Reports
PATRICK A. SIBONY, MD1
MARK J. KUPERSMITH, MD2
FOR THE OCT SUBSTUDY GROUP OF THE NORDIC
IDIOPATHIC INTRACRANIAL HYPERTENSION TREATMENT TRIAL*
1 gain in VA. There was significantly greater decrease in central
Department of Ophthalmology, State University of New York at Stony
Brook, Stony Brook, New York; 2Icahn School of Medicine at Mount
Sinai, Mt. Sinai Roosevelt and the New York Eye and Ear Infirmary,
New York, New York
*A list of the OCT Substudy Group of the NORDIC Idiopathic
Intracranial Hypertension Treatment Trial is available online
(www.aaojournal.org).
Financial Disclosures: The authors have no proprietary or commercial
interest in any materials discussed in this article.
Supported in part by U10 EY017281-01A1, U10 EY017387-01A1,
3U10EY017281-01A1S1
Trial registration: clinicaltrials.gov identifier: NCT01003639
Author Contributions:
Conception and design: Sibony
Analysis and interpretation: Sibony, Kupersmith
Data collection: Sibony, Kupersmith
Obtained funding: Not applicable
Overall responsibility: Sibony, Kupersmith
Correspondence:
Patrick A. Sibony, MD, Department of Ophthalmology, State Univer-
sity of New York at Stony Brook, Health Sciences Center, L2, Room
152, Stony Brook, NY 11794-8223. E-mail: patrick.Sibony@
stonybrookmedicine.edu.
References
1. Paton L, Holmes G. The pathology of papilloedema: a histo-
logical study of sixty eyes. Brain 1911;33:389–432.
2. Lepore FE. Toward a definition of papilledema: a historical
review, 1851-1911. Surg Neurol 1982;17:178–80.
3. Paton L. Papilledema and optic neuritis: A retrospect. Arch
Ophthalmol 1936;15:1–20.
4. OCT Substudy Committee for the NORDIC Idiopathic Intra-
cranial Hypertension Study Group. Baseline OCT measure-
ments in the idiopathic intracranial hypertension treatment trial,
part I: quality control, comparisons, and variability. Invest
Ophthalmol Vis Sci 2014;55:8180–8.
5. Sibony PA, Kupersmith MJ, Feldon SE, et al. Retinal and
choroidal folds in papilledema. Invest Ophthalmol Vis Sci
2015;56:5670–80.
Bevacizumab or Dexamethasone
Implants for DME: 2-year Results
(The BEVORDEX Study)
Both vascular endothelial growth factor inhibitors and steroids
given intravitreally have demonstrated superior visual acuity (VA)
benefits to laser and/or sham for center-involving diabetic macular
edema (DME).1
The BEVORDEX study was the first head-to-head randomized
clinical trial of bevacizumab versus a slow-release intravitreal
dexamethasone implant (DEX-implant; Ozurdex; Allergan Inc.,
Irvine, CA) for DME. This study was conducted in accordance
with the Declaration of Helsinki and was approved by local Human
Research Ethics Committees. We previously reported the meth-
odology and the primary and 12-month secondary outcomes.2 At
12 months, we reported no difference between the groups in
proportion of eyes achieving the primary endpoint of a 10-letter
macular thickness with fewer intravitreal injections in the DEX-
implant group compared with the bevacizumab group at 12
months. However, a greater number of eyes in the DEX-implant
group lost vision, mainly owing to cataract.
Eyes continued in the trial for another year on the same treat-
ment allocation (i.e., bevacizumab every 4 weeks or DEX-implant
every 16 weeks, both as required). Sixty-eight of the 88 enrolled
eyes (77%) completed the 24-month trial. The CONSORT flow-
sheet (Supplementary Fig 1, available at www.aaojournal.org)
shows that of the 20 eyes (from 13 patients) that exited the study
early, 10 had been assigned to DEX-implant and 10 to
bevacizumab.
The VA improvement seen at 12 months in both groups was
maintained at 24 months, with 20 of 46 DEX-implantetreated
eyes (43%) and 19 of 42 bevacizumab-treated eyes (45%)
achieving
10 letter VA gain (P ¼ 0.99). The proportion of
bevacizumab-treated eyes with a
10 letter VA gain was com-
parable with other trials of discontinuous anti-vascular endo-
thelial growth factor therapy in DME (e.g., Prospective
Randomized Trial of Intravitreal Bevacizumab or Laser Therapy
in the Management of Diabetic Macular Edema [BOLT] at 49%
and Diabetes Retinopathy Clinical Research Network Protocol I
at 49%). although baseline VA, inclusion criteria, and retreat-
ment strategies were different.3,4
The mean improvement in VA was 6.9 letters in DEX-
implante treated eyes (95% CI, 2.7e11.1) and 9.6 letters (95%
CI, 6.9e12.3) in bevacizumab-treated eyes (P ¼ 0.30; Fig 1A). At
baseline, 26 of 88 study eyes (29.5%) were pseudophakic; 10
randomized to bevacizumab and 16 to DEX-implant. In pseudo-
phakic eyes, the improvement in VA in DEX-implantetreated eyes
was similar to bevacizumab-treated eyes (Fig 1B). In phakic eyes,
there was a difference in mean VA change between the 2 treatment
groups between the 12- and 24-month time-points (Fig 1C), with
the DEX-implant group experiencing worse VA. This likely
represented development of cataract in the DEX-implant group
with subsequent improvement in vision by 24 months after cataract
surgery, with 11 of 30 DEX-implantetreated eyes (37%) and 2 of
32 bevacizumab-treated eyes (6%) undergoing cataract surgery
during the study. It is possible a larger study may have identified a
statistically significant greater mean improvement in VA in favor
of bevacizumab in phakic eyes.
Although there was a significantly greater reduction in central
macular thickness in the DEX-implant group at 12 months, the
graph of central macular thickness over time (Supplementary Fig 2,
available at www.aaojournal.org) shows that the bevacizumab
group gradually caught up so that there was no difference
between the groups at 24 months. This pattern was also reflected
in regression of hard exudates from the foveal center.5
Eyes randomized to receive bevacizumab received more
injections (mean; 9.1; median, 9.0; SD, 3.1) than those ran-
domized to the DEX-implant (mean, 2.8; median, 3.0; SD, 0.9)
during the first 12 months of treatment. However, the difference
was less pronounced in the second year of treatment, with the
mean number bevacizumab injections being 4.8 (median, 2.0;
SD, 5.1) compared with 2.2 (median, 2.0; SD, 1.2) DEX-implant
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 Ophthalmology Volume 123, Number 6, June 2016

Figure 1. Mean visual acuity (VA) according to treatment type from baseline to 24 months. Mean VA was recorded every 4 weeks and standard error bars
are included for (A) all eyes entering the trial, (B) eyes that were pseudophakic on entering the study (the mean improvement in VA was 8.9 letters [95%
CI, 2.0e13.4] for those treated with the dexamethasone implant and 7.7 letters [95% CI, 3.03e14.8] for those treated with bevacizumab; P ¼ 0.77), (C) eyes
that were phakic on entering the study (the mean improvement in VA was 5.8 letters [95% CI, 0.07e11.5] for those treated with the dexamethasone
implant and 10.2 letters [95% CI, 7.17e13.3] for those treated with bevacizumab; P ¼ 0.19).

injections. Over 2 years, the number of bevacizumab intravitreal
injections was comparable with the number of ranibizumab in-
jections in the deferred laser cohort of Diabetes Retinopathy
Clinical Research Network Protocol I.4 The 5-year results from
the Diabetes Retinopathy Clinical Research Network Protocol
I trial reported a significant decrease in the number of ranibi-
zumab injections required for DME in years 3 through 5, so
the difference in treatment load may be less significant after
2 years of intensive anti-vascular endothelial growth factor
therapy.1
One bevacizumab-treated eye lost
10 letters, whereas 5 of 46
DEX-implantetreated eyes had this degree of vision loss. In 2 eyes
in the DEX-implant group and 1 eye in the bevacizumab group
with a history of laser-treated proliferative diabetic retinopathy,
neovascularization developed after cataract surgery. There was 1
patient with undiagnosed syphilis who developed acute posterior
placoid chorioretinopathy after receiving a DEX-implant to that
eye.2 There were no cases of endophthalmitis or retinal
detachment. There was no new systemic safety signal.
As expected, DEX-implantetreated eyes had higher rates of
increased intraocular pressure. An increase in intraocular pressure
by
5 mmHg from baseline at any visit, occurred in 34 of 46
DEX-implantetreated eyes (74%) and 20 of 42 bevacizumab-
treated eyes (48%), with 10 of 46 DEX-implantetreated eyes
(22%) requiring the addition of topical ocular hypotensives,
whereas no bevacizumab-treated eyes required this. Remem-
bering eyes with advanced or uncontrolled glaucoma were
excluded from entry, no study eye underwent incisional glaucoma
drainage surgery similar to the low rates seen in other trials of
Ozurdex in DME (0.6% in the MEAD trial and 0% in the
PLACID trial).1
A strength of this study was the opportunity to use the
DEX-implant every 16 weeks. Previous industry-sponsored studies
have failed to reach predefined primary endpoints because of the
mistaken belief that the DEX-implant usually has a therapeutic
effect lasting 6 months.1
In conclusion, the 24-month results of the BEVORDEX study
identified no significant difference in the primary endpoint of
proportion of eyes with a 10-letter gain in VA between bev-
acizumab and DEX-implant treatment, with both agents providing
good improvements. The burden of injections was significantly
greater with bevacizumab. However, the DEX-implant group had
more cases of visual loss, mainly in eyes that were phakic at
baseline. Elevated intraocular pressure in the DEX-implant group
could largely be managed with topical therapy. Therefore, the
DEX-implant could be considered a second-line treatment option
in phakic patients with DME, whereas potentially a first-line
treatment option in pseudophakic patients.

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 Reports
SAMANTHA FRASER-BELL, PHD, FRANZCO1
LYNDELL L. LIM, DMEDSCI, FRANZCO2
ANNA CAMPAIN, PHD1
HEMAL MEHTA, MA, FRCOPHTH1
CHRISTINE ARONEY, MBBS1
JACLYN BRYANT, BAPPSCI (ORTHOPTICS)1
JI LI, BSC, MBBS1
GODFREY J. QUIN, PHD, FRANZCO1,3
IAN L. MCALLISTER, FRANZCO4
MARK C. GILLIES, PHD, FRANZCO1
1
Save Sight and Eye Health Institute, Sydney Medical School,
University of Sydney, Sydney, NSW, Australia; 2Centre for Eye
Research Australia, University of Melbourne, Royal Victorian Eye and
Ear Hospital, East Melbourne, Victoria, Australia; 3Ophthalmology
Department, Australian School of Advanced Medicine, Macquarie
University, Sydney, NSW, Australia; 4Lions Eye Institute, Centre for
Ophthalmology and Visual Science, University of Western Australia,
Australia
Financial Disclosures: The authors made the following disclosures:
M.C.G.: Grants e Allergan; Personal fees e Bayer; Consultant e
Allergan, Novartis, Bayer; Expert testimony e Bayer
S.F.-B.: Grants e Allergan
L.L.L.: Consultant e Bayer, Novartis, Abbvie, Allergan; Speaker fees
e Bayer, Abbvie
Funded by a project grant (632667) from the National Health and
Medical Research Council (NHMRC), which was supplemented by an
unrestricted educational grant from Allergan Pharmaceuticals.
Author Contributions:
Conception and design: Fraser-Bell, Lim, Campain, Mehta, Aroney,
Quin, McAllister, Gillies
Analysis and interpretation: Fraser-Bell, Lim, Campain, Mehta, Aroney,
Bryant, Li, Gillies
Data collection: Fraser-Bell, Lim, Mehta, Aroney, Bryant, Li, Quin,
McAllister, Gillies
Obtained funding: Fraser-Bell, Lim, Gillies
Overall responsibility: Fraser-Bell, Lim, Campain, Mehta, Gillies
Correspondence:
Hemal Mehta, MA, FRCOphth, Save Sight and Eye Health Institute,
Sydney Medical School, University of Sydney, 8 Macquarie Street,
Sydney 2000, NSW, Australia. E-mail: HM@cantab.net.
References
1. Mehta H, Gillies M, Fraser-Bell S. Perspective on the role of
Ozurdex (dexamethasone intravitreal implant) in the manage-
ment of diabetic macular oedema. Ther Adv Chronic Dis
2015;6:234–45.
2. Gillies MC, Lim LL, Campain A, et al. A randomized clinical
trial of intravitreal bevacizumab versus intravitreal dexametha-
sone for diabetic macular edema: the BEVORDEX study.
Ophthalmology 2014;121:2473–81.
3. Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year pro-
spective randomized controlled trial of intravitreal bevacizumab
or laser therapy (BOLT) in the management of diabetic macular
edema: 24-month data: report 3. Arch Ophthalmol 2012;130:
972–9.
4. Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year
follow-up of ranibizumab plus prompt or deferred laser or
triamcinolone plus prompt laser for diabetic macular edema.
Ophthalmology 2011;118:609–14.
5. Mehta H, Fraser-Bell S, Yeung A, et al. Efficacy of dexa-
methasone versus bevacizumab on regression of hard exudates
in diabetic maculopathy: data from the BEVORDEX rando-
mised clinical trial. Br J Ophthalmol 2015 Nov 4. http://dx.doi.
org/10.1136/bjophthalmol-2015-307797. pii: bjophthalmol-
2015e307797 [Epub ahead of print].
Aryl Hydrocarbon
Receptor-Interacting Protein-Like 1
in Cancer-Associated
Retinopathy
Paraneoplastic syndromes constitute symptoms from organs distant
from a malignant neoplasm present in the body, and are in many
cases mediated by immune cross-reactivity between the neoplasm
and normal host tissue. Cancer-associated retinopathies (CAR) are
rare retinal disorders associated with autoantibodies directed to
various retinal antigens. The immune response initially arises to
suppress a tumor growth, ultimately resulting in rapid, bilateral,
and painless loss of vision.1 If a subsequent clinical investigation
reveals an underlying malignancy, the retinal damage is
categorized as a paraneoplastic syndrome.2
We report on the identification of aryl hydrocarbon receptor
interacting protein-like 1 (AIPL1), a retinal and pineal glande
specific protein, as the autoantigen in a patient with CAR and ma-
lignant osteosarcoma. The study was performed in accordance with
the Declaration of Helsinki and ethics committee approval was ob-
tained (application number UP02-415). The patient was a previously
healthy 13-year-old girl without any family history of autoimmunity
or ophthalmic disorders. She suffered from pain of varying intensity
in her right heel with simultaneous progressive photosensitivity and
bilateral gradually increasing visual loss. Ophthalmologic exami-
nations revealed a rapid decline in visual acuity over 3 months, from
1.0 to 0.2 in the left eye, and from 0.8 to 0 in the right eye. Optical
coherence tomography showed a thinning of retinal layers, indi-
cating retinal atrophy (Fig 1A, available at www.aaojournal.org).
Full-field electroretinogram demonstrated a reduction of rodecone
function with >90% compared with the response some months
before the patient developed blindness (Fig 1B). At the age of 15, two
years after the onset of symptoms of visual loss, her vision had
deteriorated to a stage at which she only could distinguish between
dark and light. Owing to the severity of the visual loss, the initial
medical attention was focused on the eyes. Eventually, the
patient’s pain in the heel was investigated and routine skeletal x-
ray examination of the foot did not show any abnormality (Fig 2A,
left). However, magnetic resonance imaging indicated an
edematous tumor in right calcaneus (Fig 2A, right). Biopsy of the
calcaneus and cytological examination after decalcification
revealed a small cell tumor (Fig 2B). Because the tumor cells did
not show typical chromosomal abnormalities seen in Ewing
sarcoma, the tumor was classified as osteosarcoma. Using a serum
sample from the patient, a healthy control, and an anti-AIPL1 anti-
body, human retinal tissue was immunostained. Using the CAR
serum, this revealed a strong staining of the synaptic region of the
photoreceptor cells, with an overlap with anti-AIPL1 antibody
staining. A similar staining pattern was not seen with serum from a
healthy control (Fig 2C-E).
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