Brent Siesky

Dysfunctional regulation of ocular blood flow: A risk factor for glaucoma?

Primary open angle glaucoma (OAG) is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell death and associated visual field loss. OAG is an emerging disease with increasing costs and negative outcomes, yet its fundamental pathophysiology remains largely undetermined. A major treatable risk factor for glaucoma is elevated intraocular pressure (IOP). Despite the medical lowering of IOP, however, some glaucoma patients continue to experience disease progression and subsequent irreversible vision loss. The scientific community continues to accrue evidence suggesting that alterations in ocular blood flow play a prominent role in OAG disease processes. This article develops the thesis that dysfunctional regulation of ocular blood flow may contribute to glaucomatous optic neuropathy. Evidence suggests that impaired vascular autoregulation renders the optic nerve head susceptible to decreases in ocular perfusion pressure, increases in IOP, and/or increased local metabolic demands. Ischemic damage, which likely contributes to further impairment in autoregulation, results in changes to the optic nerve head consistent with glaucoma. Included in this review are discussions of conditions thought to contribute to vascular regulatory dysfunction in OAG, including atherosclerosis, vasospasm, and endothelial dysfunction.

Measuring and interpreting ocular blood flow and metabolism in glaucoma.

There is a growing body of evidence suggesting that vascular dysfunction is related to several prominent ophthalmic diseases, including glaucoma. The vast majority of studies providing data on ocular circulation and disease pathophysiology use a relatively small number of complicated ocular blood flow imaging techniques. Although these imaging technologies are not commonly used in clinical settings, understanding the medical literature characterizing ocular blood flow requires familiarity with their methodology and function. This review highlights the imaging technologies most commonly used to investigate ocular blood flow, including color Doppler imaging, confocal scanning laser ophthalmoscopic angiography with fluorescein and indocyanine green dye, Canon laser blood flowmetry, scanning laser Doppler flowmetry, and retinal photographic oximetry. Each imaging techniques ability to define vascular function and reveal pathology is discussed as are limitations inherent to each technology. The ultimate goal of this review is to provide the physician with a clinically relevant foundation for differentiating the various ocular blood flow outcome measures often presented in the literature and determine how they are related to ocular health and disease.

Use of colour Doppler imaging in ocular blood flow research.

The main objective of this report is to encourage consistent quality of testing and reporting within and between centres that use colour Doppler imaging (CDI) for assessment of retrobulbar blood flow. The intention of this review is to standardize methods in CDI assessment that are used widely, but not to exclude other approaches or additional tests that individual laboratories may choose or continue to use.

Effects of exercise on intraocular pressure and ocular blood flow: A review

Glaucoma is a disease characterized by progressive optic neuropathy resulting in retinal ganglion cell death, which affects approximately 68 million people worldwide. Risk factors include intraocular pressure (IOP), genetics, race, age, and vascular factors. Exercise is known to affect IOP and systemic cardiovascular factors and, therefore, may affect glaucoma pathophysiology. This review discusses the results of articles relevant to glaucoma, IOP, ocular blood flow (OBF), and exercise. Isometric and dynamic exercises have been studied with respect to effects on IOP and OBF. Isometric exercise results in an acute decrease in IOP, which correlates with hypocapnia. Dynamic exercise results in a more pronounced but also short duration decrease in IOP. Physical fitness is associated with lower baseline IOP but diminished acute IOP-lowering response to exercise. Upon cessation of exercise, values return to pretrained levels within 1 month. In glaucoma patients, these IOP-lowering effects are greater than in healthy subjects. In healthy subjects, OBF is unchanged during exercise due to vascular autoregulation. This autoregulation fails at ocular perfusion pressures greater than 70% above baseline. In conclusion exercise in glaucoma patients results in acutely lowered IOP and lower baseline IOP. The effects of exercise on the prevention of glaucoma and glaucomatous progression remain unknown. The role of exercise in glaucoma management should be investigated.

Literature Review and Meta-Analysis of Topical Carbonic Anhydrase Inhibitors and Ocular Blood Flow

The purpose of this literature review and meta-analysis was to determine what, if any, effects topical carbonic anhydrase inhibitors have on ocular hemodynamics in humans. A literature review and meta-analysis was conducted to investigate the effects of topical carbonic anhydrase inhibitors on ocular blood flow. Thirty-five articles were evaluated according to the inclusion criteria with 13 manuscripts meeting requirements for statistical analysis. Each studys effect size, defined as the change in blood flow measures after treatment with topical carbonic anhydrase inhibitors, was estimated using the weighted mean difference. Based on this meta-analysis, we conclude that topical carbonic anhydrase inhibitors increase ocular blood flow velocities in the retinal circulation, central retinal and short posterior ciliary arteries, but not in the ophthalmic artery.

Ocular pulse amplitude in normal tension and primary open angle glaucoma

Purpose(1) To investigate the relationship of ocular pulse amplitude (OPA) with intraocular pressure (IOP) and corneal thickness. (2) To evaluate OPA in patients with primary open angle and normal tension glaucoma (NTG). MethodsPatients with NTG (n=28), primary open angle glaucoma (POAG) (n=19), and age-matched healthy controls (n=22) underwent 2 consecutive Goldmann and dynamic contour tonometry measurements within 1 month. Central corneal thickness was also measured. A regression model was applied to compare OPA between the diagnostic groups. ResultsOPA increased with rising IOP (slope 0.026/0.033 and P=0.002/<0.0001 for Goldmann/Dynamic tonometry), whereas corneal thickness did not influence pulse amplitude measurements (slope−0.0017/−0.0013 and P=0.11/0.21 after correction for Goldmann/Dynamic tonometry). In a multivariate model correcting for IOP and corneal thickness, OPA was reduced in patients with NTG (P=0.014/0.017 corrected for Goldmann/Dynamic tonometry) or POAG (P=0.015/0.014). ConclusionsOPA is reduced in normal tension and POAG patients compared with healthy controls. OPA is influenced by IOP, but not by corneal thickness.

The Circadian Variations in Systemic Blood Pressure, Ocular Perfusion Pressure, and Ocular Blood Flow: Risk Factors for Glaucoma?

Intraocular pressure, a major risk factor for glaucoma, is known to vary throughout the day, yet glaucoma continues to progress in some patients despite it being well controlled. It is important to understand how other glaucomatous risk factors are affected by circadian variations. The purpose of this review is to analyze the literature concerning circadian variations in systemic blood pressure, ocular perfusion pressure, and ocular blood flow and to identify consensus findings regarding their impact on glaucoma. This review suggests that nonphysiologic nocturnal blood pressure dipping and wider circadian fluctuations in ocular perfusion pressure are linked with the development and progression of glaucoma. No consensus concerning circadian variations in ocular blood flow exists in the current literature, and future investigations of nocturnal changes in blood flow and glaucoma progression are required.

The role of transforming growth factor β in glaucoma and the therapeutic implications.

Glaucoma is a progressive optic neuropathy frequently associated with elevated intraocular pressure, ocular vascular changes and extracellular matrix remodelling at the optic nerve head and in the trabecular meshwork. The pathogenesis is multifactorial and complex, but many recent studies have suggested that transforming growth factor-β (TGF-β) plays a major role in the process. Significantly elevated levels of TGF-β have been identified in the anterior chamber of glaucomatous eyes. TGF-β has also been shown to directly cause increased intraocular pressure. It is believed that this occurs through complex interaction with the trabecular meshwork, leading to decreased aqueous humour outflow. These processes occur through specific interactions with various proteins and signalling molecules also present in ocular tissues. By understanding the role that TGF-β plays in the pathogenesis of glaucoma, alternative therapeutic agents can be developed, which target these pathways and improve and assist in the management of disease. This review will cover previous investigative studies and discuss the current understanding of TGF-βs role in glaucoma and how it may serve as a potential therapeutic target.

Intraocular Pressure, Blood Pressure, and Retinal Blood Flow Autoregulation: A Mathematical Model to Clarify Their Relationship and Clinical Relevance

PURPOSE This study investigates the relationship between intraocular pressure (IOP) and retinal hemodynamics and predicts how arterial blood pressure (BP) and blood flow autoregulation (AR) influence this relationship. METHODS A mathematical model is developed to simulate blood flow in the central retinal vessels and retinal microvasculature as current flowing through a network of resistances and capacitances. Variable resistances describe active and passive diameter changes due to AR and IOP. The model is validated by using clinically measured values of retinal blood flow and velocity. The model simulations for six theoretical patients with high, normal, and low BP (HBP-, NBP-, LBP-) and functional or absent AR (-wAR, -woAR) are compared with clinical data. RESULTS The model predicts that NBPwAR and HBPwAR patients can regulate retinal blood flow (RBF) as IOP varies between 15 and 23 mm Hg and between 23 and 29 mm Hg, respectively, whereas LBPwAR patients do not adequately regulate blood flow if IOP is 15 mm Hg or higher. Hemodynamic alterations would be noticeable only if IOP changes occur outside of the regulating range, which, most importantly, depend on BP. The model predictions are consistent with clinical data for IOP reduction via surgery and medications and for cases of induced IOP elevation. CONCLUSIONS The theoretical model results suggest that the ability of IOP to induce noticeable changes in retinal hemodynamics depends on the levels of BP and AR of the individual. These predictions might help to explain the inconsistencies found in the clinical literature concerning the relationship between IOP and retinal hemodynamics.

Color Doppler imaging and ocular pulse amplitude in glaucomatous and healthy eyes.

Purpose To determine factors influencing color Doppler imaging (CDI) measurements, to compare retrobulbar flow velocities between patients with glaucoma and healthy controls, and to describe the correlation between CDI and ocular pulse amplitude (OPA). Methods Patients with normal tension (n=28) or primary open angle glaucoma (n=19) and healthy controls (n=22) underwent CDI and OPA measurements. Intraocular pressure, corneal thickness, blood pressure, and heart rate were also measured. Spearman correlations were used to explore relations among these variables. A regression model for repeated measures was applied to compare between diagnostic groups the flow velocity indices in the retrobulbar vessels. Results Retrobulbar diastolic blood flow velocities correlated with diastolic blood pressure and perfusion pressure (range of Spearman rho [ρ] coefficients=0.25–0.28; P=0.044–0.013 for the different vessels). Corneal thickness showed a positive correlation with systolic and diastolic flow velocities in the central retinal artery (ρ=0.29 and 0.31; P=0.017 and 0.011 for peak systolic and end diastolic velocity, respectively). Systolic and diastolic blood flow velocities were reduced in the retrobulbar vessels of patients with normal tension glaucoma (P=0.0004) as well as primary open angle glaucoma (P=0.003) compared to healthy controls. A correlation was found between OPA and the resistive index in the retrobulbar vessels of the healthy controls (range ρ=0.42–0.53; P=0.059–0.014). Conclusions Retrobulbar blood flow velocities are reduced in patients with primary open angle glaucoma and normal tension glaucoma. Blood pressure and corneal thickness may influence CDI measurements. OPA correlates with the resistive index in CDI.