Charles E. Riva

Regulation of retinal blood flow in health and disease

Optimal retinal neuronal cell function requires an appropriate, tightly regulated environment, provided by cellular barriers, which separate functional compartments, maintain their homeostasis, and control metabolic substrate transport. Correctly regulated hemodynamics and delivery of oxygen and metabolic substrates, as well as intact blood-retinal barriers are necessary requirements for the maintenance of retinal structure and function. Retinal blood flow is autoregulated by the interaction of myogenic and metabolic mechanisms through the release of vasoactive substances by the vascular endothelium and retinal tissue surrounding the arteriolar wall. Autoregulation is achieved by adaptation of the vascular tone of the resistance vessels (arterioles, capillaries) to changes in the perfusion pressure or metabolic needs of the tissue. This adaptation occurs through the interaction of multiple mechanisms affecting the arteriolar smooth muscle cells and capillary pericytes. Mechanical stretch and increases in arteriolar transmural pressure induce the endothelial cells to release contracting factors affecting the tone of arteriolar smooth muscle cells and pericytes. Close interaction between nitric oxide (NO), lactate, arachidonic acid metabolites, released by the neuronal and glial cells during neural activity and energy-generating reactions of the retina strive to optimize blood flow according to the metabolic needs of the tissue. NO, which plays a central role in neurovascular coupling, may exert its effect, by modulating glial cell function involved in such vasomotor responses. During the evolution of ischemic microangiopathies, impairment of structure and function of the retinal neural tissue and endothelium affect the interaction of these metabolic pathways, leading to a disturbed blood flow regulation. The resulting ischemia, tissue hypoxia and alterations in the blood barrier trigger the formation of macular edema and neovascularization. Hypoxia-related VEGF expression correlates with the formation of neovessels. The relief from hypoxia results in arteriolar constriction, decreases the hydrostatic pressure in the capillaries and venules, and relieves endothelial stretching. The reestablished oxygenation of the inner retina downregulates VEGF expression and thus inhibits neovascularization and macular edema. Correct control of the multiple pathways, such as retinal blood flow, tissue oxygenation and metabolic substrate support, aiming at restoring retinal cell metabolic interactions, may be effective in preventing damage occurring during the evolution of ischemic microangiopathies.

Laser Doppler flowmetry in the optic nerve

Laser Doppler flowmetry (LDF) is a technique that measures relative average velocity, number and flux (number times velocity) of red blood cells in a tissue. In this paper, we demonstrate its application in the optic nerve head tissue, describe the laser delivery and light scattering detection schemes and investigate the effect of the distance between the sites of illumination and detection. We also provide evidence that the flow measured by LDF varies linearly with actual blood flow in the optic nerve and examine the question of the depth of the sampled volume. Experiments in anesthetized cats illustrate potential applications which make use of the high temporal resolution of LDF. These include the response of blood flow to changes in the composition of the breathing gases and changes induced by neuronal stimulation with multiple and single flashes.

Retinal Autoregulation in Open-angle Glaucoma

The macular blood flow response to an induced change in intraocular pressure (autoregulation) was studied using the blue field entopic phenomenon in 11 open angle glaucoma patients, eight glaucoma suspects and 13 normal volunteers. A suction cup was used to raise the intraocular pressure (IOP) above its resting state (IOPrest). IOPmax, the highest acutely increased IOP for which blood flow can be maintained constant by autoregulation, was 24.9 +/- 1.5 mmHg (+/- 1 SD) in the glaucoma patients, 30.8 +/- 4.6 mmHg in the glaucoma suspects and 29.9 +/- 3.6 mmHg in the normal subjects. The values for IOPmax - IOPrest were 3.7 +/- 4.3 mmHg, 4.7 +/- 3.3 mmHg, and 14.3 +/- 3.1 mmHg, respectively. After the release of the suction cup, a hyperemic response was observed by 16 of 17 normal eyes, 10 of 14 glaucoma suspect eyes and only 9 of 19 glaucomatous eyes. These results suggest an abnormal autoregulation of macular retinal blood flow in open-angle glaucoma.

Use of laser speckle flowgraphy in ocular blood flow research

Acta Ophthalmol. 2010: 88: 723–729

Visually evoked hemodynamical response and assessment of neurovascular coupling in the optic nerve and retina

The retina and optic nerve are both optically accessible parts of the central nervous system. They represent, therefore, highly valuable tissues for studies of the intrinsic physiological mechanism postulated more than 100 years ago by Roy and Sherrington, by which neural activity is coupled to blood flow and metabolism. This article describes a series of animal and human studies that explored the changes in hemodynamics and oxygenation in the retina and optic nerve in response to increased neural activity, as well as the mechanisms underlying these changes. It starts with a brief review of techniques used to assess changes in neural activity, hemodynamics, metabolism and tissue concentration of various potential mediators and modulators of the coupling. We then review: (a) the characteristics of the flicker-induced hemodynamical response in different regions of the eye, starting with the optic nerve, the region predominantly studied; (b) the effect of varying the stimulus parameters, such as modulation depth, frequency, luminance, color ratio, area of stimulation, site of measurement and others, on this response; (c) data on activity-induced intrinsic reflectance and functional magnetic resonance imaging signals from the optic nerve and retina. The data undeniably demonstrate that visual stimulation is a powerful modulator of retinal and optic nerve blood flow. Exploring the relationship between vasoactivity and metabolic changes on one side and corresponding neural activity changes on the other confirms the existence of a neurovascular/neurometabolic coupling in the neural tissue of the eye fundus and reveals that the mechanism underlying this coupling is complex and multi-factorial. The importance of fully exploiting the potential of the activity-induced vascular changes in the assessment of the pathophysiology of ocular diseases motivated studies aimed at identifying potential mediators and modulators of the functional hyperemia, as well as conditions susceptible to alter this physiological response. Altered hemodynamical responses to flicker were indeed observed during a number of physiological and pharmacological interventions and in a number of clinical conditions, such as essential systemic hypertension, diabetes, ocular hypertension and early open-angle glaucoma. The article concludes with a discussion of key questions that remain to be elucidated to increase our understanding of the physiology of ocular functional hyperemia and establish the importance of assessing the neurovascular coupling in the diagnosis and management of optic nerve and retinal diseases.

Altered Retinal Vascular Response to 100% Oxygen Breathing in Diabetes Mellitus

The effect of 100% oxygen breathing on retinal blood flow was investigated using laser Doppler velocimetry in 19 normal eyes, and in 41 eyes of insulin treated diabetic patients. Of the diabetic eyes studied, nine had no retinopathy, 18 had background diabetic retinopathy, seven had proliferative diabetic retinopathy, and seven had proliferative diabetic retinopathy that had been previously treated by argon panretinal photocoagulation. Five minutes of 100% oxygen breathing produced an average decrease in blood flow of 61% (SD = 8) in normal eyes, 53% (SD = 10) in NR eyes, 38% (SD = 13) in background diabetic retinopathy eyes, 24% (SD = 18) in proliferative diabetic retinopathy eyes and 54% (SD = 8) in panretinal photocoagulation eyes. In six eyes with proliferative retinopathy measured before and after panretinal photocoagulation, a significant increase in vascular response to O2 was observed following photocoagulation (Wilcoxon signed rank test, P less than 0.05).

Autoregulation of human optic nerve head blood flow in response to acute changes in ocular perfusion pressure

Abstract• Background: Studies in animals have demonstrated that optic nerve head (ONH) blood flow (Fonh) is autoregulated, but there is a lack of evidence for such a process in humans. Therefore, we investigated the relationship between Fonh and mean ocular perfusion pressure (PPm) in normal volunteers when PPm is decreased through elevation of the intraocular pressure (IOP). • Methods: Laser Doppler flowmetry (LDF) was used to measure relative mean velocity (Velohn), volume (Volonh) and Fonh of blood at sites of the ONH away from visible vessels, while PPm was decreased in two ways: (1) rapidly, by IOP increments of 15 s duration, and (2) slowly, by IOP increments of 2 min duration, both by scleral suction cup in one eye of each of nine subjects. • Results: A rapid and large decrease of PPm of more than 100% induced a decrease of more than 80% in Fonh. With the slower decrease in PPm Fonh remained constant down to a PPm of ≃22 mm Hg (IOP=40 mm Hg) and then decreased, predominatly due to a decrease in Velohn. Immediately after removal of the suction cup, Fonh increased transiently by 44% above baseline. • Conclusions: This study demonstrates efficient blood flow autoregulation in the OHN, which is probably brought about by an increase in vascular capacitance. The magnitude of the reactive hyperaemia agrees with the compensatory decrease in ONH vascular resistance during IOP elevation. The time scale of the autoregulatory process and the dependence of the hyperaemia upon duration of IOP elevation suggest a metabolic mechanism of autoregulation.

Retinal vascular autoregulation in diabetes mellitus.

The blue field entoptic technique was used to study autoregulation of the macular retinal circulation in response to acute alterations of intraocular pressure in 71 diabetic eyes and 30 normals matched for age, systemic blood pressure, and ophthalmic artery diastolic pressure. IOPmax, the maximal intraocular pressure at which flow is maintained normal by autoregulation, was normal in eyes with no retinopathy (30 +/- 3.2 mm Hg) but decreased with progression of retinopathy, approaching the resting intraocular pressure in eyes with proliferative retinopathy. The hyperemia observed by normals to an acute reduction of intraocular pressure was not observed frequently in the diabetics with no retinopathy. The frequency of observation of the hyperemia decreased with progression of retinopathy and was uniformly absent in eyes with proliferative retinopathy. A group of eyes with minimal microangiopathy was found to have an abnormal IOPmax and no hyperemic response. The prognostic significance of these parameters remains to be established.

Blue field entoptic phenomenon and blood velocity in the retinal capillaries.

The blue field entoptic phenomenon consists of the perception of one’s own leukocytes (white blood cells) flowing in the macular capillaries of the retina. A method has been developed for determining the speed of the leukocytes. In this method, the motion of the leukocytes is simulated on a screen by means of a minicomputer system. The subject is instructed to match the motion of the simulated white blood cells with that of his own leukocytes. For this, he can adjust the number and the maximum and minimum speeds of the simulated particles. Measurements in five young subjects with normal fundi indicate that the speed of the leukocytes in the macular capillaries of the retina is pulsatile. Minimum and maximum speeds are approximately 0.5 and 1 mm/s.

Retinal haemodynamics in patients with early diabetes mellitus.

AIMS/BACKGROUND: The retinal circulation was investigated in a group of 19 patients with insulin dependent diabetes mellitus with less than 4 years of disease duration and no evidence of diabetic retinopathy. Results of these patients were compared with those of 16 age-matched normal controls. METHODS: Venous diameter (D) was measured from monochromatic fundus photographs. Maximum erythrocyte velocity (Vmax) was assessed by bidirectional laser Doppler velocimetry in the major retinal veins of one eye of each subject. Total volumetric blood flow rate (QT) was calculated by adding the flow rates of the major retinal veins. RESULTS: Average QT was 12% larger than normal in diabetic patients (one tailed, non-paired Students t test, p < 0.05). A statistically significant correlation was observed between QT and disease duration (r = 0.35, p < 0.04). Patients with longer disease duration tended to have somewhat larger QT. The average retinal vascular regulatory responses to hyperoxia were not significantly different from normal in diabetic patients. In these patients, however, higher blood glucose levels were associated with decreased regulatory responses to hyperoxia. CONCLUSIONS: Patients with diabetes mellitus of relatively short duration have mildly increased QT, suggesting that increased blood flow may play an early role in the development of diabetic retinal microangiopathy.