Brief Report
`
`NEOVASCULAR GROWTH FOLLOWING
`PHOTODYNAMIC THERAPY FOR
`CHOROIDAL HEMANGIOMA AND
`NEOVASCULAR REGRESSION AFTER
`INTRAVITREOUS INJECTION OF
`TRIAMCINOLONE
`
`ANITA M. LEYS, MD,*
`RUFINO SILVA, MD, MSC,†
`WERNER INHOFFEN, PHD,‡
`OLCAY TATAR, MD‡
`
`From the *Department of Ophthalmology, University
`Hospitals, Leuven, Belgium; the †Department of Oph-
`thalmology, Hospital of the University of Coimbra
`and AIBILI/AIBILI–Association for the Institute of
`Biomedical Research on Light and Image, Coimbra,
`Portugal; and the ‡Department of Ophthalmology,
`Eberhard-Karls University, Tu¨bingen, Germany.
`
`Retinal neovascularization rarely occurs in association
`with choroidal hemangioma.1 Shields et al2 studied
`the clinical manifestations of 200 consecutive cases of
`circumscribed choroidal hemangioma and observed a
`choroidal neovascular membrane in 3 cases and neo-
`vascularization of the iris in 2 cases, but they noted no
`retinal neovascularization. In 2000, photodynamic
`therapy (PDT) was introduced for symptomatic cho-
`roidal hemangioma,3 and at present, long-term results
`are available demonstrating that PDT is a most effec-
`tive and safe treatment option even after repeated
`treatment.4 Moreover, numerous small series of PDT-
`treated choroidal hemangiomas have been reported
`without mention of ocular side effects. Recently, we
`observed subtle retinal neovascularization in three un-
`treated eyes with circumscribed choroidal hemangi-
`oma and noted neovascular growth after PDT for the
`hemangioma. In two cases, the neovascularization re-
`
`Presented in part at the 11th International Congress of Ocular
`Oncology; Hyderabad, India; January 23–27, 2004; and the Fluo-
`rescein Conference of the 27th Annual Meeting of the Macula
`Society; Las Vegas, NV; February 25–28, 2004.
`Reprint requests: Anita M. Leys, Department of Ophthalmology,
`Kapucijnenvoer 33, B-3000 Leuven, Belgium.
`
`gressed after intravitreous injection of triamcinolone
`(4 mg) but recurred several months later. Repeated
`injection of triamcinolone resulted again in regression
`of the neovascularization. In the third case, a single
`intravitreal injection of triamcinolone (25 mg) induced
`regression of neovascularization, and no recurrence
`was observed during a 1-year follow-up.
`
`Case Reports
`
`Case 1
`
`A 30-year-old man had vibrations in the peripheral field of the
`right eye for several months, and visual loss and distortion were
`recently noted. Visual acuity was 20/40 in the right eye and 20/20
`in the left eye. Funduscopic examination, ultrasound analysis,
`fluorescein and indocyanine green angiography, and optical coher-
`ence tomography showed a voluminous temporomacular mass (7.0
`⫻ 7.0 ⫻ 4.8 mm) with characteristics of choroidal hemangioma
`and associated exudative detachment and macular edema. Subtle
`leakage of fluorescein from the disk and retinal neovascularization
`was present (Fig. 1, top left) but initially overlooked. After PDT (6
`mg/m2 body surface area verteporfin and a diode laser at 692 nm
`with a light dose of 50 J/cm2 and light application 5 minutes after
`intravenous administration of verteporfin), the exudative detach-
`ment vanished, and vision improved; however, leakage from neo-
`vascularization increased (Fig. 1, top right and bottom left). Three
`months after the first PDT, interpretation of results was again
`difficult, and macular fluid was again present. A second and similar
`treatment was performed at 3 months after the first PDT, and a third
`course was given at 11 months, taking into account the 4-mm
`elevation of the hemangioma and decreased vision due to subtle
`fluid. Most interesting, the disk and retinal neovascularization
`increased progressively during follow-up, and 1 year after the first
`PDT, a small vitreous hemorrhage occurred (Fig. 1, bottom right).
`Subsequently, a fourth PDT was performed to induce flattening
`of the hemangioma, and 4 mg of triamcinolone was injected in the
`vitreous with the aim to reduce macular edema and with the hope
`to diminish leakage from the neovascularization. Two months later,
`the neovascularization was clinically undetectable, and no leakage
`was noted by fluorescein angiography. The regression of new
`vessels was maintained 2 months later (Fig. 2, top left), but 10
`months after the injection, recurrence was noted (Fig. 2, bottom).
`Visual acuity was 20/30 in the right eye. The hemangioma ap-
`peared atrophic and was not associated with exudative lesions;
`ultrasound analysis showed a 2.8-mm elevation. A second intrav-
`itreal injection of triamcinolone (4 mg) induced total regression of
`the neovascularization (Fig. 2, top right). However, recurrence of
`neovascularization was noted at 6 months, and at 9 months, a third
`intravitreal injection of triamcinolone (4 mg) was administered.
`
`RETINA®, The Journal of Retinal and Vitreous Diseases, encourages authors to submit Brief Reports describing unusual findings, new
`techniques, and new instruments. Material submitted for consideration in this section of the journal is done so with the assumption that the
`data provided do not duplicate previously published material and that the material has not been submitted for consideration elsewhere. Each
`author must sign a disclosure to this effect (see Instructions to Authors for complete wording of transfer letter). Brief Reports submitted for
`this section of the journal may be subjected to the standard review process that is applied to other material submitted to RETINA®. Brief
`Reports should follow the requirements listed in the Instructions to Authors, with the following caveats: Brief Reports should not exceed 4
`pages in length; no more than 5 references should be cited; and each Brief Report should include no more than 4 figures.
`
`693
`
`Novartis Exhibit 2232.001
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`

`

`694
`
`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2006 ● VOLUME 26 ● NUMBER 6
`
`Fig. 1. Case 1. Fluorescein
`angiogram before the first
`photodynamic therapy (PDT)
`showing marked
`leakage
`from the
`temporomacular
`hemangioma and subtle leak-
`age from neovascularization
`of the disk and along the in-
`temporal vein (top
`ferior
`left). Note growth of neovas-
`cularization and the increased
`leakage at 1 month (top
`right) and at 3 months after
`the first PDT (bottom left)
`and further progression and
`hemorrhage
`after
`repeated
`PDT (bottom right).
`
`Another 10 months later (32 months after the first PDT), we
`observed mild neovascularization and no macular edema. Visual
`acuity was 20/70 with lens opacities and no other complications.
`
`Case 2
`
`A 20-year-old man had decreased vision in his left eye for 2
`months. Visual acuity was 20/20 in the right eye and 20/32 in the
`left eye. Funduscopic examination of the left eye revealed a pink
`choroidal mass (6.0 ⫻ 6.0 ⫻ 3.0 mm) in the temporal region with
`overlying subretinal fluid affecting the foveal region. Fluorescein
`and indocyanine green angiography and ultrasound analysis con-
`firmed the clinical diagnosis of exudative circumscribed choroidal
`hemangioma. Moreover,
`subtle disk neovascularization was
`present. Subsequently, PDT was applied in two courses at 3-month
`intervals using 6 mg/m2 body surface area verteporfin and a diode
`laser at 692 nm with a light dose of 50 J/cm2 and light application
`15 minutes after the start of the infusion. Three months after the
`second PDT, neovascular growth was noted with neovascular tufts
`on and at the borders of the optic nerve head and nasal to the disk.
`Another 3 months later, extension of the neovascularization and a
`subhyaloidal hemorrhage were noted. Preexisting cystoid macular
`edema was more pronounced. The hemangioma had flattened, and
`most of the exudative detachment was resolved. Another 3 months
`later, a new focus of neovascularization was noted in the infero-
`temporal macular region, and a new subhyaloidal hemorrhage was
`noted. Visual acuity was still 20/32 in the left eye. On the basis of
`the experience in Case 1 with a possible benefit of triamcinolone
`
`treatment, an intravitreous injection of 4 mg of triamcinolone was
`applied. Two months later, most of the neovascularization and
`leakage had disappeared, and visual acuity was 20/25.
`However, 6 months after the injection, recurrence of the neo-
`vascularization was noted with a similar appearance as before the
`injection (Fig. 3). Visual acuity was still 20/25, the hemangioma
`remained flattened without exudative detachment, and ocular ten-
`sion remained normal. A second injection of 4 mg of triamcinolone
`was applied to the left eye. Five weeks later, complete regression
`of the neovascularization was noted. However, recurrence was
`observed, and a third injection was administered at 9 months after
`the second injection. Five months later (37 months after the first
`PDT), visual acuity was 20/32 with mild lens opacities, chronic
`macular edema, and no new vessels. The hemangioma remained
`flattened without exudative detachment, and ocular tension re-
`mained normal.
`
`Case 3
`
`A 14-year-old boy had blurred vision in his left eye for two
`weeks. Visual acuity was 20/20 in the right eye and 20/40 in the left
`eye. Funduscopic examination revealed a temporomacular subreti-
`nal mass with associated exudative detachment. The clinical diag-
`nosis of circumscribed choroidal hemangioma was confirmed with
`ultrasound analysis and fluorescein and indocyanine green angiog-
`raphy. Optical coherence tomography revealed a submacular neu-
`rosensory detachment.
`In addition, fluorescein angiography
`showed neovascularization with leakage on the left disk (Fig. 4, top
`
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`

`

`BRIEF REPORTS
`
`695
`
`Fig. 2. Case 1. Regression of
`neovascularization
`and
`no
`leakage at 4 months after the
`first
`injection of triamcino-
`lone (top left) and at 2
`months after the second injec-
`tion (top right). Recurrence
`of neovascularization and dif-
`fuse leakage were noted at 10
`months after the first injection
`of
`triamcinolone
`and are
`shown on a 2-minute frame
`(bottom left) and a 15-minute
`frame (bottom right) of the
`fluorescein angiogram.
`
`left). Six months after the initial diagnosis, the choroidal hemangioma
`(4.8 ⫻ 13 ⫻ 11 mm) with persisting submacular neurosensory de-
`tachment was treated with PDT (using 6 mg/m2 body surface area
`verteporfin and a diode laser at 692 nm with a light dose of 100 J/cm2
`and light application for 166 seconds at 5 minutes after intravenous
`administration of verteporfin, using 2 spots). The associated exudative
`detachment and submacular neurosensory detachment regressed grad-
`ually and disappeared totally. Tumor thickness decreased (1.8 mm)
`progressively so that visual acuity of 20/20 and improvement in visual
`field was achieved at 8.5 months after PDT. However, neovascular-
`ization on the disk was more prominent (Fig. 4, top right) after PDT
`with increased leakage by fluorescein angiography (Fig. 4, bottom
`left). In the follow-up, the anatomical and functional improvement
`
`was stable so that retreatment with PDT was not considered. However,
`25 mg of triamcinolone was injected intravitreally to suppress leakage
`from the increased active neovascularization on the disk. Five weeks
`after triamcinolone injection, neovascularization was funduscopically
`undetectable. The patient had had a temporary intraocular pressure
`increase, which could be treated medically. Complete regression of
`neovascularization (Fig. 4, bottom right) with stable vision of 20/20
`without macular edema was seen at the 1-year follow-up examination.
`
`Discussion
`Retinal and disk neovascularization may occur in
`eyes with a retinal or choroidal tumor without obvious
`
`Fig. 3. Case 2. Red-free pictures showing neovascularization nasal on the disk (left), on and at the borders of the disk and inferior to the edematous
`macula (center), and in the inferotemporal region at the border of the hemangioma (right).
`
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`
`

`

`696
`
`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2006 ● VOLUME 26 ● NUMBER 6
`
`Fig. 4. Case 3. Early-phase
`fluorescein angiogram on the
`day of photodynamic therapy
`(PDT)
`shows hyperfluores-
`cence of hemangioma as well
`as of neovascularization nasal
`to the optic disk (top left).
`After PDT, note increased
`neovascularization on the op-
`tic disk (red-free picture; top
`right) with corresponding in-
`tense leakage in the late
`phases of fluorescein angiog-
`raphy (bottom left). Regres-
`sion
`of
`neovascularization
`(bottom right) was main-
`tained 12 months after the
`single injection of triamcino-
`lone (25 mg intravitreally).
`
`triggering factors such as retinal artery or vein occlu-
`sion, capillary dropout, or inflammation. The associ-
`ation of retinal neovascularization with retinal angi-
`oma is well known and is easily understood in the
`context of von Hippel disease and the inherent stim-
`ulus for ocular angiogenesis. The association of cho-
`roidal melanoma with disk and retinal neovasculariza-
`tion has been reported by several investigators.5 Some
`of these eyes had no radiation therapy and showed no
`capillary dropout or inflammatory response. Possible
`triggers for neovascular growth in these eyes include
`subtle inflammation, chronic retinal detachment with
`secondary subtle chronic retinal ischemia, and release
`of tumor angiogenic factors. Similar triggers apply for
`disk and retinal neovascularization in eyes with a
`circumscribed choroidal hemangioma.1
`Optimal management of tumor-associated neovas-
`cularization is at present unknown. On the basis of our
`own experience and that of others, the spontaneous
`evolution is unfavorable mainly as a result of the
`nature and localization of the tumor and the associated
`
`chronic serous detachment. In melanoma-associated
`neovascularization, regression of the neovasculariza-
`tion has been noted after scatter photocoagulation
`and/or plaque radiation therapy, but radiation-induced
`neovascular growth may occur in other cases. De-
`struction of a choroidal hemangioma by heavy xenon
`arc coagulation, which was a standard treatment some
`40 years ago, may also induce regression of tumor-
`associated neovascularization (personal communica-
`tion, Achim Wessing). To our knowledge, no retinal
`neovascularization has been induced by low dose ir-
`radiation of a circumscribed choroidal hemangioma,
`and this treatment option is still of benefit for large
`hemangiomas with retinal detachment. Laser photo-
`coagulation and transpupillary thermotherapy have
`been used in the treatment of symptomatic choroidal
`hemangioma with relatively good functional results.
`However, in these treatments, large retinal vessels
`overlying the hemangioma are at risk to become oc-
`cluded, which may result in visual loss and in neovas-
`cular growth. Recently, new treatment options have
`
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`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BRIEF REPORTS
`
`697
`
`become available for these complex cases, including
`PDT and antiangiogenic drugs, and experience is
`growing.
`PDT is at present widely accepted as a save and
`highly effective first-line treatment for symptomatic
`circumscribed choroidal hemangioma. Recently, a ret-
`rospective randomized study has been initiated by the
`Ophthalmic Oncology Task Force of the European
`Organization for Research and Treatment of Cancer,
`which is attempting to define the optimal guidelines
`comparing high with low dose PDT (bolus application
`of verteporfin and 100 J/cm2 versus intravenous infu-
`sion and 50 J/ cm2). As a rule, small choroidal hem-
`angiomas require only a single application of a single
`laser spot. Larger hemangiomas may require use of a
`wide-field lens or application of two or more laser
`spots and repeated PDT, and in these cases, caution is
`warranted to avoid atrophic scars in the macular area.
`Increased retinal edema shortly after the laser appli-
`cation is another possible side effect of PDT for cho-
`roidal hemangioma. Edema causes visual loss and
`probably also enhances other stimuli for neovascular
`growth. Possible angiogenic stimuli are laser-induced
`necrosis of the tumor and release of vascular endothe-
`lial growth factor after application of PDT, as has
`been reported in other conditions.3
`Intravitreous injection of triamcinolone has been
`used successfully in a range of ocular conditions as-
`sociated with macular edema, and it seems to enhance
`the therapeutic effect of PDT for age-related neovas-
`cularization. In our cases of neovascularization asso-
`ciated with choroidal hemangioma, neovascular
`growth with increased leakage was demonstrated after
`PDT, and triamcinolone induced regression of neovas-
`cularization with absence of leakage. Recurrence of
`neovascularization with leakage was found in two of
`the patients and proved to be reversible with reinjec-
`tion of triamcinolone.
`In conclusion, we observed three patients who had
`choroidal hemangioma with retinal neovascularization
`that was present before PDT but increased after PDT.
`Triamcinolone injections induced regression of neo-
`vascularization and leakage in all three patients. Two
`patients had a recurrence of neovascularization after
`several months that proved to be reversible with rein-
`jection of triamcinolone. These observations add evi-
`dence to the concept that triamcinolone may offer
`some protection when the angiogenic stimulus is high.
`The exact mechanism of action remains unknown.
`Key words: choroidal hemangioma, neovascular-
`ization, photodynamic therapy, triamcinolone, vascu-
`lar endothelial growth factor.
`
`References
`
`1. Leys AM, Bonnet S. Case report: associated retinal neovascu-
`larization and choroidal hemangioma. Retina 1993;132:22–25.
`2. Shields CL, Honavar SG, Shields JA, et al. Circumscribed
`choroidal hemangioma. Clinical manifestations and factors
`predictive of visual outcome in 200 consecutive cases. Oph-
`thalmology 2001;108:2237–2248.
`3. Barbazetto I, Schmidt-Erfurth U. Photodynamic therapy of
`choroidal hemangioma: two case reports. Graefes Arch Clin
`Exp Ophthalmol 2000;238:214–221.
`4. Michels S, Michels R, Simader C, Schmidt-Erfurth U. Verte-
`porfin therapy for choroidal hemangioma: long-term follow-
`up. Retina 2005;25:697–703.
`5. Keunen JE, Hooymans JM, Ulbig MW, Shields CL. Retinal
`neovascularization in choroidal melanoma without retinal
`ischemia. Retina 2002;22:371–374.
`
`EASY AND EFFECTIVE WAY TO REMOVE
`RESIDUAL SILICONE OIL DROPLETS IN
`PHAKIC PATIENTS
`
`DAVID G. TELANDER, MD, PHD,
`CHRISTINE R. GONZALES, MD
`
`From the Department of Ophthalmology, University
`of California at Los Angeles, Jules Stein Eye Institute,
`David Geffen School of Medicine, Los Angeles, Cali-
`fornia.
`
`In 1962, Cibis first introduced the use of silicone oil
`for the repair of retinal detachments complicated by
`proliferative vitreoretinopathy. Silicone oil continues
`to be used in vitreoretinal surgery for complicated
`retinal detachment, proliferative diabetic retinopathy
`with tractional retinal detachment, and macular holes.1
`Silicone oil is usually removed at some point after
`retinal detachment surgery to allow adequate refrac-
`tion and to avoid complications of silicone oil. Accu-
`rate refraction of a silicone-filled eye is difficult be-
`cause the higher
`refractive index of silicone oil
`relative to vitreous or aqueous induces a hyperopic
`shift. In addition, silicone oil may cause distortion and
`limit
`the best-corrected visual acuity. Silicone oil
`complications,
`including elevated intraocular pres-
`sure, bullous keratopathy, silicone oil emulsification,
`subretinal deposition of oil, cataract, and lens capsule
`opacification, are not uncommon and can be vision
`threatening.1 Silicone oil is generally removed when
`the tamponade is no longer necessary or when com-
`plications secondary to silicone oil are present.
`The surgical removal of silicone oil has its own set
`
`Reprint requests: Christine Gonzales, MD, University of Cali-
`fornia at Los Angeles, Jules Stein Eye Institute, 100 Stein Plaza,
`Los Angeles, CA 90095; e-mail: gonzales@jsei.ucla.edu
`
`Novartis Exhibit 2232.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`698
`
`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2006 ● VOLUME 26 ● NUMBER 6
`
`of risks, including recurrent retinal detachment, in-
`creased intraocular pressure, lens opacification, repro-
`liferation of proliferative vitreoretinopathy, keratopa-
`thy, and residual oil droplets.1,2 These residual
`silicone oil droplets often cause symptomatic floaters
`after the removal of silicone oil. One study found that
`⬎70% of patients had postoperative complaints of
`floaters, and after silicone oil removal, 20% of patients
`had visible silicone oil shown by biomicroscopic ex-
`amination.3 In addition, silicone oil droplets are
`known to have significant adherence to the natural
`lens or intraocular lens implant, especially silicone
`intraocular lens implants, making complete removal
`of the silicone oil droplets difficult.4
`We report an easy and effective intraoperative tech-
`nique to remove the residual droplets of silicone oil,
`which often remain adherent to the posterior surface
`of the lens in a phakic patient at the end of silicone oil
`removal surgery. This method avoids direct contact
`with the lens, which is especially important in phakic
`patients to prevent cataract development.
`
`Surgical Technique
`
`Silicone oil is removed in the phakic or pseudopha-
`kic patient using the standard two- or three-port tech-
`nique with active or passive extrusion. Residual oil
`droplets that are adherent to the posterior lens can
`often be displaced by ocular rotation alone. If these
`adherent droplets remain, then the following tech-
`nique can be used.
`A silicone-tip or “soft-tip” extrusion cannula is
`placed in the posterior chamber through the sclerot-
`omy. The silicone portion of the soft-tip cannula is
`used to touch the posterior surface of the residual oil
`droplet without contacting the posterior lens surface
`(Fig. 1). It is not necessary to start active extrusion.
`The natural affinity of silicone to silicone will over-
`come the droplet’s adherence to the lens. The soft-tip
`cannula is then removed and wiped with an instrument
`wipe if necessary. This process can be repeated as
`many times as needed. Avoiding contact with the lens
`should prevent any direct lens damage.
`
`Discussion
`
`We describe a straightforward way to remove the
`residual silicone oil droplets, which tend to remain
`adherent to the posterior surface of the crystalline lens
`after removal of silicone oil. Removal of these drop-
`lets may help decrease symptomatic floaters and other
`complications. The inherent affinity of silicone oil for
`the silicone tip of the soft-tip extrusion cannula allows
`removal of the droplet from the posterior lens surface
`without damaging the lens.4
`
`A, Schematic illustrating the extendable soft-tip cannula
`Fig. 1.
`entering the eye through the pars plana sclerotomy and making contact
`with a residual silicone oil droplet that is adherent to the posterior
`capsule of the lens. B, The adhesion forces of the silicone oil to the
`silicone soft tip facilitate the removal of the droplet from the lens
`capsule.
`
`To our knowledge, previous reports of silicone oil
`removal have not described this effective method of
`droplet removal. Multiple air–fluid exchanges have
`been suggested to remove residual silicone oil drop-
`lets; however, this strategy has not been shown to
`decrease the incidence of floaters.3 Alternative tech-
`niques that have been described to remove adherent
`droplets from silicone lenses include using agents
`such as perfluorohexyloctane to dissolve residual
`droplets5; however, these methods are more arduous,
`and their safety has not been well established in pha-
`kic patients. Our technique using the silicone soft-tip
`cannula to remove residual oil droplets may poten-
`tially decrease the incidence of postoperative floaters
`secondary to residual silicone oil droplets, while pre-
`venting lens damage. In addition, this method may be
`helpful in the removal of silicone oil droplets adherent
`to intraocular lenses. This method of droplet removal
`is safe and technically feasible and does not require
`specialized instrumentation.
`Key words: silicone oil, floaters, intraocular oil
`droplets,
`retinal detachment, vitreoretinal surgery,
`proliferative vitreoretinopathy.
`
`References
`
`1. Gallemore RP, McCuen BW. Silicone oil in vitreoretinal sur-
`gery. In: Ryan SJ, ed. Retina. St. Louis: Mosby; 2001:2195–
`2220.
`2. Federman JL, Schubert HD. Complications associated with the
`
`Novartis Exhibit 2232.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BRIEF REPORTS
`
`699
`
`use of silicone oil in 150 eyes after retina-vitreous surgery.
`Ophthalmology 1988;95:870–876.
`3. Dabil H, Akduman L, Olk J, Cakir B. Comparison of silicone
`oil removal with passive drainage alone versus passive drain-
`age combined with air–fluid exchange. Retina 2002;22:597–
`601.
`4. Apple DJ, Federman JL, Krolicki TJ, et al. Irreversible silicone
`oil adhesion to silicone intraocular lenses. A clinicopathologic
`analysis. Ophthalmology 1996;103:1555–1561.
`5. Damiana Z, Schrage N, Kirchhof B, Wenzel M. Silicone oil
`removal from a silicone intraocular lens with perfluorohexy-
`loctane. J Cataract Refract Surg 2000;26:301–302.
`
`USE OF INTRAVITREAL BEVACIZUMAB
`AS A PREOPERATIVE ADJUNCT FOR
`TRACTIONAL RETINAL DETACHMENT
`REPAIR IN SEVERE PROLIFERATIVE
`DIABETIC RETINOPATHY
`
`ERIC CHEN, MD,
`CARL H. PARK, MD
`
`From the Retina Service, Wills Eye Hospital, Phila-
`delphia, Pennsylvania.
`
`Bevacizumab (Avastin; Genentech, Inc., South San
`Francisco, CA) is an anti–vascular endothelial growth
`factor (VEGF) agent that has been approved by the US
`Food and Drug Administration as a first-line treatment
`for metastatic colorectal cancer in combination with
`chemotherapy. Recent reports on the intravitreal in-
`jection of bevacizumab show promise for targeting
`VEGF-implicated intraocular neovascularization seen
`in age-related macular degeneration and diabetic ret-
`inopathy.1– 4 We report on the use of intravitreal bev-
`acizumab as a preoperative adjunct for tractional ret-
`inal detachment repair in severe active proliferative
`diabetic retinopathy.
`
`Case Report
`
`A 27-year-old man with a history of insulin-dependent diabetes
`mellitus since 10 years of age presented with a history of prior pars
`plana vitrectomy on the right eye and panretinal photocoagulation
`to the left eye. At examination, visual acuity was 20/400 in both
`eyes. Anterior segment examination was unremarkable, and there
`was no iris neovascularization in either eye. Fundus examination
`revealed an ischemic macula with prior panretinal photocoagula-
`tion scars in the right eye. In the left eye, there was significant
`neovascularization involving the optic disk. The entire region be-
`tween the temporal arcades demonstrated thick, opaque preretinal
`neovascular membranes with underlying tractional retinal detach-
`
`The authors have no proprietary interest in this work.
`Reprint requests: Carl H. Park, MD, Retina Service, Wills Eye
`Hospital, 840 Walnut Street, Suite 1020, Philadelphia, PA 19107;
`e-mail: chp5592@yahoo.com
`
`Fig. 1. Color fundus photograph of the left eye demonstrates signif-
`icant optic disk neovascularization and thick, opaque preretinal neo-
`vascular membranes with underlying tractional retinal detachment be-
`tween the temporal arcades.
`
`ment (Fig. 1). We decided to offer the patient intravitreal bevaci-
`zumab as an off-label preoperative adjunctive therapy, hypothesiz-
`ing that its antiangiogenic properties may help quiet down some of
`the abnormal vasculature before vitrectomy, decreasing the risk of
`intraoperative complications such as hemorrhage. After extensive
`discussion of potential risks and benefits, the patient consented
`with the treatment.
`Standard sterilized procedure for intravitreal injections was fol-
`lowed, including the use of topical 5% povidone/iodine, an eye
`speculum, and an antibiotic drop. The patient received 0.05 mL
`containing 1.25 mg of bevacizumab without complications, and 1
`week later, visual acuity was stable; he had no signs of infection,
`uveitis, or intraocular pressure elevation. The following week,
`although the fibrovascular scaffold still remained, a preoperative
`fundus photograph (Fig. 2) demonstrated significant regression of
`the neovascularization. The patient then underwent pars plana
`vitrectomy, successful removal of all epiretinal fibrovascular mem-
`branes, further endolaser panretinal photocoagulation, and sulfur
`hexafluoride (SF6) tamponade. Intraoperatively, it was noted that
`there was minimal bleeding during segmentation and subsequent
`delamination of the membranes. Most epicenters of neovascular-
`ization peeled with blunt dissection, suggesting that the recently
`active neovascular complex had regressed and fibrosed. His post-
`operative course was uneventful. At the 1-month follow-up, visual
`acuity had improved to 20/70, and the macula remained free of
`neovascularization or any tractional membranes (Fig. 3).
`
`Discussion
`
`Pharmacologic blockade of VEGF, postulated to be
`the factor primarily responsible for retinal angiogen-
`esis and vessel permeability, has been extensively
`investigated.5 VEGF inhibitors delivered via intravit-
`real injections such as pegaptanib sodium6 (Macugen;
`Eyetech Pharmaceuticals, Inc., New York, NY) and
`ranibizumab (Lucentis; Genentech, Inc.), currently in
`phase 3 clinical trials,7 have demonstrated a slowing
`
`Novartis Exhibit 2232.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`700
`
`RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2006 ● VOLUME 26 ● NUMBER 6
`
`Fig. 2. Color fundus photograph 2 weeks after intravitreal bevaci-
`zumab treatment reveals persistence of fibrovascular scaffolding but
`significant regression of the neovascularization.
`
`Fig. 3. Postoperative photograph shows the macula devoid of any
`neovascularization or epiretinal membranes.
`
`or even reversal of visual decline in patients with
`neovascular age-related macular degeneration. Bev-
`acizumab is the parent molecule from which ranibi-
`zumab is derived; it is a humanized monoclonal anti-
`body that targets and binds to all isoforms of VEGF.8
`In addition to wet macular degeneration, VEGF has
`also been shown to contribute significantly to prolif-
`erative diabetic retinopathy. Retinal ischemia leads to
`an increased production of intravitreal VEGF by pig-
`ment epithelial cells, pericytes, and endothelial cells,
`while inhibition of VEGF activity via successful pan-
`retinal photocoagulation decreases VEGF levels and
`inhibits retinal neovascularization.9 In this case, intra-
`vitreal injection of bevacizumab was done in an effort
`to quiet down the fibrovascular proliferation before
`vitrectomy, and its success made surgery technically
`much easier. Although intravenous bevacizumab ad-
`ministration has been associated with systemic hyperten-
`sion and thromboembolic events, intravitreal injections
`involve a 400-fold less dosage of drug and a more
`targeted delivery. In this case, there were no adverse
`effects, although the follow-up time was limited.
`The results seen in this case after intravitreal injec-
`tion of bevacizumab are encouraging. Further formal,
`prospective studies may be considered to determine
`whether this use as a preoperative adjunct, in addition
`to adequate panretinal photocoagulation, may serve to
`improve success of vitrectomy for patients with severe
`proliferative diabetic retinopathy. Other potential ar-
`eas of investigation include the duration of effect as
`well as possible dose–response studies.
`
`Key words: bevacizumab, intravitreal, proliferative
`diabetic retinopathy, tractional retinal detachment, vit-
`rectomy.
`
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