Benno L. Petrig

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.

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).

Laser Doppler flowmetry and optic nerve head blood flow

PURPOSE Ischemic disorders of the optic nerve head constitute an important cause of visual loss. The optic nerve head is supplied by two main sources of blood flow: the superficial layers by the central retinal artery and the deeper layers by the posterior ciliary arteries. This study was conducted in rhesus monkey eyes to obtain a better understanding of which part of the optic nerve head circulation is measured by laser Doppler flowmetry. METHODS By means of a fundus camera-based laser Doppler flowmetry technique to measure blood flow in the optic nerve head tissue, laser Doppler flowmetry measurements were taken at baseline and then after experimental occlusion of central retinal artery (12 eyes), posterior ciliary arteries (nine eyes), and combined occlusion of central retinal artery and posterior ciliary arteries (nine eyes). Optic nerve head, choroidal, and retinal circulations were investigated by fluorescein fundus angiography after the various arterial occlusions. RESULTS Average laser Doppler flowmetry flow during central retinal artery occlusion alone was significantly decreased (P<.001) by 39%+/-21% (mean +/- 95% confidence interval) compared with normal baseline. Combined occlusion of central retinal artery and posterior ciliary arteries reduced laser Doppler flowmetry flow even more markedly by 57%+/-27% (P<.0005), but the difference between this flow reduction and that with central retinal artery occlusion alone was not significant (P>.20). After posterior ciliary artery occlusion alone, however, measurements showed a nonsignificant increase in laser Doppler flowmetry flow of 17%+/-37%. CONCLUSIONS The findings of this study suggest that the standard laser Doppler flowmetry technique is predominantly sensitive to blood flow changes in the superficial layers of the optic nerve head and less sensitive to those in the prelaminar and deeper regions, and their relative proportions are not known. In this laser Doppler flowmetry technique, the weaker Doppler signal from the deep layers cannot be separated from the dominant signal from the superficial layers to exclusively study the circulation in the deep layers; the latter circulation is of interest in optic nerve head ischemic disorders, including glaucoma. Emerging new optical modalities of the laser Doppler flowmetry technique may help in selectively measuring blood flow in the deeper layers.

Flicker evoked increase in optic nerve head blood flow in anesthetized cats.

The effect of diffuse luminance flicker stimulation of a large area (approximately 30 degrees diameter) on red blood cell flux (F) in the optic nerve head was measured in the anesthetized cat. F increased markedly during sustained flicker. The F-response to the initiation and cessation of the stimulation was found to occur within a few seconds. Upon sustained stimulation, the increase in F reached a plateau within approximately 2 min. Its level depended upon the intensity, frequency and wavelength of the stimulation and the state of adaptation of the retina. This stimulus offers a new and powerful means of investigating blood flow regulation in the optic nerve head (ONH).

Depth of tissue sampling in the optic nerve head using laser Doppler flowmetry

Laser Doppler flowmetry (LDF) was performed on a simulated blood vessel in a model eye through optic nerve tissue sections in order to ascertain the ability to detect flow through them. LDF was performed using either near-infra-red or green laser light. Tissue section thickness ranged from 50 μm to 1000 μm. As expected, we found that our ability to detect flow with LDF decreased as we increased the thickness of optic nerve sections interposed between the LDF apparatus and the simulated blood vessel. We also found that the sampled depth of LDF increased with increasing separation of the optical detection fibre from the centre of the illuminated tissue volume. With adequate separation, we were able to detect flow with LDF through tissue sections of 1000 μm thickness using either near-infra-red or green laser light.

Diabetic Glycemic Control and Retinal Blood Flow

The effect of strict glycmic control on retinal volumetric blood flow rate (Q) was investigated in 13 insulin-dependent diabetic patients with laser Doppler velocimetry and monochromatic fundus photography. Strict glycemic control was achieved by glucose monitoring and four daily insulin injections. Q was determined in a major retinal vein at baseline and then 5days, 2 mo, and 6 mo after the institution of strict control. Level of retinopathy was assessed from stereocolor fundus photographs taken at baseline and 6 mo. After 6 mo of strict diabetic control, five eyes demonstrated progression (P) by one or more retinopathy levels, and eight eyes showed no progression (NP). At 5 days, there was a significant decrease in Q of 1.4 ± 0.9 μU/min (P < 0.005) in NP eyes and a nonsignificant increase in Q of 1.2 ± 1.7 μU/min in P eyes. Changes in Q from baseline observed at 5 days were strongly correlated with changes in retinopathy level at 6 mo (r = 0.79, P <0.005). No significant changes in Q from baseline were observed at 2 and 6 mo. A lack of decrease in Q at 5 days was associated with the progression of retinopathy that occurs in some patients after the institution of strict glycemic control and may serve as a predictor for progression of retinopathy.

Effect of pure O2-breathing on retinal blood flow in normals and in patients with background diabetic retinopathy

The noninvasive Laser Doppler velocimetry technique was applied in normal volunteers and in patients with background diabetic retinopathy to determine retinal blood flow during pure oxygen breathing at atmospheric pressure. In normal subjects, five minutes of oxygen breathing produced a 63 +/- 6% decrease in retinal blood flow. In the diabetic patients blood flow decreased by only 36 +/- 15%. A significant correlation between the decrease in blood flow and that of the diameter of the veins was found in the diabetic patients. This was not the case for the normal subjects.

Retinal blood flow regulation and the clinical response to panretinal photocoagulation in proliferative diabetic retinopathy

Bidirectional laser Doppler velocimetry and monochromatic fundus photography were used to investigate retinal hemodynamics before and after panretinal photocoagulation (PRP) in 25 eyes of 23 diabetic patients with proliferative retinopathy. After PRP, there was a significant decrease in retinal volumetric blood flow rate and an increase in the retinal vascular regulatory response to hyperoxia (R). A significant association was found between the presence or absence of regression of neovascularization and the increase or decrease in R after PRP. Eyes that showed regression of neovascularization had significantly larger average R after PRP than eyes that did not show regression. Lack of improvement in R after PRP may be related to the presence of remaining ischemia or hypoxia in eyes that continue to show proliferation after PRP.

New insights into ocular blood flow at very high altitudes

Little is known about the ocular and cerebral blood flow during exposure to increasingly hypoxic conditions at high altitudes. There is evidence that an increase in cerebral blood flow resulting from altered autoregulation constitutes a risk factor for acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) by leading to capillary overperfusion and vasogenic cerebral edema. The retina represents the only part of the central nervous system where capillary blood flow is visible and can be measured by noninvasive means. In this study we aimed to gain insights into retinal and choroidal autoregulatory properties during hypoxia and to correlate circulatory changes to symptoms of AMS and clinical signs of HACE. This observational study was performed within the scope of a high-altitude medical research expedition to Mount Muztagh Ata (7,546 m). Twenty seven participants underwent general and ophthalmic examinations up to a maximal height of 6,800 m. Examinations included fundus photography and measurements of retinal and choroidal blood flow, as well as measurement of arterial oxygen saturation and hematocrit. The initial increase in retinal blood velocity was followed by a decrease despite further ascent, whereas choroidal flow increase occurred later, at even higher altitudes. The sum of all adaptational mechanisms resulted in a stable oxygen delivery to the retina and the choroid. Parameters reflecting the retinal circulation and optic disc swelling correlated well with the occurrence of AMS-related symptoms. We demonstrate that sojourns at high altitudes trigger distinct behavior of retinal and choroidal blood flow. Increase in retinal but not in choroidal blood flow correlated with the occurrence of AMS-related symptoms.