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 technique's 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.     

Pulsatile ocular blood flow investigation in asymmetric normal tension glaucoma and normal subjects

AIMS—This study was designed to investigate pulsatile ocular blood flow (POBF) in normal tension glaucoma (NTG) patients and in normal controls. NTG patients with unilateral field loss were evaluated to compare POBF values between eyes with and without field loss.
METHODS—POBF measurements from more than 1500 subjects were collected during a period of 6 months from six optometric centres. Subjects with systemic vascular diseases (such as systemic hypertension and diabetes), ophthalmic diseases, a positive family history of glaucoma, and those individuals receiving treatment with systemic β blockers were excluded on the basis of a questionnaire. For comparison, 95 NTG patients with unilateral field loss, selected from 403 consecutive patients with NTG, underwent POBF testing. For each individual age, sex, intraocular pressure, refraction, and pulse rate were entered into a database.
RESULTS—Data from 777 subjects were included in the analysis. POBF measurements of patients and subjects were compared allowing for differences in age, sex, intraocular pressure, refraction, and pulse rate. POBF was significantly lower in eyes of NTG patients with and without field loss (p <0.001 and p = 0.01 respectively). Eyes of NTG patients with field loss showed significantly lower POBF than the contralateral eyes with normal field (p < 0.001).
CONCLUSIONS—POBF was significantly lower in eyes of NTG patients with and without field loss than in normal subjects, suggesting that differences in ocular blood perfusion are relevant to the development of NTG and are detectable from the early stage of the disease. Furthermore, the finding of lower POBF in NTG eyes with field loss than in the contralateral eyes with normal field suggests that haemodynamic differences between fellow eyes contribute to determine the side of onset of the disease.

Keywords: pulsatile ocular blood flow; normal tension glaucoma; visual field asymmetry     

开角型青光眼小梁切除前后搏动性眼血流量比较研究

目的：以OBF仪对开角型青光眼（primary open angle glaucoma,POAG)患者手术前后的搏动性眼血流量（pulsatile ocular blood flow,POBF）值及眼压进行测量，探讨POAG患者行小梁切除术后眼内血流变化。方法：本院诊断及手术治疗的POAG患者39例39眼，均在本院行小梁切除术，术中加用0．2g.．L^-1丝裂霉素C(mitomycin C,MMC)抗瘢痕，测量项目包括搏动眼血流量，脉搏周期内眼压变化值（pulse amplitude of IOP,PA IOP）,脉搏周期内眼容积变化值（pulse amplitude of volume,PV）,心率（pulse/heart rate,HR），最大眼压（Max-IOP），最小眼压（Min-IOP），平均眼压（Max-IOP Min-IOP）/2,Average IOP(Ave-IOP),手术前测量时间为药物治疗前，手术后测量时间为手术后1－2周，手术前后比较采用配对t检验，Ave-IOP的变化值与OBF的变化值作相关分析，结果：POAG患者手术后POBF，PV增高，Ave-IOP降低，差异有统计学,意义，Ave-IOP的变化值与OBF的变化之间有相关关系r=0.674,t=5.552,P=0.000，结论：POAG患者行小梁切除术后眼压降低有助于眼血流改善，但并不意味着所有POAG患者眼血流都得到改善，推测POAG发病部分原因是血管自身调节功能及供血异常。     

青光眼药物对眼部血液循环的影响

尽管眼压被认为是青光眼发病的主要危险因素,越来越多的证据显示,眼部缺血也对青光眼发病起着重要作用。由于当前所用的许多青光眼药物对血管系统有影响,因此评价这些药物对眼部循环的作用有着重要意义。本文就6大类局部降眼压药物对眼血流的影响进行综述。     

Pulsatile ocular blood flow in patients with pseudoexfoliation

Purpose: Pseudoexfoliation syndrome is oneof the most frequent causes of open-angleglaucoma and is statistically significantassociated with a high risk of hypertension, angina,myocardial infarction or stroke and retinal veinthrombosis. The aim of this study was toevaluate the pulsatile ocular blood flow (POBF)in pseudoexfoliation syndrome without(PEX) and with glaucoma (PEG).Methods: Seventeen eyes with PEX, 17 withPEG and 11 normal eyes of age-matchedpatients were enrolled. A complete ophthalmologicalexamination included measuring thePOBF with the Langham Pneumotonometer as well asthe nerve fiber layer thickness byscanning laser polarimetry (GDx^TM). Results: The blood flow parameters, pulsevolume and POBF, were statisticallysignificant different between normals and patientswith PEG (p < 0.003, t-test). A negativecorrelation between the intraocular pressure andthe POBF was found for all eyes tested.Analysis of GDx? parameters showed a negativecorrelation for the ``number'' with thePOBF and a positive one for ellipse modulation.Conclusion: Although pseudoexfoliation is reportedto be a systemic diseasemeasurement of the POBF could not detect any differencebetween normals and PEX, but wasstatistically significant different in PEG.Assessments of nerve fiber layer thickness asdetermined by scanning laser polarimetry alsoshowed a correlation with POBF in someparameters tested.     

The association of ocular blood flow with haemorheological parameters in primary open‐angle and exfoliative glaucoma

Purpose: To evaluate the ocular blood flow velocities and haemorheological parameters in patients with primary open‐angle glaucoma (POAG), exfoliative glaucoma (XFG) and exfoliation syndrome (XFS) and to compare their results with those of healthy controls. Methods: Twenty‐five patients with POAG (group 1), 25 patients with XFG (group 2), 25 patients with XFS (group 3) and 25 healthy controls (group 4) were included in the study. Ocular blood flow velocities of ophthalmic artery (OA), central retinal artery (CRA) and short posterior ciliary arteries (SPCAs) were measured using colour Doppler imaging (CDI). Haemorheological parameters (erythrocyte elongation and aggregation index, aggregation amplitude, aggregation half‐life, plasma viscosity, haematocrit) were measured in venous blood samples of all patients. Results: The peak systolic velocity (PSV) and end‐diastolic velocity (EDV) values were lower and resistive indices (RI) were higher for the OA, CRA and SPCA of glaucomatous (groups 1 and 2) patients compared with those of controls (group 4) (PSV: OA, 40.4 ± 11.3 versus 52.6 ± 12.8 cm/second, p < 0.001; CRA, 12.9 ± 2.9 versus 15.3 ± 4.2 cm/second, p = 0.02; SPCA, 21.7 ± 6.6 versus 26.6 ± 8.3 cm/second, p = 0.013) (EDV: OA, 10.3 ± 4.3 versus 14.2 ± 5.1 cm/second, p < 0.001; CRA, 3.7 ± 1.1 versus 4.5 ± 1.3 cm/second, p = 0.025; SPCA, 5.2 ± 1.8 versus 7.7 ± 3.2 cm/second, p = 0.001) (RI: OA, 0.75 ± 0.05 versus 0.66 ± 0.07, p < 0.001; CRA, 0.73 ± 0.08 versus 0.68 ± 0.10, p = 0.223; SPCA, 0.70 ± 0.10 versus 0.63 ± 0.11, p = 0.004). There were no statistically significant differences between the haemorheological parameters of glaucomatous and non‐glaucomatous patients. The reduction in ocular blood flow velocities in groups 1, 2 and 3 were not associated with changes in haemorheological parameters. Conclusion: Our results suggest that impairment of the retrobulbar blood flow in POAG and XFG is not associated with alterations in haemorheological parameters.     

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. Design: Cross‐section analysis from a longitudinal, prospective study. Participants: Eighty‐four open‐angle glaucoma patients (20 diabetic open‐angle glaucoma patients and 64 non‐diabetic open‐angle glaucoma patients) Methods: Patients were analyzed for ocular structure, ocular perfusion pressure (OPP), retrobulbar blood flow and retinal capillary perfusion. Statistical analysis was performed by SPSS version 18.0. Comparisons between groups were made as well as multivariate linear regression analysis. Main Outcome Measure: Retrobulbar blood flow and the retinal microcirculation. Results: Central retinal artery peak systolic velocity was 13.5% lower in diabetic patients (P = 0.007). In diabetic open‐angle glaucoma patients, ocular perfusion pressure positively correlated with central retinal artery and temporal posterior ciliary artery peak systolic velocity (R = 0.476, P = 0.039 and R = 0.529, P = 0.02, respectively), and with central retinal artery and nasal posterior ciliary artery resistance index (R = 0.537, P = 0.018 and R = 0.566, P = 0.012 respectively). Average retinal nerve fibre layer positively correlated with central retinal artery peak systolic velocity and temporal posterior ciliary artery end diastolic velocity (R = 0.501, P = 0.029 and R = 0.553, P = 0.019, respectively), and negatively correlated with superior and inferior retinal avascular space in the diabetic group (R = ?0.498, P = 0.030 and R = ?0.700, P = 0.001, respectively); no correlations were found in the non‐diabetic group. Negative correlations between retrobulbar and retinal circulations were only found in the diabetic open‐angle glaucoma patients, whereas positive correlations between retinal flow and non‐flow were only found in non‐diabetic open‐angle glaucoma patients. Conclusion: Diabetes may interfere with normal vascular regulation and contribute to glaucoma progression.     

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.     

灯盏细辛对青光眼血流的影响

目的 观察灯盏细辛片对眼压已控制的青光眼血流的影响。方法 采用前瞻性、随机、双盲、安慰剂对照的方法,将眼压已控制的中晚期青光眼患者42例(眼),随机分为年龄匹配的治疗组(22例)和对照组(20例)。治疗组口服灯盏细辛,对照组口服安慰剂,连续6个月,每月复诊1次。采用彩色多谱勒成像系统测量眼动脉、睫状后短动脉及视网膜中央动脉的血流动力学参数变化。结果 治疗组与对照组6个月中眼压分别为(14.30±2.48)mmHg和(14.44±2.02)mmHg(P=0.841)。治疗组治疗6个月后眼动脉阻力指数较治疗前降低0.059(P=0.009)。灯盏细辛对血压、眼灌注压和脉搏无影响。结论 灯盏细辛可降低眼动脉阻力指数,但不能证明其具有直接改善青光眼视乳头血流的作用,对青光眼血流的影响有待进一步证实。     

Analysis of risk factors that may be associated with progression from ocular hypertension to primary open angle glaucoma

Background: As a multifactorial disease, glaucoma may be associated with pressure‐dependent and pressure‐independent factors. Ocular hypertension (OHT) may develop into primary open angle glaucoma (POAG) for many patients. Groups with OHT and POAG were compared for pressure‐dependent and independent risk factors. A high prevalence of any factor(s) could indicate a contribution to progression from OHT to POAG. Methods: A sample of patients with POAG (n = 438) and with OHT (n = 301) were selected from those attending a tertiary referral private glaucoma practice, and data were collected regarding age and intraocular pressure at the time of diagnosis, sex, family history of glaucoma, systemic hypertension, diabetes, Raynaud's phenomenon, migraine and myopia. Results: After multivariate analysis, older age at time of diagnosis (χ²₅ = 73.89, P < 0.001), myopia (odds ratio [OR] = 1.5, 95% confidence interval [CI] 1.0?2.2; P < 0.05), a family history of glaucoma (OR = 1.6, 95% CI 1.1?2.3; P < 0.01) and a high intraocular pressure (χ²₄ = 16.96; P = 0.002) were found to be more prevalent among those with POAG. No other significant differences could be found between the two groups. Conclusion: Patients who have OHT may be at higher risk of developing POAG if they also have myopia, a family history of glaucoma or are of older age.     

Effect of systemic moxaverine on ocular blood flow in humans

Purpose: A number of common eye diseases are associated with ocular perfusion abnormalities. The present study aimed to investigate whether systemically administered moxaverine improves ocular blood flow. Methods: Sixteen healthy volunteers were studied in this randomized, double‐masked, placebo‐controlled, two‐way crossover study. Moxaverine in a dose of 150 mg was administered i.v. Ocular haemodynamic parameters were measured before and after drug administration. Retinal arterial and venous diameters were measured with a retinal vessel analyser. Retinal blood velocity was assessed using laser Doppler velocimetry and choroidal and optic nerve head blood flow was measured with laser Doppler flowmetry. Results: Moxaverine increased choroidal blood flow (22.6 ± 27.9%), an effect which was significant versus placebo (p = 0.015). Red blood cell velocity in retinal veins tended to increase by 13.6 ± 13.3% after infusion of moxaverine, but this effect was not significant compared with placebo (p = 0.25). In the optic nerve head moxaverine also tended to increase blood flow (11.8 ± 12.7%), but, again, this effect was not significant versus placebo (p = 0.12). Neither moxaverine nor placebo had an effect on retinal arterial diameters. In retinal veins moxaverine tended to induce vasodilation (2.6 ± 2.8%) and to increase blood flow (19.6 ± 16.5%), but these effects were not significant (both p = 0.12). Conclusions: The present study indicates an increase in choroidal blood flow after systemic infusion of a single dose of moxaverine in healthy subjects. Further studies are warranted to investigate whether these effects are also seen after longterm treatment in patients with ocular vascular disease.     

Portsmouth visual field database: an audit of glaucoma progression

Aim

To explore visual field (VF) progression in a cohort of secondary care-treated glaucoma and ocular hypertensive (OHT) patients.

Methods

We extracted VFs from our database drawn from our normal clinical practice. VF series from 4177 eyes from 2208 patients who had five or more VFs were obtained, the ‘better'' eye was selected and the rate of VF progression was calculated using mean deviation (MD) data.

Results

The median rate of progression for the whole sample was −0.1 dB/year (interquartile range (IQR) −4 to 0 dB/year) over a median of 6.7 years (IQR 4.9–8.7). Of 2208 patients, 477 (21.2%) progressed at >−0.5 dB/year; 46 (2.1%) progressed at >−2.0 dB/year. Of those with a ‘final MD'' of worse than −10 dB (N=244) in their better eye; 14.0% were ‘fast progressors'' (>−2 dB/year), 33.7% ‘moderate progressors'' (−1 to −2 dB/year), and 28.8% ‘slow progressors'' (−0.3 dB to −1 dB/year). Of those with ‘initial MD'' better than −3 dB and those with worse than −3 dB, 31/1679 (1.8%) and 213/529 (40.3%) respectively, had a final MD of worse than −10 dB.

Conclusion

Fast progressors, while important, are relatively rare. Moderate and slow progressors make up the majority of the progressing population within this data set. The risk of significant visual loss is much higher in those with initial damage. With increasing life expectancy, moderate and slow progressors may become increasingly clinically important.     

Technical Note: How many readings are required for an acceptable accuracy in pulsatile ocular blood flow assessment?

PURPOSE: Pulsatile ocular blood flow (POBF) assessment aids the diagnosis of ocular diseases with defective ocular haemodynamics, such as glaucoma. Although each successful POBF measure given by the instrument represents five 'repeatable' pulses, there has been no study verifying how repeatable they are. There is also no report on the minimal number of measurements for an acceptable accuracy. METHODS: Forty-three healthy young subjects were recruited and each subject had five consecutive POBF measurements obtained from one randomly selected eye. The coefficient of variation was calculated from the raw data of the five 'repeatable' pulses. The average from five consecutive measurements was considered as the standard for comparison with the first, average of the first two, the first three and the first four measurements. The 95% limits of agreement were determined using the Bland and Altman approach. RESULTS: The coefficient of variation was greater than the manufacturer's claim of within 10%. The mean (+/-S.D.) POBF calculated from five consecutive measures was 732.5 +/- 243.2 microL min(-1). The mean (+/-S.D.) difference between the standard POBF and the first, average of the first two, the first three and the first four measurements was (in microL min(-1)): 12.5 +/- 59.8, 7.8 +/- 42.1, 9.6 +/- 32.5 and 3.7 +/- 19.6 respectively. The corresponding 95% limits of agreement were (in microL min(-1)): +/-117.2, +/-82.6, +/-63.8 and +/-38.4 respectively. CONCLUSIONS: As the five 'repeatable' pulses were not as repeatable as the manufacturer claims, practitioners should not rely on one single POBF measure. An average of three consecutive measurements will be adequate to detect the minimum reported difference in POBF between glaucoma and normal patients.     

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     

Pulsatile ocular blood flow in healthy Koreans

PURPOSE: To determine the normal reference range of pulsatile ocular blood flow (POBF) values in healthy Korean subjects and to find out the factors that may affect them. METHODS: A total of 280 eyes of 280 normal subjects were included in this study. Best corrected visual acuity (BCVA), intraocular pressure (IOP), axial length, POBF, systemic blood pressure, and pulse rate were measured. The mean, standard deviation, range, and the 5th and 95th percentiles of POBF were calculated, and the influences of various parameters to POBF were determined by multiple regression analyses. RESULTS: The mean POBF value was 766.0+/-221.6 microl/min in men and 1021.1+/-249.5 microl/min in women. The 5th and 95th percentiles for POBF values were 486.0 microl/min and 1140.0 microl/min in men and 672.0 microl/min and 1458.0 microl/min in women. The POBF values were significantly influenced by gender, mean blood pressure, pulse rate, and axial length. CONCLUSIONS: Even though the POBF values were influenced by gender, BP, and axial length, we could define the normal reference range of POBF in healthy Koreans.     

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.     

三种降眼压药物对眼部血流的影响

目的 观察３种常用的降眼压药物连续滴用１周后对眼部血流的影响。方法 选择原发性开角型青光眼或高眼压症患者３２例,分为３组,分别滴用０．５％左旋丁萘酮心安、０．５％噻吗心安及０．１％地匹福林１周,均为每日２次。将患者滴药前、后１周在激光扫描眼底镜下拍摄的荧光素、吲哚青绿视网膜和脉络膜务管造影录像带作为分析资料,利用计算机视频图像处理技术和相应测量软件,以单盲测量３组患者的眼部血流动力学目标。在正式测     

Clinical clues of vascular dysregulation and its association with glaucoma

Vascular dysregulation is a condition in which blood flow is not properly distributed to meet the demands of different tissues and could lead to overperfusion or underperfusion. Vascular dysregulation can be primary (occurring alone) or secondary (associated with other disorders, usually autoimmune diseases), and is caused by an imbalance between vasodilator and vasoconstrictor substances produced mainly locally by the vascular endothelium. In most circumstances of vascular dysregulation, the level of endothelin-1 is increased, leading to vasospasm. Vascular dysregulation is present in at least some subgroups of patients with glaucoma, and in these individuals it might have some important therapeutic consequences. In this article we review the evidence linking vascular dysregulation and glaucoma, and evaluate the clinical characteristics that might suggest the presence of vascular dysregulation in the glaucoma patient.