OCULAR HEMODYNAMICS DURING INDUCED OCULAR HYPERTENSION IN MAN

MILTON BEST, M.D., AND HIDENAO TOYOFUKU, M.D. New York, New York

When ocular hypertension is induced in experimental animals, fiuorescein angiog-raphy demonstrates that this markedly de­creases the velocity of blood flow in the ret­ina and choroid, especially as diastolic pres­sure is approached within the eye.1·2 Ernest and Potts3 reported, however, that the cho­roidal vasculature was more susceptible than the retinal circulation to elevated intraocular pressure. Further, Swietliczko and David2

report that the peripapillary choroid and op­tic disk vessels, in particular, demonstrate a marked susceptibility to ocular hypertension. At levels of intraocular pressure that were equal to or exceeded diastolic pressure, the peripapillary choroid remained ischémie while the remainder of the choroid fluor-esced.

Fiuorescein angiographie studies in man reveal a similar differential susceptibility of the retinal and choroidal circulations to ele­vated intraocular pressures.4"8 Small eleva­tions of intraocular poressure delay peak fluorescence in the peripapillary choroid to a significantly greater extent than in the reti­nal circulation.7 At levels of intraocular pressure just below systolic ophthalmic ar­tery pressure, fiuorescein proceeds slowly through the retinal arteries and capillaries while the choroidal vasculature does not fluoresce.4"6 Although these studies demon­strate that the choroid is more susceptible to elevated intraocular pressure, they have not quantitated the hemodynamic effects of changes in intraocular pressure in man. In

From the Department of Ophthalmology, New York Medical College, Center for Chronic Disease, and the Bird S. Coler Hospital, Welfare Island, New York. This study was supported by Public Health Service Grants HE13660-0S and 69-869 from the American Heart Association.

Reprint requests to Milton Best, M.D., New York Medical College, Center for Chronic Disease, New York, New York 10017.

view of the increasing evidence that altera­tions in ocular blood flow are of great impor­tance in the pathogenesis of glaucomatous optic atrophy, this investigation was under­taken to study the quantitative effects of ele­vated intraocular pressure on retinal and choroidal blood flow in man.

MATERIALS AND METHODS

Nine normotensive subjects with normal ocular examinations were selected for study. They ranged in age from 21 to 60 years. Routine fiuorescein angiography was per­formed on each patient after intravenous in­jection of 5 ml of 10% fiuorescein. On three or four successive days, fiuorescein angiog­raphy was repeated on each patient at three preselected elevated levels of intraocular pressure.

An automatic suction ophthalmodyna-mometer was used to increase intraocular pressure to the desired level.8 On each visit, intraocular pressure was measured by appla-nation tonometry and the pupil was dilated with 10% phenylephrine and 2% cyclopento-late HC1. The temporal conjunctiva was then anesthetized with a cotton-tipped applicator soaked with proparacaine HC1. A suction cup was applied to the anesthetized area and held in place by creating a small amount of suction with the ophthalmodynamometer. The disk was visualized through the Zeiss fundus camera and the amount of suction re­quired to produce diastolic pulsation and systolic collapse of the central retinal artery was determined. These values were con­verted to intraocular pressure using previ­ously established calibration charts for the suction cup used in this study.9

Introacular pressure was then established at 40, 60, or 80 mm Hg by creating an ap­propriate amount of suction. While intraocu­lar pressure was maintained at this level, flu-

932

VOL. 74, NO. 5 OCULAR HEMODYNAMICS 933

orescein was injected and angiograms were recorded over a one- to two-minute period. At the termination of angiography, the suc­tion cup was removed and intraocular pres­sure was immediately measured to assure that no ocular hypertensive response had oc­curred to the cycloplegic agent.

The timing and sequence of filling in the fundus vasculature was determined at each level of intraocular pressure. The earliest ap­pearance of dye in the central retinal artery and in the major temporal retinal veins was noted and the difference between these rep­resented the retinal transit time. The same retinal vein was used for this measurement in each angiography series. Retinal venous filling time was calculated from the first ap­pearance of dye in the major temporal veins to full fluorescence of these veins.

The difference in timing of the first ap­pearance of dye in the choroidal vasculature and in the central retinal artery was termed the choroidal delay. A negative number indi­cated that fluorescence occurred in the cho-roid prior to the central retinal artery. Transit time through the choroidal circula­tion was estimated by noting the earliest ap­pearance of dye in the choroid and the time of peak background fluorescence. In most patients, the earliest appearance of dye in the choroid occurred in a mottled pattern that is characteristic of early choriocapillaris fluorescence. In some patients a distinct cho­roidal arterial phase could be seen and this was used as the point of initial choroidal fluorescence. The difference in timing be­tween this early appearance of dye in the choroid and peak background choroidal fluorescence was used as an indication of choroidal transit time.

RESULTS

Table 1 lists the results of angiography in each patient. Table 2 lists the mean values and standard errors of the critieria described above at each intraocular pressure studied.

At normal levels of intraocular pressure, dye first appeared in the choroidal vascula­

ture prior to or simultaneously with its ap­pearance in the central retinal artery in eight of the nine patients. In most patients, full choroidal fluorescence coincided with late ve­nous fluorescence, and, therefore, choroidal transit time, as defined in this study, was considerably longer than retinal transit time.

When intraocular pressure was raised to 40 mm Hg, initial retinal arterial fluores­cence was not delayed and it preceded early choroidal fluorescence by a mean of 1.0 ± 0.31 seconds (Fig. 1). Although choroidal transit time was prolonged slightly, the pat­tern of choroidal fluorescence was normal (Fig. 2 ) . In the retinal circulation, transit time was slightly prolonged and venous fill­ing time was markedly delayed.

The appearance of dye in the retinal circu­lation was significantly delayed at an intraoc­ular pressure of 60 mm Hg. Initial choroidal fluorescence was delayed even more and ap­peared a mean of 2.7 ± 0.85 seconds after initial retinal fluorescence (Fig. 3) . Transit times in both the retinal and choroidal circu­lations were markedly increased to approxi­mately twice the normal values. Retinal ve­nous filling time was three times the normal value. In most patients, the pattern of cho­roidal fluorescence was irregular with some areas of the choroid filling before others (Fig. 4) . In all patients, the peripapillary choroid filled early in the sequence of cho­roidal fluorescence and was fully fluorescent within 30-35 seconds, corresponding to lami­nar fluorescence in the retinal veins (Fig. 5).

Elevation of intraocular pressure to 80 mm Hg further delayed the timing of all the events of choroidal and retinal fluorescence except for retinal arterial appearance time which was the same as it had been at 60 mm Hg intraocular pressure. At 80 mm Hg intraocular pressure, choroidal transit time was sufficiently prolonged to occasionally permit visualization of choroidal arteries which made it possible to compare fluores-cein appearance time in retinal and choroidal vessels of comparable caliber. In these pa­tients, initial retinal arterial fluorescence

934 AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1972

TABLE 1 RESULTS OF FLUORESCEIN ANGIOGRAPHY*

Case No. and Age in Years

1. 45

2. 24

3. 24

4. 60

5. 42

6. 26

7. 24

8. 21

9. 30

Systemic Blood

Pressure (in mm Hg)

120/80

126/72

124/88

126/84

132/88

110/80

116/66

150/80

118/70

Ophthalmic Artery

Pressure (in mm Hg)

92/52

96/48

92/58

104/58

108/60

88/50

90/47

110/57

91/48

Intraocular Pressure

(in mm Hg)

15 40 60 80 15 40 60 80 15 40 80 13 40 60 80 20 40 60 20 40 60 11 40 60 16 40 60 12 40 60

Arterial Appear­

ance

13.8 13.4 17.7 21.0 16.5 19.0 18.4 18.0 15.0 17.2 18.7 15.8 15.8 18.4 19.0 20.2 17.1 21.5 11.9 12.3 18.4 16.2 19.0 20.1 17.0 11.8 18.9 11.5 14.0 17.0

Retina

Early Venous

Appearance

16.1 18.0 24.8 35.8 18.6 21.6 23.3 28.3 18.2 19.3 31.0 18.4 19.0 24.5 25.2 24.2 22.5 27.8 14.2 14.9 36.2 19.0 22.6 28.2 20.0 16.4 27.8 13.9 18.1 24.1

Late Venous Filling

21.5 26.0 41.8 64.1 22.7 25.6 27.7 36.4 24.6 30.0 53.5 21.8 24.5 34.0 40.0 36.2 44.0 47.2 18.1 20.9 61.1 23.5 30.8 58.7 26.4 27.8 51.3 19.4 24.0 37.2

Choroid

Initial Fluores­

cence

13.8 15.0 20.5 24.6 16.7 19.4 19.4 21.0 15.0 18.4 21.1 15.1 15.8 20.4 22.6 19.5 17.1 21.5 12.5 13.4 26.2 16.7 19.0 21.2 16.6 13.6 22.0 11.5 16.6 19.7

Maximum Fluores­

cence

24.6 28.1 38.6 68.0 22.7 28.0 29.9 33.5 20.6 23.8 38.9 20.2 21.9 31.2 32.6 27.9 24.5 29.3 18.1 21.0 54.7 23.5 27.2 40.0 23.5 22.8 34.0 17.5 29.5 32.8

* Time stated in seconds.

preceded chorodial arterial fluorescence by at least 2.5 seconds (Figs. 6-A and B) . The choriocapillaris subsequently filled in a splotchy pattern, initially in the vicinity of the disk (Fig. 6-C). In all patients, complete fluorescence of the peripapillary choroid oc­

curred when laminar fluorescence was visible in the retinal veins (Fig. 6-D).

DISCUSSION

This study indicates that in the normal hu­man eye the choroidal circulation is more

Intraocular Pressure

(in mm Hg)

15.2±1.05 40 60 80

Appearance Time

15.3+0.89 15.5+0.92 18.8+0.50 19.2+0.64

TABLE 2 SUMMARY OF OCULAR HEMODYNAMICS*

Retina

Transit Time

2.8+0.22 3.6 + 0.37 8.3 + 1.43

10.9 + 1.82

Venous Filling Time

5.7+0.86 9.0 + 1.76

17.8+3.04 18.7+4.6

Choroid

Delay

-0 .2+0.14 1.0 + 0.31 2.7+0.85 3.2+0.29

Transit Time

6.78+0.66 8.7 +0.90

14.9 ±2.35 20.9 ±7.67

* Time stated in seconds.

VOL. 74, NO. 5 OCULAR HEMODYNAMICS

susceptible than the retinal vasculature to acutely elevated intraocular pressure. When intraocular pressure is raised to.40 mm Hg, the arrival of dye in the central retinal artery is not delayed and retinal transit time is not

Fig. 2 (Best and Toyofuku). Angiograms at 40 mm Hg intraocular pressure reveal delay of initial choroidal fluorescence followed by normal choroidal pattern. Top: 18.4. Bottom: 23.8 seconds.

Fig. 1 (Best and Toyofuku). Angiograms at 40 mm Hg intraocular pressure demonstrate absence of choroidal fluorescence when dye initially appears in retinal arterioles. Top : control. Center : 15.2 sec­onds. Bottom : 16.8 seconds.

significantly prolonged. The appearance of dye in the choroid, however, is significantly delayed, although choroidal transit time is not significantly prolonged. These results confirm the findings of others7'10 that small elevations of intraocular pressure delay the events of choroidal filling to a greater extent than those of the retina.

When intraocular pressure is elevated to diastolic pressure levels or slightly above (60 mm Hg) , fluorescein appearance time in the central retinal artery is delayed and retinal

935

936 AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1972

transit time is prolonged significantly. Simi­lar but more marked effects are produced in the choroid. At this level of intraocular pres­sure, the early pattern of choroidal fluores-

Fig. 3 (Best and Toyofuku). Angiograms at 60 mm Hg intraocular pressure reveal a delay in cho­roidal fluorescence so that dye appears in retinal arterioles (Top: 18.0 seconds) before initial cho­roidal fluorescence (Bottom: 20.2 seconds).

77m T^

Fig. 4 (Best and Toyofuku). Angiograms at 60 mm Hg intraocular pressure demonstrate an irregu­lar pattern of early choroidal fluorescence followed by diffuse choroidal filling. Top: 26.6 seconds. Cen­ter: 29.6 seconds. Bottom: 42.3 seconds.

VOL. 74, NO. 5 OCULAR HEMODYNAMICS 937

cence is irregular but the peripapillary cho­roid is completely fluorescent within 35 sec­onds. At levels of intraocular pressure as high as 80 mm Hg, when choroidal circula­tion is markedly slowed, peripapillary cho­roidal fluorescence is well advanced while other scattered areas of choroid contain no dye. These results demonstrate that the peri­papillary choroidal capillaries are perfused at a relatively high pressure. Since the peri­papillary choroid supplies blood to the pre-

Fig. S (Best and Toyofuku). Angiograms at 60 mm Hg demonstrate that peripapillary choroid fills early in sequence of choroidal fluorescence (Top: 22.1 seconds) and is fully fluorescent in early retinal venous phase (Bottom: 25.7 seconds).

laminar portion of the optic nerve,2-4 it would appear that nourishment to the optic nerve head can be maintained over a wide range of intraocular pressures in the normal eye.

Similar angiographie studies6'11·12 in pa­tients with glaucomatous damage to the optic nerve have demonstrated defects in perfu­sion of the peripapillary choroid at 60 mm Hg intraocular pressure and higher. These areas of choroidal nonfluorescence are sharply outlined and are located adjacent to the disk margin. Similar defects in peripapil­lary choroidal fluorescence have not been found in normal eyes in previous studies4"8

or in the present study at intraocular pres­sures as high as 80 mm Hg. It is possible that these perfusion defects in the peripapil­lary choroid in glaucomatous eyes result from the development of a mechanism that shunts blood away from the peripapillary choroid at elevated intraocular pressures. A possible pathway for such a shunt has been demonstrated by silicone injection studies in monkeys which demonstrate retrograde branches from the short posterior ciliary ar­teries and peripapillary choroid to the net­work of vessels in the pia mater.14'15 If a similar shunt pathway exists in man, it might be activated by chronic ocular hyper­tension.

The present study also demonstrates that, in man, the effect of actuely elevated intraoc­ular pressure on the ocular circulation dif­fers in a number of important ways from that previously described in the monkey eye.2

In man and in the monkey, at normal intra­ocular pressures, fluorescein appears in the choroid prior to its appearance in the central retinal artery. When introacular pressure is elevated to 40 mm Hg or higher in the hu­man eye, the appearance of dye in the cho­roidal circulation is delayed to a much greater extent than in the central retinal ar­tery. At diastolic pressure levels, for exam­ple, fluorescence of the central retinal artery occurs a mean of 2.7 seconds before dye ap­pears in the choroid. In the monkey eye, sim­ilar intraocular pressure levels delay initial fluorescence in the retinal circulation to a

938 AMERICAN JOURNAL OF OPHTHALMOLOGY NOVEMBER, 1972

Fig. 6 (Best and Toyofuku). Angiograms at 80 mm Hg intraocular pressure reveal a marked delay in choroidal fluorescence which permits visualization of a choroidal arterial phase. Dye initially appears in retinal arterioles (Top left: 21.0 seconds) well before its appearance in choroidal vessels of comparable caliber (Top right: 23.9 seconds). Initial fluorescence of the choriocapillaris occurs in a splotchy pattern near the disk (Bottom left: 35.8 seconds). Complete fluorescence of the peripapillary choroid occurs when laminar flow is visible in the retinal veins (Bottom right : 47.5 seconds).

greater extent than in the choroid, so that at diastolic pressure levels choroidal fluores­cence precedes retinal fluorescence by a mean of 1.5 seconds. In addition, in monkey eyes the peripapillary choroid is markedly susceptible to acutely elevated intraocular pressure in comparison to the remainder of the choroid. When intraocular pressure is el­evated to 40 mm Hg or higher in these eyes,

fluorescein angiography demonstrates a crescent or ring of ischémie choroid adjacent to or surrounding the disk. In the normal human eye, however, a similar area of juxta-papillary ischémie choroid was not demon­strated in this study at intraocular pressures as high as 80 mm Hg.

The differences in the effect of elevated intraocular pressure on hemodynamics in

VOL. 74, NO. S OCULAR HEMODYNAMICS 939

human and monkey eyes cannot be explained on the basis of different ophthalmic artery blood pressures, since ophthalmodynamom-etry has shown that diastolic and systolic pressure levels are similar in the two species. The ischémie ring of peripapillary choroid found in monkey eyes at elevated levels of intraocular pressure has been attributed to an "all or none" closure of major choroidal feeding vessels to the peripapillary tissue.2

This could result from the activation of shunt pathways of relatively low resistance from the ciliary vasculature to the pial net­work of vessels.14'15 In the normal human eye, similar shunt pathways are apparently not readily available so that acutely elevated intraocular pressure does not produce juxta-papillary choroidal ischemia.

SUMMARY

The effects of induced ocular hypertension on. ocular hemodynamics were studied in normal subjects by performing fluorescein angiography at intraocular pressures of 15, 40, 60 and 80 mm Hg. Although the velocity of blood flow is reduced in both the choroidal and retinal circulations by elevated intraocu­lar pressure, fluorescein appearance time is dealyed to a greater extent in the choroid than the retina. The most marked effects oc­cur when intraocular pressure exceeds dia­stolic ophthalmic artery blood pressure, re­sulting in irregular or splotchy patterns of early choroidal fluorescence.

In contrast to previous descriptions in monkey eyes, the present study demonstrates that in the normal human eye, the peripapil­lary choroidal capillaries are perfused at a relatively high pressure and fluoresce com­pletely at intraocular pressures as high as 80 mm Hg.

R E F E R E N C E S 1. Dollery, C. T., Henkind, P., Kohner, E. M.,

and Paterson, J. W. : Effect of raised intraocular pressure on retinal and choroidal circulation. Invest. Ophth. 7:191, 1968.

2. Swietliczko, I., and David, N. J. : Fluorescein angiography in experimental ocular hypertension. Am. J. Ophth. 70:351, 1970.

3. Ernest, J. T., and Potts, A. M. : Pathophysiol-ogy of the distal portion of the optic nerve. II. Vascular relationships. Am. J. Ophth. 66:380, 1968.

4. Blumenthal, M., Gitter, K. A., Best, M., and Galin, M. A. : Fluorescein angiography during in­duced ocular hypertension in humans. Am. J. Ophth. 69:39, 1970.

5. Blumenthal, M., Best, M., Gitter, K. A., and Galin, M. A. : Studies in ocular circulation. An analysis of the effect of induced ocular hypertension on retinal and choroidal blood flow in humans. Am. J. Ophth. 71:819, 1971.

6. Best, M., Galin, M. A., Toyofuku, H., and Blumenthal, M. : Differential fluorescein angiog­raphy of the ocular fundus. Ann. Ophth. 4:189, 1972.

7. Rosen, E. S. and Boyd, T. A. S. : New method of assessing choroidal ischemia in open angle glau­coma and ocular hypertension. Am. J. Ophth. 70: 912, 1970.

8. Galin, M. A., Baras, I., and Best, M. : Suction ophthalmodynamometry. Tr. Am. Acad. Ophth. Otolaryng. 73:335, 1969.

9. Galin, M. A., Baras, I., and Cavero, R. : Ophthalmodynamometry using suction. Arch. Ophth. 81:494, 1969.

10. Spaeth, G. L. : Fluorescein angiography in the diagnosis and management of patients suspected of having glaucoma. Read before the Spring meeting of the Association for Research in Vision and Ophthalmology, Sarasota, April 28, 1971.

11. Blumenthal, M., Best, M., Galin, M. A. and Toyofuku, H. : Peripapillary choroidal circulation in glaucoma. Arch. Ophth. 8:31, 1971.

12. Best, M., Blumenthal, M., Galin, M. A., and Toyofuku, H. : Fluorescein angiography during in­duced ocular hypertension in glaucoma. Brit. J. Ophth. 56:6, 1972.

13. Hayreh, S. S. : Pathogenesis of visual field defects. Role of the ciliary circulation. Brit. J. Ophth. 54:289, 1970.

14. Anderson, D. R. : Vascular supply to the op­tic nerve of primates. Arch. Ophth. 70:341, 1971.

15. Hayreh, S. S. : Blood supply of the optic nerve head and its role in optic atrophy, glaucoma, and oedema of the optic disc. Brit. J. Ophth. 53 : 721, 1969.