Yochai Z. Shoshani

Endothelin and Its Suspected Role in the Pathogenesis and Possible Treatment of Glaucoma

Purpose: To review the role of endothelin in intraocular pressure control, its effect on the trabecular meshwork (TM) and the outflow facility, effect on ocular blood flow and vascular regulation and the potential role of endothelin-1 (ET-1) antagonism in the therapeutic paradigm of glaucoma. Methods: A thorough review of the medical literature and a meta-analysis on the level of ET-1 in OAG patients in an attempt to demonstrate the evolving importance of endothelin in glaucoma. Results: ET-1 has been identified in the plasma in concentrations that are markedly increased in a number of systemic as well as ocular pathologies such as glaucoma where underlying vascular dysfunction and pathology play a role. It has been shown that ET-1 induces human TM cell contraction in culture and that it can affect the outflow facility. Evidence indicates that systemic ET-1 regulatory mechanisms and vascular responses to it are also altered in glaucoma. Recently, several endothelin antagonists have been shown to have a potential role in glaucoma therapy. In our meta-analysis, only patients with normal tension glaucoma (NTG) (as opposed to patients with high tension glaucoma (HTG)) had significantly higher plasma ET-1 levels compared to non-glaucomatous control. High tension glaucomaHTG patients had significant higher levels of ET-1 in the aqueous humor. Conclusions: The potential role of ET-1 antagonism in the therapeutic paradigm of glaucoma is an exciting possible new approach in the treatment of OAG patients. In NTG, ET-1 may have both a local and systemic component of vascular dysregulation, while whereas in HTG, the role of ET-1 may be dominantly localized to ocular tissue.

Impaired ocular blood flow regulation in patients with open‐angle glaucoma and diabetes

Background:  To elucidate the potential impact of diabetes mellitus on primary open‐angle glaucoma pathology through vascular deficiency.

Repeatability of retrobulbar blood flow velocity measured using color doppler imaging in the indianapolis glaucoma progression study

PurposeDetermine the repeatability of color Doppler imaging (CDI) measurements in patients with open-angle glaucoma (OAG). Patients and MethodsWe performed a cross-sectional, observational study of OAG patients participating in the Indianapolis Glaucoma Progression Study. Retrobulbar blood flow velocities and Pourcelots vascular resistance index (RI) measured with CDI were examined. Two baseline measurements were obtained 1 to 2 weeks apart at the same time of day for all participants. Peak systolic and end diastolic blood flow velocities (PSV/EDV) were measured in the ophthalmic (OA), central retinal (CRA), and nasal and temporal short posterior ciliary arteries (N/TPCA) and RI was calculated. Intraclass correlation coefficient (ICC) between the 2 baselines was calculated. ResultsOne hundred and sixteen patients with OAG [mean age 65.9 y (SD 10.9 y), 60% female] were examined in both baseline visits. In the OA, the intraobserver ICC for the PSV, EDV, and RI were all above 0.82. In the CRA, the intraobserver ICC for the PSV and RI were both above 0.8, whereas the EDV was 0.64. The intraobserver ICC in the N/TPCA for the PSV, EDV, and RI ranged from 0.71 to 0.88. The interobserver ICC was similar to the intraobserver ICC for the OA and the CRA but was lower than 0.7 in the EDV and RI of the T/NPCA. ConclusionsBlood flow velocities and calculated vascular resistance of the OA, CRA, and PCAs conducted within 2 weeks in patients with OAG are repeatable. Intraobserver CDI measurements were found more reproducible than interobserver CDI analysis.

Contrast sensitivity, ocular blood flow and their potential role in assessing ischaemic retinal disease

Purpose:  To examine the definition, evaluation methodology, association to ocular blood flow and potential clinical value of contrast sensitivity (CS) testing in clinical and research settings, focusing in patients with ischemic retinal disease.

Goldmann applanation tonometry and dynamic contour tonometry are not correlated with central corneal thickness in primary open angle glaucoma

PurposeTo compare intraocular pressure (IOP) measured by Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT) and assess their relationship to central corneal thickness (CCT) in patients with primary open angle glaucoma (OAG). Patients and MethodsGAT, DCT, and CCT were assessed in 116 patients with OAG [mean age 65.9 (10.5); 59% female] participating in the Indianapolis Glaucoma Progression Study. GAT and DCT were measured in a randomized order followed by CCT (ultrasonic corneal pachymetry) during a single study visit. Bland-Altman plots were used to evaluate the limits of agreement between tonometery methodologies whereas multivariate regression analysis was used to evaluate the influence of CCT on GAT and DCT IOP measurements. ResultsIOP values obtained by DCT and GAT showed a strong positive correlation in patients with OAG (r=0.93; P<0.001). Mean IOP measured with DCT [18.4 (5.1) mm Hg] was significantly higher (P<0.001) than GAT IOP measurements [16.5 (4.5) mmHg]. CCT did not seem to influence either GAT or DCT measurements (r=0.1025, P=0.16; r=0.05, P=0.46), respectively. The Bland-Altman data showed that the amount of disagreement between IOP assessment techniques varied, suggesting a proportional bias. ConclusionsIn this group of patients with OAG, there was a strong correlation between GAT and DCT measurements of IOP. IOP measured with DCT was consistently higher than IOP measured with GAT. Neither GAT nor DCT measurements were correlated with CCT. This data suggests that factors other than CCT may be involved in the tendency of DCT to produce higher measures of IOP than GAT.

Feasibility of creating a normative database of colour Doppler imaging parameters in glaucomatous eyes and controls

Background and aims Colour Doppler imaging (CDI) is a frequently cited methodology for quantifying ocular blood flow velocities. This investigation reviews the feasibility of creating a normative database of CDI parameters in glaucoma patients and controls. A literature search was conducted for CDI studies involving glaucomatous eyes. Using data from these studies, a weighted mean was derived for the peak systolic velocity, end diastolic velocity and Pourcelots resistive index in the ophthalmic, central retinal and posterior ciliary arteries. A multivariate analysis was performed to identify whether methodological characteristics contributed to the inter-study variance in CDI values. Data from 3061 glaucoma patients and 1072 controls were included. The mean values for glaucomatous eyes were within one standard deviation of the values for controls for most CDI parameters. Gender mix (p=0.043), intraocular pressure status (p=0.017), frequency of the ultrasound transducer (p=0.02) and whether the patients were on antihypertensive therapy (p=0.004) contributed to the variance. Methodological differences create inter-study variance in CDI values, complicating the construction of a normative database and limiting its utility. Because the mean values for glaucomatous and normal eyes have overlapping ranges, caution should be used when classifying glaucoma status based on a single CDI measurement.

Short-term effects of brimonidine/timolol and dorzolamide/timolol on ocular perfusion pressure and blood flow in glaucoma

IntroductionTo examine the comparative short-term effects of brimonidine/timolol and dorzolamide/timolol on ocular perfusion pressure and retrobulbar blood flow in patients with primary open angle glaucoma (OAG).MethodsIn a prospective, randomized, double-blind, crossover study, intraocular pressure (IOP), blood pressure (BP), ocular perfusion pressure (OPP), and retrobulbar hemodynamics were assessed in 15 patients with OAG (mean age 68.1 years, eight women) with well controlled IOP. IOP was measured by Goldman applanation tonometery and color Doppler imaging was utilized to assess the retrobulbar blood vessels before and 1 month after treatment with topical brimonidine/timolol and dorzolamide/timolol. Statistical analysis was performed by Friedman two-way analysis of variance by ranks and post-hoc Wilcoxon signed rank test for multiple comparisons with Holm’s sequential Bonferroni procedure. P values <0.05 were considered statistically significant.ResultsThe Friedman test and subsequent post-hoc analysis indicated that IOP, BP, OPP, and retrobulbar blood flow velocities did not significantly differ between brimonidine/timolol and dorzolamide/timolol after 1-month treatment administration in patients with OAG and well controlled IOP.ConclusionIn this cohort of patients with OAG, short-term treatment with brimonidine/timolol and dorzolamide/timolol results in similar effects on OPP and retrobulbar blood flow velocities.

Update and critical appraisal of combined timolol and carbonic anhydrase inhibitors and the effect on ocular blood flow in glaucoma patients

Topical hypotensive therapy with both timolol and carbonic anhydrase inhibitors has been shown to be efficacious at reducing intraocular pressure. Many prospective studies have also suggested that carbonic anhydrase inhibitors augment ocular blood flow and vascular regulation independent of their hypotensive effects. Although consistent in their findings, these studies must be cautiously interpreted due to the limitations of study design and specific blood flow imaging modalities. The purpose of this review is to appraise and critically evaluate the current body of literature investigating the effects of combined treatment with topical carbonic anhydrase inhibitors and timolol in patients with glaucoma with respect to ocular blood flow, visual function, and optic nerve head structure.

Central retinal artery originating from the temporal short posterior ciliary artery associated with intraorbital external-to-internal carotid arterial anastomoses

Although variations in the peripapillary division pattern of the central retinal artery (CRA) are common, variations in the origin of this artery are seldom reported in the literature. Herein, the authors report a variant of the CRA that originated from the temporal short posterior ciliary artery. Two intraorbital anastomoses were also noted between the internal and external carotid arterial systems: one through the lacrimal artery–middle meningeal artery to the ophthalmic artery and the other through supraorbital artery–recurrent meningeal artery to the ophthalmic artery. A brief review of CRA variations and potential clinical significances of the observed variant are discussed.

Advances in the understanding of ocular blood flow in glaucoma

Although intraocular pressure remains the only current treatable risk factor in open-angle glaucoma, several other risk factors have been reported, including insufficient ocular blood flow and low perfusion pressure. Over the past several decades, significant progress has been made in the methodologies utilized to assess ocular blood flow as well as consensus in interpreting their results. Utilizing these devices, dozens of prospective investigations have revealed altered ocular blood flow, ocular perfusion pressure and faulty vascular regulation in patients with open-angle glaucoma. Pilot research studies have found reductions in ocular circulation to be associated with various markers of structural and functional glaucoma progression. However, these pilot studies have been limited in size, scope and execution, and only larger, multicentered prospective controlled studies are capable of providing definitive proof of the vascular role in glaucoma progression.