To study the short-term effects of intravitreal bevacizumab (Avastin) on retinal blood flow velocity and compare them to clinical outcomes assessed by optical coherence tomography (OCT) and tests of visual acuity.
Methods
The Retinal Function Imager (RFI) was used noninvasively and quantitatively to measure retinal blood flow velocity. Eight patients receiving intravitreal injection of Avastin for choroidal neovascularization (CNV) were included in this study. All were imaged by the RFI preinjection and 1 and 7 days postinjection. Visual acuity (VA) and OCT were recorded preinjection and 1 month postinjection. Comparisons were performed using paired Student t test and correlation using Spearman rank test.
Results
A good correlation was found between the 1-month change in VA and OCT measurements and the short-term change induced in blood flow velocity. Arterial and venous velocity changes 1 day after the injection correlated with the VA change (p<0.05). The 1-day arterial velocity changes correlated with total macular volume (p=0.02) and venous velocity changes correlated to central macular thickness (p=0.04).
Conclusions
The RFI provides a noninvasive technique to assess early hemodynamic responses to intravitreal injection of Avastin. These early changes may prove important for better understanding of the mechanism underlying this treatment and serve as a quantitative marker for treatment optimization.
LynchS.S., ChengC.M.. Bevacizumab for neovascular ocular diseases.Ann Pharmacother2007; 41: 614-25.
4.
PournarasC.J., Rungger-BrändleE., RivaC.E., HardarsonS.H., StefanssonE.. Regulation of retinal blood flow in health and disease.Prog Retin Eye Res2008; 27: 284-330.
5.
ShamsN., IanchulevT.. Role of vascular endothelial growth factor in ocular angiogenesis.Ophthalmol Clin North Am2006; 19: 335-44.
6.
TongJ.P., YaoY.F.. Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions.Clin Biochem2006; 39: 267-76.
7.
WitmerA.N., VrensenG.F., Van NoordenC.J., SchlingemannR.O.. Vascular endothelial growth factors and angiogenesis in eye disease.Prog Retin Eye Res2003; 22: 1-29.
8.
ZhangS.X., MaJ.X.. Ocular neovascularization: implication of endogenous angiogenic inhibitors and potential therapy.Prog Retin Eye Res2007; 26: 1-37.
9.
BhuttoI.A., McLeodD.S., HasegawaT.Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration.Exp Eye Res2006; 82: 99-110.
10.
GrisantiS., TatarO.. The role of vascular endothelial growth factor and other endogenous interplayers in age-related macular degeneration.Prog Retin Eye Res2008; 27: 372-90.
11.
van WijngaardenP., QureshiS.H.. Inhibitors of vascular endothelial growth factor (VEGF) in the management of neovascular age-related macular degeneration: a review of current practice.Clin Exp Optom2008; 91: 427-37.
12.
BadalàF.. The treatment of branch retinal vein occlusion with bevacizumab.Curr Opin Ophthalmol2008; 19: 234-8.
13.
ZiemssenF., ZhuQ., PetersS., Tübingen Bevacizumab Study Group. Intensified monitoring of circadian blood pressure and heart rate before and after intravitreous injection of bevacizumab: preliminary findings of a pilot study.Int Ophthalmol2009; 29: 213-24.
14.
Wilkinson-BerkaJ.L.. Vasoactive factors and diabetic retinopathy: vascular endothelial growth factor, cycoloxygenase-2 and nitric oxide.Curr Pharm Des2004; 10: 3331-48.
15.
Saint-GeniezM., D'AmoreP.A.. Development and pathology of the hyaloid, choroidal and retinal vasculature.Int J Dev Biol2004; 48: 1045-58.
16.
Saint-GeniezM., MaharajA.S.R., WalsheT.E.Endogenous VEGF is required for visual function: evidence for a survival role on Müller cells and photoreceptors.PLoS One2008; 3: e3554.
17.
GrinvaldA., BonhoefferT., VanzettaI.High-resolution functional optical imaging: from the neocortex to the eye.Ophthalmol Clin North Am2004; 17: 53-67.
18.
NelsonD.A., KrupskyS., PollackA.Special report: Noninvasive multi-parameter functional optical imaging of the eye.Ophthalmic Surg Lasers Imaging2005; 36: 57-66.
19.
AbràmoffM.D., KwonY.H., Ts'oD.Visual stimulus-induced changes in human near-infrared fundus reflectance.Invest Ophthalmol Vis Sci2006; 47: 715-21.
20.
HanazonoG., TsunodaK., ShinodaK., TsubotaK., MiyakeY., TanifujiM.. Intrinsic signal imaging in macaque retina reveals different types of flash-induced light reflectance changes of different origins.Invest Ophthalmol Vis Sci2007; 48: 2903-12.
21.
GrinvaldA., LiekeE., FrostigR.D., GilbertC.D., WieselT.N.. Functional architecture of cortex revealed by optical imaging of intrinsic signals.Nature1986; 324: 361-4.
22.
LandaG., GarciaP.M., RosenR.B.. Correlation between retina blood flow velocity assessed by retinal function imager and retina thickness estimated by scanning laser ophthalmoscopy/optical coherence tomography.Ophthalmologica2009; 223: 155-61.
23.
BirgerY., BlumenfeldO., BartovE., Burgansky-EliashZ.. Reduced retinal blood flow velocity in severe hyperlipidemia measured by the retinal function imager.Graefes Arch Clin Exp Ophthalmol2011; 249: 1587-90.
24.
BeutelspacherS.C., SerbecicN., BarashH., Burgansky-EliashZ., GrinvaldA., JonasJ.B.. Central serous chorioretinopathy shows reduced retinal flow circulation in retinal function imaging (RFI).Acta Ophthalmol2011; 89: e479-82.
BonninP., PournarasJ.A., LazrakZ.Ultrasound assessment of short-term ocular vascular effects of intravitreal injection of bevacizumab (Avastin®) in neovascular age-related macular degeneration.Acta Ophthalmol2010; 88: 641-5.
27.
FunkM., KriechbaumK., PragerF.Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab.Invest Ophthalmol Vis Sci2009; 50: 1025-32.
28.
PapadopoulouD.N., MendrinosE., MangiorisG., DonatiG., PournarasC.J.. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration.Ophthalmology2009; 116: 1755-61.
29.
HerbstR.S., MullaniN.A., DavisD.W.Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin.J Clin Oncol2002; 20: 3804-14.
30.
AkellaN.S., TwiegD.B., MikkelsenT.Assessment of brain tumor angiogenesis inhibitors using perfusion magnetic resonance imaging: quality and analysis results of a phase I trial.J Magn Reson Imaging2004; 20: 913-22.
31.
YaoJ.C., PhanA., HoffP.M.Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b.J Clin Oncol2008; 26: 1316-23.
32.
ZhuA.X., HolalkereN.S., MuzikanskyA., HorganK., SahaniD.V.. Early antiangiogenic activity of bevacizumab evaluated by computed tomography perfusion scan in patients with advanced hepatocellular carcinoma.Oncologist2008; 13: 120-5.
33.
WillettC.G., BoucherY., di TomasoE.Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.Nat Med2004; 10: 145-7.
34.
GrunwaldJ.E., MetelitsinaT.I., DupontJ.C., YingG.S., MaguireM.G.. Reduced foveolar choroidal blood flow in eyes with increasing AMD severity.Invest Ophthalmol Vis Sci2005; 46: 1033-8.
35.
MetelitsinaT.I., GrunwaldJ.E., DuPontJ.C., YingG.S., BruckerA.J., DunaiefJ.L.. Foveolar choroidal circulation and choroidal neovascularization in age-related macular degeneration.Invest Ophthalmol Vis Sci2008; 49: 358-63.
36.
MoriF., KonnoS., HikichiT., YamaguchiY., IshikoS., YoshidaA.. Pulsatile ocular blood flow study: decreases in exudative age related macular degeneration.Br J Ophthalmol2001; 85: 531-3.
37.
SatoE., FekeG.T., MenkeM.N., Wallace McMeelJ.. Retinal haemodynamics in patients with age-related macular degeneration.Eye2006; 20: 697-702.
38.
MicieliJ.A., TsuiE., LamW-C, BrentM.H., DevenyiR.G., HudsonC.. Retinal blood flow in response to an intravitreal injection of ranibizumab for neovascular age-related macular degeneration.Acta Ophthalmol Epub2011 Jul 29.
39.
WickremasingheS.S., GuymerR.H., WongT.Y., KawasakiR., WongW., QureshiS.. Retinal venular caliber dilatation after intravitreal ranibizumab treatment for neovascular age-related macular degeneration.Clin Exp Ophthalmol Epub2011 Jun 13.
40.
FontaineO., OlivierS., DescovichD., CordahiG., VaucherE., LeskM.R.. The effect of intravitreal injection of bevacizumab on retinal circulation in patients with neovascular macular degeneration.Invest Ophthalmol Vis Sci2011; 52: 7400-5.
41.
TokluY., CakmakH.B., RazaS., AnayolA., AsikE., SimsekS.. Short-term effects of intravitreal bevacizumab (Avastin®) on retrobulbar hemodynamics in patients with neovascular age-related macular degeneration.Acta Ophthalmol2011; 89: e41-5.
42.
GoffM.J., JohnsonR.N., McDonaldH.R., AiE., JumperJ.M., FuA.. Intravitreal bevacizumab for previously treated choroidal neovascularization from age-related macular degeneration.Retina2007; 27: 432-8.
43.
ForooghianF., CukrasC., MeyerleC.B., ChewE.Y., WongW.T.. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration.Retina2009; 29: 723-31.
44.
RitterM., ElledgeJ., SimaderC.Evaluation of optical coherence tomography findings in age-related macular degeneration: a reproducibility study of two independent reading centres.Br J Ophthalmol2011; 95: 381-5.
45.
JoeresS., TsongJ.W., UpdikeP.G.Reproducibility of quantitative optical coherence tomography subanalysis in neovascular age-related macular degeneration.Invest Ophthalmol Vis Sci2007; 48: 4300-7.
46.
KrebsI., HagenS., BrannathW.Repeatability and reproducibility of retinal thickness measurements by optical coherence tomography in age-related macular degeneration.Ophthalmology2010; 117: 1577-84.
47.
Wolf-SchnurrbuschU.E.K., CeklicL., BrinkmannC.K.Macular thickness measurements in healthy eyes using six different optical coherence tomography instruments.Invest Ophthalmol Vis Sci2009; 50: 3432-7.
48.
ForteR., CennamoG.L., FinelliM.L., de CrecchioG.. Comparison of time domain Stratus OCT and spectral domain SLO/OCT for assessment of macular thickness and volume.Eye2009; 23: 2071-8.
49.
LammerJ., ScholdaC., PrünteC., BeneschT., Schmidt-ErfurthU., BolzM.. Retinal thickness and volume measurements in diabetic macular edema: a comparison of four optical coherence tomography systems.Retina2011; 31: 48-55.
50.
LeungC.K., CheungC.Y., WeinrebR.N.Comparison of macular thickness measurements between time domain and spectral domain optical coherence tomography.Invest Ophthalmol Vis Sci2008; 49: 4893-7.
