Outer retinal tubulation in diabetic macular edema following anti-vegf treatment
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1 Al-Hlfi Eye nd Vision (2015) 2:9 DOI /s RESEARCH Open Access Outer retinl tuultion in dietic mculr edem following nti-vegf tretment Ali M Al-Hlfi Astrct Bckground: To ddress the presence nd fetures of outer retinl tuultion (ORT) found in dietic mculr edem (DME) treted with nti-vsculr endothelil growth fctor (nti-vegf) nd to differentite etween ORT nd cystoid DME, which hve different plns of mngement. Methods: This ws retrospective review of totl of 514 ptients investigted with spectrl domin opticl coherence tomogrphy (OCT) in ptients with dietic mculr edem treted with nti-vegf. ORT ws seen in 12 eyes of 11 ptients. The morphologic chrcteristics of ORT nd its progress over time were exmined using OCT dt. The retinl imges were otined y horizontl nd verticl scns to nlyze the possile presence of ORT nd to explore their morphologic fetures nd loction in the retinl lyers. Results: ORT ws seen in DME treted with nti-vegf. ORT ws shown s round or ovoid hyporeflective spces with hyperreflective orders on the B-scns, mesuring 30 to 120 μm high nd 30 to 1775 μm wide. The tuules generlly remined stle over time. In retinl prctice specilizing in dvnced dietic retinopthy clinic, this ORT ws seen in 12 eyes of 11 ptients during 12-month period. ORT presented either fter receiving 0.05 ml open-lel intrvitrel injections of 0.5 mg rniizum or 1.25 mg evcizum. Conclusion: ORT is found in DME treted with nti-vegf tht my show dmge to the outer retin secondry to the severity nd chronicity of the DME. ORT my e result of underlying chronic nd severe dietic mculr edem tht my occur lter possily secondry to retinl lyers rerrngement fter severl nti-vegf injections. It is importnt to differentite etween ORT nd cystoids DME. The presence of the ORT entity lone without the presence of DME does not require further nti-vegf re-injections. Keywords: Outer retinl tuultion, Dietic mculr edem, Rniizum, Bevcizum Bckground Vsculr endothelil growth fctor (VEGF) hs significnt role in lood-retinl rrier rekdown, which leds to fluid lekge nd the development of mculr edem [1]. As VEGF introculr levels re incresed in dietic mculr edem (DME), it ws hypothesized tht lterntive or djunct therpies using VEGF inhiitors (nti-vegf) could e eneficil in reversing vision loss from mculr edem [2]. Opticl coherence tomogrphy (OCT) hs n importnt clinicl influence in ophthlmology, which is promising tool for performing high-resolution cross-sectionl imge. The first in vivo tomogrms of the humn optic disc nd mcul were estlished in 1993 [3,4]. With the widespred Correspondence: mm-ry@hotmil.com Deprtment of Surgery, Ophthlmology Division, Consultnt nd Vitreoretinl Surgeon Security forces Hospitl, PO Box 3643, Riydh 11481, Kingdom of Sudi Ari doption of spectrl domin opticl coherence tomogrphy (SD-OCT) in dignosing nd following up retinl disese, outer retinl tuultion (ORT) hs ecome more oviously well-known presence in eyes with focl disruptions of the outer retin relted to different disorders [5]. Age-relted mculr degenertion (AMD) nd inflmmtory diseses such s multifocl choroiditis or noninflmmtory diseses were oserved to hve ORT [5]. ORT hs single stright tuule or rnching tuules to complex networks s mde visile y en fce SD-OCT C-scn. It is usully situted in the outer nucler lyer of the retin nd s round or ovoid hyporeflective spces with hyperreflective orders on B-scn SD-OCT sections [5]. Curcio et l. [6] were the first to identify this ORT in histopthologic study of eyes with dvnced AMD. They found tht surviving photoreceptors seemed to rerrnge 2015 Al-Hlfi. This is n Open Access rticle distriuted under the terms of the Cretive Commons Attriution License ( which permits unrestricted use, distriution, nd reproduction in ny medium, provided the originl work is properly credited. The Cretive Commons Pulic Domin Dediction wiver ( cretivecommons.org/pulicdomin/zero/1.0/) pplies to the dt mde ville in this rticle, unless otherwise stted.
2 Al-Hlfi Eye nd Vision (2015) 2:9 Pge 2 of 5 into interconnecting tues over disciform scrs. In histopthologic nd immunofluorescence studies of utopsy eyes from ptient with retinitis pigmentos (RP), it ws demonstrted tht ptches of remining photoreceptors orgnized in rosettes, formed minly of rods, were seen with lumens contining disorgnized photoreceptor structures [6]. Histopthologiclly, rosettes oserved in mouse models with degenerted retins were mtched to tuulr elements shown in OCT findings [7]. In dult rt retins, induced injury to photoreceptors with spring of the retinl pigment epithelium (RPE) led to inner segment/outer segment (IS/OS) degenertion nd migrtion of photoreceptor nuclei in circulr pttern with resultnt rosette-like elements [8]. The im of this study ws to ddress, where possile, the presence of ORT in DME fter tretment with nti- VEGF nd to evlute their impct on clinicl prctice. Methods After pprovl y the reserch committee nd humn ethics committee (Kingdom of Sudi Ari Ministry of Interior Generl Administrtion for Medicl Services, Security Forces Hospitl Progrm RN:15/148/03), retrospective oservtionl cse study series ws performed t the Security Forces Hospitl, Riydh, Sudi Ari. The retrospective review of medicl records of consecutive ptients with DME treted with nti-vegf seen t the outptient retin clinic of Jnury 2013 through Jnury 2014 ws included. The exclusion criteri were mculr disorder ssocited with choroidl neovsculriztion (CNV), retinl dystrophies, degenertions, or inflmmtory disorders other thn DME. Ech ptient underwent ophthlmic exmintion (visul cuity, introculr pressure, iomicroscopy, nd dilted fundus exmintion) t ech visit. Dignosis of DME nd mngement ws mde for ech ptient on the sis of fundus exmintion nd confirmed with OCT. A totl of 514 ptients with DME treted with nti- VEGF were exmined with SD-OCT. ORT ws identified in 12 eyes of 11 ptients with n estimted incidence rte of 2.3%. The men ge ± stndrd devition (SD) ws 43 ± 13 yers. The est-corrected visul cuities nd ctrcts were miniml to sent in ll study sujects. All ptients received 0.05 ml open-lel intrvitrel injections of 0.5 mg rniizum nd evcizum. The SD-OCT imges of mculr retinl lyers were investigted in ll ptients with high-resolution OCT (Optos OCT SLO, United Kingdom) nd ssessed fter diltion of the pupil. In ech retinl OCT, high-density horizontl rster scns were used. 6-mm rster scns of the xil retinl sections ws performed, which simultneously cquired SD-OCT nd ner-infrred reflectnce imges. This enled precise identifiction of corresponding sites of pthology etween the different imging modlities. Horizontl nd verticl scns of the imges were performed to discover the possile presence of ORT nd to determine its prevlence, morphologic chrcter, nd loction in the retinl structures. The occurrence of ORT ws determined in ech retinl exm. When seril SD-OCT studies were ville, the progression of ORT ws ssessed over time. No cler predisposing fctors were oserved for ORT in DME treted with nti-vegf such s numer of injections, mculr thickness, cystoid edem, ptient ge nd durtion of dietes. Sttisticl nlysis Dt were collected from the medicl records of recruited sujects nd stored in spredsheet using Microsoft Excel 2010 softwre. Dt mngement nd coding were then done in Excel. Dt were nlyzed vi SPSS version 20.0 (IBM Inc., Chicgo, Illinois). Descriptive nlysis ws primrily done, where ctegoricl vriles were presented in the form of frequencies nd percentges nd continuous vriles in the form of men (±SD). Inferentil nlysis ws done in forms of comprison of pre nd post intervention mens using Wilcoxon Signed Rnks test. Comprison of proportion test ws conducted to ssess the chnge in percentge of cses tht needed injection (T-test of one smple) using SttPc (Version , SttPc Inc., nd Bloomington, MN, USA). A Figure 1 & Spectrl-domin opticl coherence tomogrphic scns corresponding to the solid white lines show circulr outer retinl tuultion structures with hyperreflective orders.
3 Al-Hlfi Eye nd Vision (2015) 2:9 Pge 3 of 5 Figure 2 & Outer retinl tuultion in ner proximity to sites of cystoids dietic mculr edem, demonstrting the distinguishing fetures of ORT (white rrows) from cystoid mculr edem (lck ovls). confidence intervl level ws set to 95% where corresponding p-vlue threshold ws identified s 0.05 nd ny output of p elow 0.05 would e interpreted s n indictor of sttisticl significnce. Results ORT ws found in 12 eyes of 11 ptients with n estimted incidence rte of 2.3%. Tretment ws with Bevcizum in 4 eyes nd Rniizum in 9 eyes. ORT ws seen in oth eyes of one ptient. The men ge of the ptients ws 50 yers (rnge, yers); 63.6% of ptients studied were mle (7) nd 36.4% were femle (4). The medin visul cuity ws 20/ 30 (rnge, 20/20 to counting fingers). There ws no significnt difference etween ptients with ORT or without ORT in men ge or men est-corrected visul cuity. ORT ws found in ll retinl OCT s round or ovoid shpes with hyperreflective mrgins surrounding centrl lumen with mixed reflectivity (Figure 1). In some cses, ORT ws identified djcent to the cystoid mculr edem (Figure 2). ORT numer in this cse study rnged from 1 to 4 on ny prticulr SD-OCT line scn. ORT verticl height rnged from 34 μm to 115 μm. ORT morphology my rise from the grdul disturnce nd rerrngement of the photoreceptor lyer with the IS/OS fter severl nti-vegf injections secondry to severe nd chronic DME. The presence of ORT lone without mculr thickening does not require further Figure 3 & Presence of ORT without thickening of the mcul due to DME does not need retretment with nti-vegf therpy.
4 Al-Hlfi Eye nd Vision (2015) 2:9 Pge 4 of 5 nti-vegf injections (Figure 3). It is difficult to detect ORT cliniclly without SD-OCT. No cler predisposing fctors were oserved for ORT in DME treted with nti- VEGF such s numer of injections, mculr thickness, cystoid edem, ptient ge nd durtion of dietes. Discussion We oserved ORT in 12 eyes with DME tht were treted with nti-vegf. ORT hs een detected in retinl diseses minly ssocited with CNV or suretinl firosis, such s neovsculr AMD nd ngioid streks cused y pseudoxnthom elsticum [5,6,9,10]. It hs lso een oserved in some cses ssocited with geogrphic trophy without CNV, such s non-neovsculr AMD nd gyrte trophy [11]. 10% of ptients with RP, Strgrdt disese, nd pttern dystrophy were reported to hve ORT [12]. Despite the pthophysiology of the tuules formtion eing uncler, ORT ppers to show common finl pthwy in mny retinl diseses whether they re inflmmtory, degenertive or neovsculr in origin. ORT hs een documented in pthologies minly involving the choroid nd RPE (such s pttern dystrophy) or photoreceptors (such s RP) suggesting tht ORT is finl stge in ptients with chronic disorder of the photoreceptors [12]. In ddition, nother study hs shown tht the outer retinl circulr or ovoid structures were reported in ptients with the Bietti crystlline dystrophy [13]. The OCT findings of the Bietti crystlline dystrophy re comprle to pst studies [14-16]. The SD-OCT scns distinctly showed tht some hyperreflective grnules were identified s crystlline deposits; despite tht, there ws no cler correltion etween the loction of ORT nd crystlline deposits [17]. ORT ws seen in ptient with non AMD entities, such s chronic centrl serous choroidoretinopthy (CSCR), pseudoxnthom elsticum, pttern dystrophy nd multifocl choroiditis [5]. In this study, the verticl height of ORT rnged from 34 to 115 μm. Similrly, the height of ORT structures rnged from 40 to 140 μm, nd the width of horizontl OCT B-scn sections rnged from 40 to 2260 μm [17]. The size of photoreceptor rosettes ws reported to e round 60 μm [6,18]. Despite the pthogenesis of ORT eing uncler, these differences pper to ct s lte stge pthwy in different retinl degenertive processes. The pst reports ssumed tht degenerting photoreceptors my pper orgnized in tuulr fshion nd tht cells in the vicinity such s retinl pigment epithelium nd glil cells my donte to the tuulr structures [5]. In the OCT series, ORT ws shown minly in ptients with CNV or suretinl firosis, nd it ws thought tht the existence of intrretinl nd suretinl exudtion from CNV destroyed the photoreceptor lyer, which would then ctivte the process of tuultion [12]. This study investigted the ssocition etween the existences of ORT in DME fter tretment with nti-vegf. The specultion is tht the ORT pthogenesis in DME treted with nti-vegf could e secondry to severe nd cystoids DME s nti-vegf therpy leds to the rerrngement of retinl lyers nd formtion of ORT. Criticl disruption of the photoreceptors nd/or pigment epithelium, with or without exudtive chnges nd scrring, seems dequte for the ctivity of tuultion to strt [12]. This study hs some limittions such s the smll numer DME treted with nti-vegf ptients with ORT, s well s the lck of control. Further studies re required to deepen our understnding of ORT s presence in ptients treted for DME with nti-vegf. Conclusions ORT my e result of underlying chronic nd severe DME tht my occur secondry to retinl lyers rerrngement fter severl nti-vegf injections. ORT is found in DME treted with nti-vegf tht my show dmge to the outer retin secondry to the severity nd chronicity of the DME. The differentition etween ORT nd cystoids DM hs role in the tretment pln. 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