Accepted foFrom the

Graduate Sc(S.K., Y.M.,and Inoue E

Inquiries tUniversity GSciences, 2-8558, Japan;

0002-9394/$http://dx.doi.

Submacular Hemorrhage in PolypoidalChoroidal Vasculopathy Treated by Vitrectomyand Subretinal Tissue Plasminogen Activator

SHUHEI KIMURA, YUKI MORIZANE, MIO HOSOKAWA, YUSUKE SHIODE, TETSUHIRO KAWATA,SHINICHIRO DOI, RYO MATOBA, MIKA HOSOGI, ATSUSHI FUJIWARA, YASUSHI INOUE, AND

FUMIO SHIRAGA

� PURPOSE: To evaluate vitrectomy with subretinal tis-sue plasminogen activator (t-PA) injection, and airtamponade, followed by intravitreal anti–vascular endo-thelial growth factor (VEGF) therapy for submacularhemorrhage in polypoidal choroidal vasculopathy (PCV).� DESIGN: Prospective, interventional case series.� METHODS: SETTING: Two clinics. PATIENTS: Fifteeneyes of 15 consecutive patients (mean age 72 ± 7 years)with submacular hemorrhage attributable to PCV. INCLU-

SION CRITERIA: PCV diagnosis with unorganized submac-ular hemorrhage greater than 500 mm thick. EXCLUSION

CRITERIA: Submacular hemorrhage attributable to macu-lar diseases (eg, high myopia, typical age-related maculardegeneration, retinal angiomatous proliferation, andangioid streaks). INTERVENTION: Vitrectomy with 4000IU t-PA injected subretinally and fluid/air exchange. Pa-tients remained facedown for 3 days after surgery. Anti-VEGF drugs were administered as exudative changesrequired. MAIN OUTCOME MEASURES: Submacular hemor-rhage displacement from the macula and changes inbest-corrected visual acuities (BCVAs).� RESULTS: Mean time from onset to surgery was 9.5 ±4.5 (range, 5–21) days. Mean follow-up period was9.4 ± 3.1 (range, 6–17) months. Surgery successfullydisplaced submacular hemorrhages from the macula inall eyes. Mean BCVA at baseline (0.98 ± 0.44) hadimproved significantly both 1 month after surgery(0.41 ± 0.25, P < .01) and at final visits (0.23 ± 0.25,P< .001). In all eyes, exudative retinal changes relapsedafter surgery but were completely resolved by anti-VEGFinjections. No complications occurred in any patients.� CONCLUSION: Treating submacular hemorrhage withvitrectomy and subretinal t-PA injection, followed byintravitreal anti-VEGF therapy, is a promising strategyfor improving visual acuity in PCV patients warranting

r publication Dec 15, 2014.Department of Ophthalmology, Okayama University

hool of Medicine, Dentistry and Pharmaceutical SciencesM.Hosokawa, Y.S., T.K., S.D., R.M., M.Hosogi, A.F., F.S.);ye Clinic (Y.I.), Okayama, Japan.o Shuhei Kimura, Department of Ophthalmology, Okayamaraduate School of Medicine, Dentistry and Pharmaceutical5-1 Shikata-cho Kita-ku, Okayama City, Okayama 700-e-mail: shuheik@cc.okayama-u.ac.jp

36.00org/10.1016/j.ajo.2014.12.020

� 2015 BY ELSEVIER INC.

further investigation. (Am J Ophthalmol 2015;159:683–689. � 2015 by Elsevier Inc. All rights reserved.)

SUBMACULARHEMORRHAGECANARISE IN A VARIETY

of diseases, including exudative age-related maculardegeneration (AMD), retinal arterialmacroaneurysm,

pathologic myopia, choroidal neovascularization of variousetiology, and trauma.1–4 Submacular hemorrhage causessudden visual loss and results in a poor visual prognosis,especially when it is not appropriately treated.4,5 Atpresent, the treatment options available for submacularhemorrhage are ‘‘nonvitrectomizing techniques,’’ withintravitreal injections of gas or tissue plasminogen activator(t-PA) or anti–vascular endothelial growth factor(VEGF) drugs or a combination of these, or ‘‘vitrectomizingtechniques,’’ with injections of t-PA or anti-VEGF drugs orgas or a combination of these administered either as intravi-treal or subretinal injections or by a combination of subreti-nal and intravitreal injections.6–18 Recently, Haupert andassociates reported that the displacement of submacularhemorrhages by vitrectomy and subretinal injections of t-PA is effective in AMD patients.11 Furthermore, both intra-vitreal and subretinal injection of anti-VEGF drugs duringvitrectomy and/or intravitreal injection of anti-VEGF drugsfollowing vitrectomy have been reported to be effective inmaintaining improved visual acuity.15–18

Polypoidal choroidal vasculopathy (PCV) is an exuda-tive maculopathy affecting vision, with a prevalence of10%–54% inAsian patients and 8%–12% in white patientswith presumed exudative AMD.19,20 Clinically, PCV ischaracterized by a complex choroidal vascular networkwith multiple, terminal, reddish-orange polypoidal le-sions.21,22 Although, in general, the natural course ofPCV is more stable than AMD, PCV has been shown tocause occasional, massive submacular hemorrhages,which eventually results in chorioretinal atrophy andpermanent vision loss.5,6,21

Previously, in PCV patients, we have reported the thera-peutic effect of surgically removing submacular hemorrhagesby retinotomy and the use of t-PA.23,24 Since theliquefaction of submacular hemorrhages by the subretinalinjection of t-PA and the displacement of submacularhemorrhages by vitrectomy with air tamponade is a simpler

683ALL RIGHTS RESERVED.

and safer surgical procedure than retinotomy withmechanical submacular hemorrhage removal, we haveinvestigated the therapeutic effect and safety of thisprocedure for submacular hemorrhage displacement inPCV patients. In addition, we have investigated thetherapeutic effect of anti-VEGF therapy following surgery.

METHODS

� STUDY DESIGN AND PATIENTS: This study was a pro-spective, interventional case series and all investigationsadhered to the tenets of the Declaration of Helsinki.Each patient was informed about the risks and benefits ofthe surgery and participation in this research study. Theirwritten informed consent for both the surgery and partici-pation in this research study was obtained. The study wasapproved by the Institutional Review Boards of OkayamaUniversity Graduate School of Medicine, Dentistry andPharmaceutical Sciences and Inoue Eye Clinic.

Fifteen eyes of 15 consecutive patients who were diag-nosed with submacular hemorrhage attributable to PCV be-tween January 8, 2012 and February 15, 2014 were recruitedto the study. Diagnosis of PCV was based on both the pres-ence of elevated orange-red lesions observed at fundus exam-ination and the presenceof characteristic polypoidal vascularlesions by indocyanine green angiography (ICGA). The sizeof the submacular hemorrhage was recorded as the greatestlinear dimension.25 The inclusion criteria used were: (1)submacular hemorrhage attributable to PCV, (2) the pres-ence of submacular hemorrhage with a thickness greaterthan 500 mm, as measured by optical coherence tomography(OCT), and (3) unorganized submacular hemorrhage, asdetermined by fundus examination, in contrast to organizedsubmacular hemorrhages, which we considered as white and/or fibrous in appearance. Patients with submacular hemor-rhage attributable to other macular diseases, such as highmyopia, typical AMD, retinal angiomatous proliferation,and angioid streaks, were excluded.

The patients’ demographic data are shown in the Table.The 1 female and 14 male patients had a mean age (6SD)of 726 7 years, with a range of 61–84 years. The time fromonset to surgery was 9.56 4.5 days (range, 2–21 days), themean diameter of submacular hemorrhages was 5.6 6 4.7disc diameters (range, 1.5–20 disc diameters), and themean thickness of submacular hemorrhages was 793 6312 mm (range, 504–1422 mm). Six eyes were pseudo-phakic preoperatively and all 15 eyes were pseudophakicpostoperatively. The mean follow-up period was 9.4 63.1 months (range, 6–17 months). The mean number ofanti-VEGF injections was 3.56 1.9 (range, 1–7). No com-plications occurred during or after surgery in any patients.

All patients underwent comprehensive ophthalmologicexaminations before and after surgery, including measure-ment of best-corrected visual acuity (BCVA) with

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refraction, using the 5-m Landolt C acuity chart, and indi-rect and contact lens slit-lamp biomicroscopy. All eyeswere examined by spectral-domain optical coherence to-mography (SD OCT) before and after surgery and atfollow-up, using commercially available instruments(Cirrus; Carl Zeiss Meditec, Inc, Dublin, California,USA; Spectralis; Heidelberg Engineering GmbH, Heidel-berg, Germany; and DRI OCT-1 Atlantis; TopconMedicalSystems, Tokyo, Japan).The main outcome measures were displacement of the

submacular hemorrhage from the macula in OCT imagesand differences between preoperative and postoperativeBCVAs.

� SURGICAL TECHNIQUE: The submacular hemorrhagedisplacement was carried out using a surgical procedureinspired by the report by Haupert and associates.11 Briefly,after a 25 gauge microincision vitrectomy was performed,4000 IU t-PA (Cliactor, Eizai, Japan) in 0.1mLwas injectedsubretinally using a 38 gauge subretinal infusion needle(MedOne, Sarasota, Florida, USA) to liquefy the submacu-lar hemorrhage,whichwas 14%–28%of thedoses previouslyused.11,13 Before finishing the operation, fluid-air exchangewas performed to displace the submacular hemorrhage.The patients remained facedown for 3 days after surgery.In 9 phakic eyes, phacoemulsifications with implantationof an intraocular lens were carried out simultaneously. Allsurgeries were performed by the same surgeon (F.S.).

� POSTOPERATIVE ANTI–VASCULAR ENDOTHELIALGROWTH FACTOR THERAPY: Intravitreal injections ofanti-VEGF reagents were performed pro re nata (PRN)when exudative and/or hemorrhagic changes, such as theaccumulation of subretinal fluid and recurrence of submac-ular hemorrhage, occurred after surgery.20 We used either0.5 mg ranibizumab (Lucentis; Genentech, Inc, SouthSan Francisco, California, USA) or 0.5 mg aflibercept(Eylea; Bayer, Basel, Switzerland).

� DATA ANALYSIS: BCVAs were recorded as decimalvalues and converted to the logarithm of the minimal angleof resolution (logMAR) units for statistical analysis. Thepreoperative, 1 month, and final postoperative BCVAswere compared using the Mann-Whitney U test. P valuesless than .05 were considered significant. All statistical an-alyses were performed using SPSS for Windows version17.0 (SPSS, Inc, Chicago, Illinois, USA). Data arepresented as means 6 standard deviation (SD).

RESULTS

� ANATOMICAL RESULTS: Submacular hemorrhages hadbeen successfully moved away from the macula to the infe-rior periphery in all eyes during surgery and were absorbed

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TABLE. Characteristics of Patients Undergoing Submacular Hemorrhage Displacement Owing to Polypoidal Choroidal Vasculopathy

Case No. Sex Age (y)

Disease

Duration (d)

Lesion Size

(Disc Diameter) Lens Status

BCVA (logMAR) Ellipsoid

Line at the

Final Visit

Follow-up

(mo)

Postoperative Anti-VEGF Therapy

Pre 1 Month Final Reagents (No. of Treatments)

1 Male 75 6 10 Phakic 1.22 0.70 0.10 þ 17 Ranibizumab (5)

2 Male 62 2 6 Pseudophakic 0.52 0.15 0.10 � 13 Aflibercept (6)

3 Male 78 7 8 Pseudophakic 1.30 0.40 0.22 þ 12 Aflibercept (1)

4 Male 67 9 2 Pseudophakic 1.22 1.05 1.05 � 12 Aflibercept (5)

5 Male 80 12 6 Pseudophakic 1.52 0.52 0.22 þ 12 Aflibercept (7)

6 Female 84 10 1.5 Phakic 1.00 0.15 0.22 þ 10 Aflibercept (2)

7 Male 70 8 20 Phakic 0.70 0.22 0.05 þ 9 Aflibercept (6)

8 Male 73 7 2.5 Phakic 1.10 0.30 0.05 þ 9 Ranibizumab (3)

9 Male 77 21 5 Phakic 2.00 0.30 0.15 þ 8 Aflibercept (1)

10 Male 62 15 3 Pseudophakic 1.00 0.52 0.15 þ 8 Aflibercept (3)

11 Male 66 10 3 Phakic 0.52 0.30 �0.08 þ 7 Ranibizumab (1)

12 Male 73 14 1.5 Phakic 1.00 0.52 0.40 � 6 Aflibercept (3)

13 Male 61 5 3 Phakic 0.30 0.22 0.10 þ 6 Aflibercept (2)

14 Male 79 7 3.5 Phakic 0.82 0.70 0.40 � 6 Aflibercept (3)

15 Male 71 10 10 Pseudophakic 0.40 0.15 �0.08 þ 6 Aflibercept (4)

BCVA ¼ best-corrected visual acuity; VEGF ¼ vascular endothelial growth factor.

FIGURE 1. Graph showing the best-corrected visual acuity(BCVA) of patients with polypoidal choroidal vasculopathy atbaseline, 1 month after surgery for submacular hemorrhage,and at their final clinic visits. Postoperative BCVAs were bothsignificantly improved compared to baseline BCVA. Errorbars represent standard deviations. logMAR, logarithm of theminimal angle of resolution; *P < .01; **P < .001.

FIGURE 2. Scatterplot comparing best-corrected visual acu-ities (BCVAs) before surgery and at the final clinic visits in pa-tients with submacular hemorrhage attributable to polypoidalchoroidal vasculopathy. logMAR [ logarithm of the minimalangle of resolution.

thereafter. In all eyes, postoperative anti-VEGF therapywas administered as necessary and exudative and/or hemor-rhagic manifestations attributable to polypoidal lesions hadresolved completely by the patients’ final visits. In addition,inner segment ellipsoid zones were detectable in the mac-ula in 11 of 15 eyes (73%) at these final visits.

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� POSTOPERATIVE VISUAL OUTCOME: Mean BCVAs atbaseline (0.98 6 0.44) had improved significantly both1 month after surgery (0.41 6 0.25, P < .01) and at finalvisits (0.236 0.25, P< .001; Figures 1 and 2). The final vi-sual acuity had improved by more than 0.3 logMAR unitsin 13 of 15 eyes and was unchanged in the remaining 2

685OIDAL CHOROIDAL VASCULOPATHY

FIGURE 3. Results of submacular hemorrhage displacement in Patient 5, an 80-year-old man with polypoidal choroidal vasculop-athy. (Top left) Fundus photograph at initial visit showing submacular hemorrhage. (Top right) Indocyanine green angiography(ICGA) at initial visit showing polypoidal lesions (arrows). (Second right) Spectral-domain optical coherence tomography (SDOCT) at initial visit showing dense submacular hemorrhage (asterisk) and retinal pigment epithelium detachment (arrow heads).(Center left) Fundus photograph 1 week after surgery showing reduced submacular hemorrhage. (Bottom left) Fundus photograph3 months after surgery showing disappearance of submacular hemorrhage. (Third right) ICGA 3months after surgery showing disap-pearance of polypoidal lesions. (Bottom right) SD OCT image 8 months after surgery showing disappearance of submacular hemor-rhage. Best-corrected visual acuity (logarithm of the minimal angle of resolution) improved from 1.52 before surgery to 0.20 at thefinal visit.

eyes (Figure 2). Twelve of 15 eyes (80%) achieved final vi-sual acuities of 0.3 or better. Final visual acuity showed nosignificant correlation with either disease duration or hem-orrhage size or preoperative visual acuity.

Figures 3 and 4 show the clinical results for 2 PCV pa-tients with submacular hemorrhages who underwent vit-rectomy, subretinal injection of 4000 IU t-PA, andintravitreal injection of air, followed by anti-VEGF ther-apy. In both patients, the submacular hemorrhages weremoved to the inferior periphery. SD OCT images showedthe complete regression of submacular hemorrhages atthe patients’ final clinic visits.

686 AMERICAN JOURNAL OF

DISCUSSION

AT PRESENT, THE TREATMENT OPTIONS AVAILABLE FOR

submacular hemorrhage can be broadly divided into‘‘nonvitrectomizing techniques’’ and ‘‘vitrectomizing tech-niques.’’ Both approaches have been combined with intra-vitreal injection of t-PA or anti-VEGF or gas or acombination of these.4–11 However, the intravitrealinjection of gas into nonvitrectomized eyes can causesudden retinal detachment and vitreous hemorrhage.6–10

Using a vitrectomizing technique it is possible to usesubretinal injections of t-PA or anti-VEGF or air or a

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FIGURE 4. Results of submacular hemorrhage displacement in Patient 11, a 66-year-old man with submacular hemorrhage attribut-able to polypoidal choroidal vasculopathy. (Top left) Fundus photograph at initial visit showing submacular hemorrhage. (Bottom left)Spectral-domain optical coherence tomography (SD OCT) at initial visit showing dense submacular hemorrhage and pigment epithe-lium detachment (PED). (Top center) Fundus photograph 1 week after surgery showing submacular hemorrhage moved to the inferiorperiphery. (Bottom center) SD OCT image 2 weeks after surgery showing complete disappearance of submacular hemorrhage andPED. (Top right) Fundus photograph at 8 months after surgery showing complete disappearance of submacular hemorrhage. (Bottomright) SDOCT image 8 months after surgery showing disappearance of submacular hemorrhage and PED. Best-corrected visual acuity(logarithm of theminimal angle of resolution) improved from 0.53 before surgery to 0.30 1week after surgery and 0.07 at the final visit.

combination of these and also to combine subretinal andintravitreal injections of different therapeutic agents.4–18

Interestingly, intravitreal injections of t-PA have beenshown to be less effective than subretinal injections incompletely liquefying submacular hemorrhages.14

In an animal model, intravitreal t-PA has been reportednot to diffuse through the intact neural retina, so wouldnot reach subretinal clots.26 By contrast, vitrectomy withsubretinal t-PA injection and gas tamponade, which wasinitially conceived and adopted by Haupert and associates,has been shown to have fewer vitreoretinal complicationsand a high rate (50%–85%) of complete submacular hemor-rhage displacement.11,12,14–18,27,28 In this study, wemodifiedtheir surgical procedure, using a lower dose of 4000 IU t-PA,which was 14%–28% of the doses previously used, and usingpostoperative treatment with anti-VEGF drugs.11,13We sawno vitreoretinal complications and achieved completesubmacular hemorrhage displacement in all eyes. Theseresults indicate that this surgical procedure is a promisingstrategy in the treatment of submacular hemorrhagesattributable to PCV.

The results of our study suggest that thebest time for surgeryon submacular hemorrhages attributable to PCV may be 7–10 days after onset. Timing is a critical factor for the adequatedisplacement of submacular hemorrhages, so that a goodimprovement in visual acuity is achieved. If surgery is carriedout too early, there is a risk of t-PA causing re-bleeding aftersurgery. If it is too late, it is impossible to liquefy organizedsubmacular hemorrhages and to adequately displace them.In this study, we carried out submacular hemorrhage displace-ments at 9.5 6 4.5 days from onset (range, 2–21 days; seeTable).We did not see any re-bleeding or organizing submac-

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ular hemorrhages. However, to fully address the optimal timefor displacing submacular hemorrhages, further studies withlarger numbers of patients will be needed.In this study, retinal exudative changes recurred in all eyes

after submacular hemorrhage displacement. We thereforeinjected an anti-VEGF reagent PRN and this maintainedthe postoperative improvements seen in visual acuity. Ourresults are consistent with previous reports describing the ef-ficacy of anti-VEGF therapy after submacular hemorrhagedisplacement in AMD patients.15–18 Recently, varioustreatment protocols for anti-VEGF reagents have been pro-posed inAMD, includingmonthly injections and treat-and-extend regimens, as well as PRN.29–31 Further studies toclarify the most appropriate injection protocol are needed,particularly considering reports concerning the effect ofvitrectomy on the pharmacokinetics of anti-VEGF re-agents.32–34

Although this study was limited by a small sample sizeand relatively short follow-up periods, our results suggestthat vitrectomy, subretinal injection of t-PA (4000 IU)to liquefy the submacular hemorrhage, and air tamponadeto displace the submacular hemorrhage, followed by anti-VEGF therapy, might be effective and safe for the treat-ment of submacular hemorrhage associated with PCV. Inour treatments, rapid displacement of submacular hemor-rhage from the macula and subsequent inhibition of exuda-tive and/or hemorrhagic changes owing to anti-VEGFtherapy resulted in excellent visual outcomes. Further ran-domized controlled clinical studies involving a larger num-ber of patients are needed to determine the impact that thistreatment strategy could have in the management ofsubmacular hemorrhage associated with PCV.

687OIDAL CHOROIDAL VASCULOPATHY

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTERESTand none were reported. None of the authors received funding for this work from any external organization. Contribution of authors: design and conduct ofstudy (S.K., Y.M., F.S.); data collection (S.K., Y.S., T.K., S.D., R.M., A.F., Y.I.); management, analysis, and interpretation of data (S.K., Y.M., F.S.);writing the article (S.K.); and critical revision and final approval of article (S.K., Y.M., M.Hosokawa, Y.S., T.K., R.M., M.Hosogi, A.S., Y.I., F.S.).

REFERENCES

1. Bennett SR, Folk JC, Blodi CF, Klugman M. Factors prog-nostic of visual outcome in patients with subretinal hemor-rhage. Am J Ophthalmol 1990;109(1):33–37.

2. Avery RL, Fekrat S, Hawkins BS, Bressler NM. Natural his-tory of subfoveal subretinal hemorrhage in age-related macu-lar degeneration. Retina 1996;16(3):183–189.

3. Scupola A, Coscas G, Soubrane G, Balestrazzi E. Natural his-tory of macular subretinal hemorrhage in age-related maculardegeneration. Ophthalmologica 1999;213(2):97–102.

4. Okubo A, Arimura N, Abematsu N, Sakamoto T. Predictablesigns of benign course of polypoidal choroidal vasculopathy:based upon the long-term observation of non-treated eyes.Acta Ophthalmol 2010;88(4):e107–114.

5. Uyama M, Wada M, Nagai Y, et al. Polypoidal choroidalvasculopathy: natural history. Am J Ophthalmol 2002;133(5):639–648.

6. Jung JH, Lee JK, Lee JE, Oum BS. Results of vitrectomy forbreakthrough vitreous hemorrhage associated with age-related macular degeneration and polypoidal choroidalvasculopathy. Retina 2010;30(6):865–873.

7. Ohji M, Saito Y, Hayashi A, Lewis JM, Tano Y. Pneumaticdisplacement of subretinal hemorrhage without tissue plas-minogen activator. Arch Ophthalmol 1998;116(10):1326–1332.

8. Chen CY, Hooper C, Chiu D, Chamberlain M, Karia N,Heriot WJ. Management of submacular hemorrhage withintravitreal injection of tissue plasminogen activator andexpansile gas. Retina 2007;27(3):321–328.

9. Tsymanava A, Uhlig CE. Intravitreal recombinant tissueplasminogen activator without and with additional gas injec-tion in patients with submacular haemorrhage associated withage-related macular degeneration. Acta Ophthalmol 2011;90(7):633–638.

10. Hattenbach LO, Klais C, Koch FH, Gumbel HO. Intravitre-ous injection of tissue plasminogen activator and gas in thetreatment of submacular hemorrhage under various condi-tions. Ophthalmology 2001;108(8):1485–1492.

11. Haupert CL, McCuen BW, Jaffe GJ, et al. Pars plana vitrec-tomy, subretinal injection of tissue plasminogen activator,and fluid-gas exchange for displacement of thick submacularhemorrhage in age-related macular degeneration. Am JOphthalmol 2001;131(2):208–215.

12. Olivier S, ChowDR, Packo KH,MacCumberMW, AwhCC.Subretinal recombinant tissue plasminogen activator injec-tion and pneumatic displacement of thick submacular hemor-rhage in age-related macular degeneration. Ophthalmology

2004;111(6):1201–1208.13. Fine HF, Iranmanesh R, Del Priore LV, et al. Surgical out-

comes after massive subretinal hemorrhage secondary to age-related macular degeneration. Retina 2010;30(10):1588–1594.

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14. Hillenkamp J, Surguch V, Framme C, Gabel V-P, Sachs HG.Management of submacular hemorrhage with intravitrealversus subretinal injection of recombinant tissue plasminogenactivator. Graefes Arch Clin Exp Ophthalmol 2010;248(1):5–11.

15. Treumer F, Klatt C, Roider J, Hillenkamp J. Subretinal coap-plication of recombinant tissue plasminogen activator andbevacizumab for neovascular age-related macular degenera-tion with submacular haemorrhage. Br J Ophthalmol 2009;94(1):48–53.

16. Arias L, Mones J. Transconjunctival sutureless vitrectomywith tissue plasminogen activator, gas and intravitreal beva-cizumab in the management of predominantly hemorrhagicage-related macular degeneration. Clin Ophthalmol 2010;4:67–72.

17. Treumer F, Roider J, Hillenkamp J. Long-term outcome ofsubretinal coapplication of rtPA and bevacizumab followedby repeated intravitreal anti-VEGF injections for neovascularAMD with submacular haemorrhage. Br J Ophthalmol 2012;96(5):708–713.

18. van Zeeburg EJ, van Meurs JC. Literature review of recombi-nant tissue plasminogen activator used for recent-onsetsubmacular hemorrhage displacement in age-related maculardegeneration. Ophthalmologica 2013;229(1):1–14.

19. Yannuzzi LA, Ciardella A, Spaide RF, Rabb M, Freund KB,Orlock DA. The expanding clinical spectrum of idiopathicpolypoidal choroidal vasculopathy. Arch Ophthalmol 1997;115(4):478–485.

20. Koh A, Lee WK, Chen L-J, et al. EVEREST study: efficacyand safety of verteporfin photodynamic therapy in combina-tion with ranibizumab or alone versus ranibizumabmonother-apy in patients with symptomatic macular polypoidalchoroidal vasculopathy. Retina 2012;32(8):1453–1464.

21. Uyama M, Matsubara T, Fukushima I, et al. Idiopathic poly-poidal choroidal vasculopathy in Japanese patients. ArchOphthalmol 1999;117(8):1035–1042.

22. Spaide RF, Yannuzzi LA, Slakter JS, Sorenson JJ, Orlach DA.Indocyanine green videoangiography of idiopathic polypoidalchoroidal vasculopathy. Retina 1994;15(2):100–110.

23. Shiraga F, Matsuo T, Yokoe S, et al. Surgical treatment ofsubmacular hemorrhage associated with idiopathic polypoi-dal choroidal vasculopathy. Am J Ophthalmol 1999;128(2):147–154.

24. Matsuo T, Shiraga F, Takasu I. Planned two-step vitrectomyfor extremely large and thick subretinal hematoma. ActaOphthalmol Scand 2001;79(5):533–537.

25. Photodynamic therapy of subfoveal choroidal neovasculariza-tion in age-related macular degeneration with verteporfin:one-year results of 2 randomized clinical trials–TAP report.Treatment of age-related macular degeneration with photo-dynamic therapy (TAP) Study Group. Arch Ophthalmol

1999;117(10):1329–1345.

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26. Kamei M, Misono K, Lewis H. A study of the ability of tissueplasminogen activator to diffuse into the subretinal space af-ter intravitreal injection in rabbits. Am J Ophthalmol 1999;128(6):739–746.

27. Guthoff R, Guthoff T,Meigen T, GoebelW. Intravitreous in-jection of bevacizumab, tissue plasminogen activator, and gasin the treatment of submacular hemorrhage in age-relatedmacular degeneration. Retina 2011;31(1):36–40.

28. MayerWJ, Hakim I, Haritoglou C, et al. Efficacy and safety ofrecombinant tissue plasminogen activator and gas versusbevacizumab and gas for subretinal haemorrhage. ActaOphthalmol 2011;91(3):274–278.

29. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab forneovascular age-related macular degeneration. N Engl J Med2006;355(14):1419–1431.

30. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosingregimen with intravitreal ranibizumab for neovascular

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age-related macular degeneration: year 2 of the PrONTOStudy. Am J Ophthalmol 2009;148(1):43–58.

31. Abraham P, Yue H, Wilson L. Randomized, double-masked,sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 2. Am JOphthalmol 2010;150(3):315–324.

32. Kakinoki M, Sawada O, Sawada T, Saishin Y, Kawamura H,Ohji M. Effect of vitrectomy on aqueous VEGF concentra-tion and pharmacokinetics of bevacizumab in macaque mon-keys. Invest Ophthalmol Vis Sci 2012;53(9):5877–5880.

33. Christoforidis JB,WilliamsMM,Wang J, et al. Anatomic andpharmacokinetic properties of intravitreal bevacizumab andranibizumab after vitrectomy and lensectomy. Retina 2013;33(5):946–952.

34. Ahn SJ, Ahn J, Park S, et al. Intraocular pharmacokinetics ofranibizumab in vitrectomized versus nonvitrectomized eyes.Invest Ophthalmol Vis Sci 2014;55(1):567–573.

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Biosketch

Shuhei Kimura, MD, PhD, is an Assistant Professor, Department of Ophthalmology, Okayama University, Okayama,

Japan. After graduation of Okayama University Graduate School of Medicine, he completed the residency in

ophthalmology and retina fellowship at Okayama University Hospital. He specializes in vitreoretinal surgery.

689.e1 APRIL 2015AMERICAN JOURNAL OF OPHTHALMOLOGY