Arch Ophthalmol 2011 Yeh

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roid, corticosteroid, and sex hor-mone deficiencies).6,19 Radiationtherapy greatly increases the life-long risk of secondary malignantneoplasms (glioblastoma multi-forme, malignant astrocytoma, me-ningioma, bone and soft-tissue sar-coma, and malignant melanoma) inchildren with TRB who are already

predisposed to secondary cancerso w i ng to thei r g er m l i ne RB1mutations.20

Treatment of TRB using theToronto Protocol and intrathecaltopotecan combined with cy-tarabine, followed by consolida-tion with autologousperipheral stemcell transplant after supralethalchemotherapy avoidstheneedfor ra-diation therapy and, in some in-stances, extends survival.

Author Affiliations: Division of Hematology and Oncology (DrsDimaras, Doyle, and Chan), andDepartments of Pediatrics (DrsDimaras, Doyle, and Chan), Oph-

thalmology and Visual Science(Drs Heon and Gallie), Pathology(Dr Halliday), and DiagnosticImaging (Dr Babyn), The Hospitalf o r S i c k C h i l d r e n , T o r o n t o ,Ontario, Canada, and Division of Hematology and Oncology (DrStrahlendorf), Departments of Pediatrics (Dr Strahlendorf) andOphthalmology (Dr Paton), Chil-dren’s and Women’s Health Cen-tre of British Columbia and Uni-v e r s i t y o f B r i t i s h C o l u m b i a,Vancouver, Canada.

Correspondence: Dr Chan, Divi-sion of Hematology and Oncology,The Hospital for Sick Children, 555University Ave, Toronto, ON M5G1X8, Canada ([email protected]).Financial Disclosure: None re-ported.Funding/Support: This study wassupported in part by grants to DrChan from The Ontario Institute for

Cancer Research and to Dr Galliefrom the Canadian RetinoblastomaSociety and the Royal Arch Masonsof Canada.

1. De Potter P, Shields CL, Shields JA. Clinicalvariations of trilateral retinoblastoma: a re-port of13 cases. J Pediatr Ophthalmol Strabismus.1994;31(1):26-31.

2. Kivelä T. Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associ-

ated with primary ectopic intracranialretinoblastoma. J Clin Oncol. 1999;17(6):1829-1837.

3. PaulinoAC. Trilateral retinoblastoma:is thelo-cation of the intracranial tumor important?Cancer . 1999;86(1):135-141.

4. Dunkel IJ, Jubran RF, Gururangan S, et al.Trilateral retinoblastoma: potentially curablewith intensive chemotherapy. Pediatr BloodCancer . 2010;54(3):384-387.

5. Duffner PK, Cohen ME, Voorhess ML, et al.Long-term effects of cranial irradiation on en-docrine function in children with brain tu-mors: a prospective study. Cancer . 1985;56(9):2189-2193.

6. Kiltie AE, Lashford LS, Gattamaneni HR. Sur-vival and late effects in medulloblastoma pa-tients treated withcraniospinal irradiationun-der three years old. Med Pediatr Oncol. 1997;

28(5):348-354.7. Palmer SL, Goloubeva O, Reddick WE, et al.

Patterns of intellectualdevelopment amongsur-vivors of pediatric medulloblastoma: a longi-tudinal analysis. J Clin Oncol. 2001;19(8):2302-2308.

8. Duffner PK, Horowitz ME, Krischer JP, et al.Thetreatment of malignantbrain tumors in in-fants and very youngchildren: anupdateof thePediatric Oncology Group experience. NeuroOncol. 1999;1(2):152-161.

9. Blaney SM, Poplack DG. Neoplastic meningi-tis: diagnosis andtreatment considerations. MedOncol. 2000;17(3):151-162.

10. Chan HS, Gallie B, Munier FL, Popovic M.Chemotherapy for retinoblastoma. Ophthal-mol Clin North Am. 2005;18(1):55-63, viii.

11. Blaney SM, Heideman R, Berg S, et al. Phase Iclinical trial of intrathecal topotecan in pa-

tientswith neoplasticmeningitis. J Clin Oncol.2003;21(1):143-147.12. Chan HS, Canton MD, Gallie BL. Chemosen-

sitivity and multidrug resistance to antineo-plastic drugs in retinoblastoma cell lines. An-ticancer Res. 1989;9(2):469-474.

13. Dimaras H, Heon E, Budning A, et al. Retino-blastoma CSF metastasis cured by multimo-dality chemotherapy without radiation. Oph-thalmic Genet. 2009;30(3):121-126.

14. Dai S, Dimaras H, Heon E, et al.Trilateral reti-noblastoma with pituitary-hypothalamicdysfunction. Ophthalmic Genet. 2008;29(3):120-125.

15. Linn Murphree A. Intraocular retinoblastoma:thecase for a new group classification. OphthalmolClin North Am. 2005;18(1):41-53, viii.

16. Finger PT; 7th Edition, AJCC-UICC Ophthal-mic Oncology Task Force. The 7th edition

AJCC staging system for eye cancer: an inter-national language for ophthalmic oncology. Arch Pathol Lab Med. 2009;133(8):1197-1198.

17. Chan HS, DeBoer G, Thiessen JJ, et al. Com-bining cyclosporin with chemotherapy con-trols intraocular retinoblastoma without re-quiring radiation. Clin Cancer Res. 1996;2(9):1499-1508.

18. Sikic BI. Modulation of multidrug resistance:at the threshold. J Clin Oncol. 1993;11(9):1629-1635.

19. Duffner PK. Long-term effects of radiationtherapy on cognitive and endocrine functionin children with leukemia and brain tumors.Neurologist. 2004;10(6):293-310.

20. Eng C, Li FP, Abramson DH, et al. Mortalityfrom second tumors among long-term survi-vors of retinoblastoma. J Natl CancerInst. 1993;85(14):1121-1128.

Acute Macular OuterRetinopathy (AMOR):

A Reappraisal of AcuteMacular Neuroretinopathy

Using Multimodality Diagnostic Testing

Acute macular neuroretinopathy(AMNR) is a rare retinal conditionthat features the sudden onset of bi-lateral central scotomata, which maybe preceded by a viral prodrome insome patients. Acute macular neu-roretinopathy may be difficult to di-agnose because of the subtle or evenabsent findings on funduscopic ex-amination and fluorescein angiog-

raphy. Bos and Deutman1

initiallydescribed AMNR in 4 patients withparacentral scotomata, slightly de-creased visual acuity, and reddish,wedge-shapedintraretinal lesionsdi-rected toward the fovea. Because of the acuteonset of the symptoms andbased on their theory that the moresuperficial layers of macular retinawere involved, the term AMNR wasadopted.

Herein, we describe 2 patientswith features of AMNR in whomAmsler gridtesting, infrared imaging,

spectral-domain optical coherencetomography (SD-OCT), fundus au-tofluorescence, and multifocal elec-troretinogram (mfERG) were usefulincharacterizingtheprecisestructuraland functional deficits of this condi-tion.Thelocalizationofstructuraldefi-citstotheouterretinaandphotorecep-torlayer using SD-OCT andevidenceof depressed cone amplitudes usingmfERG in both patients were moreconsistent with photoreceptor andouter retinal dysfunction. Hughes etal2 previously reported 2 cases of

AMNRthatfeaturedouterretinalstruc-turalchangesusingSD-OCT.Thefunc-tionalandanatomic deficitsobservedinourpatientsusingmultimodalitydi-agnostic testing, combined with thepreviousstructuralcharacterizationof AMNR,2-5 are supportive of the pro-posed nomenclature acute macular outerretinopathy (AMOR)tomoreac-curately describethis unique clinicalentity.2

Helen Dimaras, PhDElise Heon, MD John Doyle, MDCaron Strahlendorf, MDKatherine E. Paton, MDWilliam Halliday, MDPaul Babyn, MDBrenda L. Gallie, MDHelen S. L. Chan, MBBS

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Report of Cases. Case 1. A 24-year-oldwomanhadsevere fatigue, head-aches, and intermittent photopsias,followed by bilateral central scoto-mata 1 week later.

Visualacuities were 20/25 OD and20/20OS. Amsler grid testing showeda well-defined boot-shaped scotomain the right eye and a wedge-shapedscotoma in the left eye (Figure 1).Color visionwith Ishihara plate test-ing was normal in both eyes.No rela-tiveafferentpupillary defect wasseen.Slitlamp examination showed noanterior chamber or vitreous cells.Dilated funduscopic examinationand fluorescein angiography wereunremarkable.

Infrared imaging showed a well-defined boot-shaped image in the

right eye and a wedge-shaped im-age in the left eye, which corre-sponded precisely to the scotomatadefined by Amsler grid testing. Fun-dus autofluorescence imagingshowed subtle hypoautofluores-cence corresponding to these af-fected areas. The mfERG showedsubnormal amplitudes of the cen-tral responses with normal implicittimes consistent with a regionalabnormality of local retinal re-sponses in the form of central conedysfunction (Figure 1). Spectral-domain optical coherence tomogra-phy showed thinning of the photo-r ecepto r o uter seg m ents andirregularities of the outer retinal ar-chitecture (Figure 2). Fluores-cein and high-speed indocyanine

green angiography were unremark-able. The findings were most con-sistent with AMNR and no treat-ment was recommended.

At the final follow-up visit 4months later, the patient’s symp-toms were improved and visual acu-ities were 20/20 OU. Funduscopicexamination showed brown discol-oration of the parafoveal region andmild retinal pigment epithelial ir-regularities, which were moreprominent than the findings on ini-tial examination. Spectral-domainoptical coherence tomographyshowed persistent abnormalities of the outer retina.

Case 2. A 17-year-old healthy girlhad fevers and flulike symptoms for3 days followed by visual photop-

Right eye Left eye

A B F G

C D H

E J

I

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Field view Field view

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Figure 1. Amsler grid testing drawn by patient 1 shows a boot-shaped deficit in the right eye with the toe of the boot in the inferonasal quadrant of the Amsler grid(A). Fundus photograph shows a subtle reddish hue in the parafoveal region (B) whereas infrared imaging (C) highlights the boot-shaped abnormality. Fundus

autofluorescence also shows subtle changes in the same region (D). Multifocal electroretinogram demonstrates decreased amplitudes of the cone photoreceptorresponses with normal implicit times in the right eye (E). Amsler grid testing shows a wedge-shaped scotoma in the left eye (F) and the fundus photograph isnormal (G). Infrared imaging shows decreased reflectance in the wedge-shaped distribution nasal to the fovea (H) and fundus autofluorescence shows subtlehypoautofluorescence in this region (I). Multifocal electroretinogram shows diminished amplitudes of the central cone responses nasal to fixation ( J).






sias and 2 discrete shadows in theleft eye. She was asymptomatic in theright eye.

Visual acuities were 20/20 OU.Amsler grid testing showed 2 areasof visual blur; both areas were tem-poral to the fovea inthe left eye. Norelative afferent pupillary defect wasobserved. The anterior segment ex-

amination wasunremarkable in botheyes. Dilated funduscopic examina-tion was normal in the right eye. Asubtle, slightly abnormal foveal re-flex was seen in the left eye, but thefunduscopic examination was oth-erwise unremarkable.

The infrared reflectance imagehighlighted 2 discrete abnormal im-ages nasal to the fovea, which cor-responded precisely to the patient’sscotomata (Figure 3). Spectral-domain optical coherence tomogra-phy revealed attenuation of the in-

ner segment–outer segment junctionin the abnormal parafoveal areaiden-tified by infrared imaging. A fluo-resceinangiogram showedsubtlehy-pofluorescence in these areas in thelate frames of the angiogram. ThemfERG showed subnormal ampli-tudes of the cone responses in theleft eye to a greater degree than thatobserved in the right eye, with nor-mal implicit times. At the 4-monthfollow-up, the patient’s symptomsremained stable. Her visual acu-ities were 20/20 OU and the fundu-

scopic lesions in the left eye weremore easily seen than on her priorexamination. Specifically, there were2 reddish-brown lesions nasal to thefovea, similar in size and characterto the images previously seen by in-frared imaging (Figure 4).

Comment. Our patients’ character-istic histories, clinical features, andfindings were most consistent withthe entity described as AMNR.1,3 Re-cent reports have suggested that in-frared imaging is valuable in high-

lighting the macular lesions of AMNR 3,4 and SD-OCT has facili-tated identification of the anatomi-cal abnormalities present.2,5

In our 2 patients, multimodalitydiagnostic testing allowed a precisediagnosisof AMNRandprovided ad-ditional insight into the disease pro-cess. Infrared imaging and SD-OCT provided information about thestructural defects corresponding to

the patients’ scotomata. Fundus au-tofluorescence showed subtle areasof hypoautofluorescence in both pa-

tients. Although these changes werenot as prominent as the infrared andSD-OCT abnormalities, the re-

A B

C D

200 µm

200 µm

Figure 2. Elevation map of the right eye using spectral-domain optical coherence tomography showsinverted boot-shaped central area (A) with a focal outer nuclear layer and photoreceptor innersegment–outer segment junction attenuation (B) on the horizontal raster scan (inset, B). Elevation map ofthe left eye (C) shows thinning of the nasal parafoveal region in a wedge-shaped distribution withcorresponding outer nuclear layer and photoreceptor inner segment–outer segment junction changes (D)on the horizontal raster scan (inset, D).

A B

C D

E F G

200 µm

200 µm

Figure 3. Infrared imaging of patient 2’s left eye shows 2 discrete areas of decreased reflectance, whichcorresponded to her symptoms (A). Spectral-domain optical coherence tomography shows attenuation ofthe inner segment–outer segment junction and outer retinal architectural abnormalities including focalthinning of the outer nuclear layer (B). The abnormal inferonasal parafoveal region (C) also demonstratedsimilar outer retinal architectural changes (D). Fundus autofluorescence showed mildhyperautofluorescence surrounding hypoautofluorescent areas corresponding to the lesions nasal to thefovea (white arrows, E). A venous laminar phase angiogram showed patchy choroidal filling (F) and asubtle area of hypofluorescence corresponding to the lesions in the late venous frames of the angiogram(yellow arrows, G).






gional decreasein intrinsictissue au-tofluorescence suggested patho-logic changes at the level of theretinal pigment epithelium and pos-sibly involving the outer retina. The

additional use of mfERG high-lighted the functional deficits of these patients despite better than20/25 visual acuity. Specifically, bi-lateral reduction of central re-sponses of outer retinal origin withnormal implicit times was identi-fied in both patients. This was es-pecially helpful in identifying ab-normal photoreceptor function inthe asymptomatic eye of patient 2.

Our findings are consistent withprior reports of outer retinal archi-tectural changes observed with SD-OCT in AMNR.2,5 The addition of mfERG to precisely identify conephotoreceptor dysfunction pro-vided a correlation of a functionaldeficit to the structural changesobserved in the outer retina. Al-though we did not identify a cho-roidal or retinal vascular perfusiondefect by fluorescein angiographyor indocyanine green angiography

testing, focal hypofluorescence inthe region of the macular lesionswas observed on fluorescein angi-ography of patient 2. This couldrepresent inner choroidal ischemia

or blockage of choroidal fluores-cence from a focal inflammatoryaccumulation with resultant over-lying outer retinal architecturaldisruption.

The term AMNR was originallyapplied to this condition becauseof the acute onset of presentationand the theory that the superficialmacular retina was involved; givenour observations correlating func-tional and structural aspects of thisdisease, the term acute macular outer retinopathy may be more

appropriate.

Author Affiliations: Casey Eye In-stitute, Oregon Health and Sci-ences University, Portland.

Correspondence: Dr Francis, Ca-sey EyeInstitute, Oregon Retinal De-generation Center, 3375 SW Ter-williger Blvd, Portland, OR 97239([email protected]).Financial Disclosure: None re-ported.Funding/Support: This research issupported by an unrestricted grant

from Research to Prevent Blind-ness anda career development awardto Dr Francis. Dr Yeh has receivedsupport from the Heed Ophthal-mic Foundation and the Ronald G.Michels Foundation. Drs WeleberandFrancis receive support from theFoundation Fighting Blindness.

1 . Bos P J, Deu tman A F. A cu te mac ularneuroretinopathy. Am J Ophthalmol. 1975;80(4):573-584.

2. Hughes EH,Siow YC,Hunyor AP.Acutemacu-lar neuroretinopathy: anatomic localisationof thelesion with high-resolution OCT. Eye (Lond).2009;23(11):2132-2134.

3. Turbeville SD,Cowan LD,Gass JD. Acutemacu-

lar neuroretinopathy: a review of the literature.Surv Ophthalmol. 2003;48(1):1-11.

4. CorverHD, Ruys J,Kestelyn-Stevens AM,De Laey JJ , Ler oy BP. Two cas es of acu te mac ula rneuroretinopathy. Eye (Lond). 2007;21(9):1226-1229.

5. Neuhann IM, Inhoffen W, Koerner S, Bartz-Schmidt KU, Gelisken F. Visualization and fol-low-upof acutemacularneuroretinopathy withthe Spectralis HRAOCT device. Graefes ArchClin Exp Ophthalmol. 2010;248(7):1041-1044.

Interferon- Release Assay in Tuberculous Scleritis

Scleritis is a painful, often chronic,andpotentially destructiveocular in-flammation caused by either infec-tious agents or noninfectious im-mune reactions. Tuberculosis (TB)is one possible infectious cause of scleritis. In this report, we describe3 patients in whom use of an inter-feron (IFN)- release assay as-sisted in the diagnosis of tubercu-lous scleritis.

Report of Cases. Case 1. A 29-year-old woman was referred for bilat-

eral anterior scleritis refractory totopical corticosteroids. On exami-nation,corrected visual acuitieswere1.2 with normal intraocular pres-sure in both eyes. The sclera wasmarkedly hyperemic in all 4 quad-rants bilaterally (Figure 1A). Mildinflammatory cells were present inthe anterior chambers in both eyesbut the fundi were unremarkable.Laboratory investigations revealed

Field view

A

C Field view

B

D

Right eye Left eye

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Figure 4. Fundus photographs of patient 2 at the final 4-month follow-up were unremarkable in the righteye (A) but showed reddish, oval lesions in the left eye (B). Multifocal electroretinogram demonstratedsubnormal amplitudes with normal implicit times in the right eye (C), but these changes were moreprominent in the region between the disc and the fovea in the left eye (D).

Steven Yeh, MDThomas S. Hwang, MDRichard G. Weleber, Prof Robert C. Watzke, MDPeter J. Francis, MD, PhD



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