Ken Tomita

Real-Time Measurement of Human Optic Nerve Head and Choroid Circulation, Using the Laser Speckle Phenomenon

A modification of a previously described instrument that used the laser speckle phenomenon for noncontact two-dimensional analysis of the fundus tissue circulation was devised so that tissue circulation in the optic nerve head (ONH) or choroid of the human eye could be measured on a real-time basis. The fundus was illuminated by a diode laser spot and the image speckle was recognized by an area sensor. A quantitative index of blood velocity, normalized blur (NB), was calculated by a logistic board every 0.125 seconds for 7 seconds. Using this modified device, the average NB of the measurement field in the temporal ONH, free of visible surface vessels (NBONH), and that in the posterior choroid (NBch) of normal human eyes were measured. The coefficients of reproducibility of 1-minute interval measurements were 11.7% for the NBONH) and 8.7% for the NBch (each, an average of 5 pulses), and those of 24-hour interval measurements were 13.0% (NBONH) and 9.7% (NBch). The pulsatile component average of NBONH was 38.4% of mean NBONH; of NBch, 26.6% of the mean NBch.

Topical Latanoprost and Optic Nerve Head and Retinal Circulation in Humans

The purpose of the present study was to study the effect of a single instillation of latanoprost on the human optic nerve head (ONH) and retinal circulation. Using laser-speckle tissue blood flow analysis, normalized blur (NB; a quantitative index of tissue blood velocity) was measured every 0.125 sec at a temporal ONH site free of visible surface vessels. Measurements were averaged for 3 cardiac cycles (NB(ONH)). Color Doppler Imaging (CDI) was also used to evaluate peak systolic blood velocity (PSV), endo-diastolic velocity (EDV), and resistive index (RI) in the central retinal artery (CRA) and mean blood velocity (MV) in the central retinal vein (CRV). One drop of 0.005% latanoprost was instilled into one eye and its vehicle into the other in eleven healthy volunteers in a double-blinded manner. Measurements of bilateral NB(ONH), CDI parameters, intraocular pressure (IOP), blood pressure (BP), and pulse rate (PR) were performed before, and 45, 90, 180, and 270 min after instillation. After a single instillation of latanoprost or the vehicle, there was no significant bilateral difference throughout the experimental period. The difference in NB(ONH) between that before and at each time point of measurement (delta NB(ONH)) in the latanoprost-treated eyes was significantly higher between 45 and 270 min after instillation than that in vehicle-treated eyes (P = 0.0003 to 0.0156); ANOVA for repeated measurements also revealed significant difference between both eyes (P < 0.00001). BP, PR, and NB(ONH) in the eye that received only the vehicle, PSV, EDV, and RI in the CRA in both eyes, and MV in the CRV in both eyes changed little. Tissue blood velocity in the ONH increased at least temporarily following a single instillation of topical latanoprost. Although the mechanism of the increase is unclear, the effects of latanoprost on ONH tissue circulation in humans may have clinical implications.

Acute effects of cigarette smoking on tissue circulation in human optic nerve head and choroid-retina.

OBJECTIVE To study the acute effects of cigarette smoking on tissue circulation in the human optic nerve head (ONH) and choroid-retina. DESIGN Nonrandomized, comparative trial (sequential self-controlled). PARTICIPANTS Nine healthy habitual smokers (age, 28 +/- 4 years; number of cigarettes smoked per day, 27 +/- 10; length of smoking history, 10 +/- 4 years; mean +/- standard deviation). INTERVENTION Using the laser speckle method, normalized blur (NB) value, a quantitative index of tissue blood velocity, was measured every 0.125 second and averaged over three pulses across an area located in the temporal site of the ONH free of visible surface vessels (NB(ONH)) and across an area located halfway between the macula and the ONH with no discrete vessels visible (NB(ch-ret)). NB(ONH), NB(ch-ret), and intraocular pressure (IOP) in one randomly chosen eye, and blood pressure (BP) and pulse rate (PR) were measured before and 1, 5, 10, 15, 20, 25, 30, 45, 60, and 90 minutes after sham smoking using a short drinking straw as a cigarette substitute (control). One week later, NB(ONH), NB(ch-ret), and IOP in the same eye, and BP and PR were measured after cigarette smoking according to the same time schedule as in the control experiment. MAIN OUTCOME MEASURES NB(ONH) and NB(ch-ret). RESULTS In the control experiment, all parameters examined showed no significant change during the experimental period. Differences in NB(ONH) and NB(ch-ret) before and after actual smoking were significantly greater than those in the control experiment (analysis of variance, P = 0.0000, 0.0000). BP and PR were significantly increased between 1 and 30 minutes after actual smoking as compared with control data, while IOP showed no significant change at any time of measurement. CONCLUSIONS These results indicated that cigarette smoking increased tissue blood velocity in the ONH and possibly in the choroid in habitual smokers.

TIME CHANGE OF NICARDIPINE EFFECT ON CHOROIDAL CIRCULATION IN RABBIT EYES

PURPOSE To investigate the time course of effects of intravenous administration of a calcium antagonist, nicardipine, on the choroidal circulation of rabbit eyes using a laser speckle tissue circulation analyzer. METHOD The rabbit fundus was illuminated by a diode laser spot and its image speckle was detected by an image sensor. The difference between the average of the speckle intensity (Imean) and the speckle intensity for successive scannings was calculated, and the ratio of Imean to this difference was defined as normalized blur (NB); a quantitative index of tissue blood velocity. The average NB over the field measured (0.620.62 mm in the choroid) was calculated to give Nb(av). Under general anesthesia, 0.4 ml/kg of 0.01% nicardipine hydrochloride dissolved in physiological saline was injected intravenously in a group of albino rabbits (control group) for measurement in the choroid (nicardipine groups). To serve as control, 0.4 ml/kg of physiological saline was injected in other groups of albino rabbits (control groups). Nb(av) was recorded at 1-min intervals for the first 5 min and at 5-min intervals for the next 85 min. During the experiment mean femoral arterial blood pressure (FABPm), pulse rate (PR), arterial blood pH, Pco2 and Po2 body temperature (BT) and intraocular pressure (IOP) were also monitored. Before and 45 min after nicardipine administration, the choroidal blood flow measurement using the microsphere technique and the Nb(av) measurement were carried out in the same eye in another group of rabbits. RESULTS Only the rabbits which did not show any significant change in the PR, pH, Pco2, Po2 and BT during the experiment were accepted. FABPm in the nicardipine group dropped to the minimum at 1 min postadministration and this level remained significantly lower than that in the control group up to 15 min post-injection, while te 10P did not show any significant change. The Nb(av) in the nicardipine group showed a significant increase after the FABPm return to the baseline, which was maintained throughout the experiment. The averaged increase between 30 and 90 minutes after administration was 27 +/- 1% (mean +/- S.E.M., n = 10). Relative increase in choroidal blood flow determined by the microsphere technique showed a good correlation (r = 0.90, P < 0.001, n = 12) with those determined by Nb(av) after nicardipine administration. CONCLUSIONS The present result indicates that the time course of drug effects on the choroidal circulation can be noninvasively and sensitively followed by Nb(av) measurements. Further, it was shown that nicardipine may have considerable potential for the treatment of ocular diseases associated with insufficient choroidal blood flow and that nicardipines effects here observed deserve to be further studied in humans.

Effect of Topical Unoprostone on Circulation of Human Optic Nerve Head and Retina

The purpose of the present study was to study the effect of topical unoprostone on the circulation of human optic nerve head (ONH) and retina in normal subjects. Using laser-speckle tissue blood flow analysis, normalized blur (NB), a quantitative index of tissue blood velocity, was measured every 0.125 sec at a temporal ONH site, free of visible surface vessels. Measurements were averaged for 3 cardiac cycles (NB(ONH)). Color Doppler imaging (CDI) was also used to evaluate peak systolic blood velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) in the central retinal artery (CRA) and mean blood velocity (MV) in the central retinal vein (CRV). For baseline comparison (Day 0), recordings of bilateral NB(ONH) and intraocular pressure (IOP), blood pressure (BP), and pulse rate (PR) were recorded in healthy volunteers before, and 45, 90, 180, and 270 min after instillation of one drop of unoprostone vehicle. On Day 1 (the day after baseline measurements), and twice daily for 7 days, one drop of 0.12% unoprostone was instilled into one eye and its vehicle into the other in a double-blinded manner. Measurements as on Day 0 were recorded on Days 1 and 7. CDI measurements were performed before and at 45 and 180 min after morning instillation on Days 1 and 7. During baseline recordings, there were no significant changes in any parameters. After administration of topical unoprostone, IOP was significantly lower bilaterally with more reduction in the unoprostone-treated eyes on Day 7. On Day 7, the NB(ONH) of the unoprostone-treated eyes was significantly higher 45 min after instillation than baseline (P = 0.035 with Bonferronis correction). Analysis of variance for repeated measurements also revealed significant difference between Day 0 and Day 7 (P = 0.0017). BP, PR, NB(ONH) in the eye that received only the vehicle, PSV, EDV, and RI in the CRA in both eyes, and MV in the CRV in both eyes changed little. Tissue blood velocity in the ONH increased, at least temporarily, following instillation of unoprostone twice daily for 7 days. Although the clinical implication of the increase is unclear, the effects of topical unoprostone on human ONH circulation deserve further consideration.

The acute effects of cigarette smoking on human optic nerve head and posterior fundus circulation in light smokers

Purpose To study the acute effects of cigarette smoking on tissue circulation in the optic nerve head (ONH) and posterior fundus in smokers with a short smoking history.Methods Ten healthy smokers whose length of smoking history was within 2 years (age 25 ± 1 years; smoking index (number of cigarettes smoked per day x length of smoking history in years) 16 ± 4, mean ± SE) were included in the study. Using the laser speckle method, normalised blur (NB) value, a quantitative index of tissue blood velocity, was measured every 0.125 s and averaged over three pulses across an area located in the temporal site of the ONH free of visible surface vessels (NBonh) and across an area located halfway between the macula and the ONH with no discrete vessels visible (NBch-ret)- NBonh, NBch-ret and intraocular pressure (lOP) in one randomly chosen eye, and blood pressure (BP) and pulse rate (PR) were measured before, and 1, 5, 10, 15, 20, 25, 30, 45, 60 and 90 min after sham smoking. One week later, NBonh, NBch-ret and lOP in the same eye, and BP and PR were measured after cigarette smoking according to the same time schedule as in the control experiment.Results After sham smoking, no parameter showed a significant change during the experiment. Differences in NBonh from the baseline were not significant between the smoking experiment and sham smoking experiment, while NBch-ret showed a significant difference at 30 min. Inter-group difference in the time course of the difference from baseline was significant (ANOVA, p = 0.0246, 0.0021). BP and PR were significantly increased between 1 and 20 min after smoking while lOP showed no significant change at any time of measurement.Conclusions In light smokers, cigarette smoking showed little effect on tissue blood velocity in the ONH and slightly decreased that in the posterior fundus, suggesting a significant increase in vascular resistance in these tissues.

Effects of Topical Adrenergic Agents on Tissue Circulation in Rabbit and Human Optic Nerve Head Evaluated With Laser Speckle Tissue Circulation Analyzer

The effects of topical adrenergic agents on the tissue circulation of the optic nerve head (ONH) were studied in animal and human eyes with use of a laser speckle tissue circulation analyzer. Drugs studied were nipradilol, a beta1-2-blocker with weak alpha-blocking and nitroglycerinlike activities; bunazosin, a selective alpha1-blocker; carteolol, a beta1-2-blocker with intrinsic sympathomimetic activity; and betaxolol, a selective beta1-blocker. In the animal experiment, one eye each of nine albino rabbits received 0.25% nipradilol (N = 9) twice daily for 15 days or 0.01% bunazosin (N = 10) twice daily for 20 days; the fellow eye received the vehicle of each drug in a randomized masked design. Normalized blur (NB) in an area of ONH free of visible surface vessels, a quantitative index of peripheral blood velocity in ONH, was measured under general anesthesia before treatment and 2 hours after the last instillation on the 15th or 20th day. At 15 days, intraocular pressure and NB in the nipradilol-treated eyes decreased by 4.3 mm Hg (P < 0.01) and increased by 15.9% (P < 0.01), respectively, while those in the vehicle-treated eyes showed little change. At 20 days NB in both bunazosin- and vehicle-treated eyes showed little change, while intraocular pressure decreased only in the bunazosin-treated eyes (P < 0.01). In the human volunteer experiment NB was averaged over five pulses (mean NB) in both eyes before and 1.5, 3.0 and 4.5 hours after a 30 microL instillation of the vehicle of carteolol or betaxolol to serve as a control. Intraocular pressure, blood pressure and pulse rate were also measured. One week later a 30 microL drop of 2.0% carteolol (N = 6) or 0.5% betaxolol (N = 10) was instilled in one randomly chosen eye and the vehicle for each drug in the other eye, and those parameters were measured as above in a double-masked manner. In the carteolol experiment, mean NB in both eyes was significantly higher at 3 hours than it was in the control experiment (P < 0.05), while intraocular pressure was significantly lower in both eyes and blood pressure and pulse rate showed little change. In the betaxolol experiment, intraocular pressure at 1.5 hours and blood pressure at 4.5 hours were significantly lower than those in the control experiment (P < 0.05), while mean NB and pulse rate showed little change. In summary, using the laser speckle method we found that topical nipradilol and carteolol increase ONH blood velocity in rabbits and humans, respectively. This finding suggests that some topical beta-blockers used clinically may influence the ONH tissue circulation in patients and that this method may be used in clinical situations to assess the effect of various drugs on ONH circulation.

Effect of Topical Timolol on Tissue Circulation in Optic Nerve Head

The effects of topical 0.5% timolol on tissue circulation in the albino rabbit optic nerve head (ONH) were investigated using a laser speckle tissue circulation analyzer. In the first experiment, the normalized blur (NB) value, a quantitative index of tissue blood flow velocity in the ONH, intraocular pressure (IOP), blood pressure, and pulse rate were measured under general anesthesia before, and 30, 60, 90, and 120 minutes after a 20 microL instillation of timolol in one eye and the vehicle in the other eye in a masked, randomized manner. In the second experiment, one eye of a rabbit received timolol twice daily for 20 days and the fellow eye received the vehicle in a masked, randomized manner. Every 5 days IOP was measured and the NB in the ONH and IOP were measured before treatment and 2 hours after the last instillation on the 20th day. After a single instillation of timolol, PR showed a maximum reduction of 12% and IOP in the timolol-treated eyes showed a maximum decrease in 25%. NB in the ONH and BP did not show any significant change during the experiment. After a 20-day treatment with timolol, IOP showed a maximum decrease of 25% in the timolol-treated eyes and 16% in the vehicle-treated eyes. The NB in the timolol-treated eyes increased significantly by 16% (P < 0.01), whereas that in the vehicle-treated eyes showed no significant change. It was suggested that long-term topical timolol with a normal drug regimen caused a significant increase in the peripheral blood velocity in the ONH only in the timolol-treated eyes, at least partly, by local penetration of the drug. Ocular penetration of topically applied timolol is thought to be similar between rabbit and human eyes. Therefore, the present results may have clinical implications.

Effect of topical carteolol on tissue circulation in the optic nerve head

The effect of topical 2% carteolol on tissue circulation in the albino rabbit optic nerve head (ONH) was investigated using a laser speckle tissue circulation analyzer. In the first experiment, the normalized blur (NB) value, a quantitative index of tissue blood flow velocity in the ONH, intraocular pressure (IOP), blood pressure (BP), and pulse rate were measured under general anesthesia before as well as 30, 60, 90, and 120 minutes after a 20-microL instillation of carteolol in one eye and the vehicle in the other eye in a masked, randomized manner. In the second experiment, one eye of a rabbit received carteolol twice daily for 20 days and the fellow eye received the vehicle in a masked, randomized manner. The IOP was measured every 5 days, and the NB in the ONH and IOP were measured before treatment and 2 hours after the last instillation on the 20th day. After a single instillation of carteolol, pulse rate showed a maximum reduction of 15%, and IOP in the carteolol-treated eyes showed a maximum decrease of 22%. The NB in the ONH and BP did not show any significant change during the experiment. After 20-day treatment with carteolol, IOP showed a maximum decrease of 25% in the carteolol-treated eyes and 21% in the vehicle-treated eyes. The NB showed a significant increase of 15% (P < 0.01) in the carteolol-treated eyes and 11% (P < 0.01) in the vehicle-treated eyes. It was indicated that long-term topical carteolol increased the blood velocity in the ONH tissue both in the carteolol- and vehicle-treated contralateral eyes in albino rabbits.

Effect of Topical Carteolol on Iridial Circulation in Pigmented Rabbit Eyes

The effect of a single instillation of topical carteolol on iridial tissue circulation of pigmented rabbits was studied. The blood flow rate and a quantitative index of tissue blood velocity (NBiris) were measured simultaneously, using the microsphere technique and the laser speckle method, before and 2 hours after the instillation of 20 microliters of 2% carteolol or the vehicle. Consecutive changes of intraocular pressure and NBiris were also studied at 30-minute intervals for 2.5 hours after a single instillation of 2% carteolol in one eye and the vehicle in the contralateral eye. To provide a control, intraocular pressure and NBiris were measured according to the same schedule after the vehicle instillation in both eyes. Two hours after carteolol instillation, iridial blood flow rate and NBiris significantly increased to 127 +/- 8% and 122 +/- 9% (mean +/- SEM, n = 8) of the baseline. Unilateral instillation of carteolol significantly reduced intraocular pressure by about 9 mm Hg in both the carteolol- and vehicle-treated eyes (P < 0.001, analysis of variance); and NBiris was significantly increased by about 20% in both eyes (P < 0.001, analysis of variance), compared with control eyes.