The Effect of Silicone Ocular Surgical Deviceson Serum IgG Binding to Silicones

SAAD SHAIKH, MD, LAWRENCE S. MORSE, MD, PHD, RANDALL M. GOLDBLUM, MD,JEFFREY D. BENNER, MD, HAL BURNETT, MD, AND JEFFREY CASPAR, MD

● PURPOSE: To determine whether silicone mate-rials used in retinal detachment repair and cataractsurgery increase serum IgG binding to silicone andidentify correlations with complications of ocularsurgery.● METHODS: Serum from 49 patients who hadocular surgery using silicone materials was exam-ined. Patient groups included scleral buckling (n 525), silicone oil tamponade (n 5 3), scleral buck-ling and silicone oil tamponade (n 5 9), andsilicone lens implants after cataract extraction(n 5 12). Convalescent samples for all patientsand preoperative samples from 19 patients (18scleral buckling and one silicone oil tamponade)were examined. Postoperative complications weremonitored for up to 108 months (mean, 10.7months; mode, 1.5 months; range, 1 to 108months). Samples were evaluated for the extent ofIgG binding to silicones using a micromodificationof a previously described enzyme-linked immu-nosorbent assay method.● RESULTS: In 19 patients, IgG binding levels inpreoperative samples were 21 arbitrary units (AU)or less. Of the 25 buckling patients, one developedcomplications; however, in all patients the postop-erative levels of IgG binding to silicone were low(2.2 to 20.0 AU). Although four silicone lenspatients developed mild complications, none dis-played postoperative IgG binding levels of greaterthan 20 AU. Three patients who underwent both

scleral buckling and silicone oil tamponade devel-oped complications; one of these patients, who wasalso noted to have systemic connective tissuedisease, had a significant elevation in postoperativeserum IgG binding to silicone.● CONCLUSIONS: Statistically significant eleva-tions of serum IgG binding to silicone were notedpostoperatively in only one patient who had asystemic connective tissue disease. The complica-tion rate and frequency of enhanced serum IgGbinding to silicone was low, making correlationsto surgical complications difficult. Examination ofmatched samples suggested that if ocular exposureto silicone implants enhances the level of serumIgG binding to silicones, it must be a rare eventthat should not alter the clinical use of theseimportant devices. (Am J Ophthalmol 1998;126:798–804. © 1998 by Elsevier Science Inc. Allrights reserved.)

E VEN BEFORE THEIR INTRODUCTION FOR AUG-

mentation mammoplasty in 1963,1 silicone im-plants were already being used in ocular surgery

in the form of intraocular silicone oils for the repairof difficult retinal detachments2 and later as elas-tomers in scleral buckles for retinal detachmentrepairs.3 More recently, silicone elastomers havealso been used in ocular surgery as nasolacrimal ductstents, glaucoma valve devices, and as intraocularlens implants.

Silicones have been widely used in medical im-plants and prostheses, because of their ideal physicaland chemical properties and the general perceptionthat they are biologically inert. As with experimen-tal implantation of other forms of silicones, scleralbuckles used in retinal detachment surgery have

Accepted for publication June 15, 1998.From the Department of Ophthalmology (Drs Shaikh, Morse, Ben-

ner, Burnett, and Caspar), University of California, Davis, California,and Children’s Hospital (Dr Goldblum), Galveston, Texas.

Correspondence to Lawrence S. Morse, MD, PhD, UC Davis De-partment of Ophthalmology, 4860 Y St, Ste 2400, Sacramento, CA,95817; fax: (916) 734-6992; e-mail: lsmorse@ucdavis.edu

© 1998 BY ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED.798 0002-9394/98/$19.00PII S0002-9394(98)00282-7

been shown to induce a foreign body responseconsisting of formation of a fibrous capsule and alocal inflammatory reaction in rabbits.4 Some formsof silicone gels have also been shown to act asimmunologic adjuvants in animal models,5 andsome investigators have observed an increased fre-quency of antinuclear antibodies in breast implantpatients.6,7

A recent study suggests that some individuals maymount a specific antipolymer immune response afterexposure to silicone from silicone breast implantsand that the response may correlate with the sever-ity of immunologic symptoms.8 More specific immu-nologic interactions with silicones have beendifficult to characterize. Several published reportsindicate that the serum from some patients withsilicone implants exhibits enhanced binding of IgGto various silicone-containing test materials9,10; thistype of reaction appears to be quite rare. Althoughthe nature of this enhanced binding of serum IgG tosilicone has not been fully elucidated and remainscontroversial, in some implanted patients it mayserve as a marker for the propensity to developintense local inflammatory reactions to siliconematerials, as in the case of ventriculoperitonealshunts.11,12

In light of these reports, the effects of ocularsilicone materials on the level of serum IgG bindingto silicones were examined and any correlationsbetween these levels and postoperative adverse localreactions in patients who underwent retinal detach-ment repair with silicone scleral buckles or siliconeoil and in patients who underwent cataract surgerywith silicone intraocular lens were evaluated.

SUBJECTS AND METHODS

THIS STUDY WAS APPROVED BY THE HUMAN SUBJECTS

Committee of the University of California, Davis;all subjects gave informed consent. Clinical subjectsincluded patients from the UCDMC vitreoretinalclinic and private ophthalmology offices who hadbeen exposed to silicone in the form of siliconescleral buckles for rhegmatogenous retinal detach-ment or silicone oil used for retinal tamponade invitreoproliferative retinal detachment.

Twenty-five patients underwent only extraocular

surgery for retinal detachment repair using encir-cling silicone scleral buckles. Postoperative bloodsamples were obtained on all these patients. Inaddition, preoperative blood samples were obtainedon 18 of these patients. Fifteen patients underwentintraocular surgery for retinal detachment usingsilicone oil tamponade or cataract extraction withimplantation of a silicone intraocular lens. Onlypostoperative blood samples were drawn in these 15patients, except for one who also underwent sili-cone oil tamponade for a retinal detachment, inwhom a preoperative serum sample was also ob-tained. Postexposure serum samples were also ob-tained from nine patients who underwent combinedintraocular and extraocular surgery (silicone oiltamponade and scleral buckling for retinal detach-ment).

All postexposure samples were obtained at least 4weeks after surgery (range, 1 to 108 months; mode,1.5 months). Exclusion criteria for all patientsincluded previous exposure to silicone materials(from ocular or other surgery), or a history of uveitisor of rheumatoid or connective tissue disease.

Serum samples were stored frozen in polypro-pylene tubes before assay. Serum IgG binding tosilicone elastomer was assayed using a microplatemodification of a previously described enzyme-linked immunosorbent assay.9 In this assay, longitu-dinally split 1-cm–long fragments of silicone tubing(0.095-mm; Dow Corning, Midland, Michigan)placed in the wells of a round-bottomed polystyrenemicrotiter plate were used as the solid phase. Serialdilutions of the sera in 0.05-M phosphate bufferedsaline (pH 7.4) containing 0.05% Tween 20 (SigmaChemical Co, St Louis, Missouri) (PBS-T) wereprepared in the wells and incubated for 3 hours at 37C without shaking. After washing the plates withTween-saline using an automated plate washer (Ti-tertek, Costa Mesa, California), rabbit antibody tohuman IgG, conjugated to horseradish peroxidase(Dako, Carpinteria, CA) and diluted 1:1,000 inPBS-T was added to each well and incubated for 2hours.

After a further washing, the amount of enzymeconjugate bound to the tubing section was deter-mined using enzyme substrates; the product wasquantified using an enzyme immunoassay reader(Titertek). On each plate a sample of serum from

SERUM IGG BINDING TO SILICONES USED IN OCULAR SURGERYVOL. 126, NO. 6 799

one of the original ventriculoperitoneal shunt pa-tients (patient 1 of Goldblum and associates9) wasused to develop a standard IgG binding curve. Thevalue for this serum was set at 100 arbitrary units(AU), and the results from the test sera werecalculated from that standard curve. Controls in-cluded a normal serum (negative control) and assaysof each serum sample in microtiter wells that didnot contain a silicone fragment.

RESULTS

THE RESULTS OF THE SERUM IGG BINDING TO SILICONE

for the normal control serum assayed on each platewas consistently less than 5 AU. Using the frag-ment-based assay reported by Goldblum and associ-ates,9 standard binding curves were performed forboth positive and negative control sera. The rela-tionship between the binding curves for differentsera was maintained when the same experiment wasrepeated twice on different days. A high variabilityrate was noted between the optical density values ofreplicate wells on the same plates (average coeffi-cient of variability 5 9% to 21%) for six different

plates. This variability could not be reduced byaltering the incubation or washing conditions or bytransfering the sections to new microtiter platesbefore running the enzymatic reaction.

To establish the normal values for the patientpopulation requiring ocular surgery who had notpreviously been exposed to silicone materials or hada history of autoimmune disease, preoperative serumsamples were examined on 19 patients, including 18who underwent encircling scleral buckle proceduresand one who underwent silicone oil tamponade forretinal detachments.

The range of values was 3 to 58 AU (Figures 1and 2), but only one patient had a level that wasgreater than 21 AU. This patient had preoperativeand postoperative levels of 58 AU and 17 AU,respectively; these values represent averages frominitial (83 AU [preoperative] and 29 AU [postop-erative]) and repeat (33 AU [preoperative] and 5AU [postoperative]) assay results of the same pre-and postoperative serum samples). That these val-ues decreased after surgery suggests that the highoriginal value may have been the result of a tran-sient abnormality in that patient’s serum. Thepatient did not have any complications on follow-

FIGURE 1. Changes in serum IgG binding to silicones after exposure to ocular implants, plotted with regard tolength of exposure to silicone. Results are expressed as a proportion of the same positive run in each assay (AU).

AMERICAN JOURNAL OF OPHTHALMOLOGY800 DECEMBER 1998

up. As a group, there was no significant difference inthe mean values for serum IgG binding to siliconebetween the pre- and postoperative samples, regard-less of whether the patient with the high initialvalues was included (paired t test, preoperativecontrol group 10.14 6 12.95 AU; postoperativegroup 6.86 6 5.12 AU, P 5 .22) or excluded (pairedt test, preoperative control group 7.48 6 5.94 AU;postoperative group 6.29 6 4.62 AU, P 5 .48) fromthe analysis.

The relationships between the serum IgG bindingassay results on the pre- and postoperative samplesand the duration of the postoperative exposure areshown in Figure 1. Notably, the IgG binding valuemore often decreased than increased after exposure.The assays also did not vary much over a range ofexposure to scleral buckle elements for 4 to 16weeks. Figure 2 shows that same pre- and postoper-ative data distributed on the basis of patient age. Nodifferences in silicone binding values were observedbetween patients of various ages.

The Table summarizes the results of IgG bindingassays on the sera from the 25 patients who under-went only scleral buckling procedures for retinaldetachment. Of the seven patients who had postex-

posure samples only, all had serum binding values ofless than 13 AU. One of these patients developed alocal complication, which entailed extrusion of thescleral buckle that had been previously placed 9years ago. Of the 18 patients who had both pre- andpostoperative samples, none developed any localcomplications of his or her scleral buckles. Thehighest postoperative level observed was 20 AU,and the mean for the group was not statisticallydifferent from the mean of the preoperative values(P 5 .23, Student t test).

The Table also presents data for patients whounderwent intraocular surgery in the form of sili-cone oil tamponade for retinal detachments orcataract extraction with placement of silicone in-traocular lens implants, respectively. Of the threepatients who underwent silicone oil tamponade forretinal detachment, none developed postoperativecomplications or displayed elevated levels of serumIgG binding to silicone (all ,5.0 AU). Of the 12patients who underwent cataract extraction andimplantation of silicone intraocular lens implants,the levels of IgG binding to silicone for sera ob-tained after silicone implantation for nine of thepatients were at or below negative control values

FIGURE 2. Changes in serum IgG binding to silicones after exposure to ocular implants, plotted with regard topatient age. Results are expressed as a proportion of the same positive control run in each assay (AU).

SERUM IGG BINDING TO SILICONES USED IN OCULAR SURGERYVOL. 126, NO. 6 801

(,5 AU) and the rest were 20 AU or less. Only twopatients developed posterior capsule opacificationthat required Nd:YAG capsulotomy (postoperativeserum values of 20 AU and ,5 AU). Two otherpatients developed hazy posterior capsules (postop-erative serum values of 10 AU and ,5 AU). Noother complications were observed, including anyevidence of pigmentary deposits on the anteriorsurface of the intraocular lenses.

Nine patients underwent combined extraocularand intraocular surgery in the form of scleral buck-ling procedures and silicone oil tamponade forretinal detachment (Table). All these patients hadonly postexposure samples obtained.

One patient had significantly elevated levels ofserum IgG binding to silicone (70.0 AU, P 5 .0001,Student t test) compared with control values. Thispatient, an 89-year-old woman, had a history ofretinal detachment that was treated with an encir-cling scleral buckle and subsequent silicone oiltamponade. Her scleral buckle later extruded, andshe required another scleral buckle along withfurther silicone oil tamponade. She had also re-quired bilateral silicone stents for obstructed naso-lacrimal ducts that were eventually extruded. Thispatient was subsequently found to have a systemicconnective tissue disease associated with an ele-vated antinuclear antibody serology. Two otherpatients developed complications: one who hadmultiple scleral buckle revisions and eventual ex-trusion along with development of silicone oilkeratopathy and another with scleral buckle extru-

sion. Neither of these patients had serum IgG valuesgreater than 5 AU.

DISCUSSION

IN LIGHT OF RECENT STUDIES SUGGESTING A CORRE-

lation between antibodies to silicone and postoper-ative complications8–10 we sought to identifycorrelations between serum IgG binding to siliconesand local postoperative complications in patientswho had undergone silicone oil tamponade orscleral buckling procedures for retinal detachmentsas well as in patients who underwent cataractextraction with the placement of silicone intraocu-lar lens implants. No correlation was found betweenlevels of serum IgG binding to silicones and thepostoperative course in any group of patients. Inpatients who had both pre- and postexposure serumIgG binding levels determined, the activity ap-peared to increase slightly in only two, neither ofwhom had any postoperative complications. Thelevels in the other patients were either low and didnot change or actually decreased after exposure.

Of the 49 patients in this study, only one hadstatistically significant elevations in serum IgGbinding to silicones. However, that patient devel-oped postoperative complications that included ex-trusion of bilateral silicone nasolacrimal duct stentsafter a previous history of multiple scleral bucklerevisions and silicone oil tamponade procedures.The patient’s elevated IgG levels and complicated

TABLE. Summary of Clinical and Laboratory Data: Postexposure Serum Titers Only

Patient Groups n

No.

Female

Mean

Age

Exposure Duration (mos)

Serum IgG Binding to

Silicone

(1control 5 100 units)Postoperative

ComplicationsMean Mode Range Mean Mode Range

Extraocular exoplants (scleral buckles) 25 7 55 9.0 1.5 1–108 6.1 ,5 ,5–20 1

Intraocular silicone implants (cataract

extraction with silicone intraocular lens)

12 6 72 4.5 4.5 1–13 7.6 ,5 ,5–20 4

Intraocular silicone implants (silicone oil

tamponade for retinal detachment)

3 2 45 6.0 1.5 1.5–10 ,5.0 ,5 ,5 0

Combined intraocular and extraocular

surgery (scleral buckle 1 silicone oil

tamponade)

9 3 56 24.5 10 2–101 14.6 ,5 ,5–70 3

AMERICAN JOURNAL OF OPHTHALMOLOGY802 DECEMBER 1998

postoperative course raise the possibility of immu-nologic sensitization, because the multiple previousprocedures might have sensitized the patient forenhanced production of IgG after repeated expo-sures to silicone in the form of scleral buckles andsilicone oil tamponade as well as Silastic nasolacri-mal duct stents. If such a sensitization processoccurs, it must be an unusual event because otherpatients who had undergone similar repeated pro-cedures did not display enhanced serum IgG bindingto silicone or postoperative complications. An al-ternative explanation may be that the high level ofserum IgG binding to silicones may be similar tothat reported in patients with rheumatoid arthritis(which we retrospectively discovered the patienthad) and other connective tissue diseases.11 Nopreoperative serum from this patient was availableto examine for the effects of her implants on serumIgG binding. None of the other patients in thisstudy had connective tissue disorders.

The data from the silicone intraocular lens pa-tients suggest that the implant does not induceenhanced serum IgG binding to silicones. There wasno significant elevation of serum IgG binding tosilicone obtained from postsilicone exposure inthese patients. It is not possible to say whether thereis any association between serum IgG binding tosilicones and the recently reported complication ofpigmented cellular membranes13 or deposits on sil-icone intraocular lenses, because this complicationwas not observed in any of these patients.

Wolf and colleagues in their study of antibodiesto silicone in breast implant patients raised concernthat patients with diabetes mellitus might displayelevated levels of antibodies because of their dailyexposure to silicone that was used as a lubricatingagent on needles and syringes.10 Our results, whichare similar to the aforementioned study, showed nocorrelation between serum IgG binding to siliconesand a history of diabetes mellitus or with regard toage, procedure type, or length of exposure to sili-cone (Figures 1 and 2).

The ability of this study to recognize small differ-ences in IgG binding to silicone after exposure tosilicone ocular implants and to establish correla-tions between local complications and serum IgGbinding may have been limited by a number offactors. Preoperative samples were only available on

a subgroup of patients who had scleral bucklesimplanted. In addition, the small number of post-operative complications in all groups except inthose who received multiple implants reduced thelikelihood of demonstrating an association betweenserum IgG binding values and local reactions to thesilicone implants. The ability of the enzyme-linkedimmunosorbent assay method used in this study todiscriminate small differences in IgG binding mayalso be a limiting factor.

A recent study by Rose and associates11 evaluatedthe assays described by Wolf and colleagues10 andGoldblum and co-workers,9 the latter being similarto those used in the current study. It was concludedthat both assays produced the expected results onthe samples provided and an increased frequency ofelevated binding results on sera from patients withsilicone implants. However, the researchers alsonoted that most patients with connective tissuediseases had enhanced IgG binding to siliconedisks.11 This suggests that factors other than siliconeexposure may alter the level of serum IgG binding tosilicone elastomers, especially in older patients, whohave a higher level of autoantibodies. Such factorsmay make it difficult to recognize small changes inserum binding levels or correlations between symp-toms of local inflammation at the implant site andIgG binding results, if they do occur. Both Rose andassociates11 and van Oss and Naim12 raise concernsabout “nonspecific” binding of IgG to silicone,although the latter only present data on two sera,one of which was from a patient with multiplemyeloma that had an extremely high IgG concen-tration. Clearly, further optimization of assays andtesting will be necessary to prove or disprove thatenhanced binding of serum IgG to silicone andpostoperative complications in this study are causedby specific antibodies.

Despite the limitations of this study, it is the firstknown attempt to document changes in serum IgGbinding to silicones by comparing pre- and postex-posure sera. Statistically significant elevations ofserum IgG binding to silicone were noted postoper-atively in only one patient, who had a systemicconnective tissue disease. The complication rateand frequency of enhanced serum IgG binding tosilicone was low, making correlations to surgicalcomplications difficult. Furthermore, analysis of this

SERUM IGG BINDING TO SILICONES USED IN OCULAR SURGERYVOL. 126, NO. 6 803

group of patients over extended periods of time afterocular silicone implantation suggests that if serumIgG binding to silicone is ever significantly in-creased by this type of exposure, it must be a rareevent that should not alter the clinical use of theseimportant devices.

REFERENCES

1. Cronin TD, Gerow FJ. Augmentation mammoplasty: Anew “natural feel” prosthesis. Transactions of the ThirdInternational Congress of Plastic Surgery. Excerpta MedicaInternational Congress Series, 1964;66:41–49.

2. Cibis PA, Becker B, Okun E, Canaan S. The use of liquidsilicone in retinal detachment surgery. Arch Ophthalmol1962;68:590–599.

3. Lincoff HA, Barar I, McLean J. Modification to theCustodis procedure for retinal detachment. Arch Ophthal-mol 1965;73:160–163.

4. D’Hermies F, Korobelnik JF, Savoldelli M, Chauvaud D,Pouliquen Y. Miragel versus silastic used as episcleralimplants in rabbits: an experimental and histopathologiccomparative study. Retina 1995;15:62–67.

5. Hill SL, Landavere MG, Rose NR. The adjuvant effect of

silicone gel and silicone elastomer particles in rats. CurrTop Microbiol Immunol 1996;210:123–137.

6. Lewy RI, Ezrailson E. Laboratory studies in breast implantpatients: ANA positivity, gammaglobulin levels, and otherautoantibodies. Curr Top Microbiol Immunol 1996;210:337–353.

7. Press RI, Peebles CL, Kumagai Y, Ochs RL, Tan EM.Antinuclear autoantibodies in women with silicone breastimplants. Lancet 1992;340:1304–1307.

8. Tenenbaum SA, Rice JC, Espinoza LR, Cuellar ML, Ply-male DR. Use of antipolymer antibody assay in recipients ofsilicone breast implants. Lancet 1997;349:449–454.

9. Goldblum RM, Pelley RP, O’Donell AA, Pyron D, HeggersJP. Antibodies to silicone elastomers and reactions toventriculoperitoneal shunts. Lancet. 1992;340:510–513.

10. Wolf LE, Lappe M, Peterson RD, Ezrailson EG. Humanimmune response to polydimethylsiloxane (silicone):screening studies in a breast implant population. FASEB J1993;7:1265–1268.

11. Rose NR, Landavere M, Kuppers RC. Silicone bindingimmunoglobulins in human sera. Curr Top MicrobiolImmunol 1996;210:269–276.

12. van Oss CJ, Naim JO. Aspecific immunoglobulin bindingto hydrophobic surfaces. Curr Top Microbiol Immunol1996;210:85–91.

13. Carlson DW, Barad JP, Parsons MR. Reduced visionsecondary to pigmented cellular membranes on siliconeintraocular lenses. Am J Ophthalmol 1995;120:462–470.

Authors InteractivetWe encourage questions and comments regarding this article via theInternet on Authors Interactivet at http://www.ajo.com/ Questions, com-ments, and author responses are posted.

AMERICAN JOURNAL OF OPHTHALMOLOGY804 DECEMBER 1998