HEMORRHAGIC RECURRENCE OF
`NEOVASCULAR AGE-RELATED
`MACULAR DEGENERATION NOT
`PREDICTED BY SPECTRAL DOMAIN
`OPTICAL COHERENCE TOMOGRAPHY
`
`Ron Margolis, MD, K. Bailey Freund, MD
`
`Purpose: To report a case in which a patient with neovascular age-related macular
`degeneration developed a large submacular hemorrhage 2 days after spectral domain
`optical coherence tomography imaging, which revealed no intra- or subretinal fluid.
`Methods: A noninterventional case report.
`Results: A 93-year-old woman with neovascular age-related macular degeneration was
`seen for a regular follow-up examination 3 years after treatment with verteporfin photo-
`dynamic therapy in which lesion quiescence was achieved. Visual acuity was stable at
`20/200, and spectral domain optical coherence tomography scans using 2 different
`instruments revealed no intra- or subretinal fluid. Two days after clinical examination and
`imaging, the patient presented with a large submacular hemorrhage and 5/400 vision.
`Conclusion: Hemorrhagic exudation from choroidal neovascularization in age-related
`macular degeneration may occur suddenly, even in the absence of fluid detected by
`spectral domain optical coherence tomography.
`RETINAL CASES & BRIEF REPORTS 4:1– 4, 2010
`
`From the Vitreous Retina Macula Consultants of
`New York, New York, New York.
`
`Advances in the treatment of neovascular age-re-
`
`lated macular degeneration (AMD) have included
`photodynamic therapy (PDT) and the intravitreal an-
`tivascular endothelial growth factor (VEGF) drugs
`such as bevacizumab and ranibizumab.1-4 In the TAP1
`and VIP2 studies, patients received treatment with
`PDT if fluorescein angiography showed leakage from
`choroidal neovascularization (CNV). In contrast, in
`the ANCHOR3 and MARINA4 trials, patients were
`treated with intravitreal ranibizumab monthly for 2
`years regardless of CNV activity. Because of the bur-
`
`Supported by The Macula Foundation, Inc. and the Heed Fel-
`lowship (to R.M.).
`The authors have no proprietary interest to report.
`Reprint requests: K. Bailey Freund, MD, Vitreous Retina Mac-
`ula Consultants of New York, 460 Park Avenue, 5th Floor, New
`York, NY 10022; e-mail: kbfnyf@aol.com
`
`den of monthly injections, additional studies have
`looked at alternative dosing strategies with the inten-
`tion of reducing the number of treatments without
`compromising visual results. In the PIER trial,5 when
`patients were switched from monthly to quarterly in-
`jections of ranibizumab, they subsequently lost the
`vision they had gained with monthly injections. How-
`ever, the PrONTO trial6 demonstrated that a variable
`dosing regimen using optical coherence tomography
`(OCT) as a guide for retreatment could potentially
`achieve the same visual results as monthly injections
`but with fewer treatments.7 Another commonly used
`dosing regimen referred to as “treat and extend” is
`also guided by the presence of intra- or subretinal fluid
`on OCT. With this strategy, the time interval between
`injections is gradually extended as long as no fluid is
`seen (J. P. Levine et al, unpublished data). There have
`been questions of whether OCT is always a reliable
`measure of neovascular activity. For instance, OCT
`provides little information regarding the size of neo-
`
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`RETINAL CASES & BRIEF REPORTSℜ ● 2010 ● VOLUME 4 ● NUMBER 1
`
`Fig. 1. Optical coherence to-
`mography scan through the
`right fovea with the Topcon
`3D-OCT 1000 (A and B) and
`Cirrus HDOCT (C and D)
`showing a chronic intraretinal
`cavitary space with no sub-
`retinal fluid.
`
`vascular lesions and cannot differentiate certain lesion
`components such as polypoidal neovascularization or
`subretinal fibrosis from actively proliferating well-
`defined Type 2 (subretinal) neovascularization. With
`these concerns in mind, we report a patient with
`neovascular AMD, stable for 3 years after PDT, who
`developed a large submacular hemorrhage 2 days after
`a clinical examination, and spectral domain OCT re-
`vealed stable findings and no intra- or subretinal fluid.
`
`Case Report
`
`In September 2005, a 90-year-old woman presented with bilat-
`eral neovascular AMD. There was a history of hypertension con-
`trolled with enalapril. She was not taking aspirin or any other
`anticoagulants. Visual acuities were 20/400 and 20/200 in the right
`and left eyes, respectively. Fluorescein angiography showed bilat-
`eral Type 3 neovascularization (retinal angiomatous proliferation)
`of less than 1 disk diameter in size. Two bilateral verteporfin PDT
`treatments combined with intravitreal triamcinolone acetonide in-
`jections were performed in each eye. After treatment, the right eye
`stabilized with no recurrent angiographic leakage or fluid noted on
`OCT. The left eye experienced continued exudation and was
`treated with multiple intravitreal injections of anti-VEGF agents,
`including bevacizumab and ranibizumab. On a routine evaluation 3
`years after the second PDT treatment, visual acuity was 20/200
`bilaterally with a small area of clinically inactive, subfoveal sub-
`retinal fibrosis in the right eye. There was no fluid, lipid, or
`hemorrhage detected clinically or on fundus photography.
`A small amount of subretinal fluid overlying a similar lesion was
`noted in the left eye. High-density 6 ⫻ 6-mm raster scans were
`performed centered on the fovea with a resolution of 512 ⫻ 128
`A-scans using 2 different spectral domain OCT instruments: Cirrus
`
`HD-OCT (Model 3000, Carl Zeiss Meditec, Dublin, CA) and the
`Topcon 3D-OCT 1000 (Topcon, Tokyo, Japan). In addition, 5
`high-resolution (4096 A-scan) horizontal line scans centered at the
`fovea were performed on the Cirrus HD-OCT unit. Foveal thick-
`ness in the right eye measured 139 ␮m on the Topcon instrument,
`which was unchanged from the measurement of 141 ␮m on the
`patient’s visit 10 weeks earlier. Review of all OCT cuts revealed a
`stable, small, focal intraretinal cavitary space in the right eye
`(Figure 1). This space was not considered to represent active
`leakage but rather loss of retinal tissue, because reduced retinal
`thickness and loss of the nuclear and plexiform layers were seen on
`OCT; it was unchanged from multiple prior OCT scans during a
`3-year period, including the prior visit, and there was no leakage on
`previous fluorescein angiography. The left eye was retreated with
`intravitreal ranibizumab for a small amount of subretinal fluid
`detected on OCT. Two days later, the patient returned with rapidly
`worsening vision in the right eye. Visual acuity was 5/400, and
`examination revealed a large submacular hemorrhage consistent
`with recurrence of CNV (Figure 2).
`
`Discussion
`
`The advent of PDT and antivasogenic treatments
`for neovascular AMD has greatly improved visual
`outcomes compared with thermal laser photocoagula-
`tion. However, the best criteria to use for retreatment
`remain uncertain. Using OCT to assess CNV activity
`and direct treatment has become a common approach
`in the management of neovascular AMD, in part be-
`cause of the noninvasive nature of this form of imag-
`ing and the ease and speed of obtaining this data. Also,
`unlike fluorescein angiography, in which interpreta-
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`RECURRENCE OF NEOVASCULAR AMD
`
`3
`
`Fig. 2. Color photographs of
`the right eye showing a small
`area of clinically inactive sub-
`foveal fibrosis (A) 2 days be-
`fore development of a large
`submacular hemorrhage (B).
`
`tion is often based on subjective interpretations, OCT
`technology provides quantitative measures of retinal
`thickness and subretinal fluid. The retreatment criteria
`chosen for the PrONTO trial were largely based on a
`clinical impression that OCT could detect the earliest
`signs of recurrent fluid in the macula (macular cysts or
`subretinal fluid) after the ranibizumab injections were
`stopped.6 However, even in the PrONTO trial, two of
`the four criteria for retreatment required no OCT
`guidance: appearance of new classic CNV and new-
`onset hemorrhage. These elements accounted for 20%
`of the reinjections performed in this study. The TAP
`and VIP trials of verteporfin PDT were performed
`before the widespread use of OCT technology, and
`retreatment guidelines relied on fluorescein angio-
`graphic evidence of leakage.1,2 High-resolution OCT
`is reported to have almost 100% sensitivity for cystoid
`macular edema and almost always correlates with
`leakage seen on fluorescein angiography.8-10 How-
`ever, a discrepancy between OCT and angiography in
`the detection of macular edema has been reported in
`up to 5% of cases.10 Eter and Spaide11 reported that
`some patients who had PDT for neovascular AMD
`had leakage by fluorescein angiography that did not
`correspond to any observable fluid on OCT. It is,
`therefore, conceivable that both OCT instruments
`used in our patient failed to detect early changes that
`may have predicted the submacular hemorrhage that
`occurred.
`The PrONTO trial demonstrated visual outcome
`data similar to the MARINA and ANCHOR trials of
`ranibizuamb while reducing the total number of injec-
`tions by ⬃50%. It is potentially significant that most
`clinical practices deviate from the rigorous testing of
`visual acuity with the Early Treatment Diabetic Reti-
`nopathy Study chart as was used in the PrONTO
`study. Clinicians have taken the PrONTO results a
`step further and are commonly implementing a “treat
`and extend” strategy. In this regimen, the time interval
`
`between examinations and intravitreal injections is
`gradually increased by 1- to 2-week increments as
`long as there are no signs of reexudation either clini-
`cally or on OCT. This interval is gradually extended to
`a maximum of 8 weeks to 12 weeks with the goal of
`finding a stable maintenance interval that keeps the
`macula “fluid-free.”
`When treating patients on an “as-needed” basis with
`either anti-VEGF monotherapy or combination ap-
`proaches, we observed a subset of patients who expe-
`rienced recurrent exudation with submacular hemor-
`rhage shortly after a stable eye examination in which
`the Stratus OCT (Carl Zeiss Meditec) did not detect
`fluid before the event (J. P. Levine et al, unpublished
`data). Although angiography was not performed, the
`presence of a large submacular hemorrhage implied
`active CNV. This finding suggested that we were
`missing fluid present in the intervals between the six
`radial cuts that are often used with the time-domain
`Stratus OCT device. The current report demonstrates
`that severe recurrent hemorrhagic exudation can occur
`shortly after imaging showing absence of fluid de-
`tected with the much higher resolution and scan den-
`sities of the new spectral domain OCT technology.
`This is particularly concerning given that recurrent
`exudation after discontinuation of intravitreal anti-
`VEGF therapy is to be expected. Also, as many as
`33% of eyes previously treated with PDT will have a
`recurrence of CNV within 18 months after their last
`treatment.12 Perhaps there are certain patients such as
`those with preserved foveal function, juxtafoveal le-
`sions, or poor vision in the fellow eye who would do
`better on a maintenance regimen even in the absence
`of fluid detected by OCT to reduce the risk of sudden
`and catastrophic recurrences. However, even with
`monthly dosing of ranibizumab, loss of visual acuity
`occurred in 5% to 10% of patients in the ANCHOR
`and MARINA studies. There are currently no pub-
`lished prognostic factors that are used to identify
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`RETINAL CASES & BRIEF REPORTSℜ ● 2010 ● VOLUME 4 ● NUMBER 1
`
`patients at high risk for treatment failure, and there is
`no way to predict whether anti-VEGF treatment would
`have prevented the submacular hemorrhage that oc-
`curred in our patient.
`The case presented highlights two important limi-
`tations to our current understanding of the pathophys-
`iology of neovascular AMD and its optimal treatment.
`First, what is the earliest sign of CNV recurrence, and
`how is it best detected? Although OCT is currently
`used to detect fluid and direct treatment, other factors
`such as visual acuity or angiography may be more
`predictive in certain patients. Second, should treat-
`ment be administered only if CNV activity is detected
`or should maintenance therapy be given even without
`signs of neovascular activity? Future studies may help
`answer these questions and identify patients who are
`at risk for CNV recurrence.
`Key words: age-related macular degeneration, op-
`tical coherence tomography, recurrence, submacular
`hemorrhage.
`
`References
`
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