Background/aims Previous studies suggest that vascular abnormalities are involved in the pathogenesis of open-angle glaucoma. This study aims to examine the relationship of baseline retrobulbar blood flow measurements with functional and structural glaucomatous progression in patients with open-angle glaucoma over 4 years.
Methods In this study, 112 patients with open-angle glaucoma were examined at baseline and 78 with retrobulbar blood flow assessments were followed to 4 years. Colour Doppler imaging was used to evaluate retrobulbar blood flow. Structural disease progression was examined with optical coherence tomography and Heidelberg Retinal Tomography III. Functional disease progression was monitored with automated perimetry using Humphrey visual fields. Mixed-model analysis of covariance was used to test for significance of changes from baseline to 4-year follow-up. Two-sample t tests and χ2 tests were used to test for baseline blood flow differences between patients who progressed and those who did not progress.
Results Patients who progressed structurally had a statistically significant lower baseline mean ophthalmic artery peak systolic velocity (PSV) (p=0.024) and ophthalmic artery end diastolic velocity (EDV) (p=0.012) compared with those who did not progress. Similarly, a lower baseline mean ophthalmic artery PSV (p=0.031) and ophthalmic artery EDV (p=0.005) were associated with patients who progressed functionally compared with those who did not progress after 4 years.
Conclusions In this study population, lower baseline ophthalmic artery blood flow velocities were associated with simultaneous structural and functional glaucoma progression after 4 years.
- Optic Nerve
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Primary open-angle glaucoma (OAG) is a multifactorial optic neuropathy characterised by progressive retinal ganglion cell death and a characteristic visual field loss. Elevated intraocular pressure (IOP) has been identified as a major risk factor for OAG and current treatments focus on reducing and controlling the IOP to limit disease progression. Despite advances in pharmacological and surgical interventions, however, it is well established that glaucoma progression is still observed in some patients with IOP reduction. Additionally, a high percentage of individuals with elevated IOP do not develop glaucoma.1–4 Each of these findings suggests that glaucoma progression is multifactorial in origin and there are other underlying contributing factors in the disease onset and progression.5 ,6 This has led to the evaluation of ocular blood flow and its role in glaucoma.
Ischaemia to the optic nerve and reduced ocular blood flow has been shown to contribute to the pathogenesis and progression of glaucoma.7 ,8 Several systemic and localised vascular abnormalities have been linked to OAG including arterial hypertension, nocturnal hypotension, optic disc haemorrhage, migraines and age-related changes of the vasculature.9–12 In addition, a decreased ocular perfusion pressure has been linked to an increase in OAG prevalence, incidence and progression.13–17 Patients with OAG have been found to have reduced blood flow in the retinal, choroidal and retrobulbar circulations which is associated with glaucomatous functional and structural disease progression.18–23 However, the results from these studies are varied, and the exact relationship between ocular blood flow and glaucoma progression has not been fully delineated.
Many of these previous studies are limited by small sample sizes, often involve a heterogeneous group of patients including glaucoma suspects and do not evaluate both functional and structural glaucoma progression in parallel. We previously reported findings detailing the association between reductions in retrobulbar and retinal blood flow over time with structural glaucomatous progression.24 Here, we present data from a large 4-year longitudinal study detailing the relationship between retrobulbar blood flow and simultaneous structural and functional glaucoma progression.
Material and methods
A cohort of patients with OAG were enrolled in this study and examined at baseline and every 6 months for 4 years at the Glaucoma and Diagnostic Center at Indiana University School of Medicine. All patients signed an informed consent prior to initiation of this study, which adhered to the tenets of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board committee at the Indiana University School of Medicine.
All participants were required to meet the following inclusion criteria: age 30 years or older, confirmed OAG in at least one eye by a glaucoma specialist, best-corrected visual acuity of 20/60 or better in the study eye, and acceptable reliability indices in previous Humphrey visual field examinations.
Patients were excluded for the following reasons: Humphrey visual field damage consistent with a mean deviation (MD) less than −15 decibels or a clinically determined threat to fixation in both hemifields, evidence of pseudoexfoliation or pigment dispersion, history of acute angle-closure glaucoma or a narrow occludable anterior chamber angle, history of chronic or recurrent inflammatory eye diseases, history of intraocular trauma, severe or progressive retinal disease, any abnormality preventing reliable applanation tonometry, cataract surgery within the past year, resting pulse <50 bpm, or severe cardiovascular, renal or pulmonary disease.
One qualified eye was randomly assigned as the observational study eye for each subject. All patients were questioned for their clinical history, assessed for IOP by Goldmann applanation tonometry, and evaluated for best-corrected visual acuity. To limit reproducibility bias with imaging, a single experienced operator with over 10 years of experience performed all measurements in the same order and at the same time of the day for each patient.
Retrobulbar blood flow velocities and vascular resistance were measured with the Philips HDI 5000 colour Doppler imaging (CDI) system with the microvascular small parts clinical option using a 7.5 MHz linear probe (Philips Ultrasound, Bothell, Washington, USA). Peak systolic velocity (PSV) and end diastolic velocity (EDV) were determined for the ophthalmic artery (OA), central retinal artery (CRA), nasal posterior ciliary artery (NPCA) and temporal posterior ciliary artery (TPCA). The Pourcelot's resistive index (RI) was calculated (RI=(PSV−EDV)/PSV)) for each vessel. Retrobulbar blood flow velocities obtained by CDI were standardised by using a printout at each visit to ensure that velocities were taken from nearly the same location in each vessel. CDI was selected as the imaging modality of choice because of its known reproducibility at measuring retrobulbar blood flow velocities and calculating the RI.25
Visual function was assessed by automated perimetry with the Humphrey Field Analyzer II, using the 24-2 Swedish Interactive Threshold Algorithm standard (white III stimulus) V.4.1 (Carl Zeiss Mediatec, Dublin, California, USA). Visual field progression was determined using the Humphrey Glaucoma Progression Analysis software. Functional glaucoma progression was defined as two consecutive visits with an Advanced Glaucoma Intervention Study (AGIS) score increase ≥2 from baseline or MD decrease ≥2 from baseline.
Peripapillary retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) parameters were assessed by optical coherence tomography (OCT) (Stratus software V.4.0, Zeiss Meditec, Dublin, California, USA). The examination was performed and repeated until good-quality analysis (signal strength <7) was obtained. Measurements were made along a circle concentric with the optical disc (Fast RNFL thickness acquisition protocol) to assess RNFL thickness. The mean RNFL thickness and cup/disc vertical and horizontal ratios were calculated by OCT using the existing software. Topographic analysis of the ONH was performed using Heidelberg Retinal Tomography III (HRT-III) (Heidelberg Engineering, Heidelberg, Germany). The HRT-III was a secondary modality to OCT and was used to supplement evaluation for subtle RNFL and ONH changes. Structural progression was defined as two consecutive visits with an RNFL thickness decrease ≥8% and/or horizontal or vertical cup/disc ratio increase by ≥0.2 from baseline.
Statistical analysis involved performing a mixed-model analysis of covariance to test for significant change from baseline to 4-year follow-up. Two-sample t tests and χ2 tests were used to analyse differences in baseline data between patients who progressed and those who did not progress.
In this study, 112 patients with OAG were enrolled according to the prior listed inclusion and exclusion criteria and 78 patients with retrobulbar blood flow assessments using CDI were followed through to 4 years. Overall baseline characteristics of the population revealed a mean age 64.9±11.0 years; female (n=68), male (n=44); African descent (n=29), European descent (n=83); non-insulin-dependent diabetes mellitus (n=21), no diabetes mellitus (n=91).
In this study population, the RI significantly increased in all four retrobulbar vascular territories when compared with 4-year follow-up. The EDV decreased in all vessel groups, but the change was only significant in the OA and CRA. In addition, the PSV decreased in the OA and CRA, but increased in the NPCA and TPCA—no PSV change was significant (table 1).
Structural and functional changes were assessed in 83 patients over the course of the study to 4 years. Findings revealed that the IOP decreased from baseline to 4 years. Functional visual field loss occurred as evidenced by the MD decrease and the AGIS score increase. Additionally, structural progression was noted as the cup/disc horizontal and vertical ratios increased over this 4-year monitoring period. The average RNFL thickness increased from baseline to 4-year follow-up, though the change was not significant (table 2).
In this study population, patients who progressed structurally (n=75) had a statistically significant lower baseline mean OA PSV of 24.25 (p=0.024) and mean OA EDV of 5.81 (p=0.012) compared with those who did not progress (n=37). Similarly for functional progression, a statistically significant lower baseline mean OA PSV of 23.42 (p=0.031) and mean OA EDV of 5.41 (p=0.005) were found to be associated with patients who progressed (n=35) compared with those who did not progress (n=77). No significant difference was found in the baseline retrobulbar blood flow resistivity indices in all four-vessel groups between patients who progressed and those who did not progress. In addition, there was no difference in the retrobulbar blood flow velocities of the CRA, NPCA and TPCA between patients found to have structural and/or functional progression at 4 years and those who did not progress (table 3).
Vascular implications in OAG pathophysiology have been previously identified in many small prospective trials. The Baltimore Eye Study, a larger population-based prevalence survey of ocular disease among black and white residents in communities of east Baltimore found OAG to be associated with an alteration in factors related to ocular blood flow and a breakdown of autoregulation. In this investigation, lower perfusion pressure (blood pressure IOP) was strongly associated with an increased prevalence of primary OAG, showing a sixfold increase in risk for those in the lowest category of perfusion pressure.14 Similarly, the Egna-Neumarkt Glaucoma Study, which involved 4297 patients more than 40 years of age, found reduced diastolic perfusion pressure to be an important risk factor for primary OAG.15 While these larger studies show the importance of perfusion to ocular tissues, they did not directly measure ocular blood flow biomarkers.
In this study, patients with OAG who experienced structural progression had a statistically significant lower baseline mean OA PSV and OA EDV compared with those who did not progress. These findings are supported by previous studies where Calvo et al reported that OA EDV and mean velocity were reduced in subjects who converted to glaucoma based on Moorfields Regression Analysis.22 Jimenez-Aragon et al found that the EDV and RI of the OA and CRA were significantly different between subjects who structurally progressed compared with those who did not progress.23 Additionally, Calvo et al reported that an OA RI value higher than 0.75 was associated with the development of glaucoma.22 In support of this reported finding, the OA mean RI was >0.75 in our patient population that progressed both functionally and structurally.
Our study also found a statistically significant lower baseline OA PSV and OA EDV to be associated with functional progression after 4 years. Galassi et al, who studied the association of retrobulbar blood flow on functional progression over a 7-year period, also reported that a lower OA EDV and higher OA RI correlated with visual field deterioration in primary patients with OAG.19 Martinez et al reported that in patients with OAG, diminished retrobulbar blood flow is linked to visual field deterioration, and that the RI of the OA or short posterior ciliary arteries may reliably predict functional progression.20 These findings support the idea that a reduction in retrobulbar blood flow may be a contributing factor to the glaucomatous ONH and MD changes that we observed in our study population. Interestingly, we did not find biomarkers in the short posterior ciliary arteries, which perfuse the ONH, in our cohort of patients with OAG with progression. Although the literature is in strong agreement with our findings of the OA, anatomically the short posterior ciliary arteries would logically seem to be a target to observe reductions in blood velocities or increases in vascular resistance in OAG due to the tissue they perfuse. The lack of significant association in these specific groups of vessels may be due to the higher variability of their measurement, a steal phenomenon from other vascular beds may be masking an overall reduction in ocular perfusion from these vessels, and/or the magnitude of changes seen in these vessels may be smaller than the detectability of the changes observed in the OA.25
Based on these previous studies, there is significant evidence that supports the involvement of retrobulbar blood flow in the pathogenesis of glaucoma, but the direct link between specific retrobulbar vessel abnormalities and glaucomatous progression is not well established. We recognise that our study is not without limitations as it lacked a control group of healthy, non-glaucoma patients, thereby limiting our ability to draw correlations between ocular blood flow and changes that may be seen in healthy controls. Despite this limitation, our prospective observational study has a unique strength in that it revealed lower baseline OA velocities to be associated with parallel structural and functional glaucomatous disease progression after 4 years and provides further support that vascular abnormalities are involved in the progression of OAG.
Contributors All authors made a substantial contribution to the study design and acquisition and interpretation of the data. Each author participated in drafting or revising the manuscript and approved submission of this version for publication.
Funding Supported by an unrestricted grant from Research to Prevent Blindness (New York, New York, USA). The funding party did not have any role in the study design, collection of data, analysis of data, writing of the manuscript or decision to submit the manuscript.
Competing interests AH would like to disclose that he receives remuneration from Stemnion, Biolight, Nano Retina, AdOM, Science Based Health, Isarna Therapeutics, and Ono Pharmaceuticals for serving as a consultant. He also holds an ownership interest in AdOM, Nano Retina and Oxymap. All relationships listed above are pursuant to Indiana University's policy on outside activities.
Ethics approval Obtained by the Indiana University School of Medicine Institutional Review Board. All patients signed an informed consent prior to initiation of this study, which adhered to the tenets of the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This submitted manuscript contains the original data findings of the retrobulbar blood flow, functional progression, and structural 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 continues to be collected by AH and BS, who have been the primary investigators in this study since its initiation.