Mi!@tiiiiii!itiSM
`Intravitreal Injection of Triamcinolone
`for Diffuse Diabetic Macular Edema
`
`Jost B. Jonas, M D; Ingrid Kreissig, MD; Anrje Sofker, MD; Roberl F. Degenring, MD
`
`Oblective: To evaluate the clinical outcome of an in(cid:173)
`travitreal injection of triamcinolone acetonide as treat(cid:173)
`ment of diffuse diabetic macular edema.
`
`Pmticlpants: This prospective, interventional, clinical case
`series study included 20 patients (26 eyes) who received
`an intravitreal injection of 25 mg of triamcinolone ace(cid:173)
`tonide for treatment of diffuse diabetic macular edema.
`Mean±SD follow-up timewas6.64±6.10 months. The study
`group was compared with a control group of 16 patients
`who underwent macular grid laser coagulation.
`
`Main Outcome Measures: Visual acuity and intra(cid:173)
`ocular pressure.
`
`nificantly (P<.001), from 0.12±0.08 at baseline to a maxi(cid:173)
`mum of0.19±0.14 during follow-up. Seventeen (81%)
`of 21 eyes with a follow-up period of more than 1 month
`had improved visual acuity. In the control group, visual
`acuity did not change significantly. In the study group,
`intraocular pressure increased significantly (P<.001),
`from 16.9± 2.5 mm Hg to a mean maximal value of
`21.3±4.7 mm Hg, and decreased significantly (P =.03)
`to 17. 7 ±4. 7 mm Hg at the study's end.
`
`Conclusion: lntravitreal injection of 25 mg of triam(cid:173)
`cinolone acetonide may be beneficial for improving vi(cid:173)
`sual acuity in patients with clinically significant diffuse
`diabetic macular edema.
`
`Results: In the study group, visual acuity improved sig-
`
`Arch Ophthalmol. 2003;121:57-61
`
`D IABETIC MACULAR edema
`
`is one of the main rea(cid:173)
`sons for reduced visual
`acuity in patients with
`diabetic retinopathy. Ac(cid:173)
`cording to the results or the study on the
`early treatment of diabetic retinopathy, dia(cid:173)
`betic macular edema has usually been
`treated by focal laser coagulation ofleak(cid:173)
`ing circumscribed retinal areas, unless the
`whole macular region is diffusely af(cid:173)
`fected.1 In eyes with diffuse macular
`edema , laser treatment cannot be fo (cid:173)
`cused on localized retinal leakage spots
`since the entire macula is involved. A rec(cid:173)
`ommendation for grid laser treatment cov(cid:173)
`ering the whole macular region with a fine
`net of small laser coagulation spots has
`been controversial, since randomized pro(cid:173)
`spective studies proving the efficacy of this
`treatment have n ot yet been published.
`In view of the uncertainties in the
`treatment of diffuse diabetic macular
`edema, we undertook the present study to
`assess whether an intravitreal injection of
`crystalline cortisone might be effective in
`reducing macular edema and improving
`visual acuity.
`
`METHODS
`
`The study included the 20 patients (26 eyes)
`who received an intravitreal injection of crys(cid:173)
`talline triamcinolone acetonide as treatment of
`clinically significant diffuse macular edema. All
`of the patients were fully informed about the
`experimental character of the therapy. All of
`the patients signed an informed consent. The
`ethics committee of the university had ap(cid:173)
`proved the study following the tenets of the
`Declaration of Helsinki. Mean ±SD age of the
`patients was 66.9 ±8.9 years (median, 67.6
`years; range, 49.4-79.6 years), and mean± SD
`refractive error was +0.40± 1.62 diopters (D)
`(median, 0.00 D; range, - 1.75 to +6.0 D).
`Mean ± SD visual acuity was reduced to
`0.12 ± 0.08 (median, 0.10; range, 0.03-0.32).
`Visual acuity was measured as best-corrected
`visual acuity. The patients had experienced a
`loss of vision for at least l year, and visual acu(cid:173)
`ity had been constant for at least 3 months prior
`to inclusion in the study. Fluorescein angiog(cid:173)
`raphy showed diffuse macular edema. We used
`digital fluorescein angiograms, on which the
`size of the area with fluorescein leakage was
`measured for the late phase of the angiogra(cid:173)
`phy . Additionally , the preinjection angio(cid:173)
`grams and the postinjection angiograms were
`graded in a masked fashion 10 address the ques-
`
`From the Department of
`Ophthalmology and the Eye
`Hospital, Faculty for Clinical
`Medicine- Mannheim, Ruprecht
`Karls University, Heidelberg,
`Germany. The authors have
`no proprietary interest in the
`products or companies
`mentioned in t/1is article.
`
`( REPRINTED) ARCH OPHTHALMOL/VOL 121, JAN 2003
`57
`
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`©2003 American Medical Association. All rights reserved.
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`0.4
`
`o.o. . _ _~ -~ -~ -~ -~ -~ -~ -~ -~ (cid:173)
`N.
`17
`14
`13
`9
`21
`26
`24
`7
`2wk
`6wk
`10wk 4 mo
`smo
`Presurge,y 1 d
`71110
`Visual Acuity at Given Time Interval
`
`6mo
`
`Figure 1. Diagram showing the mean±SO and the 95% confidence interval
`(Cl) of visual acuity prior to and after the first intravitreal injection of 25 mg
`ot triamcinolone acetonide.
`
`tion on which angiogram the lluorescein leakage was more
`marked. For 5 eyes (19.2%), fluorescein angiograms after the
`injection of triamcinolone were not available. Grid laser co(cid:173)
`agulation of the macular region had been performed in 9 eyes
`(35%) prior to inclusion in the study. Peripheral and macular
`focal laser coagulation, if any, had been carried out more than
`6 months prior to inclusion in the study.
`Eight eyes (30.8%) were pseudophakic, for which cata(cid:173)
`ract surgery had been performed at least 5 months prior to the
`intravitreal injection of triamcinolone. For the 18 remaining
`eyes, the degree of opacification of the lens was determined us(cid:173)
`ing slitlamp biomicroscopy and a scale ranging from O for "very
`clear lens" to S for "very pronounced," in the posterior sub(cid:173)
`capsular layer, the cortical layer, and the nuclear layer of the
`lens. Since it was an ongoing study, and because all patients
`who received an intravitreal cortisone injection were consecu(cid:173)
`tively included in the study, the follow-up period ranged be(cid:173)
`tween 1 week and 18. 2 months. Mean :1: SD follow-up time was
`6.64:1:6.10 months (median, 4.82 months; range, l week to 18.2
`momhs).
`The intravitreal injection of triamcinolone was carried out
`under sterile conditions in the operation theater with topical
`anesthesia. After a paralimbal paracentesis to puncture the an(cid:173)
`terior chamber and to reduce the intraocular volume, 0.2 ml
`of Ringer's solution containing 25 mg of triamcinolone ace(cid:173)
`tonide was transconjunctivally injected in a distance to the lim(cid:173)
`bus of 3 mm to 3.5 mm. through the pars plana into the vitre(cid:173)
`ous cavity. We used a 27-gauge needle, and the injection was
`usually performed in the temporal inferior quadrant. Care was
`taken to inject triamcinolone with most of the vehicle re(cid:173)
`moved. An oinonent containing neomycine and polymyxin was
`topically applied. After the injection . the patients were asked
`to sit up and to keep an upright position for at least 2 hours to
`prevent the cortisone crystals from settling onto the rnacular
`region. All patients were reexamined on the first day after the
`intravitreal injection.
`The patients of the study group were compared with the
`16 control group patients, who also had diffuse diabetic macu(cid:173)
`lar edema, and who did not receive an intravitreal injection of
`crystalline cortisone. Mean :1: SD age was 70.54 :1: 4.70 years,
`mean ;l; SD re&active error was +0.58 ± l.31 D. Visual acuity
`had reduced to 0.16 ± 0.08. As with the patients of the study
`group, the control group patients experienced a loss of vision
`for at least 1 year, and visual acuity had remained low for at
`least3 months prior to inclusion in the study. Fluorescein an(cid:173)
`giography performed for all these patients showed diffuse macu(cid:173)
`lar edema. For all patients of the control group, we performed
`
`grid laser coagulation of themacula. Mean:1:SD follow-up time
`was 7.04:t:3.Sl months (median, 6.20 months; range, 0.73-
`11.57 months). The control group was retrospectively formed
`by including all patients who had received a macular grid la(cid:173)
`ser treatment within a p eriod of 6 months preceding the start
`of the study, and who were matched with the study group with
`respect to age, sex, refractive error, and preoperative visual acu(cid:173)
`ity. No macular grid laser treatment was performed in this study.
`
`RI:SllL'I S
`
`ln the triamcinolone group, mean :1: SD "isual acuity im(cid:173)
`proved significantly (P<.001) from 0.12 ± 0.08 at base(cid:173)
`line of the study to a maximum of 0.19 ±0.14 during the
`follow-up period (Figure 1 ). Seventeen (81 %) of 21 eyes
`that had completed a minimal follow-up period of 1 month
`achieved better visual acuity. Improvement in viSual acu(cid:173)
`ity was statistically significant at the examinations per(cid:173)
`formed 6 weeks (P=.003), 10 weeks (P=.01), 5 months
`(P=.03), and 6 months (P= .02) after the injection (Tahle).
`Three to approximately 6 months after the injection.
`the triamcinolone crystals were resolved, and completely
`disappeared out of the vitreous cavity.
`For the 21 patients for whom fluorescein angio(cid:173)
`grams were available during the preinjection and postin(cid:173)
`jeccion periods, mean:tSD fluorescein leakage on the an(cid:173)
`giograms decreased significantly (P<.001), from 32.3 :tl3.6
`mrn2 (range, 7.28-SO.Omm2) at baseline, toa minimal value
`of 26.8 ±15.3 mm2 (range, 0.52-50.0 mm2) during the fol(cid:173)
`low-up period. Evaluated subjectively in a masked fash(cid:173)
`ion, the postinjection angiograms of all 21 patients were
`graded to show less fluorescein leakage than on the pre(cid:173)
`injection angiograms.
`One paLient received a second intravitreal injec(cid:173)
`tion of 25 mg of triamcinolone acetonide, repeatedly show•
`ing an improvement in visual acuity, with intraocular pres(cid:173)
`sure remaining unchanged.
`In the control group, visual acuity did not change
`significantly during the follow-up period. At the end of
`the follow-up period, mean±SD visual acuity measured
`0.15 ± 0.17, which was not significantly different (P= .35)
`from 0 .16 ± 0.08, as determined at baseline.
`In the study group, mean :t SD intraocular pressure
`increased significantly (P<.001), from 16.9 :1: 2.5 mm Hg
`at baseline, to a maximal value of 21.3 ± 4. 7 mm Hg (me(cid:173)
`dian, 19.0 mm Hg; range, 16-35 mm Hg) during the fol(cid:173)
`low-up period, and decreased again significantly (P = .03)
`to 17.7 ± 3 .6 mm Hg at 5 months after the injection
`(Table). The intraocular pressure measurements taken
`at the end of the follow-up period did not vary signifi(cid:173)
`cantly (P=.31) from those measured at baseline. During
`the study period, intraocular pressure was higher than 21
`mm Hg in 9 (34.6%) of the 26 study eyes. In all these eyes,
`intraocular pressure could be normalized by topical anti(cid:173)
`glaucomatous medication. Glaucomatous damage to the
`optic nerve, as determined by biomorphometry of the op(cid:173)
`tic nerve head,2 was not detected in any eye.
`In none of the patients did cortisone crystals settle
`on the macular region . They were located preretinally in
`the vitreous cortex at the 6-o'clock position, and they did
`not optically interfere with vision. In none of the eyes
`included in the study did postoperative infectious en-
`
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`

`Visual Acuity and Intra ocular Pressure Prior to and After the First lntravitreal Injection of 25 mg of Triamcinolone*
`
`Baseline
`Follow-up
`1 d
`2wk
`6wk
`2.5mo
`4 mo
`5 mo
`6 mo
`7 mo
`
`No. of Eyes
`26
`
`Visual Acuity, Mean :t SD
`0.12 10.08
`
`P Value
`
`IOP, Mean t: SD, mm Hg
`16.9 ± 2.5
`
`P Value
`
`24
`21
`17
`14
`13
`9
`7
`7
`
`0.12 :t 0.10
`0.13 :t 0.10
`0.13:t0.11
`0.16 :t 0.15
`0.17 • 0.16
`0.15-t0.12
`0.17 ± 0.13
`0.11 :t 0.08
`
`.33
`.29
`.003
`.01
`.08
`03
`.02
`.35
`
`16.1 :t3.2
`16.3 :t 3.8
`19.0 :t 4.6
`17.7 :t 4.5
`17.7 :t 5.3
`17.7;; 3.6
`18.7 :t 4.6
`18.3 ± 7.3
`
`.09
`.81
`.06
`.17
`.69
`.26
`.03
`.31
`
`Abbreviation: IOP, intraocular pressure.
`*Triamcinolone was administered as triamcinolone acetonide.
`
`dophthalmitis or proliferative viu·eoretinopathy occur.
`ln none of the eyes was a progression of diabetic reti(cid:173)
`nopathy detected.
`For the 18 phakic eyes, the degree of lens opacifi(cid:173)
`cation (mean± SD) increased slightly, from 0 .1 1±0.32
`relalive units to 0.33 ± 0.67 relalive units in the subcap(cid:173)
`sular layer of the lens; however, this change was not sig(cid:173)
`nificant (P = .16). Lens opacification was mostly un(cid:173)
`changed in the nuclear lens region (1.39 ± 0.50 vs 1.44
`± 0 .51; P =.56) and in Lhe cortical layer of the lens (1.39
`± 0. 70 relative units vs 1.44 :1:0. 70 relative units; P =.32).
`
`-------1IIIIIM!MH• 11111------
`
`For decades, corticosteroids have been used in ophthal(cid:173)
`mology to suppress intraocular inflammation and to re(cid:173)
`duce extravasation from leaking blood vessels. ln an at(cid:173)
`tempt to avoid the systemic adverse effects of steroids, and
`to have simultaneously high concentrations of cortisone
`at the site of action, Machemer, Graham, Peyman, and other
`researchers studied the possibility of injecting cortisone di(cid:173)
`rectly into the vitreous cavity in experimental settings in
`animals, as well as in selected clinical situations in pa(cid:173)
`tients.34' They found that crystalline cortisone may not have
`a toxic effect on intraocular tissue. It is in agreement with
`clinical observations of eyes into which cortisone was ac(cid:173)
`cidentally injected, and in which no major toxic reactions
`12 Correspondingly, clinical or experimen(cid:173)
`were detected Q..
`tal studies have not yet shown any direct toxic reaction from
`cortisone that is intravitreally injected in clinical treat(cid:173)
`ment trials. 13·2l! These studies revealed that a single intra(cid:173)
`ocular injection of triamcinolone may be an adjunctive treat(cid:173)
`ment for exudative age-related macular degeneration,14
`17
`15
`•
`•
`diabetic macular edema, 20•28 proliferative diabetic retinopa(cid:173)
`thy, 19 uveitic cystoid macular edema26 and severe uve(cid:173)
`itis,23 prephthisical ocular hypotony,21 and neovascular glau(cid:173)
`coma.18 Since cortisone is washed out of the eye within
`approximately 24 hours after a single intravitreal injec(cid:173)
`tion,29 Machemer has suggested using a depot form of ste(cid:173)
`roids, which, owin g to an intravitreal absorption time of
`about 2 to 5 months, p rovides cortisone for a consider(cid:173)
`ably longer period oftime than the single injection of soluble
`cortisone.30
`The results of the present study suggest that the in(cid:173)
`travitreal injection of triamcinolone may be beneficial as a
`
`treatment for diffuse diabetic macular edema. The pa(cid:173)
`tients of the study group showed a significant improve(cid:173)
`ment in visual acuity compared with that seen at baseline
`(Figure 1 and Figure 2). In contrast, the visual acuity of
`patients receiving macular grid laser therapy did not im(cid:173)
`prove. Parallel to the improvement in visual acuity, fluo(cid:173)
`rescein leakage on the angiograms decreased significantly
`among the patients of the study group during the fol(cid:173)
`low-up period (Figure 2). The r esults of the present study
`confirm p revious reports showing that the intravitreal ap(cid:173)
`plication of crystalline cortisone can improve visual acu(cid:173)
`ity in patienlS with diffuse macular edema due to diabetic
`retinopathy. ,n.3i In a r ecent, prospective, noncomparative,
`interventional case series study on 16 eyes with clinically
`significant diabetic macular edema that had failed to re(cid:173)
`spond to at least 2 previous sessions of laser photocoagu(cid:173)
`lation, Martidis et aP1 evaluated Lhe safety and effective(cid:173)
`ness of intravitreal injections of 4 mg of triamcinolone
`acetonide. They found a mean improvement in visual acu(cid:173)
`ity of2.4, 2.4 ,and 1.3 Snellen lines at the 1-month.3-month,
`and 6 -month follow-up intervals, respectively. Central
`macular thickness, as measured by optical coherence to(cid:173)
`mography, decreased by 55%, 57.5%, and 38%, respec(cid:173)
`tively, during these same intervals, from an initial pretreat(cid:173)
`ment mean of 540.3 µm. lntraocular pressure exceeded 21
`mm Hg in 5, 3, and l eye(s), respectively, during these in(cid:173)
`tervals. One eye exhibited cataract progression at 6 months.
`No other complications were noted during a mean fol(cid:173)
`low-up of 6.2 months. As we did in the present study, Mar(cid:173)
`ti dis et. aP1 concluded that the intravitreal injection of tri(cid:173)
`amcinolone may be a promising therapeutic method for
`diabetic macular edema. The improvement in visual acu(cid:173)
`ity in the patients of the present study was not constam
`for the entire follow-up period of the study. Approxi(cid:173)
`mately 5 months after the triamcinolone injection, visual
`acuity showed a tendency to decline (Figure 1). Com(cid:173)
`pared with the baseline values, however, visual acuity mea(cid:173)
`surements taken 6 months and 12 m onths after the tri(cid:173)
`amcinolone injection were still slightly higher (P=.07;
`and P= .07), respectively. For patients w h o show an ini(cid:173)
`tial im provement in visual acuity after an intravitreal in(cid:173)
`jection o f triamcinolone, and who eventually experi(cid:173)
`ence a second decline in visual acuity some time after the
`injection, an intravitreal reinjection of triamcinolone may
`be considered. 32
`
`(REPRINTED) ARCH OPHTHALMOL/VOL 121. JAN 2003
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`Figure 2. Late phase of a fluorescein angiogram prior to (A), and 3 months after (B), an intravitreal injection of triamcinolone acetonide. Note the decrease in
`tluorescein leakage after the injection.
`
`Direct toxic effects of triarncinolone on the retina and
`optic nerve were not observed in this study, as confirmed
`by other studies on eyes in which the same dosage of tri(cid:173)
`18
`21 This is
`amcinolone was injected for various reasons. I6
`·
`·
`confirmed by a recent safety and efficacy study of intra(cid:173)
`vitreal triamcinolone for treatment of cystoid macular
`edema in patients with uveitis.33 In the present study, the
`elevation of imraocularpressure above 21 mm Hg that oc(cid:173)
`curred in 9 eyes (34.6%) was not a major problem. ln all
`these eyes, intraocular pressure could be controlled by topi(cid:173)
`cal antiglaucomatous treatment until the triamcinolone
`crystals had disappeared. Glaucomatous changes in the ap(cid:173)
`pearance of the optic nerve head were not detected. Simi(cid:173)
`lar observations were made by Wingate and Beaumont's
`and Martidis et aP 1 using a dosage of 4 mg of triamcino(cid:173)
`lone acetonide, as well as in other previous studies using
`a dosage of 25 mg of triamcinolone.16 1
`2 1
`.1•
`" ·
`A major difference between previous studies on the
`intravitreal application of triamcinolone and this investi(cid:173)
`gation is the dosage of triamcinolone intravitreally injected.
`In all previousdescriptionsofintravitreal triamcinolone for
`cystoid macular edema, diabetic macular edema, and macu(cid:173)
`lar degeneration, 1➔ . I S, l 7.lo.lll.} I a dosage of4 mg of triamcino(cid:173)
`lone was used. We used 25 mg of triamcinolone acetonide
`instead 4 mg because from the beginning of our ongoing
`triamcinolone studies, now involving more than 300 pa(cid:173)
`tients with various diseases, we have used the same dosage
`of 25 mg, and we have not yet seen adverse effects that may
`be attributed to that high dosage. 16•1~•2 uu,-3,i It also holds
`true for repeated intravitreal injections of 25 mg of triam(cid:173)
`cinolone acetonide.32
`T he most important limitation of the present study
`is that it is not a randomized prospective investigation
`in wh ich the patients were randomly distribu ted be(cid:173)
`tween the study group and the control group. The con(cid:173)
`trol group and the study groups, however , were matched
`for general and ocular parameters, including preopera-
`
`tive visual acuity. Yet, in 17 of the 21 eyes with a fol(cid:173)
`low-up period of more than 1 month, visual acuity im(cid:173)
`proved after the injection of triamcinolone, whereas in
`the control group, visual acuity did not change signifi(cid:173)
`cantly. Other limitations of the study are the relatively
`small number of patients included in the study group and
`the control group, and the relatively short follow-up pe(cid:173)
`riod in che Sllldy group.
`In conclusion, in the present study, with a prospec(cid:173)
`tive, noncomparat.ive, intervention.al case series study de(cid:173)
`sign, an intravitreal injection of triamcinolone resulted
`in an improvement in visual acuity in patients with dif(cid:173)
`fuse diabetic macular edema. In agreement with previ(cid:173)
`ous studies, major adverse effects, such as an untreat(cid:173)
`able high increase in intraocular pressure, were not
`observed. Future randomized studies with a larger n um(cid:173)
`ber of patients, may show whether the results of the pre(cid:173)
`sent study, as well as of previous investigations,3' can be
`confirmed, suggesting that the intravitreal application of
`crystalline stero ids may be an additional tool in the
`armamentarium of treating cl inically significant diffuse
`diabetic macular edema.
`
`Submit!ed for publication March 19, 2002;.final revision re(cid:173)
`ceived Augusc 30, 2002; accepted September 17, 2002
`This study was presented as a poster at tl1eA1111ucil Meet(cid:173)
`ing of the American Academy of Ophthalmology, New Or(cid:173)
`leans, La, November 11-14, 2001.
`Correspondingauthor:jost B.)onas, MD, Universitats(cid:173)
`Augenhlinih, Theodor-Kutzer-U.fer 1-3, 68167 Man nheim,
`Germany (e-mai I: josl.jonas@augen.ma.uni-heidelberg.de).
`
`1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation
`for diabetic macular edema: Early Treatment Diabetic Retinopalhy Study report
`number 1. Arch 01Jhlhalmol. 1985:103:1796-1806.
`
`(REPRINTED} ARCH OPliTHALMOL/\IOL 121. JAN 2003
`60
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`Download ed From: https://jamanctwork.com/ by Amy Breitling on 02/04/2021
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`

`2. Jonas JB, Budde WM, Panda-Jonas S. Ophthalmoscopic evaluation of the optic
`nerve head. Surv Ophthalmol. 1999;43:293-320.
`3. Machemer R, Sugita G, Tano Y. Treatment of intraocu lar proliferations with in(cid:173)
`travitreal steroids. Trans Am Ophthalmol Soc. 1979;77:1 71 -180.
`4. Graham RO, Peyman GA. lntravitreal iniection of dexamethasone: treatment
`of experimentally induced endophthalmitis. Arch Ophthalmol. 1974;92:149-
`154.
`5. Tano Y, Sugita G, Abrams G, Machemer R. Inhibition of intraocular proliferation
`with intravitreal corticosteroid. Am J Ophthalmol. 1980;89:131 -136.
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`
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