SURVEY OF OPHTHALMOLOGY

MAJOR

VOLUME 34 * NUMBER 6 - MAY-JUNE 1990

REVIEW

Intraocular Pressure: New Perspectives YOSHIHIKO

SHIOSE, M.D.

Division of Ophthalmology,

Aichi Prefectural

Center of Health

Care, Nagoya, Japan

Abstract. Reevaluation

of normal intraocular pressure (IOP) was attempted to investigate possible background factors that contribute to variations in IOP. It is well known that IOP increases with age among Western populations, while in the Japanese IOP has been confirmed to decrease with aging. Such paradoxical results can not be reasonably explained without considering systemic conditions rather than local factors peculiar to different races. Accumulated evidence indicates that IOP is positively correlated with blood pressure, obesity and other cardiac risk variables. Incorporation of these factors by stratifying the sample may provide the baseline IOP in those who are different in systemic conditions. SUIT Ophthalmol 34:413-435, 1990)

Key words.

analysis

??

aging obesity

??

??

glaucoma intraocular pressure race systolic blood pressure ??

??

multiple

regression

??

Glaucoma is theoretically defined as a progressive optic neuropathy as a consequence of the elevation of intraocular pressure (IOP) above the physiological level of individuals. However, the concept of normative pressure,“4 emphasizes that it is not the statistically normal, but rather the individually normal values,“4,‘s0 that are important. While this concept is widely accepted, clinically there is no available method of determining normative IOI’, and the practice is to use conventionally termed “normal” IOP based on a large number of subjects. The upper limit of normal IOP obtained stochastically is internationally accepted as being approximately 2 1 mm Hg as a standard in the clinical diagnosis of glaucoma. However, when this level is used as a cut-off for the screening of glaucoma regardless of age, sex and race, it appears that nearly 10% of the elderly suffer from ocular hypertension in Europe and the United States.“7~75Z”‘” While most ocular hypertension represents physiologic conditions,“‘g*“‘4 many cases of glaucoma To adopt a given escape detection. ~Y.1:~,~:~.~(),10~~.104.IJ:! level of IOP as threshold is clearly artificial for

separating physiologic from pathologic conditions, and the practice has come under much criticism 34~40,67,75~103.104.I3.i,lBX It has been suggested that in view of the many statistical findings that show increase in IOP with age, the cut-off value for those above 40 years of age should be raised according to age to minimize falsepositive cases,40.‘35 but this in turn results in more false-negative cases. Moreover, we have observed that in the Japanese, unlike Europeans and Americans, the IOP decreases with age over 40 years.‘“‘3 159-‘55This finding has been supported in numerous other Japanese studies.5’,‘7,xx,““,‘~~Such conflicting findings among races cannot be attributed merely to local factors, and a multifaceted investigation that includes systemic changes associated with aging is required. In this article, existing literature on population surveys of IOP by age, sex and race are reviewed, and “normal” IOP is reevaluated with consideration of various systemic factors that might affect IOP. Possible sources of error and variations in IOP will also be discussed.

414

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34 (6) May-June

SHIOSE

1990 TABLE 1

Mean and Variation of Normal Intraocular Pressure Measured with Schiotz Tanomter

Investigators (year) Leydhecker et allo (1958) Katavisto and Samalkivix5 (1964)

10,000 11,520

Hollows and Graham75 (1966)

4,231

Alsbirk” (1970)

1,108

Kurokawag5( 1969) Shiose and Kawase’54 (1986)

Geographical location

Number of individuals

658 93,703

Bonn (West Germany) J oensusu (Finland) Ferndale, Wales England (U.K.) Umanak (Greenland) Niigata

(Japan)

Nagoya (Japan)

Sex

M

IOP SD

M+ 2SD

-

15.5

2.57

20.94

-

16.0

2.72

21.44

M F -

14.6 15.7 15.7

2.96 2.87 3.00

20.529 21.445 21.70

-

15.3

2.37

20.04

M F

14.6 15.0

2.52 2.33

19.649 19.669

$Left eye.

I. Normal Intraocular Pressure A. CONCEPT In 1958, Leydhecker et al”* collected statistics on on IOP using standardized Schiotz tonometer 10,000 individuals (20,000 eyes) with no ocular symptoms, and reported that average IOP in the total sampling was 15.5 + 2.57 mm Hg and that the distribution was regarded as normal. Assessment of distribution is usually conducted by plotting the cumulative percentage frequency on probability graph paper and seeing whether the points lie on a straight line. By this method, the degree of deviation can be noted visually. In a normal distribution, the mean is at the middle and the curves on the sides form a bell-shaped plot, with the standard deviation (SD) being equal on both sides. Under these conditions, 67% of samples should fall within the range of M -t SD, 95.0% within M ? 2SD and 99.75% in M ? 3SD. With glaucoma, however, only the abnormality on the high side is being considered, and therefore 97.5% of normal individuals should be encompassed within M + 2SD on one side. Leydhecker et allo applied this concept to their IOP study, and concluded that those who registered 20.5 mm Hg (M + 2SD) or higher could be suspected of having glaucoma and those registering 24 mm Hg (M + 3SD) or higher were definite cases of glaucoma. To date, numerous population studies have been conducted worldwide with the use of either Schiotz tonometer or applanation tonometer. The mean figures, standard deviations, and the normal upper limit based on M + 2SD are shown in Tables 1 and 2. The majority of data has been obtained in white populations of Europe and the United States, but the findings of Wallece and Lowell”’ were based on data obtained in black

Jamaicans. The data presented by Kurokawag5 and Shiose and Kawase’54 were obtained in the Japanese population. When examined according to sex, IOP in females was slightly higher than that in males (Tables 1 and 2). It is generally accepted that in the total population, the normal IOP reading is 15-16 mm Hg on the average, with SD of 2.5-3.0 mm Hg. Although the value increases with age, 21-22 mm Hg is generally considered the approximate upper limit of normal. B. DISTRIBUTION As already indicated, the normal IOP obtained stochastically based on M + 2SD is only a rough approximation and does not necessarily represent a threshold between the normal and the abnormal.40s 75,‘35The reason, aside from that of sex, age or race, is that the distribution is skewed toward the high side, as has been found in numerous studies.g~‘6~40,63~66~67~75~‘ To 80 explain this skewing, two models have been suggested. In the two-curve model, synthesis of two groups results in skewing, the normal group having a normal (Gaussian) distribution with a large peak, while the group which might be unrecognized glaucoma forms another small peak on the high value side.” If one assumes that the normal group has a perfectly Gaussian distribution, 97.5% should fall within M + 2SD (521 mm Hg) and 99.5% within M + 3SD (5 24 mm Hg). In a one-curve model assuming a log-normal distribution, the 97.5th percentile and 99.9th percentile would shift toward the high side (5 22 mm Hg and s30 mm Hg, respectively).r4’ Concerning these two models, Schwartz’4” has proposed a number of variations. Suffice it to say that the normal IOP does not necessarily represent a normal (Gaussian) distribution.

INTRAOCULAR

PRESSURE:

415

NEW PERSPECTIVES TABLE

Mran and Variation of Normal Intraocular

Investigators (year)

2

Pressure Measured with Goldmann Applanation

Number of individuals

Geographical location

Armaly” (1965)

2,316

Hollows and Graham’” (1966)

4,231

Bankes et al”’ (1968)

5,941

Des Moines Iowa (U.S.A.) Ferndale, Wales England (U.K.) Bedford (U.K.) August town Uamaica) Dally

Wallece and Lowell’” (1969) Bengtsson” ( 1972)

574 1,618

(Sweden)

Tonometel

Sex

M

IOP SD

M+ 2SD

M F M F M F M F M F

15.6 16.1 15.9 16.6 15.6 15.7 16.8 16.5 14.0 14.7

3.22 3.23 2.87 2.88 2.55 2.44 2.83 2.86 2.46 2.57

22.04 22.56 2 1.64s 22.363 20.70 20.58 22.46 22.22 18.923 19.843

#Left eye.

Goedbloed et al”” recorded the frequency distribution of IOP in more than 13,000 normal eyes, and found that the normal curve broke down when the IOP was high in the older individuals. If a normal distribution is assumed, the 95% level should be at 20.5 mm Hg. Actually the 95th percentile in males in their 30’s was at 20 mm Hg, but the value increased with age to reach 25 mm Hg for males in their 80’~“‘~ With females, IOPs were slightly higher, but the trend was similar. The study also showed that distribution of readings below 22 mm Hg was normal regardless of sex and throughout all age groups, but when the readings were higher there were deviations from the norm. This skewing became more marked with age, especially in women. In 1965, Armaly!’ conducted a statistical study based on sex and age in 2394 individuals with no ophthalmic, symptoms. He found that IOP increased with age in subjects over 40, that this trend was more marked in females than in males, and that while the distribution was completely normal in both sexes in their 20’s and 30’s, this was not true when the subjects reached 40 and above. Biomedical data accompanied by right skewness often show logarithmic normality, but these data confirmed that the distribution was not normal, even on a log sca,e,“.75

Hollows and Graham7” in their Ferndale Glaucoma Survey reported that, as in Armaly’s study,” IOP increased with age and that the distribution was normal in the young but skewed toward the high side in people over 60. Shiose and Kawaselsl studied the distribution of Schiotz tonometry data on participants in the Automated Multiphasic Health Testing Services (AMHTS) in Japan. They found that the overall distribution was approximately normal, but there was a slight deviation when the readings were 20 mm Hg or higher. Nishiyama”” and Kurokawa”’ found that Schiotz tonometer scale

readings showed a normal distribution, while conversion figures showed a slight skew to the right. Similar results on conversion figures of 1948 have been reported,7’.‘“” adding to the findings that IOP distribution among the Japanese is more nearly normal than in Europeans or Americans. Taken together, these reports suggest that the IOP distribution in the normal population shows a variable degree of skewing to the right, and that this is especially marked in the European and American elderly. When unrecognized glaucoma is included in the genera1 population, it may be expected that the trend would be more marked. Davenger and Ho1ter4’ conducted studies on a mathematicalphysical mode1 of fluid flow, and showed that constriction of the pores in the outflow channel has a definite effect on IOP. They presented a theory of physiological skewing of IOP in the normal individual toward the hypertensive side. Can this right skewness be attributed entirely to local conditions surrounding the eye? This point will be discussed further.

II. Statistics of Intraocular Pressure bY Age A. TONOMETRIC

DIFFERENCE

Hollows and Graham7” used both Schiotz and applanation tonometers on each of 423 1 subjects and found that the Schiotz readings were lower - mean IOP of 14.6 5 2.96 mm Hg for males and 15.7 ? 2.87 mm Hg for females, compared to applanation readings of 15.9 ? 2.87 mm Hg for males and 16.6 t 2.88 mm Hg for females (Tables 1 and 2). When the findings were statistically treated according to age, the applanation figures indicated a greater rise in IOP in both sexes than that indicated by the Schiotz figures. This trend was more marked in females than in males.“.“” When comparing the statistics obtained by Leydhecker et al”‘” by Schiotz

416

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34 (6) May-June

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SHIOSE

VI

IOPl

Fentales

ii

14

II

13 ?? Schiotz 0

Goldmann

tonometer applanation

?? Schiotz tonometer

0

i

Goldmann

tonometer applanaticn

tonometer

I

I

I ,

, W

4 I)-

50-

ho-

70-

80-

yr.

30-

40-

50- .

hO-

70-

80-

yr.

Figs. 1A and IB. Mean intraocular pressure by age in different population surveys on Europeans and North Americans (males and females, respectively). 1 =Goedbloed et a163; 2= Lowen et al’13; 3=Hollows and Graham75; 4=Armalyg; 9 = Hollows and 5 = Leydhecker et al lo’; 6 = Katavisto and Samalkivi85; 7 = Bankes et a116; 8 = Segal and Skwiercznska’44;

tonometer to those obtained by Armalyg by applanation tonometer (both regarded as representative studies), rise in IOP with age was definitely less in Leydheckers’ study. Since the Goldmann applanation tonometer is more accurate, the Schiotz readings may be regarded as underestimations. The Schiotz values have been revised along with standardization of the tonometer in 1909, 1924 and 1948. The newest conversion table was presented by Friedenwald in 1955.55 Some later studies, however, claimed that 1948 table values were closer to the applanation figures.4 Armaly7** studied the disparity between the Schiotz and Goldmann tonometers and reported that when the applanation values were taken as independent variables the Schiotz figures were higher in the 8-10 mm Hg range but lower at 16 mm Hg or above.’ Later studies have often showed that at 21 mm Hg and above, the Schiotz values are lower. 2’,“2,‘o6It has also been pointed out that the conversion values at 5.5 g and 7.5 g weights show biphasic characters.75 Regarding the error factors in Schiotz tonometry, Bengtsson et a122*24suggest that because of expulsion of chorodial blood through indentation, Schiotz tonometry minimizes the effects of blood pressure and age, as compared with applanation tonometry. Another important issue for evaluating Schiotz measurements is the effect of ocular rigidity. Advancing age might be expected to influence ocular rigidity due to sclerosis of the tissue,“’ but there is no firm conclusion.48 It has been shown that eyes with small radii of cornea1 curvature frequently have high rigidities and that the converse is true in

eyes with larger radii.4s Clinically, high myopic eyes tend to have a low coefficient of rigidity, while hypermetropic eyes have high ocular rigidity.48 Recently, the noncontact tonometer is often used for screening,35s’4g but with an instantaneous measurement, large deviations of individual readings sometimes occur because of pulsatile and respiratory changes, and several measurements are required for each occasion.‘23 There are, however, many advantages of this instrument; it is free from possible infection, indifferent to the effect of ocular rigidity, has no digit preference, has no need for examiner’s skill, and can easily be done on eyes with narrow lid fissure. With this tonometer there is a tendency for underestimation on the low side and overestimation on the high side of a threshold value of 18-20 mm Hg.148 Thus, the average values obtained in the general population are about 3 mm Hg lower than values obtained with applanation or Schiotz tonometers.3”“5”‘54 In summary, absolute values and distributions differ in statistics obtained with different tonometers. Thus, separate charts and tables were prepared in this presentation. Values obtained by applanation are theoretically the most accurate, but technical errors in measurement cannot be ignored.r0%16” B. SEX DIFFERENCE Figs. 1A and 1 B show statistical values according to age groups in males and females, respectively, compiled from European and American studies. There was a general tendency toward rising IOP over the age of 40, and the readings were higher

INTRAOCULAR

PRESSURE:

NEW PERSPECTIVES

and the tendency for IOP to rise was more marked in women than in men. When the figures are carefully studied, however, it is noted that even among Europeans and Americans, there is no invariable rise in IOP with age. Actually, IOP tends to drop in age groups over 70,“.“i,“J.“S especially in males. Some show virtually no change in IOP with age,“” and some show a decrease even by applanation tonometry”’ (Fig. 1A). Katavisto et a18” in Finland performed Schiotz tonometry on 5750 out-patients with no ophthalmic complaints, and found that in males there was a tendency for IOP to fall with age (age 40-49, 16.02 mm Hg; age 50-59,15.90 mm Hg; age 60-69,15.78 mm Hg; age 70-79,15.60 mm Hg; age 80-89 years, 15.44 mm Hg), while in females IOP increased after age 40 (age 40-49, 17.7 mm Hg; age 50-59, 17.8 mm Hg; age 60-69, 18.0 mm Hg; age 70-79, 18.3 mm Hg; age 80-89, 17.3 mm Hg), although the peak was reached in the 70’s and was followed by a decrease in the 80’s. In West Germany Loewen et al”” applied Schiotz tonometry to 4661 volunteers during “Glaucoma Week” and found the values for men to be: age 50-59, 17.27 mm Hg; age 60-69, 17.24 mm Hg; age 70-79,17.01 mm Hg; age 80-89, 16.39 mm Hg. In women, IOP consistently increased with age to reach 18.0 mm Hg in the 70-79 age group, but dropped to 17.65 mm Hg at age 80-89. In the Bedford (England) Glaucoma Survey, Bankes et al’” conducted applanation tonometry on volunteers over 40 years of age and found that in males, IOP rose with age until the 40’s, but decreased after 50 and was 15.1 mm Hg in the group aged 80 years and older. In females there was a rise in IOP with age from the 40’s on, peaking at 16.02 mm Hg in the 70’s and dropping to 15.43 mm Hg in the 80’s. In the United States, Kahn et a18’ studied applanation pressures of 2445 subjects who participated in the Framingham Eye Study from 1973 to 1975, and reported that mean IOPs for men and women were 16.6 and 16.8 mm Hg, respectively, at age 52-64,17.4 and 17.5 mm Hg at age 65-74, and 17.4 and 17.3 mm Hg at age 75-85. A trend of increasing 101 was noted up to 74 years in both sexes, but this was not confirmed over this age. No sex difference in IOP was found; however, this should be interpreted cautiously since the number of age groups was too limited to make a conclusion and it was not indicated whether glaucoma eyes were excluded. The complete report of the Framingham Eye Study”” on the same subjects has shown increased prevalence of definite open-angle glaucoma with age in both sexes, but twice as high in men as in women (1.9 and 1 .O%, respectively). Glaucoma eyes

417 were not excluded from the total sample; their exclusion would suggest more differences between sexes than the figures presented above. When I examined the findings by all groups of researchers, I consistently observed that women had higher average IOP than men and a more marked tendency for increase with age, with peaking at a higher age than in men. Similar results have been reported by many others.“‘“.” C. RACIAL

DIFFERENCE

Wallece and Lowell”’ applied the criteria used in the Ferndale Glaucoma Survey” to 574 of a target population of 678 blacks residing in August Town, Jamaica. They found that rise in IOP with age was more marked than that usually found in whites, the average IOP at 60-64 years of age being 17.7 mm Hg in males and 19.1 mm Hg in females. Klein and Klein”’ used data from the Health and Nutrition Examination Survey (HANES) from 197 1 to 1974 in the United States, and showed that the average IOP increased with age, but in a given age group the readings were higher in blacks than in whites. As among whites, IOP was higher in black females than in black males. Similar results have been reported by many others.~1.4ri,~‘i.“H Kass et alx” conducted a statistical study using applanation tonometry on 119 full-blooded Zuni Indians who live in an isolated colony in New Mexico and whose customs and dietary habits are completely different from those of other Americans. They reported that the average IOP was lower than that of age-matched Americans outside the reservation, and that there was no rise in IOP with age. In Japan, Shiose’“‘,“‘:‘-‘“” conducted surveys on approximately 200,000 subjects who underwent automated multiphasic tests from 1972 to 1981 (Schiotz tonometer, 1972-1977; noncontact tonometer, 1978-1981). About 20,000 subjects were examined per year and the data were processed on an annual basis. For the statistical analysis those who were known to have glaucoma were eliminated from the data. As shown in Fig. 2, average IOPs of males’ right eyes measured with Schiotz tonometer were: age 40-49, 14.9 mm Hg; age 50-59, 14.6 mm Hg; age 60-69, 14.4 mm Hg; over age 70, 14.2 mm Hg. The noncontact tonometer revealed much lower figures; corresponding values were 40-49, 12. I ; 50-59, 11.8; 60-69, 11.7; and over 70, 10.7 mm Hg. Thus, age-dependent decrease of IOP was consistently observed with both types of tonometers. These results were in agreement with those of numerous studies conducted by other -Japanese invesand tigators using Schiotz, ii.‘i7,XX.“iapplanation,'?" noncontact tonometers.” Decrease in IOP with age was more marked in men, beginning at 50, while in

418

Surv Ophthalmol

34 (6) May-June

1990

SHIOSE

z!!

20 19 18 17 -

--t

Schiotz tonoinettr (194 t&b)

-+-

Schidz tonometer W54 tebb)

14 -

-o-

&hiotz tonometer (1955 td

13 -

--t

Noncontect to&meter VlO)

16 15 -

12 11 s

I

30%

I

40-

I.

I

50-

I

60-

70- year

Age Fig. 2. Mean intraocular pressure by age in Japanese. 1 = Hoshizumi”; 2 = Kurokawag5; 3 = Shiose’54 (males); 4 = Kitajima8g; 5 = Shiose154 (males). women significant years.151,154 D. COMMON

lowering

of IOP started

at 60

FINDINGS

The statistical findings described above were that IOP in a normal population varied with sex, age and race. When the effect of age on IOP was studied, the trend among Europeans and Americans was opposite that found in Japanese after 40 years of age. From an epidemiological standpoint, it has been stressed that direct comparison of the results obtained from different study designs must be done cautiously, especially in prevalence studies.s’,‘03~104 However, certain variables must be considered in this kind of study, e.g., size of the sample, exclusion of known glaucoma cases, and type of population a sample representing a normal population is preferred. Studies on outpatients at an eye clinic6’ss5 or participants in a “Glaucoma Fair”16p’13 might have some bias in their results, since the sample consists of more self-selected subjects. Admittedly, consistent observations made by differently designed methods should be critically evaluated. What must be studied most carefully is not the apparent diversities, but the common features observed in these investigations, as follows: 1) Up to the age of 40, IOP is relatively constant regardless of race and sex,g*1’,75,151*153 and approximates normal distribution.g,75 2) After the age of 40, IOP may increase or decrease depending on race, but it is almost without exception higher in females than in males 3,9.11, 16,67,75,151,153

3) Even among Europeans and Americans, IOP tends to drop in the elderly, more markedly in males, according to many studies.g*16~75*85~113 4) After the age of 40, regardless of sex and age, standard deviations tend to increase with age. 9,11,75,151,153 The difference between males and females in the older group might be attributed to hormonal changes in post-menopausal women,g but the differences between the races in the age groups over 40 may represent something more than mere physiological aging - for instance, the effect of differences in the body constitution peculiar to the race, dietary habits, and environmental conditions which affect the occurrence of adult diseases. In typical statistical studies on IOP,g,75,10* patients who complain of ophthalmic problems or suffer from ocular diseases have been excluded, but patients have not been excluded based on systemic adult diseases. This would possibly create a qualitative difference in the background of subjects of different races, even though they may be regarded as “normal.”

III. Variation of Intraocular Pressure A. DIURNAL

VAiUATION

Like all biological parameters, IOP exhibits a circadian rhythm. In a normal individual, the daily fluctuation ranges from 3 mm Hga6 to 6 mm Hg. ‘OS15’Variations that exceed 10 mm Hg are considered to be pathologica1.g0~125It has been reported that in the normal individual, IOP is high in the morning and drops in the afternoon.20,47,86,101 Lennon et al”’ at a glaucoma screening center used the

INTRAOCULAR

PRESSURE:

same cut-off level for morning and afternoon examinations in a screening clinic and compared the results obtained in randomly assigned patients. They reported that positive screenings occurred more frequently in the morning. Similar results were obtained by Perkins”‘” in the Bedford Glaucoma Survey. There have been, however, a number of reports describing peak pressures during dayit has been time. ‘z”‘.‘~~ Because of these differences, asserted that statistically obtained results should be clearly distinguished from individual variations.‘7” As for the mechanism of diurnal variation in IOP, a role of adrenocortical steroid has been suggested. It has been reported that 34 hours before the peak time for IOP, plasma cortisol shows an analogous change.“’ B. SEASONAL

VARIATION

It has been confirmed that IOP shows a seasonal variation, being low in the summer and high in the winter.“.“0.144’l~:4 In a glaucoma survey conducted in Israel, Blumenthal et al’” found that the average IOP in clinical cases was 15.7 mm Hg in the summer and 18.0 mm Hg in the winter. Studies of seasonal variation in normal individuals showed that in the overwhelming majority the IOP was lower by l-5 mm Hg in the summer than in the winter.“’ Bengtsson2” in Sweden conducted a seasonal study of IOP in 1702 persons and found that the levels were higher by about 1 mm Hg in the winter than in the summer. In Japan, Shiose’“” compared IOP readings monthly in 16,000 participants of Automated Multiphasic Health Testing Services (AMHTS) and found that there was a significant difference in the seasons, the IOP being 1.5 mm Hg lower in the summer than in the winter. Measurements were taken between 9:00 A.M. and 11:OO A.M. throughout the year. It was interesting that the systolic blood pressure in these subjects showed synchronous changes, being low in the summer and higher in the winter, the difference being about 10 mm Seasonal variation, like diurnal variation, Hg. ’-I:’ was ofdifferent magnitudes depending on the individual, the range of fluctuation being greater in glaucoma cases. C. POSTURAL

419

NEW PERSPECTIVES

VARIATION

The typical techniques for measuring IOP include the Schiotz method in which the subject is lying on his back, and the applanation method of Goldmann in which the subject is in a sitting position. The effect of postural change on IOP presents an interesting question. In pursuing this subject, the Perkins applanation tonometer,‘02.‘7” Alcon’s pneumatonograph,“‘“~“’ and the Mackay-Marg tonometer7” have been employed. In most studies it

has been found that IOP rises when the subject shifts from a sitting to a recumbent position.“,5X.7”.‘02,‘47The range of variation of IOP in the normal individual is reported to be 0.3-0.6 mm Hg. While the individual variation is large,’ this postural effect is marked in cases of ocular hypertension,“’ glaucoma,“~‘“~“’ and low tension glaucoma. ‘69 Weinreb et a117”reported that in the inverted body position, IOP of normal individuals rose to more than 30 mm Hg, and the rise was even more marked in cases of glaucoma. It is believed that this rise in IOP with postural change is the direct result of increased episcleral venous pressure.“‘,““,“‘,‘~” It has also been found that in cases of central retinal vein occlusion,“” hypertension, and diabetes,17’ the change in IOP as a result of postural change was more marked than in normal persons. These findings suggest that some abnormality in the control of intraocular pressure possibly occurs in these diseases. D. EXERTIONAL

CHANGES

It is well-known

that IOP decreases after exerPasso et al’“” subjected 10 healthy sedentary volunteers to aerobic exertion and found a drop in IOP of 5.9 + 0.6 mm Hg after a short period of exercise, but the change was transitory. When exercise conditioning was conducted for four months, IOP which was 14.3 ? 0.7 mm Hg before the regimen dropped to 13.0 5 0.9 mm Hg, which was a significant decrease from the baseline value. The decrease in IOP with exercise has been suggested to be caused by lowered blood pH and/or increase in serum osmolarity,““.‘” but it is not understood.” It has been suggested that the change may include a diurnal fluctuation in IOP,‘? and that the apparent drop in IOP may be due to repeated measurements.‘“‘.‘“” ~~Se~~lX.IOO~IIR.I~l~146

E. REFRACTIVE

ERROR

It has been shown that IOP may vary with refractive error, since IOP is found to be higher in myopits than emmetropics’~4’~“‘~~‘fi7~‘~~and there is a positive correlation between the axial length of the globe and IOP.‘“’ It has been reported that elderly myopics show marked increase in IOP.’ There are definitely more myopes than emmetropes among cases of open angle glaucoma,“‘“,“” but it is not known whether this is because high IOP is more prevalent among myopes4’,4” or because high IOP is simply observed more in myopes because there are mOre glaucoma caSeS among them.““.‘:‘~4.‘:~l.“~ The epidemiological aspect of myopia is ticular interest, since the prevalence appears fer considerably with race, and this might be ated with age specific trends of IOP. In the

of parto difassociUnited

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SHIOSE

1990

States, Sperduto et al,“jO conducted a study on prevalence of myopia in 5 195 subjects, as part of the Health and Nutrition Examination Survey (HANES) in 1971 and 1972. In whites, they found a prevalence of 25.6% at age 12-17; 29.7% at age 18-24; 25.6% at age 25-34; 24.9% at age 35-44; and 25.5% at age 45-54 years. Prevalence in blacks was almost halfthat in whites: 12.0, 10.4, 12.3, 14.8 and 17.3%, respectively. They also found that in both races more myopia was seen in women than in men below the age of 35 years.“’ The results indicated that in both white and black North Americans, myopia prevalence remained remarkably constant from the ages of 12 to 54 years, though there were progressively more low myopes (< -2 diopters) and correspondingly, fewer moderate-high myopes (- 2- - 7.9 diopters), with advancing age.‘“’ Shiose et a1’56 conducted a population-based prevalence study of myopia on 6339 subjects from seven different districts across Japan as part of the Nationwide Glaucoma Survey in 1988, and found that the prevalence of myopia was 79.0% at age 30-39 years; 60% at age 4049; 36.2% at age 50-59; 24.0% at 60-69, and 20.5% at 70 years or older. Seventy-five percent of the myopes were weak myopes (less than - 3 diopters) and the prevalence of high myopia (exceeding - 7 diopters) was less than 5% in each age group.15’j Similar results have recently been presented by Van Rens,“’ who conducted a prevalence study of refractive errors in 1395 Eskimos of the Norton Sound and Bering Strait region of Alaska as a part of Alaska Eye Survey II. Myopia was found in 67.2% of subjects aged 30-39 years, and the prevalence decreased markedly with advancing age (about 20% at age over 60 years). Measurement of axial length in this study has shown a proportional increase in frequency of myopia with greater axial length, but no clear relationship was found between axial length and age. Both Japanese and Alaskan Eskimos belong to the Mongoloid race and share many physical characteristics. The high prevalence of myopia, especially in younger generations of Mongoloids might be genetically predisposed, but it may be partly due to recent changes in lifestyle, such as educational demands and dietary habits.“’ Although age specific trends in occurrence of myopia vary among races, this does not seem to explain the difference in IOP with aging. If one assumes that IOP is higher in myopes, racial differences of IOP between whites and blacks would have been reversed according to HANES data.“j’ Age dependent increase in IOP is not paralleled with the prevalence of myopia in North Americans. On the other hand, the decrease in IOP with age in the Japanese is seemingly paralleled with occurrence of

myopia, but it is not known whether this is mere coincidence or whether some cause-effect relationship exists.‘56 F. OTHER

CAUSES

OF VARIATION

It has been reported that whereas ordinary blinking causes a 10 mm Hg rise in IOP, hard lid squeezing can raise IOP to nearly 90 mm Hg.3g Green et al’jg conducted studies with forcible eyelid squeezing over one minute (2-set squeeze, P-set rest) and found that IOP in the normal individual fell by about 2 mm Hg while there was less decrease in eyes with glaucoma and ocular hypertension. In voluntary lid fissure widening, IOP is increased.lz4 This is believed to be as a result of retraction of the upper eyelid into the orbit with consequent increase in orbital volume, which pushes the globe forward.lz4 Findings in these studies are not consistent, and the marked individual variation always poses a problem. According to Leydhecker,‘Og measurements conducted at lo-minute intervals by two experienced examiners using applanation tonometer showed variation of + 3 mm Hg. He attributed the variation to spontaneous pressure change and repetition of procedures. In Orientals applanation tonometry cannot properly be done unless the eyelid is lifted manually, creating forcible lid lissure widening; the artefactual effect of this factor cannot be ignored. In this regard, Schiotz tonometer is more suitably applied to narrow eyes, because the foot-plate of the tonometer acts as a lid-retractor. There have also been studies on the relation of IOP and humoral dynamics to female hormones, with the suspicion that IOP may fluctuate with menstrual cycle;5’,70 however, no specific correlation has been found. The association of IOP and the amount of iris pigmentation has been suggested by HANES data, in which mean IOP was highest for blacks with brown irides and progressively lower for whites with brown irides, whites with other than brown or blue irides, and whites with blue irides. However, this is not valid for the Japanese, since all have brown irides with relatively low IOP compared with Caucasians. In summary, numerous factors may possibly modify the level of IOP in normal subjects; however, none of these seems to explain the essential difference in IOP with aging between Westerners and Japanese.

IV. Systemic Influence on Intraocular Pressure Aside from genetic factors,‘“,‘R,‘07.‘37,143 there are numerous systemic factors that have been shown to

INTRAOCULAR

PRESSURE:

NEW

421

PERSPECTIVES TABLE

Contributions

Investigators

of Various

Number of Individuals

(year)

Hiller

Klein”’ (1981) U.S.A.

et a1.74 (1982),

Leske and Podgor”‘” U.S.A. Care1 et al.“” (1984) Shiose’“’

Israel

(1984) Japan

11,678

Mukltiple Other

Variables

Studied

0.08 0.06

Sex, season, Hemoglobin,

time of day, age sex, age, height,

0.05

Hematocrit,

pulse,

Hematocrit,

pulse

BP

0.08

Age Systolic

BP

0.06

Age Systolic BP Diabetes Heart Rate Heart rate Systolic BP Obesity index Systolic: BP

13,000

Pressure as Expressed by Multiple R2*

Age Systolic

Age Systolic BP Serum cholesterol Systolic BP

2,433

(lB83)

to Intraocular

Systolic BP Systolic BP Ponderal index Systolic BP

1,552 (W/M) 2,384 (W/F) 421 (B/M) 721 (B/F) 4,176

U.S.A.

Factors

Systemic Variables Entered

1,606 573

Bengtsson”” (1972) Sweden Bulpit et a1.s” (1975) U.K. Klein and

Systemic

3

sedimenration

weight rate

0.08 0.06

Sex, iris pigmentation,

0.06

Vertical

C/D

0.04

Height,

age

0.05

29 other

systemic

family income

variables

Age W/M: white males; B/M: black males; W/F: white females; B/F: black females. *Multiple R2 refers to the multiple correlation coefficient of whole model and therefore, percentage in total variation of intraocular pressure explained by the factors included.

affect IOP in the physiological condition. We shall now discuss the results of multiple regression analysis on systemic variables that appeared in Western and Japanese literatures (Table 3). A. STUDIES

ON WESTERN

Bengtsson” nations pressure and

used

with (BP)

POPULATIONS

conducted

ophthalmological

applanation

tonometry

measurements

multiple

regression

on

1606

analysis

blood

individuals, to study

the

variables as age, sex, season, time of day, and systemic blood pressure with IOP. He found that systolic blood pressure had the strongest correlation among the variables tested. He also noted that statistically there was a rise in IOP with age, but concluded that this was not the effect of age itself, but an event that was mediated by the change in systolic blood pressure which accompanies aging.‘“xY4 Bulpit et al”:4used subjects of 60 years or greater age and studied the relation of sex, age, systolic blood pressure, diastolic blood pressure, body weight, Ponderal index (body height/“m weight) and hemoglobin to IOP. They found that the greatest contributions to IOP were the systolic blood pressure and the Ponderal index. A multiple association

of such independent

examiand

multiple

R’ indicates

a

regression equation was obtained: expected applanation IOP = 0.02 systolic BP - 0.04 Ponderal index + 16 mm Hg. This showed that systolic BP and obesity independently correlated with IOP, and no significant correlation with age was found. Klein and Klein” applied multiple regression analysis to the relation of IOP and various kinds of cardiac risk factors to data obtained in the HANES, 1971-1974. Whites and blacks were studied, with the sexes being treated separately. In all groups, systolic BP had a significant positive correlation with IOP. Other items such as hematocrit, sedimentation rate, pulse rate and serum cholesterol level were entered in the regression equation, but the degree of contribution varied in each group. The effect of age, evaluated in a stepwise model, was minimal, and the authors surmised that the factor was submerged in systolic BP. By using these variables, an explanation was provided for 5-8% of the IOP changes (multiple R’). Leske and Podger’“” studied the relation of IOP to cardiac risk factors in 2433 participants in the Framingham Heart Study and Eye Study. They found that individuals in whom IOP of at least one eye exceeded 2 I mm Hg had a higher incidence of hypertension and diabetes, but no correlation was

422

Surv

Ophthalmol

34 (6) May-June

1990

SHIOSE

TABLE Simple Correlation

Table for Major Systemic Variables of Males (Shiose’53)* Obesity

Characteristic*

l-IOP Age Obesity index Systolic BP Diastolic BP Serum cholesterol Glucose tolerance test Fast blood sugar Alkaline phosphatase Red blood cell count Hemoglobin

l-IOP

Age

-0.084***

4

Index

0.164*** 0.071***

Systolic

BP 0.122*** 0.214*** 0.173***

Diastolic

Serum

BP

Cholesterol

0.114*** 0.274*** 0.211*** 0.684***

0.097*** 0.1 lo*** 0.255*** 0.066*** 0.096***

N: 15,297 subjects; ***p < 0.005; **p < 0.01; *P < 0.05. Most of these items revealed significantly high correlations with each other due to the large size ofthe it should be noted that some correlations were actually low; e.g. age and IOP.

found between open angle glaucoma and cardiovascular disease in their model. Like other investigators, they showed by multiple regression analysis that systolic BP had the strongest correlation with IOP. Here, too, it was found that when systolic BP was entered in the equation, the age effect was nulliIied.‘05 Care1 et a135studied the relation of IOP measured by noncontact tonometer to various systemic factors in 13,000 participants in the Automated Multiphasic Health Testing Services (AMHTS) in Israel. Multiple regression analysis showed that the contributions of systolic BP and heart rate were marked. Age was a fourth contributing factor, following body height, but when this was included in the equation there was no change in multiple R, establishing that the age effect was spurious. Hiller et a1,74using data from HANES, conducted multilinear regression analysis to study the association of IOP with age, sex, race (whites and blacks), iris pigmentation, systolic BP and family income in 4176 subjects aged 25-74 years. The study showed significant, positive association of IOP with systolic BP, age, and amount of iris pigmentation, and negative association with family income. Despite statistically significant associations, the proportion of variance in IOP that was explained by these variables was the same extent (about 6%) shown by others (multiple R2: 0.06).74 Results of the various studies are summarized in Table 3. All the studies agreed on the following points: systolic BP had the strongest correlation with IOP; changes in IOP that could be explained by given variables were 4-8% of the total variation; and although statistically there was a rise in IOP

Glucose Tolerance

Test 0.044*** 0.205*** 0.071*** 0.159*** 0.117*** 0.087***

sample;

however,

with age, no significant contribution of age was obtained in most studies. Other clinical research reports that show the relation of systemic hypertension to IOP are numerous*20,41,52,64,71,74,83,92,97,143,155.179Cullen

et a14l attempt_

ed to establish the physiological index of IOP by using the BP/IOP ratio, but age was not taken into consideration. As for the relation of diabetes to IOP, there have been many reports that occurrence of ocular hypertension is higher in diabetics than in nondiabetics,‘5,‘9,78,82,92,‘03 although some have reported virtual absence of any relationship.“B3’ Diabetes, it must be remembered, is frequently associated with many other cardiovascular diseases that are shown to have a positive correlation with IOP, and the role of such confounding factors should also be taken into account. B. STUDIES

ON JAPANESE

POPULATION

We have conducted a series of investigations’5’B ‘59,‘55on Japanese AMHTS participants on an annual basis for ten years, repeating multiple regression analyses on 32 systemic variables to identify major factors that contribute to IOP. Measurement of IOP was performed with either a Schiotz tonometer (1972-1977) or a noncontact tonometer (1978198 l), as a part of systemic examination conducted between 9 A.M. and 11 A.M. from Monday through Friday. In this manner, the effects of diurnal variation and seasonal changes were maximally avoided. The reasons we repeated the same analyses for years were 1) to confirm the tendency of IOP to decrease with age with two different types of tonometer, 2) to confirm the factors most frequently entered in the multiple regression equation of the

INTRAOCULAR

PRESSURE:

NEW PERSPECTIVES

TABLE 4 Simple Correlation Table for Major Systemic Variables of Males (Shiose’ “‘)* (continued)

Fast Blood Sugar

Alkaline Phosphatase

Red Blood Cell count

0.046*** 0.108*** 0.204*** 0.149*** 0.133*** 0.149*** 0.592***

- 0.025** 0.087*** - 0.029** 0.070*** 0.063*** -0.012 0.129*** 0.063***

0.054*** - 0.237*** 0.216*** 0.052*** 0.082*** 0.184*** 0.016** 0.111*** 0.048***

Hemoglobin 0.103*** -0.178*** 0.246*** 0.067*** 0.118*** 0.176*** 0.039*** 0.104*** 0.042*** 0.741***

stepwise model with the data of both tonometers, and 3) to compile sufficient numbers of subjects to be able to make a detailed stratification. Though absolute IOP values obtained by the two tonometers differed considerably, the general trend of IOP was found to be exactly the same. Schiotz data are mainly presented in this review, since the values are comparable to other studies; however, there might be underestimations from some measurements made with other tonometers.66’75 Table 4 shows simple correlations of the main items including IOP (left eye) by Schiotz tonometry in males. In the data for each year, items related to obesity (obesity index, Ponderal index, K index, body weight, chest circumference, girth, skin-fold) ranked high in simple correlation. Other items including blood pressure (systolic and diastolic) and hematology (erythrocyte count, hematocrit, hemoglobin) also tended to rank high. These were all positive correlations.‘5”‘53 The figures for simple correlation for age always ranked middle among 32 variables in each year, with negative correlation. ‘51,‘53It was notable that the contribution of age according to multiple regression analysis, unlike with simple correlation, consistently ranked high in the annual data (Table 5). Under highly standardized conditions the items that ranked high with some consistency despite considerable variation of the items entered in each year were obesity, systolic BP and age (Table 5). The prediction equation using these three items for IOP (Schiotz) of the male left eye was IOP = 0.02 obesity index + 0.02 systolic BP - 0.03 age + 11.56 (-+ 2.39) mm Hg (multiple R: 0.2 19). Obesity index was expressed as [weight/ (height - 100) x 0.91 x 100%. It is highly interesting that, whereas in the studies of Europeans and Americans the contribution of

423 age was quite uncertain, there was a significant contribution (negative correlation) of IOP in the Japanese. One possible reason for this discrepancy is that in most studies conducted in Europe and the U.S.A., multiple regression analysis was applied to the total samples with no consideration of sex. In females, systemic items such as blood pressure, obesity, etc., change dramatically at menopause; thus, there is overall instability which makes it difficult to match their data with those of males. In our own study, repeated multiple regression analyses on nearly 6000 women each year still did not show a consistency similar to that found in males when postmenopausal women were analyzed separately. A second possible reason for the discrepancy between Japanese and Western findings is that unlike simple correlation, the results obtained with multiple regression analysis greatly differ with the parameters included. Therefore, the findings should be interpreted cautiously, especially when the analysis is done with forced variables arbitrarily selected. Another factor to be considered is that, although it is established that virtually all cardiac risk factors are positively correlated with IOP, the occurrence of cardiovascular disease in the general population of Europe and the U.S.A. is much higher than in Japan; thus, there is a strong possibility that other cardiac risk factors which had not been admitted as variables in past studies may have conferred ambiguity to the effect of age.“’ Multiple regression analysis is, theoretically, a valuable method, but it provides an explanation of only a few percent of the total variation in IOP, and the multiple regression equation cannot be applied from external samples other than those for which the multiple regression equation was drawn. It may be seen from the simple correlation table (Table 4) that systemic factors display close correlations with each other (e.g. obesity and systolic BP). To eliminate these confounding factors in the prediction of IOP, an enormous number of samples was used to stratify the cases according to age, sex, systolic BP and obesity.‘“‘a’“4 The results obtained by Schiotz and noncontact tonometers are shown separately in Table 6 (data on males). Overall, IOP was high in individuals who were young, obese, and hypertensive, and low in those who were elderly, thin, and hypotensive, the difference being more than 3 mm Hg with both Schiotz and noncontact tonometers. It was also shown that when systolic BP and obesity were taken at specified levels, IOP decreased approximately linearly with age. If we assume that a man who was young, thin and hypotensive became old, obese and hypertensive, IOP would rise with age, just as among Europeans and

424

Surv

Ophthalmol

34 (6) May-June

SHIOSE

1990 TABLE

5

Sequence of Major Factors Contributing to Intraocular Pressure Among 32 Variables Entered in the Stepwise Model of Multiple Regression Equation (Shiose 15’) Schiotz 1973 (n = 11,678)

tonometer

Noncontact

1974 (n = 15,445)

1975 (n = 15,297)

1978 (n = 10,505)

obesity index***

hemoblobin level

obesity index***

K index****

systolic

systolic BP obesity index***

calcium level systolic BP

systolic

age % vital capacity inorganic phosphorus fasting blood glucose alkaline phosphatase

age % vital capacity cholesterol level diastolic BP red blood cell count

BP

age % vital capacity hemogloboin level glucose tolerance test cholesterol level alkaline phosphatase level

level level level

tonometer**

BP

age urine glucose level hematocrit alkaline phosphatase Ponderal index***** diastolic BP

level

*All subjects were men. Indicates Schiotz tonometer readings taken from 1973 to 1975; the noncontact tonometer readings were taken in 1978 only. ***Obesity index equals weight divided by height minus 100 times 0.9 times 100. ****K index equals belly circumference plus chest circumference minus height. *****Ponderal index equals height divided by the cubed root of weight. The order of items in each year varied to some extent, but obesity, systolic BP and age consistently were entered in

earlier steps of the equation. It is most likely that factors listed in early steps, especially rank l-3 are highly contributing, but factors appearing in the later steps might not be in the order of significance. This is the reason why the same _ technique was-repeated annually. Americans (see Table 6). In subpopulations obtained in this way, sample homogeneity is expected to be increased, and therefore distribution of IOP becomes more normalized compared with data obtained in the total sample, and it may be predicted that the threshold of normal IOP obtained from M + 2SD would become more reliable. Fig. 3 shows the difference in the upper limit (M + 2SD) of IOP by age in subpopulations of the highest group (obese and hypertensive) and the lowest group (lean and hypotensive) in Japanese. There might be some underestimations because of Schiotz values, but the overall trend was confirmed by noncontact values as well. The findings indicate that diversity in IOP between the two groups are minimal under the age of 40, but this becomes progressively more marked with advancing age. Based on these results, we also attempted to prepare 12 simple regression equations for IOP by age in groups stratified according to systolic BP (< 99, 100-129, 130-159, > 160 mm Hg) and body build (< 99, 100-120, > 120% of obesity index) as variables in males and females. Using appropriate programs on a personal computer, we then input sex, age, height, weight and systolic BP as factors and attempted to predict individual base-line IoP.‘55 Incidentally, the simple correlation coefficient of age for IOP was - 0.499 in the total sample, -0.525 for males when females were separately treated, and - 0.679 - - 0.696 when stratification was made by systolic BP. With further inclusion of body build, correlation leaped to -0.965 - 0.999, and an almost perfectly straight line was established between age and IOP.‘55

V, Racial Difference

in Systemic

Factors

Individual variation in physiological IOP occurs not only through genetic factors, but also through differences in bodily conditions. Since it has been seen not only in Europeans and Americans, but also in Japanese, that systolic BP and obesity are the factors that most strongly affect IOP, these items will be discussed from the viewpoint of epidemiology in different races. A. SYSTOLIC

BLOOD PRESSURE

There have been some recent studies in which systemic blood pressures were compared between cases of ocular hypertension and low tension glaucoma (LTG). Goldberg et a164found 72 Caucasians in whom systolic BP in cases of ocular hypertension was 164 & 29 mm Hg, and in cases of low tension glaucoma was 152 -+ 29 mm Hg. Shiose et a115’ found in 303 Japanese that the levels were 135 ? 17 mm Hg and 129 ? 16 mm Hg, respectively. The subjects of Goldberg et a164 were both males and females and averaged 63 years in age, while the subjects in the study of Shiose et a115’were all males and averaged 52 years in age. Thus, the data defy simple comparison, but it does appear that the racial difference is more than what might have been expected. When the results of the American Vital and Health Statistics in the National Health Survey”’ are compared with the data obtained by Aichi Prefectural Center of Health Care153 ofJapan, the prevalence of systolic BP exceeding 160 mm Hg in the general population over 40 years of age in both

INTRAOCULAR

PRESSURE:

425

NEW PERSPECTIVES

1OP mmHg tS 22; 21 20 1; 17

of

Fig. 3. The upper limit normal intraocular pressure (M + 2SD) by age in systemically different populations in Japan. The obese, hypertensive subpopulation has the highest ocular tension while the lean, hypotensive group has the lowest value; the rest of all populations are encompassed within the hatched area. As noted in the figure, the difference between the two extremes becomes progressively larger with advancing age. Armaly’s data on North Americans” are shown by an interrupted line. *Armaly MF’; §Shiose Y.‘54

TABLE Mean Intraocular Schiotz

tonometer

Pressure

6

ofApparently

(n = 64,496

Normal Japanese Population With Both Schiotz and Noncontact

StratiJ‘ied by Systolic BP, Body Build and Age, Determined Tonometers (Shiose15’)

eyes)*

Age (year) Systolict B.P. (mmHg)

Body Build*

Hypertension >150

Obese Moderate Lean Obese Moderate Lean Obese Moderate Lean

Normal tension 100-l 50 Hypotension Cl00 Noncontact

tonometer

(n = 102,706

30-39

4049

50-59

60-

16.1?2.10 16.2” 1.96 15.3s 1.99 15.4k2.40 15.1 k2.44 14.5? 2.53 14.6* 2.72 14.5k2.67 14.0 -t 2.52

15.822.65 15.5k2.61 15.2 2 3.39 15.222.55 14.822.56 14.2? 2.65 14.6k2.84 14.522.51 14.0 2 2.62

15.15 2.59 15.2 2 2.28 14.8 2 2.56 14.8? 2.63 14.6k2.69 13.9?2.82 13.7? 2.50 13.7 ‘- 2.88 13.212.73

14.9 ‘- 3.32 14.6 2 2.53 14.6t2.76 14.1 k2.88 14.02 2.79 13.5+2.80 11.8?0.73§ 13.452.87 12.8?2.17

50-59

60-

12.8r3.07 12.6k3.60 12.1 k3.08 12.0r3.08 11.6 r 2.96 ll.Or2.91 11.123.45 11.1?3.02 9.9* 2.77

12.1 23.28 12.3? 3.25 11.4?3.21 12.023.09 11.2 ? 3.06 10.6+-3.04 10.0-+2.83§ 9.2k2.73 9.2k2.46

20-29 14.5?09 16.7k3.443 15.7? 1.635 15.322.44 15.2 + 2.42 14.7 ? 2.53 14.5 * 3.548 15.7 52.42 14.4? 2.85 eyes)*

Age (year) Systolici B.P. (mmHg)

Body Build+

Hypertension > 150

Obese Moderate Lean Obese Moderate Lean Obese Moderate Lean

Normal tension 100-150 Hypotension < 100

30-39

20-29

13.3 +- 3.08 13.623.12 13.4+3.30 12.622.91 12.122.91 11.552.87 12.9k3.39 11.5Z3.10 10.7-2.71

16.2? 5.405 13.653.29s 11.7-r-1.805 12.852.82 12.Ok2.84 11.7k2.34 11.4-t-2.14$ 10.4 _c 2.606

*Data from all males excluding known glaucoma tSystolic blood pressure #Based on obesity index: weight/(height-weight) Obese Z 120, Moderate lOO- 120, Lean < 100 §Number of eyes 520

eyes. x

90(%#)

4049 13.3c3.04 12.9+-2.98 12.5k3.28 12.3k2.98 11.8-+2.93 11.3 r 2.90 11.6t3.00 11.2r3.00 10.4 r 3.00

426

34 (6) May-June 1990

Surv Ophthalmol

SHIOSE

SBP

SBP -9

U.S.A.’

m9

(blacks1

U.S.A.. 190

-

Iblacks)

'190 -

Fmles 180

.

170

-

160

-

150

-

140

.

130

-

120

.

110

.

100

-

180 -

2

Japan5

South

( ! Kunq

Africd sushnen)

100

,

I

20-

IO-

Figs. 4A and 4B.

40-

50-

60-

TO-

Systolic blood pressure

Age

20-

w.

by age in different

males and females is more than double that in Japan. Up to age 4049, the prevalence is higher in males, but after age 40, in both the U.S.A. and Japan there is a sharp rise in the occurrence of systolic hypertension in women.‘5’ When systolic BP was compared between whites and blacks residing in the U.S.A., the prevalence of hypertension was higher in blacks of all ages,80 and the rise in systolic BP after 40 was greater in females than males. This was shown in a study called Community Hypertension Evaluation Clinic Program conducted in a million subjects.16’ Thus, although there are some racial differences in systolic BP, it rises with age. It is extremely interesting that while the above phenomenon has been known in the advanced countries, there are many underdeveloped societies where systolic pressure remains unchanged’zg~‘45 or decreases60B”4*‘45 with age. In six Solomon Islands, systolic BP rises with age in women but remains unchanged in men,lzg and in Yanomano Indians residing subequatorially, systolic BP shows virtually no change with age.lz8 Among !Kung Bushmen of northern Botswana, systolic BP decreases with age in males, but in females there is a slight rise after menopause.‘6R Severs et alt4” divided the Xhosa people of South Africa into urban and tribal groups and compared their systolic BP, etc. Although the two groups were of the same race, the urban group exhibited high systolic BP which increased with age, while in the tribal group the systolic BP was low and showed virtually no rise with age. Since the level of plasma adrenalin and renin were almost identical in both groups, the authors

AV 30-

40-

50-

60-

TO-

YS-

races (males and females, respectively).

concluded that these latter items are genetically determined, but the difference in blood pressure was created by diet and tendency to obesity which accompany urbanization (Westernization).‘45 The statistics on systolic BP, something which shows marked racial variation, have been arranged according to age and sex in Figs. 4A and 4B. B. OBESITY Obesity, along with hypertension, is called a major health hazard in adults. The obese hypertensive subject has an extremely high risk of coronary heart disease and the mortality rate is high.36 It has been reported that among those over 30 years of age in the U.S.A., those who exceed by 20% or more the “desirable weight” (as defined by Metropolitan Life Insurance Company) constitute 30% of males and 40% of females.36~“0 These are more than double the frequencies in Japan.‘lg Even taking into consideration differences in standards of obesity, the frequency of obesity seems to be far higher in Europeans and Americans than in Japanese. The increase in obese individuals after the age of 40, especially among women, is seen in Japanese as well as Westerners.“““’ Members of underdeveloped societies are short and thin, but even within a given racial group, the urban population tends to be significantly more obese than the tribal group based on skin-fold thickness or Ponderal index.‘45 There is a high correlation between obesity and blood pressure. This is explained as follows: to deliver blood to the expanded vascular bed in an obese body, cardiac output is increased along with

INTRAOCULAR

PRESSURE:

427

NEW PERSPECTIVES * Value-increasing

IOP

effect

Increase in systolic hypertension, obesity and other cardiac risk factors -

Males

--

Females

** Value-decreasing

effect

Aging

I 20 Fig. 5. Hypothetical results

obtained

from

schema showing the Japanese.

I

I

I

I

I

30

40

50

60

70

major

systemic

determinants

blood volume and red cell massJ6 It is also reported that corticosteroid secretion is increased in the obese individual’4” and this possibly leads to increased cardiac output.“”

VI. Aging and Intraocular

Pressure

Among the many systemic factors, age cannot be discussed in the same dimension as other variables. This is because all biological phenomena show agedependent changes. While there are individual variations, the phenomenon of aging becomes definitely apparent in those over about 40, accompanied by increase in the incidence of various adult diseases. l’he change in IOP seen in the statistics according to age in cross-sectional studies may represent that the effect of simple aging has been overshadowed by the counter-effect of increased blood pressure, obesity, and other cardiac risk factors as shown in Fig. 5. As demonstrated by multiple regression analysis of data in the Japanese, IOP may be explained as a phenomenon resulting from the mutually neutralizing effects of physiological ocular hypotensive effect of aging and the increase in cardiac risk factors, including hypertension, obesity etc. (Fig. 5). Thus, among Europeans and Americans, the ocular hypertensive effect of hypertension and obesity overwhelms the hypotensive effect of aging, and IOP therefore increases with age. However, among the Japanese the hypotensive effect of aging has the dominant effect and lowering of IOP is the net result. High IOP in women can be explained by the high prevalence of obesity and hypertension an,ong elderly fema,es.i1”.““.‘“1.‘“i,‘71

AgeCyr.

ofintraocular

1

pressure

in normal

subjects

based on

The trend toward lower IOP in Europeans and Americans over 70 years of age, especially males, observed in a cross-sectional population may be the result of disappearance of obese hypertensive subjects through death, mainly by cardiovascular accidents, leaving only healthy individuals. It is interesting that in the presence of a comparatively higher level of obesity and hypertension, women have a longer life expectancy than men,“” so that the peak age for ocular hypertension may be at a higher age than in men. True change of IOP with age, however, cannot be determined only by cross-sectional statistics, but must be found in a longitudinal study which follows single individuals. Perkins’“’ measured IOP in 190 individuals who showed IOP of 2 1 mm Hg or higher in the Bedford Glaucoma Survey. In I32 persons in whom follow-up was possible for two years or more, 77% exhibited lowered IOP, while 23% maintained pressure at 2 1 mm Hg or above. Sjorensen et al I59 followed 55 cases with IOP of 20 mm Hg or higher for 15 years without treatment, and reported that in 20 cases (about 50%) the IOP fell below 20 mm Hg, while in 19 cases the IOP remained unchanged. LinnCrll”~” followed 92 ocular hypertensive and 45 1 normotensive subjects who were initially examined by Stromberg at Skovde,‘“’ Sweden, for 10 years without treatment. He noted overall reduction of IOP with age in both groups; the former showed a drop of 2 mm Hg from an initial reading of 25.3 mm Hg, and the latter showed a decrease of 1.5 mm Hg from 16.0 mm Hg.“” Schwartz et al’“’ followed 60 untreated cases of ocular hypertension

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for a median of 42 months, and found that while 67% showed no change, 20% exhibited lowered IOP, with only 13% showing an increase. The median value of IOP fell 1.2 mm Hg as a whole.‘4’ He also studied 43 normal patients for a median followup time of 38 months for comparison, and found that almost all patients revealed a stable trend of IOP over time.14’ The question arises whether the changes in IOP with time could be due to a statistical phenomenon of regression toward the mean, since this occurs usually when repeated measurements are made on biological variables. This phenomenon is observed in such a way that high initial measurement tends to become lower and the low initial measurement tends to become higher. Along with the line, it is unlikely that the regression toward the mean could account for the observations made in these studies, since the majority of both ocular hypertensives and normotensives revealed the same trends in 10P.““*‘4’ When the results of these longitudinal studies in Europe and the U.S.A. are reviewed, it is seen that among Westerners, too, IOP remains virtually unchanged or undergoes a decrease. The increase in IOP with age observed in cross-sectional studies may be due to the likelihood that, even though individually there is not much change in IOP, collectively there is an increase in the occurrence of obesity and hypertension in the high age groups, and this increase has a marked effect on the average value, The increase in the magnitude of standard deviation with age and the skewness of distribution toward the high side may also be attributed to the above effect.

Possible Mechanisms for the VII. Maintenance of Intraocular Pressure A. AGING CHANGE IN AQUEOUS DYNAMICS The tendency for IOP to drop with age may be mostly due to decrease in the production of aqueous humor. In studies using tonometry and tonography, Becker” showed that production of aqueous humor was relatively stable up to about age 60, but decreased thereafter. Kupferg4 compared young and old subjects and found that production of aqueous humor was significantly less in the older individuals. This observation has been reported in studies using fluorophotometry.28’3z Brubaker et a1,32 however, found that compared with the decrease in the volume of the anterior chamber with age, the decrease in the production of aqueous humor was not significant. Histologically the role of atrophy and hyalinization of ciliary process has been presented.” Gartner5’ conducted electron microscopic studies and noted vacuolization of the nonpigment-

SHIOSE ed layer of ciliary epithelium and precipitation of homogeneous material in the perivascular space around the ciliary capillaries in the aged. Since production of aqueous humor occurs through pressure-dependent inflow (ultrafiltration) and pressure-independent inflow (active secretion), inflow through both these mechanisms appear to be diminished in the elderly.‘“4 Decrease in outflow facility in the elderly is also frequently reported.““” Those who do not exhibit a rise in IOP in spite of this may be cases in whom decrease in the volume of the anterior chamber and the compensatory decrease in aqueous humor production occur.32 B. BLOOD PRESSURE The relation of systolic BP to IOP has been demonstrated in a large number of subjects.‘5’,‘54 It is a relationship which has been noted not only in Japanese, but in whites and blacks, males and females, who reside in U.S.A. The direct effect of systolic BP rather than diastolic BP has been attributed to increased ultrafiltration caused by systolic pressure peak reaching the eye.33~g’~‘54 As many clinical studies have shown, the majority of ocular hypertension may be regarded as a physiological equilibrium state in response to high blood pressure. It should be emphasized, however, that this relationship does not exist in pathologic conditions,‘05 such as glaucoma and/or malignant hypertension. When the IOP/systolic BP ratio percent in an apparently normal population is studied according to age and a given level of obesity, the ratio is approximately 13% in their 30’s, but this ratio decreases linearly with age and becomes about 9% in the 70’s in both sexes.‘54 This may reflect the fact that in hypertension in the elderly, the main factor is increase in peripheral resistance because of arteriosclerosis, while in the young it is due to increased cardiac output; thus, the effect of systolic BP on IOP becomes relatively less in elderly than younger individuals. Experimentally, however, the direct causal relationship between arterial blood pressure and IOP is negative. Bi11z6used the velvet monkey and induced stepwise hypotension by bleeding. It was found that when blood pressure was reduced from 119 mm Hg to 79-90 mm Hg, there was no change in the amount of aqueous humor formation or IOP, but further hypotension resulted in abrupt reduction in aqueous humor formation. Bill”j suggested that in the normal IOP range aqueous humor production is controlled by IOP receptors. In earlier studies, Graeves and Perkin?’ found in the asphyxiated rabbit that IOP and blood pressure rose in perfect synchrony. The explanation was that abrupt hyper-

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NEW PERSPECTIVES TABLE 7

Prevalences of Ocular Hypertension, Primmy Open Angle Glaucoma clnd Low Tension Glaucoma in Representative Population-based Studies in Western Countries

No of examinees Age range (year) High IOP range (mmHg) Prevalence A. High IOP (%) B. High IOP with field defect (%) C. Normal IOP with field defect (%) Prevalence ratio BIA (%) C/B+ C (%)

Framingham””

Dalby”

Skovde’“” (Sweden)

Ferndale’”

(U.K.)

(U.S.A.)

(Sweden)

7,275 >4O >21

4,231 40-74 >20

5,223* 52-85 >21

1,511 55-70 > 20.5

325(4.5) 26(0.36)

397(9.4) 13(0.31)

396(7.6)* 19(0.36)*

1lO(7.3) .5(0.33)

4(0.05)

7(0.17)

2 1(0.40)*

S(O.52)

8.0 13.3

3.3 35.0

4.8 52.5

4.5 61.5

Ocular hypertension: (A-B). POAG (high-tension): B. Low-tension glaucoma: C. *Number of eyes.

tension causes dilatation of ocular blood vessels and consequent increase in the volume of choroidal vascular bed. When hypertension was sustained, however, IOP gradually returned to the original level. It was therefore concluded that the relationship was a transitory one.48 However, animal experiments have made it possible to observe only the acute phase of reactions generated by unphysiologic, invasive procedures.26,6H What we really need to observe is not a pathologic condition, but the events routinely occurring in apparently healthy subjects. Regarding the relation of systemic hypertension and ocular hypertension, another possibility is control by the central nervous system. In systemic hypertension, the sympathetic nervous system, the renin-angiotensin-aldosterone system, and vasopressin are involved.’ Their mutual interaction maintains homeostasis of blood pressure.’ It has recently become evident that these systems act not only peripherally, but also through central nervous receptors, to maintain normal blood pressure.g3,‘“” In the area of ophthalmology, Duke-Elder4’ and Schmerl and Steinberg”’ suggested that the center of IOP regulation is in the diencephalon. Von Sallmann and Lowenstein’38 and Gloster and Graeves”““’ conducted experiments in which a stereotactic apparatus was used to stimulate various parts of diencephalon, and found many locations that may affect both blood pressure and IOP. In view of the fact that systemic blood pressure and IOP exhibit closely similar patterns of diurnal and seasonal variations,‘59 it is possible that some humoral regulatory mechanisms through a common pathway may exist.

C. OBESITY Regarding the role of obesity, local and systemic effects are also considered. Locally, orbital pressure may increase because of excess fat tissue, with rise in episcleral venous pressure and consequent decrease in outflow facility.39,‘94 With obesity there may be an increase in viscosity of blood through increased red cell mass, hemoglobin, and hematocrit, with consequent increase in outflow resistance of episcleral veins.33g’54 Systemically, obesity is associated with various adult diseases, with close relation not only to cardiovascular diseases, but also hyperlipemia and diabetes.“6 Virtually all cardiac risk factors have strong positive correlation with age. y’.‘5’ The fact that early entry of obesity in the multiple regression equation of a stepwise model may suggest that most other cardiac risk factors are submerged in the obesity.

VIII. Intraocular Pressure and Primary Open Angle Glaucoma (POAG) POAG is the most common type of glaucoma in the adult population, but its natural history and pathogenesis are by far the least understood. Based on clinical observations, there is good agreement that unusually high IOP causes progressive glaucomatous optic nerve damage and that intervention can modulate the rate at which this damage proceeds. This knowledge has led to the notion that the level of IOP and glaucomatous visual dysfunction is linked in what is generally assumed to be a cause and effect relationship. Glaucoma Armaly et al, I4 in the Collaborative

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Study, followed 5886 eyes for an average of 13 years and showed that the development of field defects was associated with the initial value of IOP and was six times higher in eyes with pressure exceeding 23 mm Hg than in eyes with IOPs ranging from 16-l 9 mm Hg (8.4 vs. 1.4%). David et a14” followed 61 ocular hypertensives for a mean of 43 months and found that there was a positive relationship of IOP and visual field defect. The result obtained in this study permitted rough estimation of the relative risk of subsequent glaucomatous damage among subjects whose baseline pressures were 21-25, 26-30 and over 30 mm Hg. Reinterpretation of the result revealed that the subjects with IOP of 26-30 mm Hg and over 30 mm Hg had a relative risk of 4.4 and 15.3 times higher than the IOP of of visual field 2 l-25 mm Hg. 15’Thus, the incidence defects becomes proportionally higher with IOP, but the overall incidence of glaucoma among ocular hypertensives followed for years are extremely low (0.5-I .O% per annum), 12,43.67,89,110,127,191 and the VaSt majority of ocular hypertensives were regarded as showing no pathologic changes. Table 7 shows the results from four representative epidemiological studies on Western adult populations. Since some methodological differences exist among studies, especially in terms of case-linding method and diagnostic criteria, the data defy simple comparison, but certain consistent features should be pointed out. There are considerably high prevalences of ocular hypertensives in the populations (approximately 4-9%), but proportions of subjects with visual field loss (POAG) are only 3.3-&O% among those who have high ocular tensions (Table 7). On the other hand, the proportions of low tension glaucoma among those who have glaucomatous visual field loss at the time of screening are shown to be 13.3-6 1.5% of the same populations. Differences in figures of low tension glaucoma between these studies are obviously due to the method employed for the first stage of screening; the latter three studies25*75*g6used ophthalmoscopy and/or visual field test in addition to tonometry, whereas the earliest study”j4 used only tonometry. Taking this into consideration, current thought is that the prevalence of low tension glaucoma would be ?&s of the total population of POAG in the West. Although the risk of optic nerve damage is directly related to the magnitude of IOP, the above lindings suggest that there is no fixed level to separate normal from abnormal range of pressure, since glaucomatous change may occur at any level of IOP. Many epidemiologic studies have shown an increase in prevalence of ocular hypertension with

SHIOSE age, especially in womeng~27~40~67~7.5~‘ A 7z typical study found the prevalence to be 5% in populations in their 4Os, 10% in the 50s and 15% in the 70s.‘” Similarly, prevalence of POAG is also shown to increase with age; 0.1% at 45-54 years, 0.6-0.7% at 55-64, l.l-1.3% at 65-74, and 2.3% at 75-85 years. 75,g6In favor of the above findings, it has been postulated earlier that sustained elevation of IOP is required for the development of glaucomatous damage. This is partly true; however, the expected increase in IOP does not always occur in follow-up studies, but many cases undergo decrease’10~“2~ 13z,14’,‘5gand never develop optic nerve damage. Noteworthy are the results obtained in the Japanese population that the trends in age-specific prevalence of ocular hypertension and low tension glaucoma were quite different (Fig. 6).14’ This study was conducted on 11,660 participants in the Automated Multiphasic Health Testing Services (AMHTS), using tonometry and fundus photography as the first stage of screening. The result confirmed that, consistent with the fact that IOP decreases with age, prevalence of ocular hypertension peaked at 1.5% in the 30-39 age group, but decreased thereafter to be less than 1.0% in those above 50 (Fig. 6). Previously an age specific trend was reported by Suda et al.“’ The age-dependent increase in prevalence is noted in both POAG and low tension glaucoma, but the magnitude is greater in the latter. More recently, we have attempted to conduct the Nationwide Glaucoma Survey with collaboration of seven different districts across Japan,‘56 using the same method employed in the previous study.14’ The study is still underway, but the interim results tended to confirm the same trend as appeared in the previous study.14’ The prevalence of low tension glaucoma was, however, found to be much higher in our survey on a defined population,‘56 since the average age of participants was significantly higher than that in AMHTS.14’ Studies on the Japanese population tended to indicate that low tension glaucoma increased more sharply with age than POAG did. It should be remembered that using a given cut-off (21 mm Hg) to delineate POAG and low tension glaucoma is artificial and causes an extensive overlap of those populations, since differences in normal IOP stratified by systemic factors became more manifest with age over 40 years (Fig. 3). Despite this limitation, careful interpretation of the data highlighted the following: 1) The decreasing trend in prevalence of ocular hypertension with age strongly suggests that some factors other than IOP are contributing to the development of glaucomatous nerve damage. 2) A sharp increase in prevalence of low tension glaucoma with age may indicate that pathogenical-

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Low tension glaucoma

1.5

1.0

0.5

.

50-

io-

70:

year Age

Fig. h. Age specific prevalenccs of ocular hypertension, primary open angle glaucoma, and low tension glaucoma among those who underwent automated multiphasic health tests in Japan (Shiose’4” adapted from Jprr ,I Ophthnlmol 1981). The prevalence of ocular hypertension decreases, while low tension glaucoma sharply increases, with age. Screened population = 11,660 subjects.

ly, typical low tension glaucoma is more closely associated with senile change or adult diseases at the optic nerve head than is high tension glaucoma. Some other studies of racial difference in prevalence of POAG show that the prevalence is higherh(L7:iI IX.I iP and severity is greater”“~44~“x among blacks than whites. Prevalence of this condition in Polynesians and Melanesians is reported to be lower than in whites.7c’,“’ This finding may be associated with the report that systemic adult diseases, including hypertension, are extremely low among these peoples.‘” Recently Arkell et al” conducted an epidemiological survey on glaucoma in 1686 Alaskan Eskimos of over 15 years of age. It was found that the average applanation tonometry figures were 13.6 -+ 3.0 in males and 13.8 t 2.9 mm Hg in females, which are extremely low compared with results of other surveys. With 2 1 mm Hg as the cutofl’point, the prevalence ofocular hypertension was 4 (0.2%) and that of POAG was only 1 (0.06%). There were no data available on IOP change with age. :Uthough it is not adequate to compare the data obtained by different methods, these findings positively indicated that results of epidemiologic study must be evaluated with full consideration being given to the systemic background peculiar to different races.

IX. Concluding

Remarks

In this review, the relation of systemic factors to IOP was reexamined from an epidemiologic standpoint, with inclusion of recently acquired results on the ,Japanese population. Numerous studies have

consistently indicated an especially strong association between systolic BP and IOP. The relationship of systemic blood pressure to IOP has traditionally been focused on local perfusion pressure at the optic nerve head.“~“~“‘” There have been clinical reports of exacerbation of visual impairment when antihypertensive therapy induced abrupt hypotension in hypertensive glaucoma cases.” Also, low blood pressure is more common in cases of low tension glaucoma than in (%,