roid, corticosteroid, and sex hormone deficiencies).

6,19 Radiation
therapy greatly increases the lifelong risk of secondary malignant
neoplasms (glioblastoma multiforme, malignant astrocytoma, meningioma, bone and soft-tissue sarcoma, and malignant melanoma) in
children with TRB who are already
predisposed to secondary cancers
owing to their germline RB1
mutations.20
Treatment of TRB using the
Toronto Protocol and intrathecal
topotecan combined with cytarabine, followed by consolidation with autologous peripheral stem
cell transplant after supralethal
chemotherapy avoids the need for radiation therapy and, in some instances, extends survival.
Helen Dimaras, PhD
Elise Heon, MD
John Doyle, MD
Caron Strahlendorf, MD
Katherine E. Paton, MD
William Halliday, MD
Paul Babyn, MD
Brenda L. Gallie, MD
Helen S. L. Chan, MBBS
Author Affiliations: Division of
Hematology and Oncology (Drs
Dimaras, Doyle, and Chan), and
Departments of Pediatrics (Drs
Dimaras, Doyle, and Chan), Ophthalmology and Visual Science
(Drs Heon and Gallie), Pathology
(Dr Halliday), and Diagnostic
Imaging (Dr Babyn), The Hospital
for Sick Children, Toronto,
Ontario, Canada, and Division of
Hematology and Oncology (Dr
Strahlendorf ), Departments of
Pediatrics (Dr Strahlendorf ) and
Ophthalmology (Dr Paton), Childrens and Womens Health Centre of British Columbia and University of British Columbia,
Vancouver, Canada.
Correspondence: Dr Chan, Division of Hematology and Oncology,
The Hospital for Sick Children, 555
University Ave, Toronto, ON M5G
1X8, Canada (hslchan@attglobal
.net).
Financial Disclosure: None reported.
Funding/Support: This study was
supported in part by grants to Dr
Chan from The Ontario Institute for

Cancer Research and to Dr Gallie

from the Canadian Retinoblastoma
Society and the Royal Arch Masons
of Canada.

20. Eng C, Li FP, Abramson DH, et al. Mortality

from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst. 1993;
85(14):1121-1128.

1. De Potter P, Shields CL, Shields JA. Clinical

variations of trilateral retinoblastoma: a report of 13 cases. J Pediatr Ophthalmol Strabismus.
1994;31(1):26-31.
2. Kivel T. Trilateral retinoblastoma: a metaanalysis of hereditary retinoblastoma associated with primary ectopic intracranial
retinoblastoma. J Clin Oncol. 1999;17(6):18291837.
3. Paulino AC. Trilateral retinoblastoma: is the location of the intracranial tumor important?
Cancer. 1999;86(1):135-141.
4. Dunkel IJ, Jubran RF, Gururangan S, et al.
Trilateral retinoblastoma: potentially curable
with intensive chemotherapy. Pediatr Blood
Cancer. 2010;54(3):384-387.
5. Duffner PK, Cohen ME, Voorhess ML, et al.
Long-term effects of cranial irradiation on endocrine function in children with brain tumors: a prospective study. Cancer. 1985;56
(9):2189-2193.
6. Kiltie AE, Lashford LS, Gattamaneni HR. Survival and late effects in medulloblastoma patients treated with craniospinal irradiation under three years old. Med Pediatr Oncol. 1997;
28(5):348-354.
7. Palmer SL, Goloubeva O, Reddick WE, et al.
Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis. J Clin Oncol. 2001;19(8):
2302-2308.
8. Duffner PK, Horowitz ME, Krischer JP, et al.
The treatment of malignant brain tumors in infants and very young children: an update of the
Pediatric Oncology Group experience. Neuro
Oncol. 1999;1(2):152-161.
9. Blaney SM, Poplack DG. Neoplastic meningitis: diagnosis and treatment considerations. Med
Oncol. 2000;17(3):151-162.
10. Chan HS, Gallie B, Munier FL, Popovic M.
Chemotherapy for retinoblastoma. Ophthalmol Clin North Am. 2005;18(1):55-63, viii.
11. Blaney SM, Heideman R, Berg S, et al. Phase I
clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol.
2003;21(1):143-147.
12. Chan HS, Canton MD, Gallie BL. Chemosensitivity and multidrug resistance to antineoplastic drugs in retinoblastoma cell lines. Anticancer Res. 1989;9(2):469-474.
13. Dimaras H, Heon E, Budning A, et al. Retinoblastoma CSF metastasis cured by multimodality chemotherapy without radiation. Ophthalmic Genet. 2009;30(3):121-126.
14. Dai S, Dimaras H, Heon E, et al. Trilateral retinoblastoma with pituitary-hypothalamic
dysfunction. Ophthalmic Genet. 2008;29(3):
120-125.
15. Linn Murphree A. Intraocular retinoblastoma: the
case for a new group classification. Ophthalmol
Clin North Am. 2005;18(1):41-53, viii.
16. Finger PT; 7th Edition, AJCC-UICC Ophthalmic Oncology Task Force. The 7th edition
AJCC staging system for eye cancer: an international language for ophthalmic oncology.
Arch Pathol Lab Med. 2009;133(8):1197-1198.
17. Chan HS, DeBoer G, Thiessen JJ, et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring 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 radiation
therapy on cognitive and endocrine function
in children with leukemia and brain tumors.
Neurologist. 2004;10(6):293-310.

Acute Macular Outer

Retinopathy (AMOR):
A Reappraisal of Acute
Macular Neuroretinopathy
Using Multimodality
Diagnostic Testing

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 3), MAR 2011

365

Acute macular neuroretinopathy

(AMNR) is a rare retinal condition
that features the sudden onset of bilateral central scotomata, which may
be preceded by a viral prodrome in
some patients. Acute macular neuroretinopathy may be difficult to diagnose because of the subtle or even
absent findings on funduscopic examination and fluorescein angiography. Bos and Deutman1 initially
described AMNR in 4 patients with
paracentral scotomata, slightly decreased visual acuity, and reddish,
wedge-shaped intraretinal lesions directed toward the fovea. Because of
the acute onset of the symptoms and
based on their theory that the more
superficial layers of macular retina
were involved, the term AMNR was
adopted.
Herein, we describe 2 patients
with features of AMNR in whom
Amsler grid testing, infrared imaging,
spectral-domain optical coherence
tomography (SD-OCT), fundus autofluorescence, and multifocal electroretinogram (mfERG) were useful
incharacterizingtheprecisestructural
and functional deficits of this condition.Thelocalizationofstructuraldeficitstotheouterretinaandphotoreceptor layer using SD-OCT and evidence
of depressed cone amplitudes using
mfERG in both patients were more
consistent with photoreceptor and
outer retinal dysfunction. Hughes et
al2 previously reported 2 cases of
AMNRthatfeaturedouterretinalstructuralchangesusingSD-OCT.Thefunctional and anatomic deficits observed
inourpatientsusingmultimodalitydiagnostic testing, combined with the
previousstructuralcharacterizationof
AMNR,2-5 are supportive of the proposed nomenclature acute macular
outer retinopathy (AMOR) to more accurately describe this unique clinical
entity.2

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Right eye

Left eye

Field view

100 nV
0
80 ms

Field view

100 nV
0
80 ms

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 photoreceptor
responses 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 is
normal (G). Infrared imaging shows decreased reflectance in the wedge-shaped distribution nasal to the fovea (H) and fundus autofluorescence shows subtle
hypoautofluorescence in this region (I). Multifocal electroretinogram shows diminished amplitudes of the central cone responses nasal to fixation ( J).

Report of Cases. Case 1. A 24-yearold woman had severe fatigue, headaches, and intermittent photopsias,
followed by bilateral central scotomata 1 week later.
Visual acuities were 20/25 OD and
20/20 OS. Amsler grid testing showed
a well-defined boot-shaped scotoma
in the right eye and a wedge-shaped
scotoma in the left eye (Figure 1).
Color vision with Ishihara plate testing was normal in both eyes. No relative afferent pupillary defect was seen.
Slitlamp examination showed no
anterior chamber or vitreous cells.
Dilated funduscopic examination
and fluorescein angiography were
unremarkable.
Infrared imaging showed a welldefined boot-shaped image in the

right eye and a wedge-shaped image in the left eye, which corresponded precisely to the scotomata
defined by Amsler grid testing. Fundus autofluorescence imaging
showed subtle hypoautofluorescence corresponding to these affected areas. The mfERG showed
subnormal amplitudes of the central responses with normal implicit
times consistent with a regional
abnormality of local retinal responses in the form of central cone
dysfunction (Figure 1). Spectraldomain optical coherence tomography showed thinning of the photoreceptor outer segments and
irregularities of the outer retinal architecture (Figure 2). Fluorescein and high-speed indocyanine

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 3), MAR 2011

366

green angiography were unremarkable. The findings were most consistent with AMNR and no treatment was recommended.
At the final follow-up visit 4
months later, the patients symptoms were improved and visual acuities were 20/20 OU. Funduscopic
examination showed brown discoloration of the parafoveal region and
mild retinal pigment epithelial irregularities, which were more
prominent than the findings on initial examination. Spectral-domain
optical coherence tomography
showed persistent abnormalities of
the outer retina.
Case 2. A 17-year-old healthy girl
had fevers and flulike symptoms for
3 days followed by visual photop-

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sias and 2 discrete shadows in the

left eye. She was asymptomatic in the
right eye.
Visual acuities were 20/20 OU.
Amsler grid testing showed 2 areas
of visual blur; both areas were temporal to the fovea in the left eye. No
relative afferent pupillary defect was
observed. The anterior segment examination was unremarkable in both
eyes. Dilated funduscopic examination was normal in the right eye. A
subtle, slightly abnormal foveal reflex was seen in the left eye, but the
funduscopic examination was otherwise unremarkable.
The infrared reflectance image
highlighted 2 discrete abnormal images nasal to the fovea, which corresponded precisely to the patients
scotomata (Figure 3). Spectraldomain optical coherence tomography revealed attenuation of the inner segmentouter segment junction
in the abnormal parafoveal area identified by infrared imaging. A fluorescein angiogram showed subtle hypofluorescence in these areas in the
late frames of the angiogram. The
mfERG showed subnormal amplitudes of the cone responses in the
left eye to a greater degree than that
observed in the right eye, with normal implicit times. At the 4-month
follow-up, the patients symptoms
remained stable. Her visual acuities were 20/20 OU and the funduscopic lesions in the left eye were
more easily seen than on her prior
examination. Specifically, there were
2 reddish-brown lesions nasal to the
fovea, similar in size and character
to the images previously seen by infrared imaging (Figure 4).
Comment. Our patients characteristic histories, clinical features, and
findings were most consistent with
the entity described as AMNR.1,3 Recent reports have suggested that infrared imaging is valuable in highlighting the macular lesions of
AMNR3,4 and SD-OCT has facilitated identification of the anatomical abnormalities present.2,5
In our 2 patients, multimodality
diagnostic testing allowed a precise
diagnosis of AMNR and provided additional insight into the disease process. Infrared imaging and SDOCT provided information about the
structural defects corresponding to

200 m

200 m

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

200 m

200 m

Figure 3. Infrared imaging of patient 2s left eye shows 2 discrete areas of decreased reflectance, which
corresponded to her symptoms (A). Spectral-domain optical coherence tomography shows attenuation of
the inner segmentouter segment junction and outer retinal architectural abnormalities including focal
thinning of the outer nuclear layer (B). The abnormal inferonasal parafoveal region (C) also demonstrated
similar outer retinal architectural changes (D). Fundus autofluorescence showed mild
hyperautofluorescence surrounding hypoautofluorescent areas corresponding to the lesions nasal to the
fovea (white arrows, E). A venous laminar phase angiogram showed patchy choroidal filling (F) and a
subtle area of hypofluorescence corresponding to the lesions in the late venous frames of the angiogram
(yellow arrows, G).

the patients scotomata. Fundus autofluorescence showed subtle areas

of hypoautofluorescence in both pa-

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 3), MAR 2011

367

tients. Although these changes were

not as prominent as the infrared and
SD-OCT abnormalities, the re-

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Right eye

Left eye

Field view

Correspondence: Dr Francis, Casey Eye Institute, Oregon Retinal Degeneration Center, 3375 SW Terwilliger Blvd, Portland, OR 97239
(francisp@ohsu.edu).
Financial Disclosure: None reported.
Funding/Support: This research is
supported by an unrestricted grant
from Research to Prevent Blindness and a career development award
to Dr Francis. Dr Yeh has received
support from the Heed Ophthalmic Foundation and the Ronald G.
Michels Foundation. Drs Weleber
and Francis receive support from the
Foundation Fighting Blindness.

Field view

500 nV
0

80 ms

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

gional decrease in intrinsic tissue autofluorescence suggested pathologic changes at the level of the
retinal pigment epithelium and possibly involving the outer retina. The
additional use of mfERG highlighted the functional deficits of
these patients despite better than
20/25 visual acuity. Specifically, bilateral reduction of central responses of outer retinal origin with
normal implicit times was identified in both patients. This was especially helpful in identifying abnormal photoreceptor function in
the asymptomatic eye of patient 2.
Our findings are consistent with
prior reports of outer retinal architectural changes observed with SDOCT in AMNR.2,5 The addition of
mfERG to precisely identify cone
photoreceptor dysfunction provided a correlation of a functional
deficit to the structural changes
observed in the outer retina. Although we did not identify a choroidal or retinal vascular perfusion
defect by fluorescein angiography
or indocyanine green angiography

testing, focal hypofluorescence in

the region of the macular lesions
was observed on fluorescein angiography of patient 2. This could
represent inner choroidal ischemia
or blockage of choroidal fluorescence from a focal inflammatory
accumulation with resultant overlying outer retinal architectural
disruption.
The term AMNR was originally
applied to this condition because
of the acute onset of presentation
and the theory that the superficial
macular retina was involved; given
our observations correlating functional and structural aspects of this
disease, the term acute macular
outer retinopathy may be more
appropriate.
Steven Yeh, MD
Thomas S. Hwang, MD
Richard G. Weleber, Prof
Robert C. Watzke, MD
Peter J. Francis, MD, PhD
Author Affiliations: Casey Eye Institute, Oregon Health and Sciences University, Portland.

(REPRINTED) ARCH OPHTHALMOL / VOL 129 (NO. 3), MAR 2011

368

1. Bos PJ, Deutman AF. Acute macular

neuroretinopathy. Am J Ophthalmol. 1975;80
(4):573-584.
2. Hughes EH, Siow YC, Hunyor AP. Acute macular neuroretinopathy: anatomic localisation of the
lesion with high-resolution OCT. Eye (Lond).
2009;23(11):2132-2134.
3. Turbeville SD, Cowan LD, Gass JD. Acute macular neuroretinopathy: a review of the literature.
Surv Ophthalmol. 2003;48(1):1-11.
4. Corver HD, Ruys J, Kestelyn-Stevens AM, De Laey
JJ, Leroy BP. Two cases of acute macular
neuroretinopathy. Eye (Lond). 2007;21(9):12261229.
5. Neuhann IM, Inhoffen W, Koerner S, BartzSchmidt KU, Gelisken F. Visualization and follow-up of acute macular neuroretinopathy with
the Spectralis HRA!OCT device. Graefes Arch
Clin Exp Ophthalmol. 2010;248(7):1041-1044.

Interferon-! Release Assay

in Tuberculous Scleritis

Scleritis is a painful, often chronic,

and potentially destructive ocular inflammation caused by either infectious agents or noninfectious immune reactions. Tuberculosis (TB)
is one possible infectious cause of
scleritis. In this report, we describe
3 patients in whom use of an interferon (IFN)-" release assay assisted in the diagnosis of tuberculous scleritis.
Report of Cases. Case 1. A 29-yearold woman was referred for bilateral anterior scleritis refractory to
topical corticosteroids. On examination, corrected visual acuities were
1.2 with normal intraocular pressure in both eyes. The sclera was
markedly hyperemic in all 4 quadrants bilaterally (Figure 1A). Mild
inflammatory cells were present in
the anterior chambers in both eyes
but the fundi were unremarkable.
Laboratory investigations revealed

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