`
`NEGVASCULAR GROWTH FOLLQ‘WENG
`i’HD’i‘UDYNAMEE THERAPY FOR
`Ci-iGROIDAL HEMANGlGMA AND
`NEGVASCULAR REGRESSEON AFTER
`lN'l‘iiAVi'i‘iiEOUS lNJECTiON OF
`TREAM CENQLG‘NE
`
`ANiTA M. LEYS, MEN
`RUFlNO Sll_.VA, MD, MSC,’l‘
`‘WERNER lNi-lOFFEN, PHDQ’:
`OLCAY TATAR, MD:
`
`Fraiti the *Deparnneni of Ophthalmology, Universini
`Hospitals, Leuven, Belgium: the i‘Depariment of Oph-
`thalmology, Hospital of the University of Coimbra
`and AIBILL’ZMBILFAssoeiaiioii for the institute of
`Biomedical Research an Light and Image, Coimbra,
`Portugal; and the illiepartmeitt of Ophthalmology,
`Eberhard—Karl‘s University, Tahingen, Grouchy.
`
`Retinal neovascularization rarely occurs in association
`with cheroidal hemangiorna} 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 neovascnlarization.
`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
`treatinentfi' Moreover, numerous small series of PDT-
`treated choroidal hemangionias have been reported
`without mention of ocular side effects. Recently, we
`observed subtle retinal neovasculai‘ization in three un-
`
`treated eyes with circumscribed choroidal hernangi—
`dim and noted neovascuiar growth after PDT for the
`hemangioma. in two cases, the neovascularization re-
`
`
` . . ' at the llth international Congress of Ocular
`
`
`Oncology; H
`ad, lndia; January 33-27, 2,004; and, the Fluo-
`rescein Conference of the 3’7th Annual Meeting of the l‘llacula
`Society; Las Vegas, NV; February 25-28, 2904.
`Reprint requests: Anita, M. Leys. Department of Ophthalmology,
`liapucijncnvoer 33, B—3000 Leuven. Belgium,
`
`gressed after intravitreons injection of triaincinolone
`(4 mg) but recurred several months later. Repeated
`injection of triarncinolone resulted again in regression
`of the. neovascularization. in the third case, a single
`intravitreal injection of tn’ amcinolone (25 mg) induced
`regression of neovascularization, and no recurrence
`was observed during a 1—year follow—up.
`
`Case Reports
`
`C are 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 30/40 in the right eye and 20/30
`in the left eye. Funduscopic examination, ultrasound analysis,
`lluoresccin and indocyaninc green angiography, and optical coher-
`ence tomography showed a voluminous temporomncular mass (7.0
`X 71) / 4.8 mm) with characteristics of chomidal hemangioma
`and associated exudative detachment and macular edema. Subtle
`
`leakage of lluorescein from the disk and retinal neovascularization
`was present (Fig. l, top left) but initially overlooked. After PDT (6
`trig/m2 body surface area vei‘teporfin and a diode laser at 692 not
`with a light dose of fill l/cml and light application 5 minutes after
`intravenous administration of vcrteporfinjt the exudative detach--
`nicnt vanished, and vision improved; however, leakage from non—
`vasculariration increased (Fig. l, 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 1] months, taking into account the 4—irnn
`elevation of the licmangioma and decret
`ed, vision due to subtle
`lluid. Most interesting,
`the dish and retinal neovascularizatlon
`increased progressively during follow-up, and 1 year after the first
`PDT, a small vitreous hemorrhage occurred (Fig. l, 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 aini to reduce niacular edema and with the hope
`to dirnini sh leakage from the neovascularization. Two months later,
`the neovascularization was clinically undetectable, and no leakage
`was noted by liuorescein angiograpliy. The regression of new
`vessels was maintained 2 months later iFlg 2, top left), but l0
`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 cxudan‘vc lesions;
`ultrasound analysis showed a 2.8~nnn elevation. A second intrav—
`itrcal 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‘E, The Journal of Retinal and Vitreous Diseases, encourages authors to submit Brief Reports describing unusual findings, new
`
`techniques, and new instruments. i‘vl
`'
`‘ial submitted for consideration in this section of the journal is done so wit‘
`the assumption that the
`ition cl sewherc, Ea ch
`
`
`data provided do not duplicate prev
`ly published material and that the material has not been submitted for co
`
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`l'l'ect (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 proc
`at is applied to other material submitted to RE’FHNAQ). Brief
`Reports should follow the requiren‘rents listed in the lnstriictioi‘rs to Authors, with the following (events: 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.
`
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`
`
`Fig. l. Case 1. Fluorescein
`angiogram before the
`first
`phototiynamic therapy (PDT)
`showing marked
`let tage
`from the
`tetnporomactilar
`hemangioma and subtle leak
`age from tie-Masculwization
`oi' the dish and along the in—
`ferior
`temporal
`vein
`(top
`left). Note growth at netwas~
`ctilarization and the increased
`
`lea. age
`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 ncovascularization and no macular edema.
`
`.ual
`
`acuity was 20/70 with lens opacities and no other complications.
`
`Case 2
`
`A Ziliyeareold man had decreased Vision in his left eye for 2
`
`months. Visual acuity was 30/20 in he right eye and 30/32 in the
`left eye. Funduscopic examination of the left eye re 'ealed a pink
`choroidal mass @313 X 6.0 X 3.0 min) in the temporal region with
`overlying suhretinal lluid affecting the foveal region. Fluot‘escein
` S COD--
`and indocyanine green angiography and ultrasound anal)
`firmed the clinical diagnosis of exudative circumscribed choroidal
`hemangiotna. Moreover.
`subtle dish neovasculaiization was
`present. Subsequently, PDT was applied in two courses at 3—month
`
`intervals using 6 nig/ml body surface , ea verteporiin and a, diode
`laser at 693 am with a light dose of 50 l/cm2 and light application
`l5 minutes after the start of the infusion. Three months after the
`second PDT, neovascular growth was noted with neovascular tufts
`on and at the holders of the optic nerve head and nasal to the disk.
`Another 3 months later. extension of the neovascularization and a
`suhhyaloidal hemorrhage were noted. Preexisting cystoid macular
`edema was more pronounced. The hemangiotna had flattened, and
`most of the exudative detachment was resolved. Another 3 months
`later, a new focus of netwasculaiization was noted in the infero—
`
`temporal macular region. and a new subhyaloidal henioni
`e was
`noted. Visual acuity was still 20/32 in the left eye. On the basis of
`
`the experience in Case 1 with a pos. ble benefit of triamcinolone
`
`treatment, an intravitreotis injection of 4 mg of triamcinolone was
`applied. Two months later, most of the neovascularization and
`
`leak ge had disappeared. and Visual acuity was 20/25.
`However, 6 months after the injection. recurrence of the neon
`vascularization was noted with a similar appearance as before the
`injection (Fig. 3). Visual acuity was still 20/25, the hemangioma
`remained flattened without exudati've detachment, and ocular ten
`sion remained normal. A second injection of ii mg of triamcinolone
`was applied to the left eye. Five weeks later. complete regression
`of the tieovascularization was noted. Howeyer, recurrence was
`
`' -iection was administered at 9 months after
`
`cond injection. Five months later (37 months after the first
`PUD. Visual acuity was 20/32 with mild lens opacities, chronic
`mactilar edema, and no new vessels.
`'lhe hemangioma remained
`flattened without cxudatiyc detachment, and ocular tension re-
`mained normal.
`
`CarRx
`
`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 20140 in the left
`eye. Funduscopic examination revealed a teinporoniacular suhreti--
`nal mass with assoeiateo exudative detachment. The clinical diag—
`nosis of circumscribed choroidal heniangioma was confirmed with
`ultrasound analysis and liuorescein and indocyanine green angiog—
`raphy. Optical, coherence tomography revealed a submacular neu—
`rosensory detachn‘rent.
`in
`addition.
`fluorescein
`angit'igraphy
`showed netwascularization with leakage on the left disk (Fig. 4, top
`
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`Fig. 2. Case 1. Regression of
`neovascuiarizaiion
`and
`no
`ieakage at 4 months after the
`first
`injection of
`triameino—
`ione
`(top left)
`and at
`2.
`months after the second injec—
`tion (top right}. Recurrence
`
`of neovasculariz ion and dif—
`
`fuse teak e were noted at 10
`months at or the first injection
`of
`triameinote:
`and
`are
`
`shown on a 2—minute frame
`{bottom left) and a 15-minute
`frame [bottom right) of the
`fluorescein angiogmzn.
`
`BREEF REPORTS
`
`695
`
`
`
`
`left). Six months after the initiai din C'nosis. the choroidnl heniangionm
`
`(4.8 X 13 X 1] mm) with pers ting aubmacuiar neuro,
`sory de~
`
`inehment was treated with PDT (using 6 trig/in2 body stirt’aee area
`vertepoiiin and a, diode laser at 692 um with a light dose of 100 J/ennl
`and light appiieation for 166 seconds at 5 minutes after intravenous
`administration of verteporfin. using 2 spots). The associated etxidative
`
`detachment and snbmaenlztr neurosensory detachment regre
`d grad—
`ually and disappeared, totally. Tumor driekness decreased :18 mm)
`progressively so that Visual acuity of 29/20 and improvement in Visual
`neovascuinn
`field was achieved at 8.5 months after PDT. Howe
`
`
`ization on the disk was more prominent (Fig. 4-. top rin t) after PDT
`
`With increased leakage by ituorescein angiography (_ b 4, bottom
`left). In the follow—upw the anatomieui and tunetionzil improvement
`
`was stable so that retreatrnent with PDT was not considered. However,
`25 mg of triamcinoione was injected intravitreaiiy to suppr
`Jen tags:
`
`from the increased active neovascuiarization on the disk. hve weeks
`
`after iriameinolone injection, netwaseulaiiyation was fundiiaeopi
`11y
`
`undetectable. The patient had had a temporary intraoeuiar pr sure
`inertezn'e7 which could be treated medically. Complete regression of
`
`neov
`nimizntion (Fig. 4. bottom right) with stable vision of 20/20
`without maeuiar edema was seen at the 1—year follow—up examination.
`
`Disenssien
`
`Retinal and disk neovascniarizaiion may occur in
`eyes with Z! retina! or choroitiai tumor without obvious
`
`
`
`(Ease 2. Red-free pictures showing; neovaseuiarization nasal on the disk {heft}. on and at the borders of the disk and inferior to the edematotis
`Fig. 3.
`maeulzt (center). and in the inierotemporzfl region at the border of the hemahgioma (right).
`
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`
`
`Early—phase
`Fig, u’l. Case
`
`'
`. igiogram on the
`.4
`, photodynamic therapy
`
`
`(PDT)
`shows hyperfit
`*
`cencte or" hemangioma a: veil
`as of neoyascularizati on nasal
`to the optic disk (top left),
`After PDT. note
`increased
`neovasrularization on the op-
`tic {its}; (red-free picti
`top
`
`right) with r'orrespol
`in—
`
`ten"n leakage
`in the
`late
`plr es of fluorescent angiog-
`raphy (bottom left). Rt
`res--
`sion
`of
`rleovascularh
`
`-
`[bottom right) was
`
`the
`rained l2 months after
`single injection of trianicino--
`lone (25 mg inurwitrenilyt
`
`triggering factors such as retinal artery or vein occlu-
`sion? capillary rlropont, or inflammation. The associ-
`ation of retinal neovascnlarization with retinal angi—
`oina 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 Clio—
`roidal melanoma with disk and retinal neovasculariza—
`
`tion has been reported by several investigators? Some
`or these eyes had no radiation therapy and showed no
`capillary dropout or inflammatory response. Possible
`triggers for neoyasctilar growth in these eyes include
`subtle inflamrnatiom chronic retinal detachment with
`secondary subtle chronic retinal iselieniiae and release
`of tumor angiogenic factors Similar triggers apply for
`disk and retinal neovascnlarization in eyes with a
`circumscribed choroidal lieniangionta1
`Optimal management of tumonassneiated neoyas-
`eularizarion is at present unknown. On the basis or“ 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,
`
`l’n melanoma—associated
`
`neoyascnlarization, regression of the neoyascularlza
`tion has been noted after scatter photoeoagulation
`and/or plaque radiation therapy, but radiation—induced
`neoyaseular growth may occur in other casesr Dew
`struction of a choroidal hemangioma by heavy xenon
`arc coagulation, which was a standard treatment some
`45) years ago. may also induce regression of tuninr~
`associated neoyascnlarization (personal communica—
`tion, Achirn Wessing). To our knowledge, no retinal
`neoyascularization has been induced by low dose irw
`radiation of a circumscribed choroirlal hemangioina,
`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.
`l-loweyer,
`in these treatments? large retinal vessels
`overlying the hernangiorna are at risk to become oc—
`cluded, which may result in visual loss and in neoyaa
`enlar growth. Recently? new treatment options have
`
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`BREEF REPORTS
`
`69?
`
`References
`
`become available for these complex cases, including
`PDT and tuitiangiogenic drugs, and experience is
`growing.
`PDT is at present widely accepted as a save and
`highly effective first~line treatment for symptomatic
`circumscribed choroidal hernangioma. Recently, a ret—
`rospective randomized study has been initiated by the
`Ophthalmic Oncology Task Force of the European
`Organization for Research and 'i‘reatment of Cancer,
`which is attempting to define the optimal guidelines
`comparing high with low dose PDT (bolus application
`of verteporrin and tilt) .l/crnz versus intravenous infu—
`sion and Sti
`/ crnz). As a rule, small choroidal hern-
`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 atropine 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 crmditions.3
`lntravitreous injection of triamcinolone has been
`used successfully in a range of ocular conditions as-
`sociated with inacular edema, and it seems to enhance
`
`the therapeutic effect of PDT for age—related neovas—
`cularization. in our cases of neovascularization asso-
`
`choroidal hemangioma, neovascular
`ciated with
`growth with increased lealrage 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 reinjecu
`tion of triamcinolone.
`
`ln conclusion, we observed three patients who had
`choroidal hemangioma with retinal neovascularization
`that was present before PDT but increased after PDT.
`'l‘riamcinolone injections induced regression of neon
`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 triatncinolone may offer
`some protection when the angiogenic stimulus is high.
`The exact mechanism of action remains unknown.
`
`2.
`
`DJ
`
`
`1. Le 3 AM. Bonnet. 5;. Case report: associated retinal neov 'cu—
`
`larization and clioroidal hemangiotna. Retina 19932l32 2—25.
`Shields CL, Honavar SG, Shields JA, et al. Circurusclrhed
`choroidal hemangioma. Clinical manifestations and factors
`predictive of visual outcome in 200 consecutive cases. Oph-
`thalmology 2001;108:2237—2248.
`Barbazetto l, Schniidt—Erfurth U. Photodynaniic therapy of
`choroidal licmangionia: two case reports. Graefcs Arch Clin
`Exp Ophthalinol 2000;238:2l 4—231.
`4. Michels 5% Michels R, Simader C, Sclnnidblilrfurth ll. Verte-
`poriin therapy for choroidal hemangiorna: long»tei’irt follow—
`up. Retina 2005;25:697—703.
`lieunen IE, l-looyrnans 1M, Ulbig MW, Shields CL. Retinal
`neovascularizalion in choroidal melanoma without
`retinal
`ischeniia. Retina 2002;22:371-"374.
`
`5.
`
`EASY AND EFFECTEVE VA? T0 REMGVE
`RESEDUAL SELECDNE (ill. DRGPLETS 1N
`PflAiflC ihd'l‘ililbl'i‘S
`
`DAVlD G. TELANDER, MD, PHD,
`CHRlSTlNE R. GONZALES. MD
`
`From the Department of (lphrfictinioiogy, University
`ofCaiifomia at Les Augeles, Jules Stein Eve Institute,
`Burial Geffen School ofi’ll’edlcinc, L05 Angular, Cali-1
`forum.
`
`in ”1962, Cibis first introduced the use of silicone oil
`for the repair of retinal detachments complicated by
`proliferative vitreoretinopathy. Silicone oil continues
`to he used in vitreoretinal surgery for complicated
`retinal detachment, proliferative diabetic retinopathy
`with tractional retinal detachment and macular holes.l
`
`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
`reative 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, hullous lteratopathy, silicone oil emulsification,
`subretinal deposition of oil, cataract, and lens capsule
`opaciftcatinm 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
`
`Key words: choroidal hemangioma. neovascular-
`ization, photodynarnic therapy, triamcinolone, vascu-
`lar endothelial growth factor.
`
`Reprint requests: Christine Gonzales, MD, University of Cali—
`
`fornia at Les Angelcs, Jules Stein l?)
`’ institute. till) Stein Flam,
`Los Angeles. CA 90095; email: gonzoles®jsei.ucla.edu
`
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`
`in-
`of risks, including recurrent retinal detachment,
`creased intraocular pressure, lens opacitication, repro-
`liferation of proliferative vitreoretinopathy, keratopa—
`thy, and residual oil dropletsi‘tz 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 hioinicroscopic ex—
`amination? in addition,
`silicone oil droplets are
`known to have significant adherence to the natural
`lens or intraocular lens implant, especially silicone
`intraocular lens implants, malting complete removal
`of the silicone oil droplets difficultfl
`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 phaldc
`patients to prevent cataract development.
`
`Surgical Technique
`
`Silicone oil is removed in the phakic or pseudophau
`his 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 he 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 resid ial 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 he 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
`i.
`Fig.
`entering the eye through tl’e pars plana sclerotomy and making contact
`with a residual silicone oil droplet that is adherent to the posterior
`
`cat
`lie of the lens. E. The adhesion forces of the silicone oil to the
`
`Lone 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—
`
`nitgues that have been described to remove adherent
`droplets from silicone lenses include using agents
`such as perfiuorohexyloctane to dissolve residual
`droplets-5; however, these methods are more arduous,
`and their safety has not been well established in pha—
`lric 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. ln 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.
`
`intraocular oil
`Key words; silicone oil. floaters.
`droplets.
`retinal detachment, vitreoretinal
`surgery.
`proliferative vitreoretinopathy.
`
`References
`
`l. Gallemore RP, McCuen EW. Silicone oil in vitreoretinal sur—
`gery. ln: Ryan Si. ed. Retina. St. Louis: Mosby; 300122l95—
`ooze
`
`F}
`
`Federnian ll... Schubert HD. Complications associated with the
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`Regeneron Exhibit 1065.006
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`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 T], et al. Irreversible silicone
`oil adhesion to silicone intraocular lenses. A clinicopathologic
`analysis. Ophthalmology 1996;103:1555—1561.
`Damiana Z, Schrage N, Kirchhof B, Wenzel M. Silicone oil
`removal from a silicone intraocular lens with perfluorohexy—
`loctane. J Cataract Refract Surg 2000;26:3017302.
`
`_UI
`
`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 Sen/ice, 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-
`inopathyflr4 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;
`email: 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 vasculaturc 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 .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 (SFS) tainponade. Intraoperatively. it was noted that
`there was minimal bleeding dtning 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 l—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
`
`Regeneron Exhibit 1065.007
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`NOVITC(US)00314329
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`Regeneron Exhibit 1065.007
`
`

`

`700
`
`RETINA, THE JOURNAL OF RETINAL AND VH'REOUS DISEASES U 2006 U VOLUME 26 U 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.
`
`References
`
`4.
`
`1. Rosenfeld PJ. Moshfeghi AA, Puliafito CA. Optical coherence
`tomography findings after an intravitreal injection of bevaci—
`zumab (Avastin) for ncovascular age—related macular degen—
`eration. Ophthalmic Stu'g Lasers Imaging 2005;36:331.
`2. Avery RL. Pieramiei DJ, Rabena MD, et a1. Intravitreal bev—
`acizumab (Avastin) for neovaseular age—related macular de—
`generation. Ophthalmology 2006;113:363—372.
`3. Avery RL. Regression of retinal and iris neovascularization
`after intravitreal bevacizumab (Avastin)
`treatment. Retina
`2006;26:352—354.
`Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin)
`treatment of proliferative diabetic retinopathy complicated by
`vitreous hemorrhage. Retina 2006;26:275—278.
`5. Adamis AP. Shima DT. The role of vascular endothelial
`growth factor in ocular hwlth and disease. Retina 2005;25:
`111—118.
`6. Gragoudas ES, Adamis AP, Cunningham ET Jr. Pegaptanib
`for neovascular age—related macular degeneration. N Engl
`J Med 2004;351:2805—2816.
`7. Michcls S, Roscnfeld PJ. Ranibizuinab therapy for ncovascu—
`lar age—related macular degeneration. Retinal Physician 2004;
`1:16—