivirsen. There was no elevated in- the eye following the injection. pling5,6 associated with visual field traocular pressure. Mild anterior Retinitis became inactive, and he loss,6 and marked retinal toxic side chamber inflammation and mild vit- underwent surgery to receive the effects after 495 µg doses.7 Bull’s- reitis improved while he was receiv- implant 3 weeks later. During a eye maculopathy was diagnosed af- ing topical steroids. The patient was follow-up examination 1 month ter five 330-µg doses in one case and subsequently readministered intra- after the injection, new RPE pig- after 15 injections bilaterally in an- venous ganciclovir for CMV colitis. mentary changes were found in the other. In both cases, fomivirsen was No additional intraocular injec- inferior quadrants previously unaf-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 fected by retinitis (Figure 3B). The rotemporal retina. Visual field Comment. Treatment of CMV reti- ERG revealed an absent rod re- testing results were normal in the nitis with IV ganciclovir or foscar- sponse, 50% decrease in cone area corresponding to the inferior net requires weekly injections. In- response, and a normal implicit retina. His vision remained 20/20 travitreal cidofovir is associated with time. Goldmann visual field testing OD with no cataract formation prolonged ocular hypotony. Fomi- of the right eye showed an absolute at the last follow-up examination virsen requires less frequent in- scotoma in the area corresponding 3 months after fomivirsen injec- jections. The recommended induc- to the previous CMV-affected supe- tion. tion dose of IV fomivirsen sodium is one 330-µg injection every other week for 2 doses. Subsequent main- A tenance doses are administered every 4 weeks after induction. In vitro b (Blue) 5 (Blue) 6 studies have shown that fomi- 3 4 a 1 2 virsen is active against clinical iso- lates of human CMV and drug- b (Red) 11 (Red) 9 10 8 7 8 resistant mutants of the virus. In a clinical trials, fomivirsen significantly delayed the progression of

b (Flash) (Flash) CMV retinitis in previously un- 15 16 13 14 treated patients and decreased a CMV activity in patients with refractory CMV retinitis.1 In the United States, fomivirsen is reserved as a second-line treatment B for CMV retinitis in patients who are intolerant or unresponsive to other forms of treatment. b (Flash) 5 b (Flash) 8 3 6 The only published toxicity a 1 4 profile study, to our knowledge, found that high concentrations of fomivirsen in the vitreous caused total retinal destruction in b (30-Hz Flicker) 15 b (30-Hz Flicker) 16 13 14 rabbit eyes.9 However, even at 9 a 10 a lower concentrations equivalent to human eye injection doses, destruction of the photoreceptor outer segments and RPE cell changes were Right Eye Left Eye noted.9,10 Figure 2. Case 1. Findings from electroretinogram (ERG) performed following intravitreal injection of Retinal pigment changes are fomivirsen sodium in the left eye. A, Scotopic flash ERG. B, Photopic flash ERG. The right eye results among the ocular adverse reactions show normal scotopic and photopic responses. The left eye results show absent scotopic responses; listed on the fomivirsen package la- absent flash photopic response; and decreased cone response to a 30-Hz stimulus with normal implicit 11 time. a Indicates a wave and b, b wave. (Electroretinogram test manufacturer information: Nicolet bel. Frequency of retinal pigment Biomedical, Madison, Wis.) changes is unknown. We used IV fo-

A B

Figure 3. Case 2. A, Right fundus composite photograph prior to cytomegalovirus retinitis and prior to fomivirsen sodium injection. B, New pigmentary changes in inferior quadrants 1 month after 1 intravitreal fomivirsen injection.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 mivirsen in 10 eyes of 9 patients our patient (case 2) was not con- Fomivirsen: a phosphorothioate oligonucleotide for the treatment of CMV retinitis. Ocul Im- from 1999 to 2001 as follows: stricted. His unaffected visual field and munol Inflamm. 1999;7:189-198. Eyes, No. Injections, No. normal ERG testing implicit time may 3. Jalali S, Reed JB, Mizogushi M, et al. Effect of be consistent with relative sparing of highly active antiretroviral therapy on the in- 61 cidence of HIV-related cytomegalovirus reti- 12the peripheral cones. The patient re- nitis and retinal detachment. AIDS Patient Care 13ceiving 23 injections (Table) had no STDS. 2000;14:343-346. 15pigmentary changes. This eye under- 4. Stone TW, Jaffe GJ. Reversible bull’s-eye macu- 123 lopathy associated with intravitreal fomi- went 2 ganciclovir implant proce- virsen therapy for cytomegalovirus retinitis. Most of these patients are now de- dures prior to our fomivirsen injec- Am J Ophthalmol. 2000;103:242-243. 5. Hudson HL, Boyer DS, Kupperman BD. Fu- ceased. Over 2 years, we noted pig- tions. Liquefied vitreous in this eye ture trends and experimental modalities in the mentary changes in only the 2 pa- may have had more even diffusion of therapeutics of cytomegalovirus retinitis. Oph- tients reported herein. Neither patient fomivirsen compared with other eyes thalmol Clin North Am. 1997;10:61-71. 6. Amin HI, Ai E, McDonald HR, Johnson RN. reported nyctalopia. Both patients with formed vitreous. Our case re- Retinal toxic effects associated with intravit- died within a few months after diag- ports support the view that IV fomi- real fomivirsen. Arch Ophthalmol. 2000;188: 426-427. nosis of retinal toxicity. Their pig- virsen has a narrow therapeutic in- 7. Hutcherson SL, Palestine AG, Cantrill HL, et al. 10 mentary changes persisted until last dex for retinal toxicity and should Antisense oligonucleotide safety and efficacy for follow-up. Electrophysiologic test- be used judiciously. CMV retinitis in AIDS patients. Paper presented at: 35th Interscience Conference on An- ing could not be repeated to evalu- timicrobial Agents and Chemotherapy; Septem- ate for reversibility as our patients’ sys- Sami H. Uwaydat, MD ber 17, 1995; San Francisco, Calif. Abstract 204. temic status progressively worsened. Helen K. Li, MD 8. Anderson KP, Fox MC, Brown-Driver V, et al. Inhibition of human cytomegalovirus imme- Abnormal ERG findings have been Galveston, Tex diate-early gene expression by an antisense oli- noted in patients with HIV, AIDS, and gonucleotide complementary to immediate- 12 early RNA. Antimicrob Agents Chemother. 1996; CMV retinitis. In our patients, the This article was supported by an 40:2004-2011. reduction in ERG amplitudes of the unrestricted grant from Research to 9. Flores-Aguilar M, Besen G, Vuong C, et al. Evalu- treated eye is consistent with photo- Prevent Blindness Inc, New York, ation of retinal toxicity of anti-cytomegalovirus and anti-herpes simplex virus antiviral phospho- receptor dysfunction affecting mainly NY. rothioate oligonucleotides ISIS 2922 and 4015. the rod system. This reduction may Corresponding author: Helen K. J Infect Dis. 1997;175:1308-1316. have been induced by fomivirsen Li, MD, University of Texas Medical 10. Freeman WR. Retinal toxic effects associated with intravitreal fomivirsen [letter]. Arch Oph- given that ERG responses in fellow Branch, Department of Ophthalmol- thalmol. 2001;119:458. eyes were normal. Case 2 developed ogy and Visual Sciences, 301 Univer- 11. Vitravene [package insert]. Carlsbad, Calif: ISIS Pharmaceuticals, 1998. pigmentary changes and photorecep- sity Blvd, Galveston, TX 77555- 12. Latkany PA, Holopigian K, Lorenzo-Latkany M, tor dysfunction after only 1 injec- 1106 (e-mail: [email protected]). et al. Electroretinographic and psychophysi- tion. Neither patient had ever been cal findings during early and late stages of hu- 1. Perry CM, Balfour JAB. Fomivirsen. Drugs. man immunodeficiency virus infection and cy- treated with didanosine. Unlike the 1999;57:375-380. tomegalovirus retinitis. Ophthalmology. 1997; study by Amin et al,6 visual field in 2. de Semet MD, Meenken C, van den Horn GJ. 104:445-453.

Sequential Branch Retinal Artery Occlusions Following Embolization of an Intracranial Meningioma

Therapeutic embolization is an ac- cepted component in the management of vascular tumors, arteriove- nous malformations, and active bleeding sites.1 Complications are rare, but include infarction by un- intended occlusion of vessels.1 This occurs either when particles are injected from a proximally placed catheter or when they reflux from distal vessels during flushing. Inadvertent occlusion of the ophthalmic or central retinal artery during external carotid artery embolization has been reported in 4 cases,2-4 with immediate loss of vi- Figure 1. Preembolization left external carotid arteriogram showing middle meningeal artery (asterisk), sion. We report a case in which step- parietal branch (solid arrow) to tumor (blush of small vessels), sphenoidal artery (open arrow), and wise decline of vision related to ophthalmic artery (arrowhead).

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 tomoses, provocative testing was per- A formed by injecting amobarbital and Central Retinal Artery lidocaine through the microcatheter.5 When this testing produced no- Ophthalmic Artery visual or other neurological deficits,

Meningo-Ophthalmic Branch 45- to 150-µm PVA particles sus- pended in radiographic contrast were Sphenoidal Artery slowly injected under fluoroscopic guidance into the tumor (Figure 2B). After slowed flow to the tumor was Middle Meningeal Artery seen, the microcatheter was flushed with heparinized saline to evacuate any remaining particles in the catheter. To prevent reflux of emboli that had been deposited in the distal vessels supplying the tumor, the catheter was then pulled back proximal Meningioma to the sphenoidal artery take-off (Fig- ure 2C), and contrast was injected to confirm devascularization of the me- B C ningioma. As the contrast was injected, the patient reported a sudden flash of light in the left eye, and she soon developed an inferior scotoma on that side. Polyvinyl alcohol particles retained within the catheter had evidently been flushed into the ophthalmic artery anastomosis and reached the retinal arterioles (Figure 2C). Ophthalmic examination performed 3 hours after the procedure disclosed visual acuities of 20/25 OD and 20/25 OS, and a left afferent pupil defect. Ophthalmoscopy revealed ischemic clouding of the retina superotemporally. Small, yellow- white particles were visible in retinal arterioles of the superior and inferior arcades, including the vessel Figure 2. Schematic view of tumor and retinal embolization. A, Left middle meningeal branches, including supply to convexity meningioma, and anastomosis to ophthalmic artery. B, Catheter injecting that was occluded in the superior ar- polyvinyl alcohol (PVA) particles to occlude vessels in the tumor bed. It is positioned in a meningeal cade (Figure 3A). A formal visual branch distal to the branch that leads to the sphenoidal artery. C, Catheter has been pulled back to field test (Humphrey Field Analyzer proximal meningeal artery in preparation for postembolization arteriogram. The pull-back is done to avoid Program 24-2; Humphrey Instru- reflux of loose PVA particles lying in tumor vessels. Those PVA particles residing in the microcatheter are inadvertently flushed into meningeal branches that anastomose to sphenoidal, ophthalmic, and retinal ments, San Leandro, Calif) dis- arteries. These particles occlude retinal arterioles and, as they swell, sequentially infarct the retina. closed a corresponding inferonasal scotoma (Figure 3B). Seven days later, the patient reported a further decline in vision in her left eye. progressive swelling of polyvinyl al- artery via the sphenoidal artery Ophthalmoscopy revealed enlarge- cohol (PVA) particles lodged in reti- (Figure 1 and Figure 2A). ment of the superior retinal infarct nal arterioles occurred throughout A 5F catheter was positioned in (Figure 4A) and of the corre- a period of 8 days. the left external carotid artery, and sponding scotoma (Figure 4B). The through this catheter, a 2F micro- particle in the proximal inferior Report of a Case. A 39-year-old catheter was advanced into the middle temporal arteriole had enlarged. woman underwent preresection meningeal artery supplying the le- Despite 4 mg of oral dexametha- embolization of a left-posterior sion. The patient was systemically sone taken 3 times daily, she devel- frontal convexity meningioma. A heparinized during the procedure. oped loss of the superior field one preembolization arteriogram visu- The catheter was positioned distal to day later. Visual acuity had fallen alized the middle meningeal the take-off of the sphenoidal artery to 20/400; ophthalmoscopy branches to the tumor, as well as (Figure 2B). To confirm that the cath- showed that the particle in the in- an anastomosis to the ophthalmic eter was beyond all dangerous anas- ferior temporal artery had further

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Figure 3. Fundus photographs and visual fields of the left eye on the day of procedure. A, Superior branch retinal artery occlusion as ischemic whitening. Several yellow-white polyvinyl alcohol particles are impacted within proximal retinal arterioles. B, Corresponding inferior nerve fiber bundle defect.

A B

Figure 4. Fundus photographs and visual fields of the left eye 7 days after the procedure. A, Retinal infarction has extended nasally. B, Enlargement of visual field defect, corresponding to enlarged area of infarction.

A B

Figure 5. Fundus photographs and visual fields of the left eye 8 days after the procedure. A, Retinal infarction now also involves the inferior branch artery. The particle lodged in the proximal inferior temporal retinal arteriole has enlarged. B, Visual field defect now involves the upper field, corresponding to new infarction of the inferior retina.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 enlarged, that the inferior retina was ized. A third preventive measure Corresponding author: Jonathan D. now infarcted (Figure 5A), and that would have been to remove the Trobe, MD, Kellogg Eye Center, the scotoma involved most of the vi- microcatheter used for injecting 1000 Wall St, Ann Arbor, MI 48105 sual field (Figure 5B). Follow-up ex- emboli, and to then introduce a new (e-mail: [email protected]). amination 2 months later showed a microcatheter to perform the postem- 1. Taylor W, Rodesch G. Recent advances: interven- pale left optic disc and no change in bolization arteriographic studies. The tional neuroradiology. BMJ. 1995;311:789-792. visual function. drawback to this measure is that if fur- 2. Soong HK, Newman SA, Kumar AAJ. Branch ther embolization of the tumor artery occlusion: an unusual complication of external carotid embolization. Arch Ophthal- Comment. Our patient had a rare through a distal site is found to be nec- mol. 1982;100:1909-1911. complication of therapeutic PVA em- essary, additional time and risk would 3. Mames RN, Snady-McCoy L, Guy J. Central retinal and posterior ciliary artery occlusion after par- bolization, namely, inadvertent oc- be added to the procedure. Fourth, we ticle embolization of the external carotid artery clusion of branches of the central reti- could have injected contrast dye dur- system. Ophthalmology. 1991;98:527-531. nal artery. This complication is based ing the follow-up arteriogram 4. Shimizu Y, Kiyosawa M, Miura T, Takahashi A, Tamai M. Acute obstruction of the retinal on known anastomoses between the through the guiding catheter posi- and choroidal circulation as a complication of external carotid circulation and the tioned in the external carotid ar- interventional angiography. Graefes Arch Clin 6-8 tery, rather than through the micro- Exp Ophthalmol. 1993;231:43-47. ophthalmic artery. External ca- 5. Deveikis JP. Sequential injections of amobar- rotid branches may replace the inter- catheter. This would have avoided bital sodium and lidocaine for provocative test- nal carotid artery as the predomi- the need to manipulate the micro- ing in the external carotid circulation. AJNR Am J Neuroradiol. 1996;17:1143-1147. nant supply of the ophthalmic artery catheter and would have virtually 6. Gillilan LA. The collateral circulation of the hu- in 5% of patients with otherwise nor- eliminated the risk of injecting re- man orbit. Arch Ophthalmol. 1961;65:684-694. mal cephalic vessels7 and in a much tained PVA emboli. The main dis- 7. Hayreh SS. Arteries of the orbit in the human being. Br J Surg. 1963;50:938-953 higher proportion in those with ar- advantage of this otherwise practi- 8. Ahn HS, Kerber CW, Deeb ZL. Extra- to inter- teriosclerosis, which preferentially af- cal solution is that a guiding catheter nal arterial anastomoses in therapeutic embo- must have a large enough inner lu- lization: recognition and role. AJNR Am J Neu- fects the internal carotid system. roradiol. 1980;1:71-75. Aware that this anastomosis men to allow passage of the inner mi- 9. Wakhloo AK, Juengling FD, Velthoven W, might cause a serious problem, our crocatheter and leave enough room Schumacher M, Hennig J, Schwechheimer K. Extended preoperative polyvinyl alcohol mi- interventional neuroradiologist around it to inject viscous contrast croembolization of intracranial meningiomas: (J.P.D.) positioned the catheter far dis- material. Perhaps a larger 6F guid- assessment of two embolization techniques. tal to it, performed preembolization ing catheter would have been pref- AJNR Am J Neuroradiol. 1993;14:571-582. 10. Kupersmith MJ, Berenstein A. Embolic and non- pharmacologic provocative testing, erable in this case. inflammatory occlusive vascular disease of the embolized gently without reposition- An unusual aspect of our case is visual and ocular motor system. In: Kuper- the sequential nature of the branch smith MJ, Berenstein A. Neurovascular Neuro- ing the catheter, and flushed the cath- ophthalmology. Berlin,Germany: Springer- eter after embolization. However, retinal artery occlusions occurring Verlag; 1993:126, 358. these techniques failed to prevent er- throughout a period of 8 days. We at- rant emboli from reaching the reti- tribute this phenomenon, (not pre- nal vessels. Some particles were un- viously reported) to progressive swell- doubtedly present in the catheter even ing and/or thrombus formation in after careful flushing with saline, sug- these vessels. Swelling is a feature that Bilateral Vasoproliferative gesting that it may not be possible to makes PVA a useful agent for thera- Retinal Tumors With completely remove all particles from peutic embolization, but that in- Identical Localization in a the microcatheter. creases the possibility that errant PVA Pair of Monozygotic Twins Four additional measures might particles will cause neurological defi- have prevented this complication. cits. Unfortunately, there is no anti- Vasoproliferative retinal tumors are First, embolization could have been dote to reverse the swelling of the benign vascular tumors of un- performed with particulate agents too particles. known origin that are usually lo- large to enter the anastomotic path- Although our case has unusual cated in the periphery of the lower way, but there are 2 drawbacks to this features, we doubt that inadvertent ocular fundus. They became a clini- maneuver. The first is that the size of occlusion of the retinal artery dur- cal entity in 1995 when Shields et al1 anastomoses and particles vary, mak- ing preoperative embolization via the coined the term “vasoproliferative ing it impossible to be sure that some external carotid system is as rare as tumors of the ocular fundus.” Be- particles will not enter the anastomo- the published literature would sug- fore then, these lesions were called sis. The second drawback is that large gest. An authoritative textbook10 de- presumed acquired hemangiomas, particles are less effective in devas- scribes 2 unpublished cases. In pre- angioma-like lesions, or peripheral cularizing the tumor bed.9 The sec- senting this case to gatherings of retinal telangiectasis. Histological ex- ond measure would have been to se- ophthalmologists and neuroradiolo- aminations of vasoproliferative reti- lectively occlude the anastomosis with gists, many members of our audiences nal tumors have demonstrated glial a microcoil prior to embolization of have told us of similar experiences. and vascular proliferation.2,3 These the tumor bed. This would have pre- tumors can develop idiopathically or vented small particles from entering Tina Turner, MD can be secondary to other retinal dis- the anastomosis, but this is not fea- Jonathan D. Trobe, MD orders. Concomitant phenomena, sible if the anastomosis is too small John P. Deveikis, MD such as exudative retinal detach- or tortuous to be selectively catheter- Ann Arbor, Mich ment, lipid exudates, and macular

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Figure 1. A fundus photograph shows vasoproliferative retinal tumors in the Figure 2. A fundus photograph shows a vasoproliferative retinal tumor with right eye of patient 1. The tumors are located in the inferior part of the concomitant retinal detachment in the left eye of patient 2. fundus and show marked exudation.

edema or hemorrhages, can lead to the retinal pigment epithelium. Fluo- one quarter are secondary to other the deterioration of vision. rescein angiography shows rapid fill- diseases. In our patients, no other eye ing of the tumors through a nondi- disease was evident. Report of Cases. A pair of 58-year- lated retinal-feeding arteriole and Irvine et al3 suggested renam- old monozygotic female twins diffuse leakage in the venous and late ing vascular retinal tumors as “re- sought care because of visual dete- phase of the angiogram. Our pa- actionary retinal glioangiosis.” This rioration. Both sisters had bilateral tients showed no abnormalities in suggestion reflects the hypothesis multiple peripheral vasoprolifera- the lipid metabolism and no under- that the vessel proliferation is caused tive retinal tumors (Figure 1 and lying systemic diseases. by the release of vasoproliferative Figure 2) of nearly identical spread During the differential diagno- factors from the proliferating neu- and localization in the inferior part sis, von Hippel–Lindau disease was roglial tissue. However, the actual of the ocular fundus. Fluorescein an- excluded based on its not being trigger and stimulus for this prolif- giography demonstrated exten- present in the family history, the eration remain unclear. Moreover, sively vascularized tumors that were absence of additional clinical fea- we do not know whether the neu- filling from the retinal vessels in the tures of von Hippel-Lindau disease, roglial proliferation is already pres- early phase and consecutive marked and a negative molecular genetic test ent, nor do we know what triggers fluorescein leakage in the late phase. for a mutation of the VHLD gene.4 In it in primary cases, such as the ones Because of the relatively low addition, the age of onset in our pa- described here. thickness of the tumors (1.5 mm and tients was inappropriate for von The tumors in our patients were 2.0 mm), patient 1 was treated with Hippel–Lindau disease. unusually similar in localization and bilateral cryotherapy. Her sister, who Although some similarities to extension and had also developed bi- had thicker tumors (4.6 mm and 2.5 familial exudative retinopathy may laterally in a pair of monozygotic, and mm), underwent ruthenium 106 exist, the former includes a family thus genetically similar, twins. The brachytherapy in both eyes. Both history for this with autosomal absence of underlying systemic dis- cryotherapy and ruthenium 106 dominant or X-linked inheritance, eases leads us to assume that these brachytherapy led to regression of which was not the case in our pa- are primary cases. This suggests, the vasoproliferative retinal tu- tients. Moreover, familial exuda- however, that the pathogenesis could mors. Subsequent examination of the tive retinopathy is not associated be genetically determined, to a cer- twins’ DNA band-sharing rates con- with retinal tumors, and the age of tain degree, and not entirely depen- firmed monozygosity. onset is much younger. dent on reactive changes. Coats disease also develops at Comment. To our knowledge, this a much younger age, rarely occurs Joachim Wachtlin, MD is the first description of vasopro- bilaterally, usually affects boys, and Heinrich Heimann, MD liferative retinal tumors in a pair of is characterized in advanced cases by Claudia Jandeck, MD monozygotic twins. Although vaso- massive exudation at the posterior Klaus M. Kreusel, MD proliferative retinal tumors usually pole. Similar tumorous lesions rarely Nikolaos E. Bechrakis, MD develop unilaterally, our 2 patients occur in this disease, even in very ad- Ulrich Kellner, PhD showed the typical clinical pic- vanced stages. Michael H. Foerster, PhD ture.1,2 This consists of retinal tu- The pathogenesis of vasopro- Berlin, Germany mors characterized by a pink to yel- liferative retinal tumors has yet to be low appearance on funduscopy that explained. A study by Shields et al1 This study was presented in part at the are associated with intraretinal hem- in 103 patients showed that about 10th International Congress of Ocu- orrhage, intraretinal or subretinal three quarters of vasoproliferative lar Oncology, Amsterdam, the Neth- exudate, and hyperpigmentation of retinal tumors are primary and about erlands, June 19, 2001.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 We thank Martin Digweed, PD, for performing the DNA analysis for monozygosity and Hartmut P. H. Neu- man, PhD, for screening for a mutation in the VHLD gene. Corresponding author and reprints: Joachim Wachtlin, MD, Depart- ment of Ophthalmology, University Medical Center Benjamin Franklin, Free University of Berlin, Hindenburg- damm 30, 12200 Berlin, Germany (e- mail: [email protected]).

1. Shields CL, Shields JA, Barrett J, De Potter P. Va- soproliferative tumors of the ocular fundus: classification and clinical manifestations in 103 patients. Arch Ophthalmol. 1995;113:615-623. 2. Heimann H, Bornfeld N, Vij O, et al. Vasopro- liferative tumours of the retina. Br J Ophthal- mol. 2000;84:1162-1169. 3. Irvine F, O’Donnell N, Kemp E, Lee WR. Reti- nal vasoproliferative tumors: surgical management and histological findings. Arch Ophthal- mol. 2000;118:563-569. 4. Stolle C, Glenn G, Zbar B, et al. Improved detection of germline mutations in the von Hippel- Lindau disease tumor suppressor gene. Hum Mu- Figure 1. Case 1. Left fundus photograph taken at 7 months’ gestation showing a large inferior exudative tat. 1998;12:417-423. detachment overlying the circumscribed choroidal hemangioma.

Choroidal Hemangiomas With Exudative Retinal Detachments During Pregnancy

We describe the clinical course of 3 cases of circumscribed, choroidal hemangiomata that were associated with progressive exudative detachments during pregnancy.

Report of Cases. Case 1. A 31-year- old woman, gravida 1, visited our affiliation when 7 months pregnant with a 4-week history of blurred vision in the left eye. She had a cutaneous hemangioma of the left eyelid, dilated episcleral vessels, and amblyopia. Her visual acuity was 20/13 OD and 20/1200 OS. Left fun- doscopy revealed an inferior tem- Figure 2. Case 1. Left fundus photograph taken at 5 weeks’ post partum, prior to any thermotherapy. poral, orange choroidal mass with There is a marked reduction in the subretinal fluid in this eye, which had clinical evidence of a choroidal some subretinal fibrosis. Overlying hemangioma with some subretinal fibrosis. the mass was a large inferior retinal detachment with shifting fluid ated with an exudative detach- Five weeks’ post partum, there (Figure 1). The mass (excluding ment. One month later, the exuda- was a marked reduction in the size of the overlying fluid) was 12.0ϫ12.0 tive detachment had significantly the retinal detachment (Figure 2), mm wide and 7.4 mm high; it dem- increased in size. The patient’s vi- and her visual acuity improved to onstrated high internal reflectivity on sual acuity subsequently deterio- hand motions. She had one treat- ocular ultrasound. Right fundos- rated to light perception. She was at ment of transpupillary diode ther- copy results were unremarkable. risk for developing a total retinal de- motherapy. Five months later, the The diagnosis was a circum- tachment, and therefore under- retinal detachment had completely scribed choroidal hemangioma in went an elective cesarean section at resolved, and the hemangioma was Sturge-Weber syndrome associ- 37 weeks’ gestation. replaced by scar tissue. Her pin-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 with an exudative detachment. Two weeks later, her acuity deteriorated to counting fingers as the subretinal fluid extended beyond the posterior pole to detach the inferior retina. No intervention was under- taken during her pregnancy, but the intention was to treat the patient with radiotherapy after the delivery. She was examined 4 months after childbirth. When visual acuity started to improve to 20/400 OD, the subretinal fluid was resolving spontaneously. At 9 months’ post partum, visual acuity returned to 20/ 120 OD, and the retina was entirely flat. An isolated circumscribed choroidal hemangioma was seen at the right posterior pole with associated subretinal fibrosis (Figure 4). Four years later, the retina remains flat. During the course of follow-up the Figure 3. Case 2. Right fundus photograph taken at 31 weeks’ gestation showing a large dome-shaped choroidal hemangioma has not detachment at the posterior pole, which is associated with retina striae and cystoid macular edema. changed in size. The patient has not had any further pregnancies. Case 3. A 19-year-old woman visited our affiliation 10 months after the birth of her first child. She complained of blurred vision and mi- cropisa in the right eye, which started when she was 8 months pregnant. Her vision had not improved following delivery. Her visual acuity at initial visit was 20/60 OD and 20/20 OS. She had a dome-shaped, orange choroidal mass at the posterior pole and a large inferior exudative detachment. She did not have a facial angioma or any episcleral ab- normality. The diagnosis was a solitary, circumscribed choroidal hemangioma with an associated exudative detachment. The patient was treated with argon laser photocoagulation. One month later, her vision improved, but on fundal examination, the heman- Figure 4. Case 2. Right fundus photograph taken at 9 months’post partum with no treatment. The retinal de- gioma had not responded, and the in- tachment has resolved; subretinal fibrosis is seen associated with the circumscribed choroidal hemangioma. ferior detachment remained unchanged. Two further applications of hole corrected acuity improved to detachment at the posterior pole as- argon laser photocoagulation were 20/80 OS. sociated with cystoid macular edema administered, but the retinal detach- Case 2. A 26-year-old woman, (Figure 3). ment did not resolve. The patient was gravida 1, was referred when 31 She had no visual symptoms lost to follow-up. weeks pregnant. She had a congen- because the right eye was ambly- Five years after delivery, the ital cutaneous angioma along the opic. Underlying the exudative de- patient returned with an acuity of first division of the right trigeminal tachment was a circumscribed, or- no light perception, as there was a nerve involving the right upper eye- ange choroidal mass that showed total retinal detachment. Eight lid, with dilated episcleral veins on high internal reflectivity on B-scan. months later, the eye became pain- the same side. Her visual acuity was The diagnosis was a circum- ful as the intraocular pressure rose to 20/220 OD and 20/60 OS. Fundos- scribed choroidal hemangioma in 41 mm Hg. A right enucleation was copy revealed a large dome-shaped Sturge-Weber syndrome associated subsequently performed for uncon-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 trolled secondary glaucoma. The pa- from a total retinal detachment and Report of a Case. A 66-year-old thology report confirmed the diag- secondary glaucoma, and she fi- woman with a 6-year history of pso- nosis of a choroidal hemangioma. nally required enucleation. riasis had a progressive loss of vision In summary, the effect of preg- in her right eye during the previous Comment. Little is known about the nancy on choroidal hemangiomas is 6 months. Her visual acuity was hand behavior of choroidal hemangioma unknown, although in select situa- motions OD. The conjunctiva showed in pregnancy. There is one previ- tions, there may be an apparent in- moderate chemosis and increased red- ous report of leakage from a circum- creased exudation and enlarge- ness (Figure 1A). The cornea was scribed choroidal hemangioma in ment of the lesion. While 2 of these clear with a moderate amount of pig- pregnancy, and the fluid resolved fol- 3 cases stabilized during the post- mented endothelial precipitates infe- lowing full-term normal delivery.1 partum timeframe, the clinical riorly. The anterior chamber was shal- In our case series, exudative reti- course may be quite variable. low, with trace cells and flare. The nal detachments developed during pupil was round and miotic with a re- the third trimester of pregnancy. Victoria M. Cohen, MRCOphth duced response to bright light. The All the mothers were primigravida, Paul A. Rundle, FRCOphth lens had a dense cataract that pre- but none had symptoms or signs of Ian G. Rennie, FRCS, FRCOphth vented visualization of the posterior pre-eclampsia. Blood pressure was Sheffield, England segment of the eye. Measurement monitored during the pregnancies. with applanation tonometry was 30 Cases 1 and 2 had Sturge-Weber syn- mm Hg. An ultrasonographic B-scan drome. The most frequently de- No grants or sponsors were used for examination showed a superior se- scribed ocular manifestation in this this study. rous choroidal detachment and com- syndrome is a flat diffuse choroidal The authors have no commercial plete retinal detachment without fun- hemangioma, giving the fundus the interest or conflicting relationship. nel formation (Figure 1B). typical “tomato ketchup” appear- Corresponding author: Victoria A diagnostic vitrectomy was ance, but recently circumscribed el- Cohen, MRCOphth, Department of performed, and the lens with cata- evated choroidal hemangiomatas have Ophthalmology, Addenbrooke’s Hospi- ract was removed. On examination been described.2,3 tal, Hills Road, Cambridge, England of the posterior segment of the eye, Isolated hemangiomas are CB2 2QQ (e-mail: victoria@victoriac a complete serous retinal detach- known to grow very slowly.4 Shields .freeserve.co.uk). ment was noted. The diagnosis of in- 5 et al compared ultrasound measure- 1. Pitta C, Bergen R, Littwin S. Spontaneous re- fection with microsporidia was made ments of an enlarging circumscribed gression of a choroidal haemangioma following 3 days following surgery, and the pa- pregnancy. Ann Ophthalmol. 1979;11:772-774. choroidal hemangioma with histol- 2. Scott IU, Alexandrakis G, Cordahi GJ, Murray tient was prescribed a systemic medi- ogy reports at enucleation. They dem- TG. Diffuse and circumscribed choroidal hem- cation with albendazole at a dose of onstrated that enlargement was the re- angiomas in a patient with Sturge-Weber syn- 400 mg twice a day. Eight months drome. Arch Ophthalmol. 1999;117:406-407. sult of venous congestion and was not 3. Cheung D, Grey R, Rennie IG. Circumscribed following the initial surgery, the eye due to cell multiplication.5 The al- choroidal hemangioma in a patient with Sturge was completely quiet; the silicone oil tered hemodynamic state in preg- Weber Syndrome. Eye. 2000;14:238-239. was removed, and an anterior cham- 4. Medlock RD, Augsburger JJ, Wilkinson CP, et nancy may result in engorgement of al. Enlargement of circumscribed choroidal hem- ber lens was implanted. Four months the vascular networks within a he- angiomas. Retina. 1991;11:385-388. later the eye was still quiet, and the 5. Shields JA, Stephens RF, Eagle RC, et al. Pro- mangioma, resulting in increased gressive enlargement of a circumscribed choroi- patient’s best-corrected visual acu- transudation of fluid into the subreti- dal hemangioma. Arch Ophthalmol. 1998;110: ity was 20/200 OD. nal space. This could explain the ob- 1276-1278. Examinations of the vitreous served leakage from a choroidal he- aspirate included detection of mangioma in the late stages of the level of antibodies in both the pregnancy. There may also be hor- vitreous humor and serum against monal influence on the growth of vas- Microsporidia-Induced varicella-zoster virus, herpes sim- cular malformations; however, this re- Sclerouveitis With Retinal plex virus, cytomegalovirus, and toxo- mains speculative. Detachment plasmosis. In all instances, the anti- This series demonstrates that body levels of the serum and vitreous following delivery, the subretinal Microsporidia are a rare but increas- were similar, so an intraocular syn- fluid tends to reabsorb, and the he- ingly important group of protozoa thesis of antibodies was ruled out. mangioma ceases to leak. The retina that cause infections in vertebrates Examination of the slides stained was flat at 5 months’ post partum fol- and invertebrates. Ocular involve- with hematoxylin-eosin and peri- lowing one episode of thermo- ment affecting mostly the cornea and odic acid–Schiff revealed erythro- therapy in case 1. The retina was flat conjunctiva in otherwise healthy pa- cytes, a few lymphocytes, and neu- at 9 months’ post partum with no tients has only occasionally been de- trophilic cells. A few lytic cells and treatment in case 2. However, reso- scribed.1-4 To the best of our knowl- free-melanin pigment granules were lution of an exudative detachment edge, posterior segment involvement observed. No abnormal lympho- after delivery is not always the rule, has not been described to date. We cytes were present, and no bacteria or even following the supplementary report a case of microsporidia- fungi were seen. One slide con- argon laser photocoagulation treat- induced sclerouveitis with retinal de- tained several spores that had fea- ment. The third patient suffered tachment. tures consistent with microsporidia

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Figure 2. A, Light microscopy of the protozoan revealed by examination of the vitreous aspirate. According to its morphologic characteristics, this protozoan is from the Nosema genus (hematoxylin-eosin, original magnification ϫ250). B, Fluorescent stain with Uvitex 2B of a slide from the diagnostic vitrectomy. The slide was examined under a UV microscope at a wavelength of 395 to 415 nm. The bright white spots represent the chitin in the spore walls of the microsporidia (fluorescence, original magnification ϫ250). crosporidia in their differential diagnosis. Figure 1. A, Slitlamp photograph of the right eye, with a history of progressive loss of vision for the past 6 months. The nasal conjunctiva is swollen and shows an increased redness. The cornea is clear with Holger Mietz, MD only a few endothelial precipitates. The visual acuity is hand motions OD because of a cataractous lens Caspar Franzen, MD and complete retinal detachment. B, Ultrasonographic B-scan of the right eye. A complete retinal Thomas Hoppe, MD detachment is present (arrows), and there is an anterior serous detachment of the choroid (arrowhead). Cologne, Germany K. Ulrich Bartz-Schmidt, MD (Figure 2A). The positive results of ridium africanum, Encephalitozoon in- Tu¨bingen, Germany staining with Uvitex 2B further con- testinalis, and Encephalitozoon firmed the diagnosis (Figure 2B). cuniculi. Corresponding author: Holger Mietz, To our knowledge, this is the MD, Department of Ophthalmol- Comment. To date, 4 cases of stro- first report of severe sclerouveitis with ogy, University of Cologne, 50924 mal keratitis have been reported, all retinal detachment caused by micro- Koeln, Germany (e-mail: h.mietz@ of which occurred in immunocom- sporidia. It is interesting that no such uni-koeln.de). petent patients.1-4 The genera found cases have previously been reported. include Encephalitozoon1 and No- One may speculate that thorough cy- 1. Ashton N, Wirasinha PA. Encephalitozoonosis 2-4 (nosematosis) of the cornea. Br J Ophthalmol. sema. The number of reports of topathologic examinations of vitre- 1973;57:669-674. keratoconjunctivitis are increasing ous aspirates are infrequently per- 2. Pinnolis M, Egbert PR, Font RL, Winter FC. No- and generally relate to patients who formed in cases of uveitis of unknown sematosis of the cornea: case report, including electron microscopic studies. Arch Ophthalmol. are immunoincompetent, most of origin. Fluorescent staining with Uvi- 1981;99:1044-1047. whom have acquired immunodefi- tex 2B clearly showed that the respon- 3. Font RL, Samaha AN, Keener MJ, Chevez-Barrios P, Goosey JD. Corneal microsporidiosis: report of ciency syndrome. Specific micro- sible organism in this case was a mi- case, including electron microscopic observations. sporidia identified in these cases in- crosporidium. Ophthalmology. 2000;107:1769-1775. clude Encephalitozoon hellum, Physicians confronted with a 4. Davis RM, Font RL, Keisler MS, Shadduck JA. Cor- neal microsporidiosis: a case report including ul- Trachipleistophora species, Micro- case of uveitis of unknown origin trastructural observations. Ophthalmology. 1990; sporidium ceylonensis, Microspo- should include the possibility of mi- 97:953-957.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 rected against bipolar cells of the culty seeing in dark conditions 2 Unilateral Manifestation retina. The symptoms generally through her right eye, which greatly of Melanoma-Associated spread to the other eye within an in- interfered with her stereovision. She 3,4 Retinopathy terval of 4 days to 2 months. We re- also reported shimmering lights that port a case of MAR that remained uni- fluctuated in brightness. lateral during an observation period Because an ophthalmological ex- A rare complication of cutaneous of 18 months. amination demonstrated good vi- melanoma is the development of sual acuity and no fundus alter- melanoma-associated retinopathy Report of a Case. A cutaneous ma- ations, the patient’s complaints were (MAR), a condition characterized by lignant melanoma was removed from judged to be of psychic origin. Four the acute onset of night blindness, the left leg of a 45-year-old woman in months later, a metastatic cutaneous persistent pulsating photopsias, and 1992. Because a systematic search re- melanoma was removed from her left constriction of the visual field.1 The vealed no metastasis, no further leg. She underwent chemotherapy pathogenetic mechanisms of the syn- therapy was administered. and was referred to our electrophysi- drome have been clarified by the de- One evening in January 2000, ological laboratory because of her per- tection of immunoglobulins di- she suddenly experienced diffi- sisting visual complaints.

A Sensitivity Scale, dB 0 30 1-5 30 6-10 11-15 16-20 21-25 20 20 26-30 31-35 36-40

10 10

0 0 Visual Field, Degrees Visual Field, Degrees –10 –10

–20 –20

–30 –30 –30 –20 –10 0 10 20 30 –30 –20 –10 0 10 20 30 Visual Field, Degrees Visual Field, Degrees

B Points of Measurements Points of Measurements 1 59 1 59

–5 –5

0 5% 0 5%

Normal Normal 5 5

95% 95% 10 10

15 15 Cummulative Defect, dB Cummulative Defect, dB

20 20

25 25

Figure 1. A, Visual field of the right eye (left) and left eye (right) estimated using Octopus equipment. The x- and y-axes represent dimensions of the visual field in degrees. B, Cumulative defect curves (Bebie curve) from the 59 central points in rank order cumulative sensitivity distribution.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 bilateral with some interocular la- tency difference in the appearance 3,4 A of symptoms. Although cases with unilateral normal-appearing ERGs have been reported, no evidence of melanoma-related immune activity B was found.5 In our case, some damage to the other eye might have remained undetected by the electrophysiological tests, or the C tragic outcome may have prevented a late manifestation of the disease in that eye. Nonetheless, the relatively long observation D period raises the possibility that MAR manifests unilaterally in some patients.

E Ma´rta Jana´ky, MD, PhD Andrea Pa´lffy, MD Figure 2. Electrophysiological recordings from the right eye (left) and left eye (right) of the patient. A, Lajos Kolozsva´ri, MD, PhD Scotopic, rod-isolated response. B, Maximal, dark-adapted response. C, Electroretinographic (ERG) Gyo¨rgy Benedek, MD, PhD response to red flash. D, Averaged ERG response to 50 blue flashes. E, Averaged oscillatory potentials to 50 blue flashes. Calibrations: 50 µV; 100 milliseconds. Szeged, Hungary

This work was supported by ETT/ Hungary grants 56411 and 57404. She still had a best-corrected dividual ERG and oscillatory poten- We thank Ann Milam, PhD (Uni- visual acuity of 20/20 OU. Al- tial responses to blue light flashes versity of Pennsylvania, Philadel- though an ophthalmoscopy consis- were averaged. The averaged ERG phia), for performing the immuno- tently showed no alterations in the and oscillatory potentials were chemistry test. right eye, a previously unknown greatly impaired in the right eye but Corresponding author and re- uveal nevus was detected in the normal in the left eye. prints: Gyo¨rgy Benedek, Department macular area of the left eye. Com- In the immunocytochemistry of Physiology, Faculty of Medicine, puterized perimetry (Octopus) re- test, the patient’s serum displayed University of Szeged, H-6720 Szeged, vealed a marked visual field con- strong binding to retinal bipolar POB 427, Hungary (e-mail: benedek striction and a general depression cells, similar to that of a known pa- @phys.szote.u-szeged.hu). of light sensitivity in the right eye. tient with MAR. The left eye exhibited no perimet- Five control electrophysiologi- 1. Berson EL, Lessell S. Paraneoplastic night blindness with malignant melanoma. Am J Ophthal- ric alterations (Figure 1). cal examinations together with pe- mol. 1988;106:307-311. Full-field electroretinograms rimetry and ophthalmoscopy dem- 2. Milam AH, Saari JC, Jacobson SG, et al. Auto- (ERGs) were recorded with gold- onstrated no changes during the antibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Invest foil electrodes in both eyes after following 15-month observation pe- Ophthalmol Vis Sci. 1993;34:91-100. maximal pupil dilatation and a 30- riod. Unfortunately, the patient de- 3. Kellner U, Bornfeld N, Foerster MH. Severe course of cutaneous melanoma associated para- minute period of dark adaptation. A veloped agranulocytosis in July 2001 neoplastic retinopathy. Br J Ophthalmol. 1995; stroboscopic lamp placed behind the and died of pulmonary metastases and 79:746-752. patient provided flashing lights on respiratory failure 1 month later. The 4. Boeck K, Hofmann S, Klopfer M, et al. Melanoma- associated paraneoplastic retinopathy: case re- a Ganzfeld screen. Scotopic, maxi- family did not allow an autopsy. port and review of the literature. Br J Dermatol. mal, and photopic responses were 1997;137:457-460. recorded according to the Interna- Comment. In our case, the acute 5. Fishman GA, Alexander KR, Milam AH, et al. Ac- quired unilateral night blindness associated with tional Society for Clinical Electro- night blindness, sensations of shim- a negative electroretinogram waveform. Oph- physiology of Vision recommend- mering lights, normal ERG results, thalmology. 1996;103:96-104. ations. The single-flash, rod- and constricted visual field, to- dominant ERG showed a markedly gether with the normal appearance decreased scotopic response in the of the retina and the preserved vi- right eye, whereas maximal-intensity sual acuity, were diagnostic of MAR. stimulation elicited a typical ERG The positive immunological reac- A Child With Venous Sinus that showed no abnormalities, a se- tion of the serum substantiated the Thrombosis With Initial lective b-wave depression with a pre- diagnosis. The case is peculiar be- Examination Findings served a wave (Figure 2). Both the cause the condition failed to spread of Pseudotumor Syndrome scotopic rod-isolated response and to the other eye during an 18- the maximal response in the left eye month observation period. Until re- A child with venous sinus throm- were in the normal range. Fifty in- cently, all reported MAR cases were bosis whose initial clinical findings

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 and glucose levels. An initial diagnosis of a pseudotumor syndrome was entertained. However, magnetic resonance venous imaging showed complete occlusion of right and partial occlusion of left transverse sinus (Figure) reveal- ing the diagnosis of venous sinus thrombosis. The following laboratory investigation findings were normal: complete blood cell count, coagula- tion profile, cardiolipin antibody, antinuclear antibody, rheumatoid factor, and homocysteine. Serum Lyme titers were positive for IgG and IgM at 4.1 mg/dL (Ͻ0.9 mg/dL, negative; Ͼ1.1 mg/dL, positive). Cerebro- spinal fluid polymerase chain reaction and Western immunoblot were positive for Borrelia burgdorferi. The child was treated with ac- etazolamide, low-molecular- weight heparin, and 3 weeks of intravenous ceftriaxone sodium. One month later, the headaches had resolved and the child had normal ocular motility and normal optic discs.

Comment. The incidence of venous sinus thrombosis is estimated to be 3 to 5 new cases per year at a single hospital.1 The clinical findings at initial examination Magnetic resonance venous imaging demonstrates complete lack of flow through the right transverse may be similar to pseudotumor venous sinus (short arrow) and sluggish flow through the left transverse sinus (long arrow). cerebri.1-3 In children, however, most cases of venous thrombosis have been associated with evidence of infection, otitis media, mastoid- were consistent with an isolated and cooperative. Visual acuity was itis, systemic lupus erythematosus, pseudotumor syndrome without any 20/20 OU, and color plate test re- use of oral contraceptives, or signs predisposing factors is described. sults from Ishihara plates was nor- of dehydration.4 Our case demon- mal in each eye. Ocular motility re- strates that even in the absence of Report of a Case. A 6-year-old vealed 10% bilateral abduction identifiable risk factors, venous white girl was seen at the emer- deficits. Anterior segment examina- sinus thrombosis may occur with gency department of a children’s tion results were normal. Fundus ex- only signs of increased intracranial hospital with complaints of head- amination findings revealed mild bi- pressure in children. The outcome aches for 3 weeks and diplopia for lateral disc edema. The remainder of is unpredictable with a 10% to 30% 2 days. Three weeks prior to exami- her general and neurologic exami- mortality rate; however, anticoagu- nation, she had 2 episodes of eme- nation was unremarkable; specifi- lation may improve neurologic out- sis. Findings from systemic review cally, no other cranial nerve defi- come and reduce mortality in select were negative for fever, neck stiff- cits were present. cases.1 ness, ear pain, or upper respiratory Magnetic resonance imaging Our patient had positive re- symptoms. There was no history of scans of the head were normal. sults on Lyme serologic analysis. tick bites, skin rashes, or recent Lumbar puncture disclosed an Lyme disease as a possible cause of travel. She lived in an urban com- opening pressure of 450 cm H2O. venous sinus thrombosis has not munity in Pennsylvania. The re- Cerebrospinal fluid composition been previously reported to our mainder of her medical history was showed a red blood cell count of 2 knowledge. Our case suggests that unremarkable. cells/µL; white blood cell count, 20 there may be an association be- On examination she was afe- cells/µL (85% lymphocytes, 13% tween neuroborreliosis and venous brile with normal vital signs, alert, monocytes); and normal protein sinus thrombosis.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 In conclusion, our case illus- Kammi B. Gunton, MD 1. Broderick JP. Cerebral venous thrombosis. MedLink Web site, Neurology section. 2nd 2001 trates the necessity of performing Gary R. Diamond, MD ed. Available at: http://www.medlink.com. Ac- magnetic resonance venous imag- Joseph Melvin, MD cessed January 31, 2002. ing in the presence of normal find- Philadelphia, Pa 2. Lam BL, Schatz NJ, Glaser JS, Bowen BC. Pseu- dotumor cerebri from cranial venous obstruc- ings on magnetic resonance imag- tion. Ophthalmology. 1992;99:706-712. ing and emphasizes the importance 3. Biousse V, Ameri A, Bousser M-G. Isolated in- of excluding venous sinus throm- Corresponding author and reprints: tracranial hypertension as the only sign of cerebral venous thrombosis. Neurology. 1999;53: bosis as a cause of a pseudotumor Kammi B. Gunton, MD, Department 1537-1542. syndrome in children. of Ophthalmology, St Christopher’s 4. Lessell S. Pediatric pseudotumor cerebri (idio- pathic intracranial hypertension). Surv Ophthal- Hospital for Children, Erie Avenue at mol. 1992;37:155-166. Irfan Ansari, MD Front Street, Philadelphia, PA 19134- Brian Crichlow, MD 1095.

Unfolding Fundus. Created by Patrick J. Saine, MEd, CRA, Dartmouth-Hitchcock Medical Center, Lebanon, NH.

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