Clinical science Baseline retrobulbar blood flow is associated with both functional and structural glaucomatous progression after 4 years Nicholas A Moore, Alon Harris, Scott Wentz, Alice Chandra Verticchio Vercellin, Priyanka Parekh, Joshua Gross, Rehan M Hussain, Claudia Thieme, Brent Siesky

Department of , ABSTRACT factors in the disease onset and progression.56This Indiana University School of Background/aims Previous studies suggest that has led to the evaluation of ocular blood flow and , Indianapolis, Indiana, USA vascular abnormalities are involved in the pathogenesis its role in . of open-angle glaucoma. This study aims to examine the Ischaemia to the and reduced ocular Correspondence to relationship of baseline retrobulbar blood flow blood flow has been shown to contribute to the Professor Alon Harris, measurements with functional and structural pathogenesis and progression of glaucoma.78 Department of Ophthalmology, glaucomatous progression in patients with open-angle Several systemic and localised vascular abnormal- Indiana University School of Medicine, 1160 West Michigan glaucoma over 4 years. ities have been linked to OAG including arterial Street, Indianapolis, IN 46202, Methods In this study, 112 patients with open-angle hypertension, nocturnal hypotension, USA; [email protected] glaucoma were examined at baseline and 78 with haemorrhage, migraines and age-related changes of – retrobulbar blood flow assessments were followed to the vasculature.9 12 In addition, a decreased ocular Received 27 January 2016 4 years. Colour Doppler imaging was used to evaluate perfusion pressure has been linked to an increase in Revised 17 May 2016 13–17 Accepted 25 May 2016 retrobulbar blood flow. Structural disease progression OAG prevalence, incidence and progression. Published Online First was examined with optical coherence tomography and Patients with OAG have been found to have 13 June 2016 Heidelberg Retinal Tomography III. Functional disease reduced blood flow in the retinal, choroidal and progression was monitored with automated perimetry retrobulbar circulations which is associated with using Humphrey visual fields. Mixed-model analysis of glaucomatous functional and structural disease pro- – covariance was used to test for significance of changes gression.18 23 However, the results from these from baseline to 4-year follow-up. Two-sample t tests studies are varied, and the exact relationship and χ2 tests were used to test for baseline blood flow between ocular blood flow and glaucoma progres- differences between patients who progressed and those sion has not been fully delineated. who did not progress. Many of these previous studies are limited by Results Patients who progressed structurally had a small sample sizes, often involve a heterogeneous statistically significant lower baseline mean ophthalmic group of patients including glaucoma suspects and artery peak systolic velocity (PSV) (p=0.024) and do not evaluate both functional and structural glau- ophthalmic artery end diastolic velocity (EDV) (p=0.012) coma progression in parallel. We previously compared with those who did not progress. Similarly, a reported findings detailing the association between lower baseline mean ophthalmic artery PSV (p=0.031) reductions in retrobulbar and retinal blood flow and ophthalmic artery EDV (p=0.005) were associated over time with structural glaucomatous progres- with patients who progressed functionally compared sion.24 Here, we present data from a large 4-year with those who did not progress after 4 years. longitudinal study detailing the relationship Conclusions In this study population, lower baseline between retrobulbar blood flow and simultaneous ophthalmic artery blood flow velocities were associated structural and functional glaucoma progression. with simultaneous structural and functional glaucoma progression after 4 years. MATERIAL AND METHODS A cohort of patients with OAG were enrolled in INTRODUCTION this study and examined at baseline and every Primary open-angle glaucoma (OAG) is a multifac- 6 months for 4 years at the Glaucoma and torial characterised by progressive Diagnostic Center at Indiana University School of retinal ganglion cell death and a characteristic Medicine. All patients signed an informed consent visual field loss. Elevated (IOP) prior to initiation of this study, which adhered to has been identified as a major risk factor for OAG the tenets of the Declaration of Helsinki. The study and current treatments focus on reducing and con- protocol was approved by the Institutional Review trolling the IOP to limit disease progression. Board committee at the Indiana University School Despite advances in pharmacological and surgical of Medicine. interventions, however, it is well established that All participants were required to meet the fol- glaucoma progression is still observed in some lowing inclusion criteria: age 30 years or older, patients with IOP reduction. Additionally, a high confirmed OAG in at least one by a glaucoma percentage of individuals with elevated IOP do not specialist, best-corrected visual acuity of 20/60 or To cite: Moore NA, – Harris A, Wentz S, et al. Br J develop glaucoma.1 4 Each of these findings sug- better in the study eye, and acceptable reliability Ophthalmol 2017;101:305– gests that glaucoma progression is multifactorial in indices in previous Humphrey visual field 308. origin and there are other underlying contributing examinations.

Moore NA, et al. Br J Ophthalmol 2017;101:305–308. doi:10.1136/bjophthalmol-2016-308460 305 Clinical science

Patients were excluded for the following reasons: Humphrey Peripapillary retinal nerve fibre layer (RNFL) thickness and visual field damage consistent with a mean deviation (MD) less optic nerve head (ONH) parameters were assessed by optical than −15 decibels or a clinically determined threat to fixation in coherence tomography (OCT) (Stratus software V.4.0, Zeiss both hemifields, evidence of pseudoexfoliation or pigment dis- Meditec, Dublin, California, USA). The examination was per- persion, history of acute angle-closure glaucoma or a narrow formed and repeated until good-quality analysis (signal strength occludable anterior chamber angle, history of chronic or recur- <7) was obtained. Measurements were made along a circle con- rent inflammatory eye diseases, history of intraocular trauma, centric with the optical disc (Fast RNFL thickness acquisition severe or progressive retinal disease, any abnormality preventing protocol) to assess RNFL thickness. The mean RNFL thickness reliable applanation tonometry, within the past and cup/disc vertical and horizontal ratios were calculated by year, resting pulse <50 bpm, or severe cardiovascular, renal or OCT using the existing software. Topographic analysis of the pulmonary disease. ONH was performed using Heidelberg Retinal Tomography III One qualified eye was randomly assigned as the observational (HRT-III) (Heidelberg Engineering, Heidelberg, Germany). The study eye for each subject. All patients were questioned for their HRT-III was a secondary modality to OCT and was used to sup- clinical history, assessed for IOP by Goldmann applanation tono- plement evaluation for subtle RNFL and ONH changes. metry, and evaluated for best-corrected visual acuity. To limit Structural progression was defined as two consecutive visits with reproducibility bias with imaging, a single experienced operator an RNFL thickness decrease ≥8% and/or horizontal or vertical with over 10 years of experience performed all measurements in cup/disc ratio increase by ≥0.2 from baseline. the same order and at the same time of the day for each patient. Statistical analysis involved performing a mixed-model ana- Retrobulbar blood flow velocities and vascular resistance were lysis of covariance to test for significant change from baseline to measured with the Philips HDI 5000 colour Doppler imaging 4-year follow-up. Two-sample t tests and χ2 tests were used to (CDI) system with the microvascular small parts clinical option analyse differences in baseline data between patients who pro- using a 7.5 MHz linear probe (Philips Ultrasound, Bothell, gressed and those who did not progress. Washington, USA). Peak systolic velocity (PSV) and end diastolic velocity (EDV) were determined for the ophthalmic artery RESULTS (OA), central retinal artery (CRA), nasal posterior ciliary artery In this study, 112 patients with OAG were enrolled according to (NPCA) and temporal posterior ciliary artery (TPCA). The the prior listed inclusion and exclusion criteria and 78 patients Pourcelot’s resistive index (RI) was calculated (RI=(PSV−EDV)/ with retrobulbar blood flow assessments using CDI were fol- PSV)) for each vessel. Retrobulbar blood flow velocities obtained lowed through to 4 years. Overall baseline characteristics of the by CDI were standardised by using a printout at each visit to population revealed a mean age 64.9±11.0 years; female ensure that velocities were taken from nearly the same location (n=68), male (n=44); African descent (n=29), European in each vessel. CDI was selected as the imaging modality of descent (n=83); non-insulin-dependent diabetes mellitus choice because of its known reproducibility at measuring retro- (n=21), no diabetes mellitus (n=91). bulbar blood flow velocities and calculating the RI.25 In this study population, the RI significantly increased in all Visual function was assessed by automated perimetry with the four retrobulbar vascular territories when compared with 4-year Humphrey Field Analyzer II, using the 24-2 Swedish Interactive follow-up. The EDV decreased in all vessel groups, but the Threshold Algorithm standard (white III stimulus) V.4.1 (Carl change was only significant in the OA and CRA. In addition, the Zeiss Mediatec, Dublin, California, USA). Visual field progres- PSV decreased in the OA and CRA, but increased in the NPCA sion was determined using the Humphrey Glaucoma and TPCA—no PSV change was significant (table 1). Progression Analysis software. Functional glaucoma progression Structural and functional changes were assessed in 83 patients was defined as two consecutive visits with an Advanced over the course of the study to 4 years. Findings revealed that Glaucoma Intervention Study (AGIS) score increase ≥2from the IOP decreased from baseline to 4 years. Functional visual baseline or MD decrease ≥2 from baseline. field loss occurred as evidenced by the MD decrease and the

Table 1 Change in retrobulbar blood flow findings for all patients with OAG from baseline to 4 years Baseline 4-year Change from baseline to 4 years N Mean (95% CI) N Mean (95% CI) Mean (95% CI) p Value

OA PSV 112 22.17 (19.96 to 24.62) 77 21.81 (19.50 to 24.38) −0.36 (−2.13 to 1.27) 0.669 OA EDV 112 5.43 (4.90 to 6.02) 77 4.55 (4.02 to 5.15) −1.05 (−1.62 to −0.53) 0.000* OA RI 112 0.755 (0.773 to 0.736) 77 0.793 (0.811 to 0.773) 0.044 (0.066 to 0.024) 0.000* CRA PSV 112 8.04 (7.43 to 8.65) 78 7.94 (7.26 to 8.62) −0.10 (−0.59 to 0.39) 0.688 CRA EDV 112 2.22 (2.04 to 2.43) 78 2.04 (1.85 to 2.25) −0.20 (−0.41 to 0.00) 0.046* CRA RI 112 0.707 (0.690 to 0.725) 78 0.733 (0.715 to 0.752) 0.026 (0.008 to 0.044) 0.006* NPCA PSV 111 7.53 (7.01 to 8.05) 78 7.81 (7.29 to 8.33) 0.28 (−0.12 to 0.68) 0.166 NPCA EDV 111 2.39 (2.21 to 2.59) 78 2.37 (2.17 to 2.59) −0.02 (−0.22 to 0.16) 0.804 NPCA RI 111 0.666 (0.648 to 0.684) 78 0.686 (0.666 to 0.705) 0.020 (0.001 to 0.039) 0.043* TPCA PSV 112 7.72 (7.19 to 8.24) 78 8.02 (7.45 to 8.59) 0.30 (−0.12 to 0.73) 0.157 TPCA EDV 112 2.38 (2.20 to 2.57) 78 2.35 (2.17 to 2.55) −0.02 (−0.21 to 0.15) 0.785 TPCA RI 112 0.683 (0.701 to 0.664) 78 0.701 (0.718 to 0.683) 0.019 (0.039 to 0.000) 0.049* Baseline NPCA and 4-year follow-up OA measurements were unable to be obtained in one patient due to poor image quality. *Denotes a statistically significant difference between baseline and 4-year follow-up for all patients (p<0.05). CRA, central retinal artery; EDV, end diastolic velocity; NPCA, nasal posterior ciliary artery; OA, ophthalmic artery; OAG, open-angle glaucoma; PSV, peak systolic velocity; RI, resistive index; TPCA, temporal posterior ciliary artery.

306 Moore NA, et al. Br J Ophthalmol 2017;101:305–308. doi:10.1136/bjophthalmol-2016-308460 Clinical science

Table 2 Overall change in structural and functional progression measurements from baseline to 4 years Baseline 4-year Change from baseline to 4 years N Mean (95% CI) N Mean (95% CI) Mean (95% CI) p Value

IOP 112 16.39 (15.06 to 17.72) 82 15.85 (14.40 to 17.31) −0.54 (−1.60 to 0.52) 0.314 MD 112 −3.53 (4.66 to −2.41) 83 −4.91 (−6.31 to −3.50) −1.37 (−2.11 to −0.63) 0.000* AGIS score 112 1.62 (0.97 to 2.48) 83 2.44 (1.51 to 3.71) 0.62 (0.29 to 0.91) 0.001* RNFL average thickness 112 73.36 (68.41 to 78.32) 83 73.80 (68.44 to 79.17) 0.44 (−2.23 to 3.11) 0.744 Cup/disc horizontal ratio 112 0.70 (0.65 to 0.75) 83 0.76 (0.71 to 0.81) 0.06 (0.03 to 0.10) 0.000* Cup/disc vertical ratio 112 0.687 (0.638 to 0.736) 83 0.725 (0.675 to 0.774) 0.038 (0.006 to 0.070) 0.019* Accurate IOP with applanation was unable to be obtained at 4-year follow-up in one patient. *Denotes a statistically significant difference between baseline and 4-year follow-up for all patients (p<0.05). AGIS, Advanced Glaucoma Intervention Study; IOP, intraocular pressure; MD, mean deviation; RNFL, retinal nerve fibre layer.

AGIS score increase. Additionally, structural progression was disease among black and white residents in communities of east noted as the cup/disc horizontal and vertical ratios increased Baltimore found OAG to be associated with an alteration in over this 4-year monitoring period. The average RNFL thick- factors related to ocular blood flow and a breakdown of autore- ness increased from baseline to 4-year follow-up, though the gulation. In this investigation, lower perfusion pressure (blood change was not significant (table 2). pressure IOP) was strongly associated with an increased preva- In this study population, patients who progressed structurally lence of primary OAG, showing a sixfold increase in risk for (n=75) had a statistically significant lower baseline mean OA those in the lowest category of perfusion pressure.14 Similarly, PSV of 24.25 (p=0.024) and mean OA EDV of 5.81 (p=0.012) the Egna-Neumarkt Glaucoma Study, which involved 4297 compared with those who did not progress (n=37). Similarly patients more than 40 years of age, found reduced diastolic per- for functional progression, a statistically significant lower base- fusion pressure to be an important risk factor for primary line mean OA PSV of 23.42 (p=0.031) and mean OA EDV of OAG.15 While these larger studies show the importance of per- 5.41 (p=0.005) were found to be associated with patients who fusion to ocular tissues, they did not directly measure ocular progressed (n=35) compared with those who did not progress blood flow biomarkers. (n=77). No significant difference was found in the baseline In this study, patients with OAG who experienced structural retrobulbar blood flow resistivity indices in all four-vessel progression had a statistically significant lower baseline mean groups between patients who progressed and those who did not OA PSV and OA EDV compared with those who did not pro- progress. In addition, there was no difference in the retrobulbar gress. These findings are supported by previous studies where blood flow velocities of the CRA, NPCA and TPCA between Calvo et al reported that OA EDV and mean velocity were patients found to have structural and/or functional progression reduced in subjects who converted to glaucoma based on at 4 years and those who did not progress (table 3). Moorfields Regression Analysis.22 Jimenez-Aragon et al found that the EDV and RI of the OA and CRA were significantly dif- DISCUSSION ferent between subjects who structurally progressed compared Vascular implications in OAG pathophysiology have been previ- with those who did not progress.23 Additionally, Calvo et al ously identified in many small prospective trials. The Baltimore reported that an OA RI value higher than 0.75 was associated Eye Study, a larger population-based prevalence survey of ocular with the development of glaucoma.22 In support of this

Table 3 Baseline retrobulbar blood flow findings associated with structural and functional glaucoma progression after 4 years Structural progression Functional progression

Progressed Not progressed Progressed Not progressed

N Mean (SE) N Mean (SE) p Value N Mean (SE) N Mean (SE) p Value

OA PSV 75 24.25 (0.80) 37 29.11 (2.18) 0.024* 35 23.42 (1.34) 77 26.96 (1.18) 0.031* OA EDV 75 5.81 (0.20) 37 7.19 (0.51) 0.012* 35 5.41 (0.27) 77 6.65 (0.29) 0.005* OA RI 75 0.755 (0.007) 37 0.744 (0.011) 0.528 35 0.756 (0.010) 77 0.749 (0.01) 0.520 CRA PSV 75 8.41 (0.23) 37 8.85 (0.32) 0.275 35 8.49 (0.40) 77 8.59 (0.20) 0.824 CRA EDV 75 2.46 (0.07) 37 2.54 (0.15) 0.862 35 2.53 (0.14) 77 2.46 (0.08) 0.937 CRA RI 75 0.703 (0.007) 37 0.712 (0.012) 0.464 35 0.696 (0.014) 77 0.710 (0.01) 0.341 NPCA PSV 74 7.63 (0.22) 37 7.90 (0.29) 0.479 35 7.43 (0.29) 76 7.85 (0.22) 0.280 NPCA EDV 74 2.51 (0.09) 37 2.61 (0.11) 0.385 35 2.53 (0.12) 76 2.55 (0.09) 0.849 NPCA RI 74 0.666 (0.008) 37 0.668 (0.008) 0.887 35 0.658 (0.012) 76 0.671 (0.01) 0.291 TPCA PSV 75 7.81 (0.20) 37 8.40 (0.30) 0.095 35 8.14 (0.34) 77 7.94 (0.19) 0.588 TPCA EDV 75 2.51 (0.08) 37 2.72 (0.13) 0.148 35 2.58 (0.14) 77 2.58 (0.08) 0.873 TPCA RI 75 0.677 (0.007) 37 0.675 (0.012) 0.998 35 0.682 (0.010) 77 0.673 (0.01) 0.549 Baseline NPCA measurements were unable to be obtained in one patient due to poor image quality. *Denotes a statistically significant difference from baseline to 4-year follow-up between patients who progressed functionally or structurally and those who did not progress (p<0.05). CRA, central retinal artery; EDV, end diastolic velocity; NPCA, nasal posterior ciliary artery; OA, ophthalmic artery; PSV, peak systolic velocity; RI, resistive index; TPCA, temporal posterior ciliary artery.

Moore NA, et al. Br J Ophthalmol 2017;101:305–308. doi:10.1136/bjophthalmol-2016-308460 307 Clinical science reported finding, the OA mean RI was >0.75 in our patient Data sharing statement This submitted manuscript contains the original data population that progressed both functionally and structurally. findings of the retrobulbar blood flow, functional progression, and structural Our study also found a statistically significant lower baseline progression from the 4-year portion of this study. The study is ongoing and is in the fifth year of data collection at Indiana University. Data from the ongoing study OA PSV and OA EDV to be associated with functional progres- continues to be collected by AH and BS, who have been the primary investigators in sion after 4 years. Galassi et al, who studied the association of this study since its initiation. retrobulbar blood flow on functional progression over a 7-year period, also reported that a lower OA EDV and higher OA RI fi correlated with visual eld deterioration in primary patients REFERENCES 19 with OAG. Martinez et al reported that in patients with OAG, 1 Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and diminished retrobulbar blood flow is linked to visual field deteri- glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch oration, and that the RI of the OA or short posterior ciliary Ophthalmol 2002;120:1268–79. 20 2 Leske MC, Heijl A, Hyman L, et al. Predictors of long-term progression in the early arteries may reliably predict functional progression. These manifest glaucoma trial. Ophthalmology 2007;114:1965–72. findings support the idea that a reduction in retrobulbar blood 3 Suzuki Y, Shirato S, Adachi M, et al. Risk factors for the progression of treated flow may be a contributing factor to the glaucomatous ONH primary open-angle glaucoma: a multivariate life-table analysis. Graefes Arch Clin and MD changes that we observed in our study population. Exp Ophthalmol 1999;237:463–7. Interestingly, we did not find biomarkers in the short posterior 4 Hollows RC, Graham PA. Intra-ocular pressure, glaucoma, and glaucoma suspects in a defined population. Br J Ophthalmol 1966;50:570–86. ciliary arteries, which perfuse the ONH, in our cohort of 5 Fechtner RD, Weinreb RN. Mechanisms of optic nerve damage in primary open patients with OAG with progression. Although the literature is angle glaucoma. Surv Ophthalmol 1994;39:23–42. in strong agreement with our findings of the OA, anatomically 6 Sigal IA, Ethier CR. Biomechanics of the optic nerve head. Exp Eye Res the short posterior ciliary arteries would logically seem to be a 2009;88:799–807. 7 Harris A, Sergott RC, Spaeth GL, et al. Color doppler analysis of ocular vessel blood target to observe reductions in blood velocities or increases in velocity in normal-tension glaucoma. Am J Ophthalmol 1994;118:642–9. vascular resistance in OAG due to the tissue they perfuse. The 8 Chung HS, Harris A, Kagemann L, et al. Peripapillary retinal blood flow in normal lack of significant association in these specific groups of vessels tension glaucoma. Br J Ophthalmol 1999;83:466–9. may be due to the higher variability of their measurement, a 9 Leighton DA, Phillips CI. Systemic blood pressure in open-angle glaucoma, low – steal phenomenon from other vascular beds may be masking an tension glaucoma, and the normal eye. Br J Ophthalmol 1972;56:447 53. 10 Hayreh SS, Zimmerman MB, Podhajsky P, et al. Nocturnal arterial hypotension and overall reduction in ocular perfusion from these vessels, and/or its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol the magnitude of changes seen in these vessels may be smaller 1994;117:603–24. than the detectability of the changes observed in the OA.25 11 Drance S, Anderson DR, Schulzer M. Risk factors for progression of visual field Based on these previous studies, there is significant evidence abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001;131:699–708. fl 12 Harris A, Harris M, Biller J, et al. Aging affects the retrobulbar circulation differently that supports the involvement of retrobulbar blood ow in the in women and men. Arch Ophthalmol 2000;118:1076–80. pathogenesis of glaucoma, but the direct link between specific 13 Topouzis F, Coleman AL, Harris A, et al. Association of blood pressure status with retrobulbar vessel abnormalities and glaucomatous progression the optic disk structure in non-glaucoma subjects: the Thessaloniki eye study. Am J is not well established. We recognise that our study is not Ophthalmol 2006;142:60–7. without limitations as it lacked a control group of healthy, non- 14 Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessment. Arch Ophthalmol glaucoma patients, thereby limiting our ability to draw correla- 1995;113:216–21. tions between ocular blood flow and changes that may be seen 15 Bonomi L, Marchini G, Marrafa M, et al. Vascular risk factors for primary open in healthy controls. Despite this limitation, our prospective angle glaucoma: the Egna-Neumarkt Study. Ophthalmology 2000;107:1287–93. observational study has a unique strength in that it revealed 16 Leske MC, Wu SY, Nemesure B, et al. Incident open-angle glaucoma and blood pressure. Arch Ophthalmol 2002;120:954–9. lower baseline OA velocities to be associated with parallel struc- 17 Moore D, Harris A, Wudunn D, et al. Dysfunctional regulation of ocular blood flow: tural and functional glaucomatous disease progression after a risk factor for glaucoma? Clin Ophthalmol 2008;2:849–61. 4 years and provides further support that vascular abnormalities 18 Flammer J, Orgül S, Costa VP, et al. The impact of ocular blood flow in glaucoma. are involved in the progression of OAG. Prog Retin Eye Res 2002;21:359–93. 19 Galassi F, Sodi A, Ucci F, et al. Ocular and glaucoma prognosis: Contributors All authors made a substantial contribution to the study design and a color Doppler imaging study. Arch Ophthalmol 2003;121:1711–15. acquisition and interpretation of the data. Each author participated in drafting or 20 Martínez A, Sánchez M. Predictive value of colour Doppler imaging in a prospective revising the manuscript and approved submission of this version for publication. study of visual field progression in primary open-angle glaucoma. Acta Ophthalmol Scand 2005;83:716–22. Funding Supported by an unrestricted grant from Research to Prevent Blindness 21 Zeitz O, Galambos P, Wagenfeld L, et al. Glaucoma progression is associated with (New York, New York, USA). The funding party did not have any role in the study decreased blood flow velocities in the short posterior ciliary artery. Br J Ophthalmol design, collection of data, analysis of data, writing of the manuscript or decision to 2006;90:1245–8. submit the manuscript. 22 Calvo P, Ferreras A, Polo V, et al. Predictive value of retrobulbar blood flow Competing interests AH would like to disclose that he receives remuneration parameters in glaucoma suspects. Invest Ophthalmol Vis Sci 2012;53:3875–84. from Stemnion, Biolight, Nano , AdOM, Science Based Health, Isarna 23 Jimenez-Aragon F, Garcia-Martin E, Larrosa-Lopez R, et al. Role of color Doppler Therapeutics, and Ono Pharmaceuticals for serving as a consultant. He also holds an imaging in early diagnosis and prediction of progression in glaucoma. BioMed Res ownership interest in AdOM, Nano Retina and Oxymap. All relationships listed Int 2013;2013:871689. above are pursuant to Indiana University’s policy on outside activities. 24 Tobe LA, Harris A, Hussain RM, et al. The role of retrobulbar and retinal circulation on optic nerve head and retinal nerve fibre layer structure in patients with Ethics approval Obtained by the Indiana University School of Medicine open-angle glaucoma over an 18-month period. Br J Ophthalmol 2015;99:609–12. Institutional Review Board. All patients signed an informed consent prior to initiation 25 Quaranta L, Harris A, Donato F, et al. Color Doppler imaging of ophthalmic artery of this study, which adhered to the tenets of the Declaration of Helsinki. blood flow velocity: a study of repeatability and agreement. Ophthalmology Provenance and peer review Not commissioned; externally peer reviewed. 1997;104:653–8.

308 Moore NA, et al. Br J Ophthalmol 2017;101:305–308. doi:10.1136/bjophthalmol-2016-308460