The effects of systemic medications on ocular blood flow

This article reviews the effects of systemic medications and some native vasoactive molecules on ocular blood flow (OBF). Some evidence exists for a positive effect of centrally acting calcium-channel blockers, nitric oxide precursors, adenosine, histamine, estrogens, and ginkgo biloba extract, while evidence for a negative effect on OBF exists for endothelin-1 and indomethacin. Some other molecules appear to have mixed effects, depending on the ocular vascular bed studied or the study protocol. In addition, medically induced changes in systemic blood pressure (BP) have an important impact on OBF, and the direction and magnitude of this effect may depend on the disease status of the patient and of the eye, as well as the absolute level of BP achieved. There are relatively few studies of the effects of systemic medications on OBF in glaucoma patients, and little is known of the long-term impact of such therapies on the preservation of optic nerve structure and function.     

Endothelin and its potential role in glaucoma

Endothelin is a potent vasoactive peptide occurring in 3 isotypes, ET-1, ET-2, and ET-3. Through its two main receptors, endothelin A and endothelin B, it is responsible for a variety of physiological functions, primarily blood flow control. Recent evidence from both human and experimental optic neuropathies shows involvement of endothelin and upregulation of its receptors (principally endothelin B). Experimental studies have shown that chronic ET-1 administration to the optic nerve immediately behind the globe causes neuronal damage, activation of astrocytes, the major glial cell in the anterior optic nerve, and upregulation of endothelin B receptors. This review outlines the ubiquitous role of endothelin and its potential involvement in glaucoma.     

Optic nerve blood flow in glaucoma

Background : Glaucomatous optic neuropathy often occurs in the absence of elevated intraocular pressure and, conversely, elevated intraocular pressure may occur without associated damage of the optic nerve. These findings challenge the simple explanation of intraocular pressure being the sole cause of neural loss and have led to theories of ischaemic causes of the morbidity. This paper reviews the vascular anatomy of the optic disc, the factors that control its blood flow and the existing techniques for measurement of the blood flow. It also briefly discusses the possible role of apoptosis in glaucomatous visual loss. Method : Literature review. Conclusions : The posterior ciliary artery circulation is the main source of the blood supply to the optic nerve head with additional lesser supply via the central retinal artery and the choroidal circulation. There is considerable individual variation in the distribution of this circulation and complex regulatory systems govern its function. It is likely that microcirculatory changes in the vascular supply of the optic disc play a role in glaucoma, either as the primary abnormality or as a co‐factor that increases susceptibility to damage from increased intraocular pressure through impaired auto‐regulation. Clinical trials are currently in progress for the treatment of glaucoma with systemically administered agents that are antagonists of the receptors that mediate glutamine toxicity, a factor in the process of apoptosis.     

Correlations between corneal and optic nerve head variables in healthy subjects and patients with primary open angle glaucoma

AIM: To correlate corneal variables (determined using the Pentacam) with optic nerve head (ONH) variables determined using the Heidelberg retina tomograph (HRT) in healthy subjects and patients diagnosed with primary open angle glaucoma (POAG). METHODS: Measurements were made in 75 healthy eyes and 73 eyes with POAG and correlations examined through Pearson correlation coefficients between the two sets of variables in the two subject groups. The corneal variables determined were corneal volume (CVol), central corneal thickness (CCT), overall corneal thickness (OvCT), the mean thickness of a circular zone centered at the corneal apex of 1 mm radius (zone I) and the mean thickness of several concentric rings, also centered at the apex until the limbus, each of 1 mm width (zones II to VI respectively). The ONH variables were determined using the HRT. RESULTS: The following pairs of variables were correlated in the control group: CCT-disc area (DAr) (-0.48; P<0.0001), Zone I-DAr (-0.503; P<0.0001) and Zone II-DAr (-0.443; P<0.0001); and in the POAG group: CCT-cup-to-disc area ratio (CDRa) (-0.402; P<0.0001), Zone I-CDRa (-0.418; P<0.0001), Zone II-CDRa (-0.405; P=0.006), Zone I-cup shape measure (CSM) (-0.415; P=0.002), Zone II-CSM (-0.405; P=0.001), Zone IV-height variation contour (HVC) (0.378; P=0.002); Zone V-HVC (0.388, P<0.0001).     

【In Press】 Vessel density in OCT angiography permits differentiation between normal and glaucomatous optic nerve heads

AIM: To evaluate whether optical coherence tomography angiography (OCTA) can detect altered vessel density (VD) at the optic nerve head (ONH) in glaucoma patients. Special attention is paid to the accuracy of the OCTA technique for distinguishing healthy from glaucomatous eyes.METHODS: A total of 171 eyes were examined by the OCTA system AngioVue? (Optovue): 97 eyes diagnosed with glaucoma and 74 healthy control eyes. The papillary and peripapillary VD was measured. Furthermore, the VD was correlated with different structural and functional measurements. In order to test the accuracy of differentiation between eyes with and without glaucoma, we calculated the receiver operating characteristic curve (ROC) and the area under the curve (AUC).RESULTS: The papillary and peripapillary VD in glaucomatous eyes was significantly lower than in healthy eyes (P<0.05). The VD of the nasal peripapillary sector was significantly lower than in the other sectors. The further the disease had progressed (measured by determining the thickness of the ganglion cell complex and the retinal nerve fiber layer) the greater the VD reduction. The AUC discriminated well between glaucomatous and normal eyes (consensus classifier 94.2%).CONCLUSION: OCTA allows non-invasive quantification of the peripapillary and papillary VD, which is significantly reduced in glaucomatous eyes and accurately distinguishes between healthy and diseased eyes. OCTA expands the spectrum of procedures for detecting and monitoring glaucoma.     

Pathophysiology of human glaucomatous optic nerve damage: Insights from rodent models of glaucoma

Understanding mechanisms of glaucomatous optic nerve damage is essential for developing effective therapies to augment conventional pressure-lowering treatments. This requires that we understand not only the physical forces in play, but the cellular responses that translate these forces into axonal injury. The former are best understood by using primate models, in which a well-developed lamina cribrosa, peripapillary sclera and blood supply are most like that of the human optic nerve head. However, determining cellular responses to elevated intraocular pressure (IOP) and relating their contribution to axonal injury require cell biology techniques, using animals in numbers sufficient to perform reliable statistical analyses and draw meaningful conclusions. Over the years, models of chronically elevated IOP in laboratory rats and mice have proven increasingly useful for these purposes. While lacking a distinct collagenous lamina cribrosa, the rodent optic nerve head (ONH) possesses a cellular arrangement of astrocytes, or glial lamina, that ultrastructurally closely resembles that of the primate. Using these tools, major insights have been gained into ONH and the retinal cellular responses to elevated IOP that, in time, can be applied to the primate model and, ultimately, human glaucoma.     

Association between corneal biomechanical properties and optic nerve head morphology in newly diagnosed glaucoma patients

Background: To investigate the association between corneal biomechanics and optic nerve head morphology in newly diagnosed primary open‐angle glaucoma patients. Design: Hospital based prospective study. Participants: Forty‐two untreated newly diagnosed primary open‐angle glaucoma patients. Methods: Patients underwent corneal hysteresis measurement using the Ocular Response Analyzer and confocal scanning laser ophthalmoscopy for optic nerve head topography evaluation. One eye was selected randomly for analysis. Data collected included age, race, gender, intraocular pressure and central corneal thickness. Main Outcome Measures: Multiple regression analysis (controlling for baseline intraocular pressure and disc area) was used to investigate factors associated with the following optic nerve head topographic parameters: linear cup‐to‐disc ratio and mean cup depth. Results: Mean age of participants was 66.7 ± 11.8 years. Corneal hysteresis was the only factor significantly associated with both mean cup depth (correlation coefficient [r] = ?0.34, P = 0.03) and cup‐to‐disc ratio (r = ?0.41, P = 0.01). Central corneal thickness was significantly associated with mean cup depth (r = ?0.35, P = 0.02), but not with cup‐to‐disc ratio (r = ?0.25, P = 0.13). Although a trend towards a positive association between age and cup‐to‐disc ratio was identified (r = 0.26, P = 0.08), age was not significantly associated with mean cup depth (r = 0.06, P = 0.72). When comparing fellow eyes of patients with bilateral glaucoma, the eye with higher corneal hysteresis had smaller cup‐to‐disc ratio in 75% of the cases. Conclusions: In untreated newly diagnosed primary open‐angle glaucoma patients, those with thinner corneas and mainly lower corneal hysteresis values had a larger cup‐to‐disc ratio and deeper cup, independently of intraocular pressure values and disc size.     

Changes in optic nerve head blood flow and retrobular hemodynamics following calcium-channel blocker treatment of normal-tension glaucoma

Background: Because calcium channel blockers reduce vascularresistance, they may have a clinical application in the treatment ofnormal-tension glaucoma (NTG). This study investigates changes inboth the optic disc blood flow and the hemodynamics of retrobulbarvessels in NTG patients after the systemic administration of a calcium channel blocker. Methods: Twelve eyes of 12 NTG patients (meanage 57 6 ± 15.3 years) were examined before and after a 4-weektreatment with 2 mg b.i.d. oral nilvadipine, an L-typc calcium channel blocker. By scanning laser-Doppler flowmetry (SLDF), we obtained the velocity, flow, and volume from within a 10 × 10 pixel windowplaced on the temporal rim region of the optic disc perfusion map. Byultrasound color Doppler imaging (CDI), we measured the peak systolicvelocity (PSV) and the end diastolic velocity (EDV) of the ophthalmicartery (OA), central retinal artery (CRA), nasal posterior ciliary artery (NPCA), and temporal posterior ciliary artery (TPCA). We then calculated a resistance index (RI) for each vessel. Results: After treatment, the flow and velocity of the optic disc blood flow significantly increased (P < 0.05).Nilvadipine also significantly reduced RIs of the CRA, NPCA, and TPCA(P <0 .05), and increased both the PSV of the NPCA and the EDVs of the CRA, NPCA, and TPCA. The percent change in velocity correlated significantly with the percent changes of the CRA RI and NPCA RI. Conclusions: Oral nilvadipine appears to reduce orbital vascular resistance, which consequentlyincreases the optic disc blood flow. Abbreviations.BP – blood pressure;CRA – central retinal artery;CDI – ultrasound color Doppler imaging;EDV – end diastolic velocity;NPCA – short posterior ciliary arteries located nasal to optic nerve;NTG – normal-tension glaucoma;OA – ophthalmic artery;PP – perfusion pressure;PSV – peak systolic velocity;RI – resistance index;SLDF scanning laser-Doppler flowmetry;TPCA – short posterior ciliary arteries locatedtemporal to optic nerve.     

Factors associated with topographic changes of the optic nerve head induced by acute intraocular pressure reduction in glaucoma patients

Purpose

To investigate factors associated with changes in optic nerve head (ONH) topography after acute intraocular pressure (IOP) reduction in patients with primary open-angle glaucoma (POAG).

Methods

Untreated POAG patients (IOP >21 mm Hg) were prospectively enrolled. Systemic and ocular information were collected, including central corneal thickness (CCT) and corneal hysteresis (CH). All patients underwent confocal scanning laser ophthalmoscopy and tonometry (Goldmann) before and 1 h after pharmacological IOP reduction. The mean of three measurements was considered for analysis. Changes in each ONH topographic parameter were assessed (one eye was randomly selected), and those that changed significantly were correlated with patient''s systemic and ocular characteristics.

Results

A total of 42 patients were included (mean age, 66.7±11.8 years). After a mean IOP reduction of 47.3±11.9%, significant changes were observed in cup area and volume, and in rim area and volume (P<0.01), but not in mean cup depth (P=0.80). Multiple regression analysis (controlling for baseline IOP and magnitude of IOP reduction) showed that CH (r²=0.17, P<0.01) and diabetes diagnosis (r²⩾0.21, P<0.01) were negatively correlated with the magnitude of changes in ONH parameters, whereas the cup-to-disc ratio was positively correlated (r²=0.30, P<0.01). Age, race, disc area, and CCT were not significant (P⩾0.12). Including all significant factors in a multivariable model, only the presence of diabetes remained significantly associated with all ONH parameters evaluated (P<0.01).

Conclusions

Different systemic and ocular factors, such as diabetes, CH, and the relative size of the cup, seem to be associated with the magnitude of changes in ONH topography after acute IOP reduction in POAG patients. These associations partially explain the ONH changes observed in these patients and suggest that other factors are possibly implicated in an individual susceptibility to IOP.     

Assessment of flow dynamics in retinal and choroidal microcirculation

Alterations in ocular blood flow have been implicated in mechanisms that lead to vision loss in patients with various ocular disorders such as diabetic retinopathy, glaucoma, and age-related macular degeneration. Assessment of retinal and choroidal blood flow is also a window to evaluate systemic diseases that affect microvasculature. Quantification and qualification of the blood flow in the retina and choroid help us understand pathophysiology, stratify disease risk, and monitor disease progression in these disorders. Multiple methods are used by researchers for assessment of blood flow, but a gold standard is lacking. We review commonly used methods, both invasive and noninvasive, for evaluation of blood flow, including intravital microscopy, laser Doppler velocimetry, laser Doppler flowmetry, laser interferometry, confocal scanning laser Doppler flowmetry, laser speckle flowgraphy, Doppler optical coherence tomography, blue-field entoptic simulation, retinal vessel caliber assessment, optical coherence tomography angiography, retinal function imaging, color Doppler imaging, and scanning laser ophthalmoscope angiogram. As technology evolves, better evaluation of blood flow in various ocular and systemic diseases will likely bring new perspectives into clinical practice and translate to better diagnosis and treatment.     

正常眼压性青光眼

正常眼压性青光眼患者的眼压在统计学眼压的正常范围之内,却有典型的青光眼性视野缺损及与之相关的视盘改变。故发病隐匿,常造成不可逆的视神经损害。现代研究认为其发病机制是机械因素、血管因素、自身免疫因素等多种因素的共同作用。降眼压是必要的措施,眼压降低30%以上对其病变有利。与此同时,改善视神经血流供应和保护视神经的药物正被关注。     

原发性开角型青光眼正常眼压时共焦扫描激光多普勒视网膜血流图

目的　探讨中国人中原发性开角型青光眼患者眼压在正常范围时视乳头和视网膜的血流动力学。方法　应用共焦扫描激光多普勒视网膜血流图检测 82例原发性开角型青光眼 15 0眼眼压控制在 2 2mmHg以下时视乳头和视网膜血流。结果　视乳头平均血容量、血流速和红细胞移动速率分别是 10 4 3 5± 49 2 4,3 2 43 93± 15 89 72 ,8 3 8±3 0 7;筛板处平均血容量、血流速和红细胞移动速率分别是 7 2 8± 4 18,10 8 5 5± 80 5 1,0 3 9± 0 2 5。盘沿处平均血容量、血流速和红细胞移动速率分别是 2 0 2 1± 16 86,5 2 9 91± 5 2 0 74,1 68± 1 3 2 ;盘缘外视网膜平均血容量、血流速和红细胞移动速率分别是 13 5 6± 5 97,2 5 7 90± 13 8 11,0 92± 0 46;视网膜平均血容量、血流速和红细胞移动速率分别是 17 96±6 2 3 ,3 5 0 3 9± 179 82 ,1 2 3± 0 5 7;血管、筛板和视网膜的血容量、流速和红细胞移动速率和正常眼比较都有明显下降。结论　原发性开角型青光眼患者存在着血流动力学障碍。     

Effect of Topical Unoprostone Isopropyl on Optic Nerve Head Circulation in Controls and in Normal-Tension Glaucoma Patients

Purpose To evaluate the effect of unoprostone isopropyl on microcirculation in the optic nerve head (ONH) of controls and patients with normal-tension glaucoma (NTG).Methods Thirty healthy volunteers were randomly placed in a placebo group or a control group. For ten NTG patients, one eye was selected to receive the placebo drops and the contralateral eye received the unoprostone in a masked fashion. In both studies, the intraocular pressure (IOP) and the parameters of the blood hemodynamics of the ONH were obtained before and at 1 and 2 h after the instillation. Blood flow measurements were made with a scanning laser Doppler flowmeter.Results In both control subjects and NTG patients, the changes in the IOPs after the instillation of either unoprostone or the placebo were not significant because almost all of the NTG patients had IOPs lower than 15 mmHg. Although the hemodynamic parameters were not significantly changed in the placebo-treated eyes of the controls, the eyes of the controls treated with unoprostone had mean blood velocity and flow values that were significantly higher than the baseline values 1 and 2 h after instillation (P < 0.01). The velocity values of the controls treated with unoprostone were significantly higher than in those controls receiving the placebo at 2 h postinstillation (P = 0.027). The values for the three circulation parameters (volume, velocity, flow) were significantly higher than the baseline values after instillation in the eyes of the NTG patients treated with unoprostone (P < 0.05). In contrast, none of these parameters was significantly different from the baseline in the eyes of NTG patients treated with placebo.Conclusions These results showed that unoprostone significantly increased microcirculation in the ONH in control subjects and in NTG patients without reducing the IOP significantly. Jpn J Ophthalmol 2005;49:287–293 © Japanese Ophthalmological Society 2005     

尼莫地平对开角型青光眼视盘筛板血流的作用研究

目的　观察尼莫地平对开角型青光眼视盘筛板血流的作用。方法　选择 31例 6 0眼开角型青光眼患者 ,年龄30～ 77岁 ,平均 5 2岁 ,其中女 12例 2 3眼 ,男 19例 37眼。 A组口服尼莫地平每次 2 0 m g,每日 3次 ,17例 34眼 ,连续服用 ,平均随访 4 .3月。 B组口服尼莫地平每次 4 0 mg,每日 3次 ,总共为 14例 2 6眼 ,平均随访 5 .3月。用药前后应用共焦扫描激光多普勒视网膜血流图仪测量视盘筛板的血流参数。结果　口服 2 0 m g尼莫地平组 ,血供改善 ,血流参数如下 :血流量从 9.2 9± 5 .6 9提高到 13.99± 7.4 6 ;血液流速从 15 9.4 1± 90 .15提高到 2 2 5 .70± 87.81;红细胞移动速率从 0 .5 8±0 .33提高到 0 .92± 0 .5 7。口服 4 0 m g尼莫地平组 ,血流量从6 .70± 3.2 3提高到 8.5 7± 3.93;血液流速从 113.2 5± 5 6 .36提高到 16 8.97± 74 .5 7;红细胞移动速率从 0 .4 2± 0 .2 0提高到 0 .6 1± 0 .2 6。经过 SAS统计分析软件进行配对 t检验 ,A、B 2组服药后血流参数均明显提高 ,差异具有显著性。结论　尼莫地平能有效地改善开角型青光眼视盘筛板区的血流     

Comparison of glaucoma progression evaluated with Heidelberg retina tomograph II versus optic nerve head stereophotographs

BACKGROUND: To compare disease progression in glaucoma evaluated by means of the Heidelberg retina tomograph (HRT II) or by expert clinical assessment of colour stereophotographs of the optic nerve head (ONH). METHODS: One eye each of 54 subjects with glaucoma was reviewed using the HRT II and ONH stereophotographs. The ONH stereophotographs were assessed twice each for glaucomatous progression by 2 expert observers (Drs. Buys and Trope). They were considered to be in agreement if their results were the same in 3 of 4 assessments. Progression on the HRT II was defined by using the topographic change analysis (TCA). The clinical assessments were the reference standard used to determine sensitivity and specificity of the HRT II TCA. RESULTS: The expert observers were in agreement in 50 subjects (92%). Concordance between the HRT II and ONH stereophotographs assessments was obtained in 35 patients (65%); 16 patients (30%) showed progression on HRT II only, while 3 patients (6%) showed progression on stereophotographs only. When these results were used to perform a post hoc analysis, HRT II sensitivity increased from 70% to 78% and specificity increased from 63.6% to 70%. The positive predictive value of the HRT II rose from 30.4% to 47.8%, while the negative predictive value remained at 90.3%. INTERPRETATION: Our results demonstrate only fair agreement between HRT II and clinical judgment of ONH stereophotographs for progression in glaucomatous eyes. At present, HRT II progression alone should not indicate a treatment change. HRT II change must be evaluated in conjunction with other clinical features of deterioration before altering therapy.