Gracfc's Arch Clin Exp Ophthalmol (1990) 228: 19-23
`
`Graefe's Archive
`Ophthalmology
`
`torQIN:alandE~
`
`© Springer-Verlag 1990
`
`Intravitreal silicone oil injection:
`complications and treatment of 415 consecutive patients
`
`Klaus Giinther Riedel, Veit-Peter Gabel, Lorenz Neubauer, Anselm Kampik, and Otto-Erich Lund
`Augenklinik der Universitiit, Mathildenstrasse 8, D-8000 Miinchen 2, Federal Republic of Germany
`
`Abstract. Silicone oil injection in conjunction with pars
`plana vitrectomy was carried out by five surgeons in 415
`consecutive patients using the same surgical equipment, the
`same surgical techniques and the same highly purified sili(cid:173)
`cone oil (viscosity, 5000 mPa · s). Indications for silicone oil
`injection after vitrectomy included advanced stages of pro(cid:173)
`liferative vitreoretinopathy following rhegmatogenous reti(cid:173)
`nal detachment (49%), severe proliferative diabetic retino(cid:173)
`pathy (38%), and proliferative vitreoretinopathy following
`retinal detachment due to ocular trauma (13%). Postopera(cid:173)
`tive complications were noted in a 6- to 30-month follow-up
`period. Cataractous changes of varying degree were seen
`in all phakic eyes. Silicone oil entered the anterior chamber
`in 6% of all phakic and pseudophakic eyes. Subretinal sili(cid:173)
`cone oil was noted in 4%. Other complications associated
`with the use of intravitreal silicone oil included biomicros(cid:173)
`copically visible silicone oil emulsification (0.7%), kerato(cid:173)
`pathy (5.5%), glaucoma (6% ), closure of the inferior iridec(cid:173)
`tomy (6%), and reproliferation of epiretinal and subretinal
`fibrous membranes (40%). We anticipate that the physico(cid:173)
`chemical characteristics of the highly purified silicone oil
`(viscosity, 5000 mPa·s) and the routine performance of an
`inferior iridectomy in all aphakic eyes had a positive impact
`on the low incidence of silicone-oil-related complications
`such as emulsification, keratopathy and secondary glauco(cid:173)
`ma.
`
`Introduction
`Intravitreal injection of silicone oil for the treatment of
`complicated retinal detachments has been used with increas(cid:173)
`ing frequency [15, 18, 24, 26, 30, 37, 38) since it was intro(cid:173)
`duced by Cibis et al. [7] in 1962. Despite a high success
`rate in otherwise desperate cases, it is well known that the
`use of either intraocular gas or silicone oil in combination
`with intravitreal surgery produces side effects and complica(cid:173)
`tions, limiting their efficacy and therapeutic value.
`Gas has the advantage of sufficiently high surface ten(cid:173)
`sion to facilitate the occlusion of retinal breaks; it also
`has the advantage of spontaneous absorption. However,
`its potential disadvantages include postoperative intraocu(cid:173)
`lar pressure rise, cataract formation, and a high rate of
`recurrent retinal detachments [4, 23].
`
`Offprint requests to: K.G. Riedel
`
`Intraocular silicone oil is advantageous in that it may
`provide extended or permanent retinal tamponade. Its ap(cid:173)
`plication creates no major technical problems, and its opti(cid:173)
`cal qualities enable a clear view of the fundus. However,
`the instillation of intravitreal silicone oil has been found
`to cause a significant number of related complications in(cid:173)
`cluding glaucoma, cataract formation in phakic eyes, oil
`emulsification, and keratopathy [5, 6, 9, 11, 15, 16, 18, 20,
`21, 25, 27, 31, 35, 38). Moreover, several authors have
`claimed that intraocular silicone oil is toxic to the retina
`and optic nerve and induces reproliferation of preretinal
`membranes in proliferative vitreoretinopathy and prolifera(cid:173)
`tive diabetic retinopathy [3, 10, 19, 22, 28, 35]. In view
`of the various complications of silicone oil injections re(cid:173)
`corded in the literature, the present study was undertaken
`to review our considerable recent experience at the Univer(cid:173)
`sity Eye Hospital, Munich.
`
`Materials and methods
`
`A total of 415 consecutive patients underwent intravitreal
`surgery with silicone oil injection in 1986 and 1987. An
`additional 29 patients who were surgically treated had to
`be excluded from this study due to inadequate follow-up.
`Indications for silicone oil injection included: (1) advanced
`stages ·or proliferative vitreoretinopathy following rhegma(cid:173)
`togenous retinal detachment (206 eyes, 49%), (2) prolifera(cid:173)
`tive vitreoretinopathy following ocular trauma (52 eyes,
`13%), and (3) severe proliferative diabetic retinopathy
`(157 eyes, 38%). The follow-up period ranged from 6 to
`30 months, with a mean follow-up of 14 months. All eyes
`were subjected to complete pre- and postoperative examina(cid:173)
`tions including visual acuity testing, intraocular pressure
`measurement, slit-lamp microscopy, fundus biomicroscopy
`and indirect ophthalmoscopy. Sonography was carried out
`when the media were opaque.
`The degree and extent of the proliferative vitreoretino(cid:173)
`pathy (PVR) in eyes with retinal detachment (RD) due to
`rhegmatogeneous detachment and ocular trauma were
`graded according to the classification of The Retina Society
`Terminology Committee [33]. Grade C1 PVR was present
`in 2%; grade C2 PVR, in 18%; grade C3 PVR, in 19%;
`grade 01 PVR, in 22%; grade 02 PVR, in 29%; and grade
`03 PVR, in 10% of our patients. In all eyes with prolifera(cid:173)
`tive diabetic vitreoretinopathy (PDR), vascularized vitreous
`membranes leading to retinal detachment and recurrent vit(cid:173)
`reous hemorrhage were present.
`
`Novartis Exhibit 2320.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`20
`
`All surgery was carried out by five surgeons following
`the same surgical principles and using the same instruments
`for vitrectomy and membrane peeling [37]. Highly purified
`silicone oil with a viscosity of 5000 mPa · s was manually
`injected either following a fluid-air exchange or using a
`direct fluid-oil exchange. Chorioretinal adhesion around
`preexisting or iatrogenic retinal breaks was induced by en(cid:173)
`dophotocoagulation or endocryocoagulation.
`In all, 33% of all patients in our series were aphakic
`or pseudophakic at the time of vitrectomy, and 26% re(cid:173)
`quired a lensectomy during the surgical procedure; 41 %
`remained phakic. All aphakic or pseudophakic eyes under(cid:173)
`went an inferior peripheral iridectomy. Postoperatively, all
`patients received topical steroids and antibiotics. Phakic
`and pseudophakic eyes were treated with dilating agents,
`whereas the pupil in aphakic eyes was kept narrow with
`miotic agents to prevent the silicone oil from entering the
`anterior chamber. Rarely, in patients with severe postopera(cid:173)
`tive inflammatory response, oral steroids had to be added
`to the treatment schedule.
`
`Results
`
`For analysis, complications occurring during vitrectomy
`with silicone oil injection and during follow-up in 415 con(cid:173)
`secutively treated eyes were divided into two groups: (1)
`complications not directly related to the physicochemical
`properties of silicone oil, such as entry of the oil into the
`anterior chamber in phakic or pseudophakic eyes and the
`development of large retinal tears, leading to subretinal sili(cid:173)
`cone oil injection; and (2) complications possibly related
`to silicone oil as a chemical substance, such as keratopathy,
`silicone oil emulsification, glaucoma, cataract formation in
`phakic eyes, and reproliferation of fibrovascular mem(cid:173)
`branes with retinal detachment.
`Silicone oil in the anterior chamber, which had migrated
`around the crystalline or implanted lens, was seen in 26
`of 209 phakic or pseudophakic eyes ( 6%; Fig. 1 ). The high(cid:173)
`est incidence of this complication was seen in eyes with
`PVR due to ocular trauma (21 %), followed by eyes with
`PDR (13%) and those with PVR due to rhegmatogenous
`retinal detachment (10%). Silicone oil entering the subreti(cid:173)
`nal space through large preexisting or iatrogenic tears was
`found in 4% of all eyes treated (17 of 415). Again, eyes
`
`Fig. l. Slit-lamp photograph, showing a silicone oil bubble in a
`phakic eye after vitreoretinal surgery with silicone oil injection
`
`Fig. 2. Band-shaped keratopathy in an aphakic eye, demonstrating
`corneal silicone oil contact. Vitreoretinal surgery was carried out
`for PVR following severe ocular trauma due to a foreign body
`
`with PVR due to ocular trauma (8%) showed the highest
`incidence, followed by eyes with PVR due to rhegmatogen(cid:173)
`ous detachment (5%) and those with PDR (2%).
`Keratopathy following vitrectomy with silicone oil injec(cid:173)
`tion appeared in 5.5% of all eyes treated (23 of 415). In(cid:173)
`cluded were eyes with chronic or chronically recurrent cor(cid:173)
`neal edema, with and without bullous keratopathy, and
`those with band-shaped keratopathy (Fig. 2). In eyes with
`PVR due to ocular trauma, the incidence was 12%; in those
`with PVR due to rhegmatogenous retinal detachment it
`was 6%, and in eyes with PDR, 3%. Postoperatively, 77%
`of those eyes developing keratopathy were aphakic, 15%
`were pseudophakic, and 8% contained a crystalline lens.
`Clinically significant silicone oil emulsification that was
`visible by biomicroscopy occurred in 3 of 415 eyes, repre(cid:173)
`senting 0.7% of all eyes treated. However, when silicone
`oil was surgically removed from the anterior chamber of
`phakic or pseudophakic eyes, some small oil bubbles usual(cid:173)
`ly remained within the anterior chamber and could be visu(cid:173)
`alized by gonioscopy; these oil bubbles were not included
`with the emulsification cases.
`Increases in intraocular pressure (IOP) up to 30 mmHg
`within 10 days following surgery occurred in 21 % of the
`eyes (89 of 415), whereas a rise to levels above 30 mmHg
`was observed in 13% (53 of 415) during this period. This
`complication was most frequently seen in patients with PVR
`due to ocular trauma where IOP did not exceed 30 mmHg
`in 25% and was above 30 mmHg in 15% of cases. During
`the long-term follow-up, 6% of all eyes treated (26 of 415)
`developed secondary glaucoma, 59% of these being
`aphakic. The highest incidence of this complication oc(cid:173)
`curred in eyes with PVR following ocular trauma (10%).
`followed by those with PDR (8%) and those with PVR
`due to rhegmatogenous retinal detachment (4%). In the
`majority of all eyes with elevated IOP, either no treatment
`(lOP up to 30 mmHg) or short-term antiglaucoma treat(cid:173)
`ment (IOP, > 30 mmHg) using miotics, beta blocker and/or
`carbonic anhydrase inhibitors was required in addition to
`the steroid application. Surgical procedures for secondary
`glaucoma were carried out in 26 eyes. A total of 14 eyes
`received cyclocryocoagulation. In 12 eyes with elevated
`IOP, the silicone oil had to be partially removed. Addition(cid:173)
`ally, in 26 aphakic or pseudophakic eyes, the inferior peri(cid:173)
`phal iridectomy had to be reopened either surgically
`
`Novartis Exhibit 2320.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`21
`
`rhegmatogeneous retinal detachment surgery and in 31 %
`of those with PDR.
`
`Discussion
`
`In the past few years, the use of intravitreal injections of
`silicone oil has been successful in certain complicated retinal
`detachments with PVR and PDR that were previously con(cid:173)
`sidered to be unsalvageable [5, 14, 16, 18, 20, 24, 29, 32,
`37]. In the United States, however, the use of intraocular
`silicone oil is still restricted by regulations of the Food and
`Drug Administration [13] to the surgical centers that make
`up The Silicone Study Group [34].
`Our cohort of patients was substantially homogeneous
`insofar as (1) 415 patients received intravitreal silicone oil
`within the 2-year period of this study, (2) surgery was car(cid:173)
`ried out during this period by five surgeons using the same
`surgical principles and equipment, and (3) the oil injected
`was in all cases highly purified silicone oil with a viscosity
`of 5000 mPa · s. In other studies published heretofore, the
`data were based on smaller numbers of treated eyes or were
`collected from patients undergoing surgery up to 1984 (9,
`15, 16, 18, 22, 24, 31, 32, 38]. Since that time, several im(cid:173)
`provements in both the surgical equipment and the surgical
`techniques have taken place. Furthermore, some authors
`have drawn their conclusions from patients with aphakia
`or pseudophakia who underwent inferior peripheral iridec(cid:173)
`tomy as described by Ando [1], whereas in other studies,
`patients had intravitreal silicone oil injection before the ad(cid:173)
`vent of this technique (9, 21, 24, 25, 31, 32]. In other series,
`silicone oil with different physicochemical properties (e.g.,
`viscosity of 1000, 5000 or 12500 mPa·s) was used, leading
`to an inhomogeneous group of cases (8, 24, 25].
`As previously reported by other authors [ 11, 25, 36],
`the entry of silicone oil into the anterior chamber in phakic
`or pseudophakic eyes is a rare complication. In our series,
`it occurred in 6% of all phakic or pseudophakic eyes and
`in 21 % of eyes developing PVR due to ocular trauma. We
`anticipate that partial zonulysis following either ocular
`trauma or extracapsular cataract extraction enabled the oil
`to migrate around the crystalline or implanted lens, thus
`reaching the anterior chamber. In other cases, partial zonu(cid:173)
`lysis may be caused by high infusion pressure during sili(cid:173)
`cone oil injection and endodrainage. Silicone oil was seen
`less frequently in the anterior chamber ofphakic or pseudo(cid:173)
`phakic eyes when a complete fluid-air exchange was done
`prior to the silicone oil injection. Although small oil bubbles
`may remain in the anterior chamber without causing serious
`problems, larger amounts of silicone oil can easily be re(cid:173)
`moved by injecting sodium hyaluronate through a limbal
`paracentesis and evacuating the oil through a second para(cid:173)
`centesis at the opposite site. Postoperatively, some patients
`required topical miotics to prevent the oil from reentering
`the anterior chamber. Silicone oil was seen in the subretinal
`space in 4% of our patients. This complication was most
`frequently seen in eyes that had experienced severe ocular
`trauma (8% ). Because treatment of this complication causes
`serious technical problems, it is often wise to avoid further
`surgery [32].
`Keratopathy, including chronic corneal edema and
`band-shaped keratopathy, was found in 5.5% of our pa(cid:173)
`tients. The incidence of keratopathy, presumably due to
`endothelial cell damage, was 12% in eyes with PVR follow(cid:173)
`ing ocular trauma and as low as 3% in those with PDR.
`
`Fig. 3. a Silicone oil lilling the anterior chamber of an aphakic
`eye due to secondary obstruction of the inferior iridectomy. b At
`1 h following reopening of the inferior iridectomy by Y AG laser,
`the silicone oil was entirely within the vitreous cavity, indicated
`by the light reflex (arrow) on the anterior oil surface within the
`pupil
`
`(13 eyes) or by Nd:YAG laser treatment (13 eyes) to pre(cid:173)
`vent these eyes from developing closed-angle glaucoma.
`These procedures became necessary because the iridectomy
`was secondarily closed by fibrin due either to an inflamma(cid:173)
`tory reaction within the anterior segment or to fibrous re~
`-proliferation behind the iris (Fig. 3).
`Cataract formation following intraocular silicone oil in(cid:173)
`jection was a constant finding in all phakic eyes, usually
`becoming evident within 6--12 months following surgery.
`However, the amount and the progression of opacities with(cid:173)
`in the crystalline lens varied, as some eyes exclusively pre(cid:173)
`sented minor vesicular posterior subcapsular opacities and
`others developed a dense cataract that prevented visualiza(cid:173)
`tion of the fundus. During the follow-up period, in 18%
`of all eyes operated on subsequent cataract extraction was
`performed.
`During the follow-up period, significant reproliferation
`of fibrovascular tissue, leading to partial retinal redetach(cid:173)
`ment and thus requiring a second surgical procedure, was
`found in 63 of 415 eyes treated (15%). A total of 102 addi(cid:173)
`tional eyes (25%) with massive reproliferation were consid(cid:173)
`ered inoperable, and no further surgical procedure was per(cid:173)
`formed. Combining both groups, reproliferation occurred
`in a total of 165 eyes, that is, in 40% of all eyes treated.
`Reproliferation occurred in 60% of all eyes with PVR due
`to ocular trauma, in 39% of those with PVR following
`
`Novartis Exhibit 2320.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`22
`
`In addition to the presumed toxic effect of silicone oil, in
`aphakic eyes endothelial cell damage caused during vitrec(cid:173)
`tomy by surgical procedures such as fluid irrigation, the
`use of epinephrine, air or gas insufflation and IOP rise
`must be considered in the pathogenesis of keratopathy. Ac(cid:173)
`cording to the results published by other authors, kerato(cid:173)
`pathy was found in 12%-63% of patients with a follow-up
`period comparable to ours, and turned out to be one of
`the most frequent causes for loss of vision following silicone
`oil injection during the early period of surgery [9, 11, 15,
`21, 25, 31, 38]. In most patients with corneal decompensa(cid:173)
`tion, there was a corneal silicone contact that was believed
`to cause this severe complication [9, 11, 21, 25, 31]. These
`authors expected that the incidence of corneal decompensa(cid:173)
`tion would be lower if an inferior peripheral iridectomy
`were routinely carried out in all aphakic and pseudophakic
`eyes [1, 2]. In our series, all aphakic and pseudophakic
`patients underwent an iridectomy at the 6 o'clock position.
`As recommended by Ando [1], the regular performance of
`an inferior iridectomy reduces the possibility of a pupillary
`block by the silicone oil bubble. However, we believe that
`not only did the regular performance of an inferior iridec(cid:173)
`tomy lead to a substantially lower incidence of keratopathy
`in our series, but the use of high-purity and high-viscosity
`(5000 mPa · s) silicone oil had an additional, important im(cid:173)
`pact on our results [11, 12, 16]. The chemical purity of
`the silicone oil used by our group since 1980 was determined
`by gel chromatography; the oil contains fewer low-molecu(cid:173)
`lar-weight components ( < 0.4%) and no appreciable cata(cid:173)
`lytic remnants. Both the high viscosity and the chemical
`purity presumably resulted in low incidences of silicone oil
`emulsification (0.7%) and secondary glaucoma (6%) as
`compared with other studies [8, 9, 11, 21, 25].
`In all, 34% of the patients who underwent intravitreal
`silicone oil injection at our institution showed a usually
`transient postoperative IOP rise. Our data are consistent
`with the results of other authors reporting that following
`cataract formation, a postoperative IOP rise occurs in
`2%-40% of all patients and is therefore the second most
`common complication of vitrectomy with intravitreal sili(cid:173)
`cone oil injection [8, 11, 36]. Despite the mechanical effects
`of excessive silicone oil, which were seen in 12 patients in
`our series (2.9%) and required partial oil removal, factors
`such as inflammation, hemolysis, rubeosis iridis, and pupil(cid:173)
`lary block may be responsible for the IOP rise. In
`26 aphakic or pseudophakic eyes with relative pupillary
`blocks reopening of the inferior peripheral iridectomy was
`sufficient to solve this complication. In 14 of 26 patients
`with long-lasting secondary glaucoma, the IOP increase
`could not be managed by topical or oral antiglaucoma
`agents, and these patients had to undergo cyclocryocoagu(cid:173)
`lation. With respect to the otherwise desperate situation
`of all eyes treated, secondary glaucoma and keratopathy
`were severe complications; however, the latter did not cause
`treatment failure in a substantial number of our patients.
`Lens opacification is a common finding in phakic eyes,
`generally occurring within 6-12 months following vitrec(cid:173)
`tomy with silicone oil injection [5, 9, 11, 15, 25, 29, 35,
`38]. In a series of 32 patients with phakic eyes described
`by Casswell and Gregor [5], all patients developed lens opa(cid:173)
`cities if the oil was present for longer than 10 weeks. Only
`in some eyes with early oil removal were lens opacities
`found to decrease [17]. Our findings agree with previously
`published data indicating that cataract formation is the
`
`most frequent complication in eyes containing intravitreal
`silicone oil [5, 11, 14].
`As reported by other authors, a prominent cause of
`late visual failure following vitrectomy and silicone oil injec(cid:173)
`tion is reproliferation of pre- and subretinal membranes.
`leading to recurrent retinal detachment [ 6, 9, 11, 22, 24.
`35]. At present, there is a controversy as to whether reproli(cid:173)
`feration of preretinal membranes occurs independently of
`the presence of intraocular silicone oil or is caused or trig(cid:173)
`gered by intravitreal silicone oil [3, 10, 19, 22, 28, 35]. Simi(cid:173)
`lar to the variation in the incidence of complications such
`as keratopathy and corneal edema due to the use of silicone
`oil of different degrees of viscosity and purity, the reproli(cid:173)
`feration rate in the presence of intravitreal silicone oil may
`be dependent on the physicochemical characteristics of the
`silicone oil injected. At present, however, our understanding
`of the pathogenesis of preretinal membrane proliferation
`is still inconclusive.
`Increased knowledge regarding membrane proliferation
`and further improvements in the chemical and physical
`characteristics of silicone oil will result in an optimization
`of the efficacy of intraocular silicone oil application. We
`therefore agree with other authors [9, 11, 22, 27, 31] that
`intravitreal silicone oil should currently be exclusively re(cid:173)
`served for (1) eyes with advanced stages of PDR and (2)
`eyes with otherwise intractable PVR following conventional
`surgical techniques, such as scleral buckling, vitrectomy,
`membrane peeling, endolasercoagulation, fluid-gas ex(cid:173)
`change, and postoperative laser photocoagulation.
`
`References
`
`1. Ando F (1985) lntraocular hypertension resulting from pupilla(cid:173)
`ry block by silicone oil. Am J Ophthalmol 99: 87-88
`2. Beekhuis W-H, Ando F, Zivojnovic R, Mertens OAE, Peper(cid:173)
`kamp E (1987) Basal iridectomy at 6 o"clock in the aphakic
`eye treated with silicone oil: prevention of keratopathy and
`secondary glaucoma. Br J Ophthalmol 71 : 197-200
`3. Bornfeld N, El-Hifnawi E, Laqua H (1987) Ultrastructural
`characteristics of preretinal membranes from human eyes filled
`with silicone oil. Am J Ophthalmol 103:770--775
`4. Bourgeois JE, Machemer R (1983) The results of sulfur hexaf(cid:173)
`luoride gas in vitreous surgery. Am J Ophthalmol 96:405-406
`5. Casswell AG. Gregor ZJ (1987) Silicone oil removal: I. The
`effoct on the complications of silicone oil. Br J Ophthalmol
`71:893-897
`6. Chan C, Okun E (1986) The question of ocular tolerance to
`intravitreal liquid silicone. Ophthalmology 93: 651-660
`7. Cibis PA, Becker B, Okun E (1962) The use of liquid silicone
`in retinal detachment surgery. Arch Ophthalmol 68: 590--599
`8. De Corral LR, Cohen SB, Peyman GA (1987) Effect of intravi(cid:173)
`treal silicone oil on intraocular pressure. Ophthalmic Surg
`18:446-449
`9. Dimopoulos S, Heimann K (1986) Spatkomplikationen nach
`Silikoni:ilinjektion. Langzeitbeobachtungen an 100 Fallen. Klin
`Mona ts bl Augenheilkd 189: 223-227
`10. Failer J, Faulborn J, Erb P (1984) Die Phagozytose von Silikon(cid:173)
`Olen unterschiedlicher Viskositat <lurch Peritoneal-Makropha(cid:173)
`gen der Maus. Klin Monatsbl Augenheilkd 184:450--452
`11. Federman JL, Schubert HD (1988) Complications associated
`with the use of silicone oil in 150 eyes after retina-vitreous sur(cid:173)
`gery. Ophthalmology 95: 871-876
`12. Gabel V-P, Kampik A, Burkhardt J (1987) Analysis of intrao(cid:173)
`culary applied silicone oils of various origins. Graefe's Arch
`Clin Exp Ophthalmol 225: 160--162
`13. Glaser B (1988) Silicone oil for proliferative vitreoretinopathy.
`Does it help or hinder? Arch Ophthalmol 106:323-324
`
`Novartis Exhibit 2320.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`14. Gonvcrs M (1985) Temporary silicone oil tarnponade in the
`management of retinal detachment with proliferative vitrcorc(cid:173)
`tinopathy. Arn J Ophthalrnol 100: 239-245
`15. Heimann K, Dimopoulos S ( 1984) Intra- und postoperative
`Kornplikationcn bci Silikoni:ilinjektion zur Bchandlung kornpli(cid:173)
`zierter Netzhautabli:isungcn. Klin Monatsbl Augcnhcilkd
`185:371-372
`16. Karnpik A, Gabel V-P, Spiegel D (1984) Intraokularc Tarnpo(cid:173)
`nade rnit hochviski:isern Silikoni:il bei rnassiver proliferativer Vi(cid:173)
`treo-Retinopathie. Klin Monatsbl Augenheilk 185: 368-370
`17. Kroll P, Hennckes R, Berg P (1985) Linsentriibungcn nach
`Fortschr
`Ophthalrnol
`intravitrealer
`Silikoninjektion.
`82:235-236
`18. Kroll P, Berg P, Bierrneyer H (1988) Langzeitergebnisse nach
`F ortschr Ophthalrnol
`vitreoretinaler
`Silikoni:ilchirurgie.
`85:259-262
`19. Lambrou FH, Burke JM, Aaberg TM (1987) Effect of silicone
`oil on experimental traction retinal detachment. Arch Ophthal(cid:173)
`mol 105: 1269-1272
`20. Leaver PK, Grey RH, Garner A (1979) Silicone oil injection
`in the treatment of massive prcrctinal retraction: I I. Late com(cid:173)
`plications in 93 eyes. Br J Ophthalrnol 63:361-367
`21. Lemmen K-D, Dimopoulos S, Kirchhof B, Heimann K (1987)
`Keratopathy following pars plana vitrcctorny with silicone oil
`filling. Dev Ophthalmol 13: 88-98
`22. Lewis H, Burke JM, Abrams GW, Aaberg TM (1988) Perisili(cid:173)
`cone proliferation after vitrcctorny for proliferative vitrcorctin(cid:173)
`opathy. Ophthalmology 95: 583-591
`23. Lincoff H, Coleman J, Krcissig I, Richard G, Chang S, Wilcox
`LM ( 1983) The pcrnuorocarbon gases in the treatment of reti(cid:173)
`nal detachment. Ophthalmology 90: 546-551
`24. Lucke Kil, Foerster MH, Laqua 1-1 (1987) Long-term results
`of vitrectorny and silicone oil in 500 cases of complicated retinal
`detachments. Arn J Ophthalrnol 104: 624-633
`25. Lucke K, Foerster M, Laqua 1-1 (1987) Langzeiterfahrungcn
`intraoku\arer Silikoni:il-Fiillung. Fortschr Ophthalrnol
`rnit
`84:96-98
`26. Lund OE (1967) Silikon als Glaski:irpcrersatz. Ber Dtsch Oph(cid:173)
`thalmol Ges 68: 166-169
`
`23
`
`27. McCucn BW, Juan E de, Landers MB (1985) Silicone oil in
`vitreoretinal surgery: 2. Results and complications. Ophthal(cid:173)
`mology 93: 646-650
`28. Refojo M, Leong F-L, Chung 1-1, Ueno N, Nemiroff B, Tolen(cid:173)
`tino F (1988) Extraction of retinal and cholesterin by intraocu(cid:173)
`lar silicone oils. Ophthalmology 95:614-618
`29. Roussat B, Rue\lan YM (1984) Traitement du dccollement de
`retine par vitrectornie et injection d'huile de silicone. J Fr Oph(cid:173)
`thalmol 7: 11-18
`30. Scott JD (1977) A rationale for the use of liquid silicone. Trans
`Ophthalrnol Soc UK 97: 235-237
`31. Sell Ch, McCuen BW, Landers MB, Machemer R (1987) Long(cid:173)
`term results of successful vitrectorny with silicone oil for ad(cid:173)
`vanced proliferative vitreoretinopathy. Am J Ophthalmol
`103:24-28
`32. Stilma JS, Koster R, Zivojnovic R (1986) Radical vitrectomy
`and silicone oil injection in the treatment of proliferative vi(cid:173)
`treoretinopathy following retinal detachment. Doc Ophthalrnol
`64:109-116
`33. The Retina Society Terminology Cornrnitee (1983) The classifi(cid:173)
`cation of retinal detachment with proliferative vitrcoretino(cid:173)
`pathy. Ophthalmology 90: 121-125
`34. The Silicone Study Group (1985) Proliferative vitreoretino(cid:173)
`pathy. Arn J Ophthalmol 99: 593-595
`35. Yeo JI-I, Glaser BM, Michels RG (1987) Silicone oil in the
`treatment of complicated retinal detachments. Ophthalmology
`94: 1109-1113
`36. Zborowski-Gutrnan L, Treister G, Naveh N, Chen V, Blumen(cid:173)
`thal M (1987) Acute glaucoma following vitrectomy and sili(cid:173)
`cone oil injection. Br J Ophthalrnol 71: 903-906
`37. Zivojnovic R (1987) Silicone oil in vitrcoretinal surgery. Junk,
`Dordrecht Boston Lancaster
`38. Zivojnovic R, Mertens DAE, Peperkarnp E ( 1982) Das Oiissige
`Silicon in der Arnotiochirurgie: II. Bericht iiber 280 Fiillc -
`weitcre Entwicklung dcr Tcchnik. Klin Monatsbl Augcnhcilkd
`181 :444-452
`
`Received November 21, 1988 / Accepted July 21, 1989
`
`Novartis Exhibit 2320.005
`Regeneron v. Novartis, IPR2021-00816
`
`