Changes in optic nerve head blood flow in children with cerebral malaria and acute papilloedema.

OBJECTIVE: To investigate capillary blood flow in the optic nerve head (ONH) of children with cerebral malaria. METHODS: Malawian children with cerebral malaria admitted to a paediatric research ward were examined by direct and indirect ophthalmoscopy. ONH blood flow was measured using laser Doppler flowmetry (LDF) in suitable patients. Mean blood volume and velocity were obtained from 30 to 60 s recordings from the temporal ONH and used to calculate blood flow. These were compared with admission variables, funduscopic findings and disease outcomes. RESULTS: 45 children with cerebral malaria had LDF recordings; 6 subsequently died and 5 survivors had neurological sequelae. 12 (27%) had papilloedema. The mean microvascular blood volume was higher in patients with papilloedema (3.28 v 2.54 arbitrary units, p = 0.002). The blood velocity correlated directly with haematocrit (r = 0.46, p = 0.001) and inversely with blood glucose (r = -0.49, p = 0.001). CONCLUSION: The increase in ONH microvascular blood volume in papilloedema measured by LDF is consistent with current theories of pathogenesis of papilloedema. LDF has potential as a tool to distinguish papilloedema from pseudopapilloedematous disc swellings. The relationship between blood velocity and haematocrit may relate to levels of sequestration in cerebral malaria.

Sub-foveal choroidal blood flow by LDF: measurement and application to the physiology and pathology of the choroidal circulation.

Laser Doppler flowmetry allows the measurement of relative choroidal blood flow in the sub-foveal region of the fundus (ChBF). This technique has been applied to the investigation of the regulation of ChBF in response to a variety of physiological stimuli (breathing different gas mixtures of O2 and CO2, varying the systemic and ocular blood perfusion pressures, light-dark transition and zero gravity) in normal subjects. Measurements in pathological conditions, such as diabetes, age-related macular degeneration and glaucoma indicate alterations of the response of ChBF to increased systemic blood pressure. The data provide a better understanding of the regulation of the choroidal circulation in the normal and diseased eye.

Diabetic glycemic control and retinal blood flow.

The effect of strict glycemic 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 5 days, 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 microliters/min (P less than 0.005) in NP eyes and a nonsignificant increase in Q of 1.2 +/- 1.7 microliters/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 less than 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.

Autoregulation of blood flow in the capillaries of the human macula.

The entoptic phenomenon by which one can observe leukocytes flowing in one's own parafoveal capillaries has been used to study the effect of changes in perfusion pressure on blood flow. Our measurements in humans with normal ocular fundi indicate that the retinal circulation of the parafovea is autoregulated in relation to perfusion pressure. The average time lag between a change in blood flow and the beginning of the autoregulatory response was about 46 sec., and the average duration of this response was about 48 sec. At the end of the autoregulatory response, the vascular resistance of the parafoveal segment was about 50% lower than that at normal intraocular pressure.

Subfoveal choroidal blood flow in response to light-dark exposure.

PURPOSE: To document the response of subfoveal choroidal blood flow (ChBF) in the human eye induced by light and dark exposures and provide some insight into the mechanism underlying this response. METHODS: In a group of 12 volunteers (age, 25-60 years), ChBF was measured with a confocal laser Doppler flowmeter. Wavelength of the probing laser beam was 785 nm (90 microW at the cornea). ChBF was recorded in room light, in darkness, in room light after dark adaptation, and during strong green light exposure after exposure to room light. After dark adaptation of both eyes, ChBF was also measured in one eye while only the fellow eye was exposed to strong visible light. RESULTS: Although ChBF was stable during room light condition, it decreased significantly by 15% (P < 0.01) during dark adaptation. After 6 minutes of room light following 20 minutes of darkness, ChBF was back to baseline. Strong, diffuse, green light exposure over a field of 40 degrees, as well as the probing laser beam, had no detectable effect on ChBF. No change in ChBF was detected when the fellow eye was illuminated after both eyes had been dark adapted. CONCLUSIONS: The findings did not confirm the presence of an active process of ChBF regulation in response to light exposure in humans. They demonstrate, however, a reversible decrease in ChBF that occurs after a transition from room light to darkness, which could involve a neural mechanism.

Intravenous nicardipine in cats increases optic nerve head but not retinal blood flow.

The effect of intravenously injected nicardipine on retinal and optic nerve head (ONH) blood flow was studied in 27 cats using laser Doppler velocimetry and flowmetry, respectively. A dose of 20 micrograms/kg of nicardipine had little effect on retinal blood flow. A dose of 100 micrograms/kg, however, produced a significant transient decrease in flow. By contrast, both doses produced a significant increase in ONH blood flow despite a significant decrease of the mean arterial blood pressure. Measurements of the partial pressure of oxygen (PO2) with an oxygen-sensitive microelectrode, whose tip was placed in the vitreous just in front of the optic disc, showed a significant increase in the PO2 that paralleled the increase in ONH blood flow. These results demonstrate, for the first time to the authors' knowledge, a pharmacologically induced increase in ONH blood flow and suggest that nicardipine could have a beneficial effect on ONH tissue.

Flicker-evoked responses of human optic nerve head blood flow: luminance versus chromatic modulation.

PURPOSE: To determine the response of human optic nerve head blood flow (R:F(onh)) to heterochromatic equiluminant flicker modulation and compare it to the response induced by pure luminance flicker. METHODS: In five normal volunteers, F(onh) measured at the neuroretinal rim was monitored continuously by laser Doppler flowmetry. Stimuli were generated by green and red light emitting diodes and delivered to the fundus in Maxwellian view (field of 25(o)). Both green (G:) and red (R:) illuminances were square-wave modulated, 180(o) out of phase, with a maximum value of 10.4 for G: and 2.64 lux for R: Flicker frequency was varied from 2 Hz to 40 Hz. R:F(onh) was defined as the change in F(onh) during stimulation relative to the prestimulus F(onh). RESULTS: Defining the color ratio r as R:/(R: + G:), the R:F(onh), measured for a 15-Hz flicker, was largest at pure luminance (r = 0 and 1), declined at mixed luminance and chromatic modulations, and reached a secondary maximum at r = 0.45, the value of psychophysical equiluminance. R:F(onh) versus flicker frequency displayed the characteristics of a low-pass function for the equiluminance flicker stimulus and of a band-pass function, with a maximum at intermediate frequencies, for the luminance flicker stimulus. CONCLUSIONS: R:F(onh) in humans can be evoked by heterochromatic flicker, modulated either in luminance or chromatic equiluminant conditions. R:F(onh) may be specific for luminance and chromatic modulations, similar to neural responses dominated by the magno- and parvocellular activity, respectively. These findings offer a new approach to study the neurovascular coupling at the optic nerve head in both physiological and diseased conditions involving predominantly or selectively the magno- and parvocellular pathways.

The acute effect of cigarette smoking on macular capillary blood flow in humans.

The acute effect of cigarette smoking on retinal macular blood flow was studied in 14 healthy habitual smokers using the blue field simulation technique. This technique provides a method for quantifying the velocity of leukocytes flowing in one's own macular capillaries. Subjects adjusted the mean velocity of computer simulated leukocytes moving on a CRT screen to match that of their own entoptically perceived leukocytes before, during, and immediately after smoking a cigarette. Smoking resulted in a 12 +/- 5% (SEM) increase in macular leukocyte velocity and presumably blood flow. Possible mechanisms for this increase are discussed.

Effect of flicker on macular blood flow assessed by the blue field simulation technique.

PURPOSE: To determine the effect of diffuse luminance flicker on the motion of leukocytes in the retinal macular capillaries of normal subjects. METHODS: Using the blue field simulation technique, subjects were asked to match the motion of simulated leukocytes displayed on a video monitor to that of their own entoptically seen white blood cells (WBCs). The changes in velocity and density of the WBCs were recorded after stimulation with diffuse luminance flicker of various durations (0 to 16 seconds), either immediately or at various delays (2, 4, 8 seconds) after cessation of the stimulus. RESULTS: White blood cell velocity increased as flicker duration increased from 0 to 16 seconds. After cessation of flicker, leukocyte motion decreased to baseline within 15 seconds. CONCLUSIONS: The authors' findings suggest a coupling between retinal neural activity and blood flow in the macular region of the retina. The rapidity of both the flicker-induced increase in WBC motion and the disappearance of the effect after flicker cessation resembles the time course of blood flow changes previously observed in the microcirculation of the cat optic nerve.

Autoregulation of human retinal blood flow. An investigation with laser Doppler velocimetry.

The effect of acute changes in mean retinal perfusion pressure, P (2/3 of mean brachial artery blood pressure minus IOP), on retinal volumetric blood flow rate, Q, was investigated in normal volunteers. Changes in Q were determined from Q = k X Vmax X D2, where Vmax is the center line red blood cell velocity measured from temporal veins by laser Doppler velocimetry, D is the vessel diameter obtained by monochromatic fundus photography, and k is a constant of proportionality. A suction cup was used to induce step changes in IOP and, consequently, in P. The magnitude of the steps ranged from 10-32 mmHg. During the first 30 sec after a step decrease in P, Vmax and Q were significantly smaller than at rest by an amount proportional to the decrease in P. Thereafter, Vmax and Q increased markedly towards their values at rest, although P changed comparatively little during this period of time. Time constant of the corresponding decrease in vascular resistance, R(t) = P(t)/Q(t), was approximately 45 sec. There was no significant change in D during elevated IOP. Removal of the cup induced an immediate step increase in P, Vmax, D, Q, and R. Thereafter, Vmax, D, Q, and R returned to their values at rest (time constant of the change in R was about 30 sec), while P remained nearly constant. The rapid change in vascular resistance following a step decrease and increase in P can be attributed to an active process that attempts to maintain blood flow close to normal, in spite of changes in perfusion pressure (autoregulation).(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency and luminance-dependent blood flow and K+ ion changes during flicker stimuli in cat optic nerve head.

PURPOSE: The purpose of this study was to investigate whether blood flow in the cat optic nerve head (ONH) is related to increased neuronal activity elicited by diffuse luminance flickering light stimulation. METHODS: ONH blood flow was measured by laser Doppler flowmetry in anesthetized cats during 1 to 3 minutes of flickering light stimulation at controlled luminance and frequency (n = 227 measurements in 18 cats) using either a conventional visual stimulator (repetitive short flashes) or a sinusoidally varying light stimulator. Potassium ion concentration ([K+]) changes in the vitreous humor immediately in front of the optic disk were measured with neutral carrier K+ ionophore liquid membrane microelectrodes. Effects of varying flicker frequency (2 to 80 Hz) at constant luminance were quantified. Effects of luminance were quantified by varying the modulation depth of the stimulus at constant frequency. RESULTS: Both ONH blood flow and [K+] increased during flicker stimulus with an average slope of 0.305% +/- 0.064% (SE)/microM [K+] (257 measurements in 18 cats). The peak ONH blood flow increase was 59% +/- 11% above baseline at 33.3 +/- 3.1 Hz. The peak [K+] increase was 188 +/- 42 microM above baseline at 38.3 +/- 3.3 Hz. Both ONH blood flow and [K+] changes had similar bandpass characteristics with frequency, first increasing, then dropping off at higher frequencies (122 measurements in 10 cats). Both frequency responses were described by power law functions (y = af"). Luminance responses for both ONH blood flow and [K+] changes could be fit by a modified Hill model and were 50% of maximum at light modulation depths of 21.2% +/- 4.6% and 22.5% +/- 3.7%, respectively (53 measurements in 5 cats). CONCLUSIONS: Increases in ONH blood flow were correlated with changes in [K+]. Both responses were remarkably similar, with no significant differences in the frequency for peak responses in ONH blood flow or [K+], in low- and high-frequency power law exponents of the two responses, or in the 50% response to light modulation. The results are consistent with close coupling of neuronal activity and ONH blood flow.

Total retinal volumetric blood flow rate in diabetic patients with poor glycemic control.

Total retinal volumetric blood flow rate was measured in 12 normal subjects and 18 poorly controlled diabetic patients with background diabetic retinopathy. Maximum or center-line erythrocyte velocity (Vmax) was assessed by bidirectional laser Doppler velocimetry in four to five major retinal veins of one eye of each subject. Venous diameter (D) was measured from monochromatic fundus photographs. Total venous cross-section and measured total retinal volumetric blood flow in the diabetic patients were significantly larger than normal (P = 0.001 and P = 0.02, respectively). A positive linear correlation was found between Vmax and D in normal and diabetic eyes. Volumetric blood flow rate, Q, varied with D at a power of 2.87 in normal eyes. Total volumetric blood flow correlated with total venous cross-section. It was found that Q in the temporal retina was significantly larger than in the nasal retina in normal subjects (P = 0.0008) and diabetic patients (P = 0.0002). A significant difference in Q was observed between the superior and inferior retina in diabetic patients (P = 0.03) but not in normal subjects. The retinal vascular regulatory response to 100% oxygen breathing was reduced (P = 0.019) in diabetic patients and correlated with the level of background diabetic retinopathy. A close estimate of total volumetric blood flow may be obtained from blood flow measurement in one major retinal vein and the determination of total venous cross-section. This may be important for clinical studies in which measurements of all individual retinal veins may not be feasible.

Effect of acute decreases of perfusion pressure on choroidal blood flow in humans.

PURPOSE: To investigate the relationship between choroidal blood velocity (ChBVel), blood volume (ChBVol) and blood flow (ChBF) in the foveal region of the human ocular fundus and ocular perfusion pressure and to determine whether the choroidal circulation has some autoregulatory capacity. METHODS: Measurements of ChBVel, ChBVol and ChBF were obtained by laser Doppler flowmetry in healthy subjects (age range, 21 to 57 years) with normal eye examination results. Measurements were performed at normal intraocular pressure (IOP) and during successive step increases in IOP induced by scleral suction. In experiment 1, in six eyes (five subjects), the IOP was increased rapidly, in steps of 50 to 100 mm Hg of suction pressure, which each lasted approximately 10 seconds to a level above diastolic ophthalmic artery blood pressure (IOP = approximately 72 mm Hg). In experiment 2, in 14 eyes (seven subjects), the IOP was increased slowly in four successive steps at 2-minute intervals to a level of approximately 42 mm Hg. We also determined the pulsatility of the flow parameters during the heart cycle, pulsatility = 1 - diast value/syst value. RESULTS: For both rates of suction cup increase, the relationship between ChBFm (mean ChBF over the heart cycle) and mean perfusion pressure was not linear. At high pressure, ChBFm was less affected by decreases in the pressure than expected from a passive vascular system. In some cases, no change in ChBFm was detectable, although significant changes in PChBF occurred. Further decreases in perfusion pressure resulted in a proportional decrease in ChBFm. On release of suction, a significant increase in ChBFm over baseline value was detectable in experiment 1. CONCLUSIONS: The relationship between ChBFm and ocular mean perfusion pressure appears to be bilinear and reveals some autoregulation for moderate step decreases in perfusion pressure. The temporal characteristics of the ChBFm-response suggest a neural or passive hemodynamical process rather than a myogenic or metabolic compensatory mechanism.

Is the pulsating vascular tree entoptic phenomenon an indicator of ophthalmic artery pressure?

The relation between the intraocular pressure (IOP) at which the pulsating vascular tree (PVT) entoptic phenomenon is first observed and the ophthalmic artery diastolic pressure measured by ophthalmoscopic examination of the central retinal artery was determined in 25 normal volunteers. The PVT entoptic phenomenon consists in perceiving black stripes in the shape of branches of a tree appearing and disappearing synchronously with each heartbeat when the intraocular pressure is increased. The average IOP at which the entoptic phenomenon was first observed was 51.4 +/- 7.5 mm Hg, and the average ophthalmic artery diastolic pressure was 51.8 +/- 7.5. The correlation coefficient between both sets of numbers was r = 0.97 (p less than 0.01). These results show that the ophthalmic artery diastolic pressure can be measured accurately with the perception of the PVT phenomenon as an end point. Because the perception of the phenomenon is not disturbed by ocular media opacities, this method enables the determination of the ophthalmic artery diastolic pressure in eyes where an ophthalmoscopic examination is not possible.

Autoregulation of the retinal circulation in response to decrease of intraocular pressure below normal.

The autoregulatory response of the retinal circulation to a short-term reduction in intraocular pressure (IOP) to hypotonic levels was studied in 15 normal subjects by means of the blue-field entoptic phenomenon. This phenomenon allows the perception of the leukocytes flowing in one's own retinal macular capillaries. Subjects were asked to compare the leukocyte speed in one eye with that in the fellow eye while a scleral suction cup was used to raise the IOP in one eye to levels above 25 mm Hg for approximately 12 min. The release of the suction cup caused a drop in IOP to levels between 4 and 7 mm Hg, at which time all subjects reported a higher leukocyte speed (hyperemia) in this eye than in the fellow eye. After an average of 4 min the speed was observed to be equal in both eyes. The average IOP at which the equalization occurred was 6.8 +/- 1.3 mm Hg. The retina can therefore normalize leukocyte capillary speed and presumably blood flow at IOPs at least as low as 6.8 mm Hg. The results of 16 experiments on the same eye of one subject suggest that under these experimental conditions, the lowest IOP for which the retina can fully autoregulate is around 6 to 7 mm Hg.

Laser Doppler measurement of relative blood velocity in the human optic nerve head.

The Doppler shift frequency spectrum (DSFS) of laser light scattered from red blood cells (RBCs) moving in the microcirculation of the optic nerve head has been recorded in normal volunteers by means of a fundus camera laser Doppler velocimeter. The width of the DSFS, which varies in proportion to the speed of the RBCs, has been characterized by a parameter alpha. With the use of a model for the scattering of light by tissue and RBCs and for the RBC velocity distribution, values of alpha recorded at normal intraocular pressure (IOP) suggest that the RBCs that contribute to the Doppler signal are flowing in capillaries. The parameter alpha was found to vary markedly with the IOP and with the phase of the ocular pressure pulse at elevated IOP. The return of the speed of RBCs toward normal, which is observed after a step increase of IOP above normal and after a step decrease below normal, has been attributed to an autoregulatory response of the optic nerve circulation.

Laser Doppler Velocimetry study of the effect of pure oxygen breathing on retinal blood flow.

The noninvasive Laser Doppler Velocimetry (LDV) technique was used in normal volunteers to determine retinal blood flow, F, during pure oxygen breathing at atmospheric pressure. Changes in blood flow were calculated based on Poiseuille relation, F = (pi D2/4) X Vmax, where Vmax is the red blood cell maximum or center-line velocity and D, the diameter of the vessel at the site of the LDV recordings. After five minutes of pure oxygen breathing, Vmax decreased by about 53%, vessel diameter by 12%, and retinal blood flow by about 60%. In arteries, pulsatility of red blood cell velocity (Vmax, systole/Vmax, diastole) during the cardiac cycle increased by about 10%. Decrease in red blood cell velocity was detectable within 1-1 1/2 min. From these LDV flow measurements and the changes in retinal mean circulation time (MCT) reported by other investigators, based on the relation F = v/MCT, a 45% decrease in retinal blood volume (v) during 100% O2 breathing was obtained.

Reactivity of the human retinal circulation to darkness: a laser Doppler velocimetry study.

Bidirectional laser Doppler velocimetry (LDV) and fundus photography were applied to investigate the effects of light and darkness on retinal blood flow. Blood flow had increased by an average of 67% after 5 min of darkness. This increase persisted for periods of darkness as long as 80 min (the longest period tested). The magnitude of this elevation, its time course, and its neutralization by the breathing of 100% O2 suggest that, in vivo, the retina consumes more O2 in the dark than in light. This effect is, most probably, associated with the maintenance of the photoreceptor dark current. LDV in light and darkness may become a useful probe of retinal function.

Autoregulation of retinal circulation in response to decrease of perfusion pressure.

Autoregulation of the retinal circulation in response to an acute elevation of intraocular pressure was investigated in 17 subjects (23 eyes) with no ocular abnormalities, by means of the blue field entoptic phenomenon. This phenomenon allows a person to observe leukocytes flowing in his own macular capillaries. Subjects were instructed to compare the speed of their leukocytes in one eye with that in the other eye. All subjects perceived equal speed in both eyes. During their observation of the leukocytes, the intraocular pressure (IOP) was rapidly raised in one eye to a level at which autoregulation was not sufficient to maintain normal blood flow. At that level of IOP, subjects described the leukocytes moving slower in this eye than in the fellow eye. The IOP was then decreased in steps of 2 to 3 mm Hg until the subjects reported observing equal leukocyte speeds in both eyes. The IOP at which this occurred, IOPmax, represents the highest IOP (lowest mean perfusion pressure P min) at which the retina is able to maintain normal blood average IOPmax was 29.6 +/- 2.0 mm Hg, corresponding to an average of P min of 27 +/- 6 min Hg and demonstrating that a decrease of 36% or less in perfusion pressure is adequately compensated by retinal vascular autoregulation.

Nitric oxide and choroidal blood flow regulation.

PURPOSE: Nitric oxide (NO) has been found to be an endothelial-derived relaxing factor mediating the vasodilatation that results from the stimulation of muscarinic endothelial receptors. It also has been identified as a putative neurotransmitter of parasympathetic origin in choroidal perivascular autonomic fibers. The authors investigated a potential role of NO in choroidal blood flow (ChBF) regulation. METHODS: Local ChBF in the tapetal region of 26 anesthetized cats was measured by laser Doppler flowmetry. Cats were infused through the femoral vein with increasing dosages of acetylcholine (ACh); N omega-nitro-L-arginine (NNL-A), a specific inhibitor of NO synthesis; L-arginine; and D-arginine. ChBF and mean arterial pressure (MAP) were continuously recorded. RESULTS: Infusion of 20 micrograms/minute ACh induced a 68% increase in ChBF despite a 9% decrease in MAP. Infusion of 16 mg/minute NNL-A attenuated the ACh-induced increase in ChBF by 46% and increased MAP by 40%. Infusion of different dosages of NNL-A without prior administration of ACh caused ChBF to fall below and MAP to rise above baseline in a dose-dependent fashion. Infusion of L-arginine prior to ACh infusion enhanced by 27% the ACh-induced increase in ChBF, whereas D-arginine had no effect on this increase. CONCLUSIONS: These findings suggest the presence of a local vasodilatory cholinergic mechanism in the choroid, inducing the release of NO. They also suggest that release of NO in the choroid may maintain basal blood flow to this tissue.