Intravitreal Injection of Triamcinolone Acetonide 9

9.1Introduction

The introduction of pars plana vitrectomyin clinical ophthalmology by RobertMachemer and colleagues was a profound

paradigm change which opened up new av-enues for the treatment of ocular diseases,such as proliferative vitreoretinopathy,which up to that time had been incurable[79]. It was again Robert Machemer whotogether with Yasuo Tano, Gholam Peyman,Stephan Ryan and other researchers fur-

Intravitreal Injection of Triamcinolone AcetonideJost B. Jonas1

9

∑ Intravitreal triamcinolone acetonide may offer a possible adjunctive treatmentfor intraocular edematous and neovas-cular disorders

∑ The best response after intravitreal triam-cinolone acetonide injection in terms ofgain in visual acuity was obtained for eyeswith intraretinal edematous diseases such as diffuse diabetic macular edema,branch retinal vein occlusion, centralretinal vein occlusion, and pseudophakiccystoid macular edema

∑ Visual acuity increased and degree of intraocular inflammation decreased ineyes with various types of non-infectiousuveitis including sympathetic ophthalmia

∑ Intravitreal triamcinolone may be useful as angiostatic therapy in eyes with irisneovascularization and proliferative ischaemic retinopathies

∑ Intravitreal triamcinolone may possibly behelpful for exudative age-related maculardegeneration, alone or in combinationwith photodynamic therapy

∑ In eyes with chronic, therapy resistant,ocular hypotony, intravitreal triamcinolonecan induce an increase in intraocular pres-sure and may stabilize the eye

∑ Complications of intravitreal triamcinolonetherapy include secondary ocular hyper-tension in about 40 % of the eyes injected,cataractogenesis, postoperative infectiousand non-infectious endophthalmitis, andpseudo-endophthalmitis

∑ Intravitreal triamcinolone injection can becombined with other intraocular surgeriesincluding cataract surgery

∑ Cataract surgery performed some monthsafter the injection did not show a markedlyelevated rate of complications

∑ If vision increases after the intravitreal triamcinolone injection, the injection may be repeated

∑ The duration of the effect of a single intravitreal injection of about 20 mg triamcinolone acetonide ranges between 2 and 9 months

Core Messages

1 The author has no proprietary interest in this chapter.

09_Holz_Jonas 02.02.2005 13:28 Uhr Seite 143

ther extended the role the vitreous, andparticularly the vitreous cavity, may play inthe treatment of intraocular diseases. Con-sidering the vitreous cavity as a drug reser-voir, Machemer and others started to injecttriamcinolone acetonide intravitreally, sothat intraocular diseases became locallytreatable, like a skin scratch being treatedby ointment. In a first attempt, Peyman,Machemer and colleagues suggested the in-travitreal application of steroids to reducethe proliferation of cells, particularly in pa-tients with aggressive proliferative vitreo-retinopathy and infectious endophthalmi-tis [4, 21, 33, 39, 80, 81, 87, 111, 112, 118, 119].Crystalline triamcinolone acetonide in-stead of soluble steroids was taken, sincesoluble cortisone is washed out of the eyewithin approximately 24 h after a single in-travitreal injection [111, 112].

Intravitreal triamcinolone acetonide hasa considerably longer absorption time than intravitreal soluble cortisone [6, 42,43,45,73,80].The intravitreal application ofdrugs allows extremely high concentra-tions of the drug at its site of acquired ac-tion, and simultaneously decreases oravoids systemic side effects [26]. Based onthe studies by Machemer and others, theintraocular diseases for which intravitrealtriamcinolone acetonide has been appliedso far include disorders associated with anabnormal proliferation of cells and dis-eases associated with intraretinal and sub-retinal edema. Examples are proliferativediabetic retinopathy [54, 64], diabetic mac-ular edema [50, 84, 65, 85], exudative age-related macular degeneration [15, 24, 31, 57,66, 69, 71, 76, 95, 96, 102, 104, 115], presumedocular histoplasmosis syndrome [38], cen-tral retinal vein occlusion [13, 34, 38, 56, 93],branch retinal vein occlusion [17, 72], neo-vascular glaucoma with or without cataractsurgery [51, 55, 61], proliferative vitreo-retinopathy [29, 52, 67], chronic pre-ph-thisical ocular hypotony [53, 106], chronic

uveitis [3, 8, 11, 25, 83, 114, 123], persistentpseudophakic cystoid macular oedema [7,22, 59, 77], perifoveal telangiectasias [1, 82],sympathetic ophthalmia [47], ischaemicophthalmopathy [60], immunologic cornealgraft reaction [44], extensive exudativeretinal detachment [46], radiation inducedmacular oedema [116], and other disorderssuch as cystoid macular oedema due toretinitis pigmentosa [110], endocrine or-bitopathy [101], Vogt-Koyanagi-Haradasyndrome [2] and others [37, 90, 113]. It hasalso been applied in combination with in-traocular surgery to visualize the vitreousand for other purposes [12, 86, 100, 109].

The effect of intravitreal triamcinoloneacetonide may be differentiated into amainly anti-edematous effect and a possi-bly antiangiogenic effect.

9.2Anti-edematous Effect of Intravitreal Triamcinolone Acetonide

9.2.1Diabetic Macular Edema

Recent studies have suggested that intravit-real triamcinolone acetonide may be usefulto increase visual acuity in patients withdiffuse diabetic macular edema [50, 64, 65,84, 85]. The patients of a study groupreceiving intravitreal triamcinolone ace-tonide compared with patients of controlgroups without intravitreal injections oftriamcinolone acetonide showed a signifi-cant increase in visual acuity during thefollow-up. Using a dosage of about 20 mgtriamcinolone acetonide, the increase in vi-sual acuity was most marked for the first3–6 months after the injection, and was ob-servable for a period of about 6–9 months[73]. Using a dosage of 4 mg triamcinoloneacetonide, the duration of a reduction inthe macular thickness as measured by opti-

144 Chapter 9 Intravitreal Injection of Triamcinolone Acetonide


cal coherence tomography was less than6 months [85]. At the end of the follow-up,visual acuity measurements returned to thebaseline values with no significant differ-ence between baseline values and the meas-urements obtained at the end of the follow-up. In a multiple linear regression analysis,improvement in visual acuity after the in-travitreal injection of triamcinolone ace-tonide was significantly correlated with alower degree of macular ischaemia, a lowerpreoperative visual acuity, and a moremarked macular edema. Change in visualacuity after the intravitreal triamcinoloneinjection was statistically independent ofage and gender. It has remained unclear sofar whether and how much triamcinoloneacetonide crystals injected into the vitreousbody may influence the vitreoretinal inter-face. One may suspect that the crystals dueto their weight may lead to a posterior vit-reous detachment if the vitreous was notalready detached prior to the injection. Aposterior vitreous detachment may have asdisadvantage a possibly increased risk ofrhegmatogenous retinal detachment. Sofar, however, there have been no reports inthe literature of a markedly elevated rate ofretinal rhegmatogenous detachments as acomplication in the follow-up of patientswho received an intravitreal injection oftriamcinolone acetonide [32, 70]. The ad-vantage of a posterior vitreous detachmentin patients with diabetic retinopathy maybe a reduction of macular edema as sug-gested by studies on pars plana vitrectomyin patients with diffuse diabetic macularedema, and a decreased risk of retinovit-real proliferations.

9.3Pars Plana Vitrectomy for ProliferateDiabetic Vitreoretinopathy Combined with IntravitrealTriamcinolone Acetonide

Due to the anti-inflammatory and antian-giogenic effects of triamcinolone ace-tonide, the latter has been used in combina-tion with pars plana vitrectomy in patientswith proliferative diabetic retinopathy [18,19, 23, 28, 99, 120]. A pilot case series studyincluding 29 patients suggested that intrav-itreal injection of triamcinolone with mostof the vehicle removed may be well tolerat-ed [54]. A following non-randomized com-parative investigation consisted of a studygroup of 32 eyes undergoing pars planavitrectomy with intravitreal triamcinoloneacetonide, and a control group of 32 eyeswhich was matched with the study groupfor preoperative and intraoperative parameters, and which underwent parsplana vitrectomy for proliferative diabeticretinopathy without intravitreal injectionof triamcinolone acetonide [64]. The studygroup and control group did not vary sig-nificantly in the rate of postoperative reti-nal detachment, re-pars plana vitrectomy,postoperative enucleation and phthisis bul-bi, and in best postoperative visual acuity,visual acuity at the end of the study, andgain in visual acuity. It was concluded thatintravitreal triamcinolone acetonide didnot show a higher than usual rate of post-operative complications, and that, as acorollary, the adjunct use of intravitreal tri-amcinolone acetonide combined with parsplana vitrectomy as treatment of prolifera-tive diabetic retinopathy had not shown amarked therapeutic benefit.

9.3 Pars Plana Vitrectomy for Proliferate Diabetic Vitreoretinopathy 145


9.4Intravitreal Triamcinolone Acetonidefor Treatment of Central Retinal VeinOcclusion

Cystoid macular edema is one of the ma-jor causes of decreased vision in patientswith central retinal vein occlusion.With theexception of retinal laser coagulation ineyes with early iris neovascularization,other therapeutic options have not beenproven effective in increasing visual acuityafter central retinal vein occlusion. Recentstudies on intravitreal triamcinolone ace-tonide have also addressed macular edemadue to central retinal vein occlusion [13,34, 38, 56, 93]. In a prospective comparativenon-randomized clinical interventionalstudy, gain in visual acuity was significant-ly higher in the study group, confirmingother reports on the beneficial effect of in-travitreal triamcinolone acetonide on mac-ular edema and visual acuity in patientswith central retinal vein occlusion. Theresults additionally suggested that the in-crease in visual acuity after the intravitrealinjection of triamcinolone acetonide maynot last permanently in eyes with centralretinal vein occlusion. After a significantincrease in visual acuity in the first3 months after the injection, visual acuityshowed a tendency to decline towards theend of the follow-up. Correspondingly, fi-nal visual acuity and preoperative visualacuity did not vary significantly. Anotherpositive effect of intravitreal triamcinoloneacetonide in eyes with ischaemic centralretinal vein occlusion may be an antiangio-genic effect possibly decreasing the risk ofneovascularization [18, 19, 23, 28, 49, 99].

9.5Branch Retinal Vein Occlusion Treatedby Intravitreal TriamcinoloneAcetonide

Due to its anti-edematous and antiangio-genic effects as shown in experimental in-vestigations and clinical studies, intravitre-al triamcinolone acetonide has also beenused in pilot studies on central retinal veinocclusions [17, 72]. In a recent prospectivecomparative non-randomized clinical in-terventional study with an intravitreal in-jection of 20–25 mg of triamcinolone ace-tonide in the study group, the patients ofthe study group experienced a significantincrease in visual acuity, while the patientsof the control group did not show a signifi-cant change in visual acuity during the fol-low-up [72]. Comparing study group andcontrol group with each other, gain in visu-al acuity was significantly more marked inthe study group for the measurements ob-tained 1 and 2 months after baseline. It con-firmed another study in which intravitrealtriamcinolone acetonide reduced macularedema in eyes with branch central retinalvein occlusion [17].

9.6Intravitreal Triamcinolone Acetonidefor Pseudophakic Cystoid MacularEdema

Severe postoperative cystoid macular oede-ma can be a complication of phakoemulsi-fication with implantation of an intraocu-lar lens. It has usually been treated bytopical, peribulbar, and systemic applica-tion of steroids or non-steroidal anti-in-flammatory agents. Recently, intravitrealtriamcinolone acetonide has been used fortreatment of persisting pseudophakic cys-toid macular oedema [7, 22, 59]. Patients



who developed cystoid macular edema af-ter cataract surgery and who received anintravitreal injection of triamcinolone ace-tonide showed an increase in visual acuityfrom 0.26±0.13 to a mean best visual acuityof 0.60±0.19 [59]. There was no clear ten-dency suggesting a decrease in visual acu-ity towards the end of the follow-up period.The increase in visual acuity was statistical-ly independent of the time interval betweencataract surgery and the intravitreal injec-tion of triamcinolone acetonide.

9.7Intravitreal Triamcinolone Acetonidefor Cystoid Macular Edema AfterPenetrating Keratoplasty

Long-standing cystoid macular edema can occur rarely after penetrating kerato-plasty. A recent report suggests that intrav-itreal triamcinolone acetonide may be anadditional tool in the treatment of this con-dition [49]. An additional advantage of in-traocular steroids in the treatment of cys-toid macular edema after penetratingkeratoplasty may be the suppression of animmunologic graft reaction as describedrecently [44, 105].

9.8Intravitreal Triamcinolone Acetonideand Central Serous Chorioretinopathy

In a previous report on a patient who had long-standing central serous chori-oretinopathy recurring continuously for6 years, an intravitreal injection of triamci-nolone acetonide did not result in a resolu-tion of the subfoveal accumulation of fluid,suggesting that for this type of macular dis-order, intravitreal injection of triamci-nolone acetonide may not have a therapeu-tically positive effect (own data). It agrees

with other recent studies on patients withcentral serous chorioretinopathy for whichpreceding steroid therapy has been detect-ed to be a risk factor [35].

9.9Foveal Telangiectasias

For foveal telangiectasias, intravitreal in-jection of triamcinolone acetonide has alsobeen used. In two reports, intravitreal tri-amcinolone acetonide increased visualacuity, while in a third study only one out oftwo patients experienced an increase invisual acuity [1, 82].

9.10Antiangiogenic Effect of IntravitrealTriamcinolone Acetonide

9.10.1Regression of Neovascular Iris Vesselsby Intravitreal TriamcinoloneAcetonide

The possibly antiangiogenic effect of tri-amcinolone acetonide, which has beenpostulated by both experimental investiga-tions and clinical studies on patients re-ceiving triamcinolone acetonide for treat-ment of exudative age-related maculardegeneration, was observed in an investi-gation of 14 eyes with neovascular glauco-ma due to proliferative diabetic retino-pathy or ischaemic central retinal veinocclusion [51, 55, 61]. All patients receivedan intravitreal injection of about 20 mgacetonide as the only procedure (n=4 eyes),or in combination with additional proce-dures such as goniosynchiolysis (n=1) andtransscleral peripheral retinal cryocoagu-lation. Postoperatively, degree of iris neo-vascularization decreased significantly(p=0.02). Considering only the four pa-

9.10 Antiangiogenic Effect of Intravitreal Triamcinolone Acetonide 147


tients for whom the intraocular cortisoneinjection was the only procedure per-formed, mean intraocular pressure de-creased from 26.5 ±12.1 mmHg to 21.75±11.3 mmHg.

9.10.2Cataract Surgery Combined with Intravitreal TriamcinoloneAcetonide in Eyes with Iris Neovascularization

In patients with dense cataract and irisneovascularization due to ischaemic retino-pathies, the lens opacification prevents atranspupillary laser coagulation of the reti-na. An intraocular intervention such ascataract surgery will, however, lead to amarked postoperative inflammation if irisneovascularization is additionally present.In that clinical situation, cataract surgeryhas been combined with an intravitreal in-jection of triamcinolone acetonide [51]. Inthe postoperative period, visual acuity in-creased, and without additional retinal ab-lative treatments, iris neovascularizationmarkedly regressed within the first 5 weeksafter surgery. The study suggested that in-travitreal triamcinolone acetonide may bea useful adjunctive treatment tool in eyeswith iris neovascularization undergoingcataract surgery, and that intravitreal tri-amcinolone acetonide may have an antian-giogenic effect.

9.11Exudative Age-Related MacularDegeneration

Since exudative age-related macular degen-eration is a neovascular and edematousdisease, and since studies have shown thattriamcinolone acetonide may have an an-tiangiogenetic, antiproliferate and anti-

edematous effect, intravitreal triamci-nolone acetonide has increasingly beenused as a treatment option for exudativeage-related macular degeneration [15, 24,31, 57, 66, 69, 71, 76, 95, 96, 102, 104, 115].

In 1995, Penfold and colleagues startedto inject triamcinolone acetonide intravit-really in an effort to treat exudative age-re-lated macular degeneration medically [96].In 1998, Challa and co-workers [15] evaluat-ed safety and efficacy of intravitreal triam-cinolone after a follow-up of 18 months inpatients with exudative age-related macu-lar degeneration considered unsuitable forlaser photocoagulation. In the non-ran-domized clinical pilot study, 30 eyes of 28patients were treated with an intravitrealinjection of triamcinolone (4 mg). Of the20 eyes with initial visual acuity of 0.10 orbetter, vision was stabilized in 11 eyes(55 %), while six eyes (30 %) suffered severevisual loss (six or more lines).Visual acuityimproved in three of ten eyes with an initialvision of 3/60 or worse. The authors con-cluded that a single intravitreal injection of4 mg triamcinolone may be reasonably welltolerated and helpful in the treatment ofexudative age-related macular degenera-tion. In a randomized clinical trial, Danisand colleagues examined the effects of in-travitreal injection of 4 mg triamcinoloneacetonide on the visual and clinical courseof exudative age-related macular degenera-tion in 27 patients who were compared witha non-treated control group [24]. The au-thors found that visual acuity was signifi-cantly (p<0.005) better in the treated groupcompared with control subjects at 3 and6 months follow-up. Increase in intraocularpressure was present in 25 % of treated pa-tients, but was controlled with topical med-ication. Progression of cataract was morefrequently detected in the treated group.The authors concluded that intravitreal tri-amcinolone acetonide may provide an im-provement in visual acuity in exudative



age-related macular degeneration. Theseclinical studies were supported by experi-mental studies on the effect of intravitrealcortisone on experimental subretinal neo-vascularization and other types of intraoc-ular proliferation of blood vessels [14, 18, 19,23, 28, 30, 35, 97–99, 120, 121].Another recentinvestigation including 71 eyes with exuda-tive age-related macular degenerationdemonstrated a significant increase in vi-sual acuity after an intravitreal injection of25 mg of triamcinolone acetonide [66]. Theimprovement in visual acuity was signifi-cant at 1 month (p=0.04) and 2 months(p=0.04) after the injection. About3–5 months after the injection, visual acuityhad decreased so that the visual acuity atthe end of the follow-up did not differ sig-nificantly (p=0.17) from the baseline val-ues. Altogether, 48 (66.2 %) eyes gained invisual acuity during the follow-up [66]. Arecent report on a single patient who re-peatedly received intravitreal injections oftriamcinolone acetonide (about 20–25 mg)demonstrated after each injection a re-in-crease of visual acuity during a period ofseveral months [57]. In another recentprospective comparative non-randomizedclinical interventional study including 115patients receiving an intravitreal injectionof about 20 mg triamcinolone acetonideand a control group of 72 patients withouttreatment, visual acuity increased signifi-cantly (p=0.03) in the study group, and de-creased significantly (p=0.01) in the con-trol group, at 1 month and 3 months afterstudy start [76]. Between the study groupand control group, the differences inchange of visual acuity were significant(p=0.001). In the study group, the numberof patients with an increase in visual acuityof 2 or more Snellen lines was significantly(p=0.001) larger than in the control group.Correspondingly, the number of patientswith a decrease of 2 or more Snellen lineswas significantly (p=0.007) smaller in the

study group. Forty-three (37.4 %) patientsof the study group increased in best visualacuity by 2 or more Snellen lines. The re-sults of these studies are partially in con-trast to a recent study by Gillies and col-leagues, who found no effect of 4 mg ofintravitreal triamcinolone acetonide on thedevelopment of severe visual loss over afollow-up period of 1 year [31]. One of thereasons for the discrepancy between the in-vestigation performed by Gillies and col-leagues and the other studies may be thedifference in the dosage of triamcinoloneacetonide injected. Another reason may bethat in the study by Gillies and colleagues,reinjections were not performed. It wouldfit with the observation that the peak invisual acuity occurred about 2–5 monthsafter an injection of about 20 mg. Interest-ingly, Gillies and co-workers found a statis-tically significant and therapeutically posi-tive effect of intravitreal triamcinolone onthe size of the subfoveal neovascularization3 months after the injection. It is in agree-ment with experimental studies on an an-giostatic effect of intravitreal cortisone onexperimental subretinal neovasculariza-tion and other types of intraocular bloodvessel proliferation as well as with investi-gations on the antiphlogistic effect of in-travitreal triamcinolone acetonide [14, 18,19, 23, 28, 30, 35, 97–99, 120, 121]. An addi-tional reason for the discrepancy betweenthe study by Gillies and colleagues and theother investigations may be that Gillies’ in-vestigation included patients with the clas-sic type of subfoveal neovascularization,which is associated with a worse prognosiscompared to the occult type of subfovealneovascularization.

Another recent investigation looked forfactors influencing visual acuity after anintravitreal injection of triamcinoloneacetonide as treatment of exudative age-re-lated macular degeneration [69]. A postin-jection increase in visual acuity was signif-

9.11 Exudative Age-Related Macular Degeneration 149


icantly (p<0.001) and negatively correlatedwith preoperative visual acuity, and it wassignificantly (p=0.035) larger in eyes withretinal pigment epithelium detachmentthan in eyes with minimally classic sub-foveal neovascularization. Postinjectionchange in visual acuity was statistically in-dependent of age, refractive error, gender,and duration of follow-up. The results sug-gested that for eyes with a preoperativevisual acuity of less than 0.20, intravitrealinjection of triamcinolone acetonide canresult in an increase in visual acuity. Eyeswith a preoperative visual acuity of higherthan 0.20 may lose visual acuity after theinjection. It does, however, not necessarilymean that the loss in visual acuity after theintravitreal injection was due to the intrav-itreal injection itself. It might have beenthat the eyes with loss in visual acuity afterthe injection would have lost more in visu-al acuity if the intravitreal injection hadnot been performed. The type of subfovealneovascularization was another factor in-fluencing gain in visual acuity after the in-travitreal injection. Eyes with a detachmentof the retinal pigment epithelium showed asignificantly higher increase in visual acu-ity than eyes with a minimally classic sub-foveal neovascularization in which visualacuity did not markedly change after theintravitreal injection. It may have clinicalimportance, since photodynamic therapyhas not been shown to increase visual acu-ity in patients with retinal pigment epithe-lium detachment.

In another investigation, the duration ofthe effect of intravitreal triamcinolone ace-tonide on visual acuity in patients with ex-udative age-related macular degenerationwas evaluated (own data). The prospectiveclinical interventional case series study in-cluded 42 patients with exudative age-relat-ed macular degeneration, who had shownan increase in visual acuity by at least 2Snellen lines after an intravitreal injection

of about 20–25 mg triamcinolone ace-tonide. Within the 1st week after the injec-tion, visual acuity started to increase sig-nificantly (p=0.008) to reach a plateau-likemaximum at 1–6 months after the injec-tion.Visual acuity returned to baseline val-ues 8–9 months after the injection. It maysuggest that triamcinolone may be rein-jected about 6–9 months after a primarysuccessful injection.

In a consequent study, the effect of in-travitreal reinjections of triamcinoloneacetonide as treatment for exudative age-related macular degeneration was investi-gated [71]. The study included 13 patientswith progressive exudative age-relatedmacular degeneration with occult, or pre-dominantly occult, subfoveal neovascular-ization. All patients had shown an increaseor stabilization of visual acuity after a firstintravitreal injection of about 20 mg triam-cinolone acetonide. They received a secondintravitreal injection of about 20–25 mg tri-amcinolone acetonide 3.1–18 months afterthe first injection. Visual acuity increasedsignificantly (p=0.005 and p=0.003, respec-tively) after the first and after the secondinjection, respectively. Increase in visualacuity was found for ten (77 %) patients af-ter the first and after the second injection,respectively. The peak of visual acuity, andin a chronologically parallel manner, thepeak in intraocular pressure elevation, oc-curred 2–5 months after each injection. In-terestingly, the peak of the increase in visu-al acuity occurred at about 2–5 monthsafter the injections with no marked differ-ence in the time of the peaks between the first injection and the reinjection.It suggests that a reinjection of triamci-nolone acetonide may be performed about3–5 months or later after an initial injectionif the first injection was associated with anincrease in visual acuity. In a chronologi-cally parallel manner, the peak of the eleva-tion in intraocular pressure was about



2–5 months after the injection. It shows thatpatients after an intravitreal injection oftriamcinolone acetonide must be followedup closely for several months to detect asteroid induced increase in intraocularpressure. Besides the chronological corre-lation between an increase in visual acuityand an elevation of intraocular pressure,the postinjection increase in visual acuitywas statistically independent of the eleva-tion in intraocular pressure.

9.12Intravitreal Triamcinolone Acetonidefor Proliferative Vitreoretinopathy

In a pilot study, intravitreal triamcinoloneacetonide was applied in combination withpars plana vitrectomy for treatment of pro-liferative vitreoretinopathy [52]. The studygroup included 16 patients who underwentpars plana vitrectomy for treatment of pro-liferative vitreoretinopathy and who re-ceived an intravitreal injection of about20 mg triamcinolone acetonide at the endof surgery.A control group consisted of 144patients undergoing pars plana vitrectomyfor proliferative vitreoretinopathy withoutintravitreal triamcinolone acetonide. Dur-ing the follow-up (mean 1.64 months), in-traocular inflammation and postoperativepain were significantly lower in the studygroup. The study suggested that intravitre-al triamcinolone acetonide with most ofthe vehicle removed may not be toxic to in-traocular structures, and that it reducespostoperative intraocular inflammation.

A second study included 33 patients un-dergoing pars plana vitrectomy with sili-cone oil endotamponade for complicatedproliferative vitreoretinopathy due to pre-ceding retinal detachment surgeries or dueto traumatic retinal lesions [67]. After amean follow-up of 8.6±6.6 months, retinalre-detachment was detected in ten (30 %)

patients. In five of the ten patients with reti-nal re-detachment, the detachment wasobserved within the first 3 months aftersurgery. The shortest intervals betweensurgery and detection of re-detachmentwere 1 week and 3 weeks. In two patients,triamcinolone acetonide crystals settled onthe macular region. Three months aftersurgery, the crystals had completely re-solved. Upon ophthalmoscopy, no tissuedamage in the region, where the triamci-nolone acetonide crystals had settled, wasdetected. The recurrence rate of retinal de-tachments of about one-third was relative-ly high in that study. It was unexpected inview of the presumed anti-inflammatoryand antiproliferative properties of steroidssuch as triamcinolone acetonide. It may beexplained, however, by the results of a pre-vious experimental study in which triamci-nolone acetonide inhibited the prolifera-tion of rabbit dermal and conjunctivalfibroblasts in cell culture at 150 mg/l,but paradoxically increased proliferationalmost twofold at concentrations rangingfrom 1 to 30 mg/l under identical cultureconditions [10]. In contrast, Chandler andcolleagues observed a protective effect ofintravitreal triamcinolone acetonide if itwas injected simultaneously with, or priorto, fibroblasts into the vitreous cavity ofrabbit eyes, in reducing the rate of retinaldetachment [16].

As long as the influence of low concen-trations of steroids on the proliferation ofretinal pigment epithelium cells has re-mained unclear, intravitreal triamcinoloneacetonide may, therefore, cautiously be tak-en as adjunct treatment of proliferative vit-reoretinopathy. It has also remained un-clear so far whether and how a silicone oilendotamponade influences the pharmako-kinetics of intraocular triamcinolone ace-tonide [43], and whether the location of theretinal re-detachments in the inferior fun-dus were incidentally or causally in spatial

9.12 Intravitreal Triamcinolone Acetonide for Proliferative Vitreoretinopathy 151


relationship to the triamcinolone acetonidecrystals which also settled in the inferiorfundus periphery.

Enaida and colleagues used triamci-nolone acetonide in combination with parsplana vitrectomy and found between thestudy group with triamcinolone acetonide(n=94 eyes) and the control group withouttriamcinolone acetonide (n=83 eyes) nosignificant difference in frequency of im-proved vision after surgery, rate of an in-traocular pressure higher than 21 mmHgafter the operation, and frequency of anadditional filtering surgery [27]. The studygroup had a slightly lower incidence of re-operations caused by preretinal fibrousmembrane formation than in the controlgroup. In another study, Kimura and co-workers used triamcinolone acetonide ashelp in peeling of the internal limitingmembrane [78].

9.13Cataract Surgery After IntravitrealTriamcinolone Acetonide

Since steroids applied in a high dosage maylead to several changes such as alterationsin collagenous structures as well as in theimmunologic status, intraocular surgeryperformed after an intravitreal applicationof triamcinolone acetonide may have anunusual spectrum of complications. Arecent case series study included 22 pa-tients presenting with cataract who hadprogressed after a single or repeated intra-vitreal injection of about 20 mg of triamci-nolone acetonide for treatment of exuda-tive age-related macular degeneration ordiffuse diabetic macular oedema [68]. Dur-ing routine phacoemulsification surgery,an intraoperative dialysis of the lenszonules with vitreous prolapse occurred inone (4.5 %) eye. During the postoperativefollow-up, an optically significant decen-

tration of the intraocular lens or infectiousendophthalmitis was not encountered inany patient. It was concluded that cataractsurgery after single or repeated intravitrealinjections of about 20 mg triamcinoloneacetonide may not harbour a markedlyelevated frequency or a markedly changedprofile of complications of standardcataract surgery, and that the cataracto-genic effect of intravitreal triamcinoloneacetonide is not a major contraindicationto using triamcinolone acetonide intravit-really.

9.14Chronic Pre-phthisical OcularHypotony

In contrast to ocular hypertension, whichcan often successfully be cured by a wholearray of antiglaucomatous medical andsurgical methods, progressive ocular hy-potony can be an untreatable conditioneventually leading to blindness and painfulphthisis bulbi. In an attempt to use a sideeffect of steroids as desired effect, triamci-nolone acetonide was injected intravitreal-ly in three eyes with long-standing pre-ph-thisical ocular hypotony [53, 106]. In allthree patients, intraocular pressure andvisual acuity increased after the injectionwas associated with a stabilization of theeyes. It may suggest that in some eyes with long-standing pre-phthisical ocularhypotony, intravitreal injection of triamci-nolone acetonide can be beneficial in in-creasing intraocular pressure and stabiliz-ing the eye.



9.15Uveitis

Intravitreal triamcinolone acetonide hasadditionally been used for treatment oftherapy-resistant chronic uveitis [3, 8, 11, 25,26, 83, 114, 123]. In these studies, a markedregression of intraocular inflammation, areduction of cystoid macular oedema, andan increase in visual acuity was observed.An alternative to intravitreal triamcinoloneacetonide has been the use of intraocularslow-release devices containing fluoci-nolone with a longer duration of action inthe treatment of uveitis [40].

9.16Future Studies

In view of the possible neuroprotective ef-fect of steroids, intravitreal triamcinoloneacetonide has been considered to be of usefor the treatment of acute optic neu-ropathies such as non-arteritic anterior is-chaemic optic neuropathy or arteritic ante-rior ischaemic optic neuropathy, and acutecentral or branch retinal artery occlusion.

9.17Complications of Intravitreal Injectionsof Triamcinolone Acetonide

The clinical studies on intravitreal triamci-nolone acetonide have shown several sideeffects of the therapy. One of the two mostcommon side effects of intravitreal triam-cinolone acetonide was the steroid-inducedelevation of intraocular pressure [5, 62, 63,74, 122]. A recent prospective clinical inter-ventional comparative non-randomizedstudy included 253 consecutive patients(280 eyes) receiving an intravitreal injec-tion of 20–25 mg triamcinolone acetonide

as treatment for diffuse diabetic macularedema, exudative age-related macular de-generation, retinal vein occlusions, uveitis,and cystoid macular edema (own data).Intraocular pressure readings higher than 21 mmHg, 30 mmHg, 35 mmHg, and40 mmHg, respectively, were measured in94 (36.2 %) patients, 22 (8.5 %) patients, 11(4.2 %) patients, and 4 (1.5 %) patients,respectively. Triamcinolone induced in-traocular pressure elevation was treated byantiglaucomatous medication in all butthree (1.0 %) eyes, for which filtering sur-gery was performed. About 40 % of the pa-tients developed a secondary ocular hyper-tension with values above 21 mmHg,starting about 1 week after the injection fora few eyes, and occurring for most eyes,which developed an ocular hypertension,about 1–2 months after the intravitreal in-jection of 20–25 mg triamcinolone ace-tonide. Younger age and pre-baselinediagnosis of glaucoma were significantlyassociated with triamcinolone induced oc-ular hypertension. Intraocular pressure in-crease during follow-up was significantlycorrelated with higher gain in visual acuity.Triamcinolone responders and triamci-nolone non-responders did not vary signif-icantly in gender, refractive error, diabetesmellitus,and reason for treatment. If triam-cinolone acetonide was reinjected, thechange in intraocular pressure after thereinjection was similar to the change in in-traocular pressure after the first injection.

Diagnosis of diabetes mellitus or pres-ence of a clinically significant diffuse dia-betic macular edema did not influence thereaction of intraocular pressure after theinjection. This may agree with previousrandomized clinical trials in which dia-betes mellitus was not a major risk factorfor glaucoma [92]. From a clinical point ofview, diagnosis of diabetes mellitus maynot be a contraindication against intravit-real application of triamcinolone acetonide

9.17 Complications of Intravitreal Injections of Triamcinolone Acetonide 153


as previous studies have also demonstrated[50, 54, 64, 65, 84, 85].

Interestingly, an increase in intraocularpressure was associated with an increase in visual acuity. Multifactorial regressionanalysis revealed that the increase in in-traocular pressure was significantly associ-ated with a higher gain in visual acuityduring follow-up. This finding might be ex-plained by the pathophysiology of leakingretinal capillaries. If the macular capillariesexhibit an increased permeability, theamount of leakage might depend on thetransmural pressure gradient as the differ-ence between the pressure in the vessel andthe pressure in the space surrounding thevessel, i.e. intraocular pressure. If intraocu-lar pressure is elevated, the pressure differ-ence between the intraluminal space andthe extraluminal space will be decreased,eventually leading to a smaller amount offluid leaking through the wall of the vessel.This agrees with previous studies in whichelevation of intraocular pressure was asso-ciated with a decrease in pseudophakic cys-toid macular oedema [20, 88].

The rise in intraocular pressure startedat about 1 week after the injection, and themeasurements returned to the baselinevalues after about 9 months. These figuresare valid for a dosage of about 20–25 mg tri-amcinolone acetonide. Many eyes showophthalmoscopically visible triamcinoloneacetonide crystals in the vitreous for a sim-ilar period as the increase in intraocularpressure lasts. This suggests that when thetriamcinolone acetonide crystals have re-solved, intraocular pressure may return toits baseline level, and that the triamci-nolone induced increase in intraocularpressure is reversible. This concurs withprevious studies on reaction of intraocularpressure after topical application of corti-costeroids [63].

Those patients who received a secondinjection of 20–25 mg triamcinolone ace-tonide showed a similar reaction of in-traocular pressure to after the first injec-tion [71]. This suggests that if after a firstinjection, intraocular pressure remains inthe normal range, intraocular pressure mayalso remain in the normal range after a sec-ond injection. In a similar manner, if in-traocular pressure increases after the firstinjection, a similar rise in intraocular pres-sure may be expected after a second injec-tion. So far, there have been no reports of apermanent rise in intraocular pressureafter an intravitreal injection of triamci-nolone acetonide.

Comparing studies using differentdosages of triamcinolone acetonide for in-travitreal injection may suggest that thehigher the dosage, the longer the durationof steroid-induced ocular hypertension [5,62, 63, 122]. The figures of the frequency ofsecondary ocular hypertension may not bedirectly correlated with the dosage inject-ed. If further studies confirm this assump-tion, it may be explained by the fact thatalready relatively low triamcinolone ace-tonide dosages are so high that all steroidreceptors may be occupied by triamci-nolone already at the relatively low dosagesof 2 mg or 4 mg of triamcinolone acetonide.One has to take into account that the eyemakes up about 0.01 % of the body volume.Assuming an equal distribution of triamci-nolone acetonide throughout the body, anintravitreal injection of 4 mg is equal to anintragluteal injection of 40 g, and an intra-vitreal injection of 25 mg triamcinoloneacetonide is equal to a quarter of a kilo-gram injected intragluteally.



9.17.1Postinjection InfectiousEndophthalmitis

In recent studies on patients receiving anintravitreal injection of triamcinolone ace-tonide, the frequency of postinjection in-fectious endophthalmitis ranged between0/700 and 8/992 (0.87 %) [9, 48, 58, 89, 91,94]. The risk of infectious endophthalmitismay partially depend on the setting of theinjection itself. The studies suggest that ifthe injection is performed under sterileconditions, the risk may be less.

Histologically, eyes with intravitreal tri-amcinolone acetonide and infectious en-dophthalmitis show a marked destructionof the whole globe. The most striking find-ing can be that some areas show a massiveinfiltration by granulocytes, while other ar-eas can be almost completely devoid of in-flammatory cells [48]. Between both areas,there is a sharp demarcation line. There is a morphallaxia-like histology in which a dense infiltration of granulocytes issharply demarcated by tissue areas whereinflammatory cells are almost completelymissing. Such a histology, normally charac-teristic of demarcation and destruction ofnecrotic anaemic tissue like intrauterineresorption of a dead fetus, may be ex-plained by the intraocular presence of highconcentrations of triamcinolone acetonide.As a steroid, it may have inhibited the im-migration of granulocytes into those areasin which the triamcinolone acetonide crys-tals are present. This histopathologic pat-tern is not commonly found in globesenucleated due to foudroyant infectiousendophthalmitis, which is normally char-acterized by a marked destruction of all in-traocular structures with dense infiltrationof all ocular structures by inflammatorycells. The morphology of infectious en-dophthalmitis in eyes with intravitreal

triamcinolone acetonide may be paralleledby the clinical observation that patientswith infectious endophthalmitis after anintravitreal injection of triamcinolone acetonide usually show almost no pain,which is rather uncommon for infectiousendophthalmitis in eyes without intra-ocular steroids [91]. The lack of inflamma-tory cells migrating into the eye may be thehistologic correlate of the clinical observa-tion.

9.17.2Postinjection Sterile Endophthalmitis

A “sterile endophthalmitis” has been de-scribed to occur after an intravitreal injec-tion of triamcinolone acetonide [91, 94,108]. One may speculate whether the sol-vent agent of triamcinolone acetonide, ifnot removed prior to the injection, may becausative for the sterile intraocular inflam-mation after the injection. It has been in-conclusive so far whether the solvent agentshould be removed before triamcinoloneacetonide is injected. The disadvantage ofremoval of the solvent agent is that thedosage becomes inaccurate [107].

9.17.3Postinjection Pseudo-endophthalmitis

If triamcinolone acetonide crystals arewashed from the vitreous cavity into theanterior chamber, they usually settle downin the inferior anterior chamber angle,mimicking a hypopyon [52, 117]. The diag-nostic problem is the differentiation be-tween a painless hypopyon caused by apostinjection infectious endophthalmitisand a pseudo-hypopyon due to triamci-nolone acetonide crystals. Using high mag-nification slit lamp biomicroscopy usually

9.17 Complications of Intravitreal Injections of Triamcinolone Acetonide 155


reveals the crystalline structure of triamci-nolone acetonide. Triamcinolone acetonidecrystals in the anterior chamber usuallydisappear spontaneously and may not needto be removed. There have been no reportsso far of corneal endothelial damage ordamage to the trabecular meshwork by thecrystals. If the intravitreal injection is per-formed in the direction of the centre of thevitreous cavity, a pseudo-hypopyon mayonly rarely occur. If, however, the injectiontouched the posterior chamber, the triam-cinolone acetonide crystals may not betrapped by the vitreous body but may par-tially be washed into the anterior chamber.

9.17.4Rhegmatogenous Retinal Detachment

Since the triamcinolone acetonide injec-tion is carried out into the vitreous cavityleading to a dearrangement of the structureof the vitreous body, and because an abnor-mal vitreous may exert a traction on theretina leading to a rhegmatogenous retinaldetachment, a potential complication of theintravitreal injection may be a rhegmatoge-nous retinal detachment. In a recent studyof 348 eyes receiving an intravitreal injec-tion of about 20 mg triamcinolone ace-tonide as treatment of exudative age-relat-ed macular degeneration, diabetic macularoedema, retinal vein occlusions, persistentpseudophakic cystoid macular degenera-tion, and uveitis, none of the eyes devel-oped a rhegmatogenous retinal detach-ment or retinal lesions [32, 70]. This holdstrue particularly for the inferior mid-peripheral area of the fundus, where thetriamcinolone acetonide crystals havesettled in the preretinal vitreal cortex; forthe superior midperipheral and peripheralfundus where a vitreous traction might beinduced by the weight of the triamcinoloneacetonide crystals settled at 6 o’clock;

and for the far periphery of the fundus,where retinal traction by vitreous if incar-cerated into the injection site might haveresulted.

9.17.5Postinjection, Steroid Induced Cataract

In a recent study of 144 phakic eyes whichconsecutively received an intravitreal in-jections of about 20 mg triamcinoloneacetonide for diffuse diabetic macularoedema, exudative age-related macular de-generation, and branch retinal vein occlu-sion, cataract surgery was performed in 20 (13.9 %) eyes 17.4±9.1 months (median,12.7 months; range, 8.0–35.5 months) afterthe intravitreal injection (own data). Out ofthe 20 eyes undergoing cataract surgery, 19(95 %) eyes had received one intravitrealinjection, and one (5 %) eye had receivedtwo previous injections. It was concludedthat in the elderly population of patientswith exudative age-related macular degen-eration, diffuse diabetic macular oedemaor branch retinal vein occlusion, intra-vitreal high-dosage injection of triamci-nolone acetonide leads to clinically signifi-cant cataract with eventual cataract surgeryin about 15–20 % of eyes within about 1 yearafter the intravitreal injection.

9.18Toxic Effects

Direct toxic effects of triamcinolone ace-tonide on the retina and optic nerve havenot yet been observed, independently ofthe dosage used [18]. Correspondingly, arecent safety and efficacy study of an in-travitreal fluocinolone acetonide sustaineddelivery device as treatment for cystoidmacular edema in patients with uveitis and other clinical and experimental studies



has not shown a toxic effect of intraocularsteroids [123]. The same result was found byHida, Machemer and co-workers [36]. Itmay be of importance that triamcinoloneacetonide is usually not found in the serumshortly after its intravitreal application,suggesting that major systemic side effectsmay not be very probable [26].

9.19Safety of Intravitreal Injections of Triamcinolone Acetonide IncludingHigh-Dose Reinjections

In a recent prospective randomized studyby Gillies and colleagues, the safety of a sin-gle intravitreal injection of triamcinoloneacetonide (4 mg) in patients with subfovealchoroidal neovascularization caused byage-related macular degeneration was eval-uated [32]. Out 75 eyes assigned to studytreatment and 76 eyes assigned to placebo,there were no moderate or severe adverseevents related to the surgical procedure ineither group. Triamcinolone-treated eyeshad a significantly increased risk of devel-oping mild or moderate elevation of the in-traocular pressure. Topical glaucoma med-ication reduced intraocular pressure toacceptable levels in all patients. There wassignificant progression of cataract in thetriamcinolone-treated eyes. The authorsconcluded that despite a significant adverseevent profile, intravitreal triamcinolone isgenerally well tolerated by the human eyeas long as patients are carefully followed upby their surgeon and treated appropriately,when necessary.

Another recent case-series study includ-ed 46 patients who received at least two in-travitreal injections of about 20 mg triam-cinolone acetonide for treatment of diffusediabetic macular oedema, exudative age-related macular degeneration, secondaryangle-closure glaucoma due to iris neovas-

cularization, central retinal vein occlusion,branch retinal vein occlusion, non-infec-tious uveitis, Coats’ disease and exudativeretinal detachment of unknown aetiology[75]. The second injection was carried outat 6.7±3.4 months. Nine eyes received athird injection 8.0±4.6 months after thesecond injection, two eyes received four in-jections 9.5 and 10.8 months after the thirdinjection, and one eye received altogethersix injections. After none of the reinjec-tions were complications or side effects de-tected other than those already known tooccur after a single intravitreal injection oftriamcinolone acetonide. After the first,second and third injections, respectively,intraocular pressure remained within thenormal range in 24 (51 %), 25 (53 %), and 5(56 %) eyes, respectively. Those eyes with-out a rise in intraocular pressure above21 mmHg after the first injection did notshow an elevation of intraocular pressureafter a repeated injection. Mean maximalintraocular pressures after the first, secondand third injections, respectively, did notvary significantly (p>0.50). The results sug-gest that intravitreal high-dosage reinjec-tions may be tolerated by eyes within amean follow-up of about 21 months afterthe first injection or about 10 months afterthe last injection; that an increase in in-traocular pressure may be not moremarked after a repeated injection than afterthe first injection; and that side effects orcomplications may not occur more fre-quently after reinjections of triamcinoloneacetonide than after a primary intravitrealhigh-dosage injection.

In summary, intravitreal triamcinoloneacetonide has increasingly been applied asa treatment option for various intraocularneovascular and edematous proliferativedisorders. The best response in terms ofgain in visual acuity after the intravitrealinjection of triamcinolone acetonide wasfound in eyes with intraretinal edematous

9.19 Safety of Intravitreal Injections of Triamcinolone Acetonide Including High-Dose Reinjections 157


diseases such as diffuse diabetic macularoedema, branch retinal vein occlusion, cen-tral retinal vein occlusion, and pseudopha-kic cystoid macular oedema. Visual acuityincreased and degree of intraocular in-flammation decreased in eyes with varioustypes of non-infectious uveitis includingsympathetic ophthalmia. Intravitreal tri-amcinolone may be useful as angiostatictherapy in eyes with iris neovascularizationand proliferative ischaemic retinopathies.Possibly, intravitreal triamcinolone may behelpful as adjunct therapy for exudativeage-related macular degeneration, possiblyin combination with photodynamic thera-py. In eyes with chronic, therapy resistant,ocular hypotony, intravitreal triamci-nolone can induce an increase in intraocu-lar pressure and may stabilize the eye.The complications of intravitreal triamci-nolone therapy include secondary ocularhypertension in about 40 % of the eyesinjected, cataractogenesis, postoperativeinfectious and non-infectious endoph-thalmitis, and pseudo-endophthalmitis. In-travitreal triamcinolone injection can becombined with other intraocular surgeriesincluding cataract surgery. Cataract sur-gery performed some months after the in-jection does not show a markedly elevatedrate of complications. If vision increasesand eventually decreases again after an in-travitreal triamcinolone acetonide injec-tion, the injection can be repeated. The du-ration of the effect of a single intravitrealinjection of triamcinolone ranged between2 and 9 months, probably depending on thedosage used. Intravitreal triamcinoloneacetonide may offer a possibility for ad-junctive treatment of intraocular oedema-tous and neovascular disorders. One has totake into account the side effects and thelack of long-term follow-up observations.

As for any new therapy, however, one hasto be very careful since long-term experi-ence is not yet available. There are many

open questions as yet unanswered. What isthe best dosage for which disease and forwhich clinical situation? Is the proliferationof retinal pigment epithelium cells in highconcentrations of triamcinolone acetonidedecreased and, paradoxically, in low con-centrations increased? What is the bestmode of application of triamcinolone ace-tonide, is the subtenon application, the sub-conjunctival application or the retrobulbarapplication better than the intravitreal in-jection? Are there other complications thanthose already described in clinical studiesor after accidental injection of triamci-nolone acetonide into the vitreous cavity?Is it necessary to remove the solvent agentprior to the intraocular injection, and howshould the solvent agent be removed? Themost fascinating point may be that the in-travitreal injection of triamcinolone ace-tonide together with previous clinical expe-riences on the use of intravitreal antibioticsand virustatic drugs makes one understandthat retinal diseases, particularly maculardisorders, become locally treatable diseasessince rather high intraocular concentra-tions of drugs become achievable and sys-temic side effects may mostly be avoided.

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70. Jonas JB, Kreissig I, Degenring RF (2004) Reti-nal complications of intravitreal injections oftriamcinolone acetonide. Graefes Arch ClinExp Ophthalmol 242:184–185

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74. Jonas JB, Degenring RF, Kamppeter BA (2004)Filtering surgery after intravitreal triamci-nolone acetonide injection. J Glaucoma 13:261

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Intravitreal Injection of Triamcinolone Acetonide 9