Unfortunately, the skewed distribution also means that an abnormal IOP must be defined empirically – that is, an abnormal pressure is one that causes optic nerve damage in a particular eye. Because eyes differ markedly in their susceptibility to the effects of pressure, it is difficult to know a priori what level of IOP will be harmful to a given patient. Some individuals develop glaucomatous damage at IOPs near the population mean, whereas others maintain normal optic nerves and visual function for many years despite IOPs of 30 or even 40 mmHg.

Similar mean IOPs are found using applanation and Schiøtz tonometry (see Table 4-1). Given the theoretic and practical shortcomings of Schiøtz tonometry, this suggests some combination of compensating errors for the indentation technique.

As a general rule, IOPs are similar in the right and left eyes of normal individuals. Although differences of 4 mmHg or more

between the eyes are seen in less than 4% of normal individuals,189,190 such differences are common in patients with glaucoma.

Davanger189 reported that 10% of patients with glaucoma had pressure differences greater than 6 mmHg. Lee and co-workers found in a population cross-sectional study that IOP asymmetry between the two eyes of the same older patient was often associated with undiagnosed glaucoma, whether the IOP was more than or less than 21 mmHg.191

Elevated IOP or the presence of glaucoma are associated with a decreased life expectancy according to the Framingham Eye Study.192 This association still persists even after the data are corrected for the usual factors associated with decreased life expectancy, such as age, gender, body mass, smoking, diabetes, and hypertension.

Factors that influence intraocular pressure

Many different factors affect IOP (Table 4-3). A few of the more important factors are discussed here.

Age

Most studies find a positive correlation between IOP and age.181,193–195 The effect of increasing age on IOP is the result, at

least in part, of increased blood pressure, increased pulse rate, and obesity.196,197 The Barbados Eye Study showed that the highest

correlations with IOP were age, systemic hypertension, and history of diabetes but female gender, larger body mass index, darker complexion, and positive family history of glaucoma.198 Except for age and positive family history, these correlations did not hold for actual glaucoma. It is unclear whether the rise in IOP with age represents an increase for all individuals or a greater skewness of the data – that is, a greater minority of the people having higher pressure while the majority show no change. One careful study of aqueous dynamics in normal subjects covering two different age groups showed a reduction in aqueous production as well as a reduction in uveoscleral outflow with age.199 It should be pointed

out that a number of studies find little correlation between IOP and age.197,200 In addition, one investigative team found that IOP declined with age in a group of Japanese workers.201,202 This trend

of decreasing IOP with age in normal Japanese eyes was confirmed

in a 10-year longitudinal study.203 In a study of Koreans, IOP also declined with age but increased with body mass index.204 In one important and interesting study that included both longitudinal follow-up as well as cross-sectional data in 70 000 Japanese subjects, IOP declined with age when looking at the cross-sectional data but actually increased with age in the longitudinal data.205 This suggests that some differences in IOP exist between different age groups that can not be explained by chronologic aging.

Sex

It has been reported that women have higher IOPs than men, especially after age 40.181 However, this finding was not confirmed in another study.206 The Barbados Eye Study showed that women were more likely to have high IOP without glaucoma damage and men were more likely to have open-angle glaucoma.207

Race

In the United States, blacks have higher IOPs than whites.194,208,209 In part, this difference appears to be racial or genetic. There is one report that the Zuni Indians of New Mexico have relatively low IOPs.210 It is unclear whether this phenomenon is caused by genetic or environmental factors. Because the definitions of, and differences between, various racial and ethnic groups are increasingly indistinct, it is difficult to predict the ultimate clinical utility of these observations.

Heredity

There appears to be a hereditary influence on IOP,181,211,212 which is polygenic in nature.210,213 A number of studies have indicated

that first-degree relatives of patients with open-angle glaucoma have higher IOPs than the general population.181,214 In contrast,

one study found that spouses have similar levels of IOP, which suggests that there are important environmental influences as well.215

Diurnal variation

Over the course of the day, IOP varies an average of 3–6 mmHg in normal individuals.216–223 Patients with glaucoma have much wider

swings of IOP that can reach 30 mmHg or even 50 mmHg in rare cases.216,218,221,224 In many people the diurnal variation of IOP fol-

lows a reproducible pattern, with the maximum pressure in the midmorning hours and the minimum pressure late at night or early in

the morning. However, some individuals peak in the afternoon or evening, and others follow no consistent pattern.221,224–228 In general,

normal, open-angle glaucoma and normal-pressure glaucoma patients have their peak in the morning with the nadir in the afternoon.229 One study suggests that any male with a borderline IOP measured midday should have a repeat measurement early in the morning, as males, in particular, may have wider diurnal swings.230 In general, the

two eyes show similar diurnal curves but there is a significant difference in how the right and left eye vary in their IOP.231

Many patients have a nocturnal surge in IOP.This increase in IOP is only partly explained by postural changes.232,233 Furthermore, this

same group showed that the pressure elevation is most likely towards the end of the dark cycle whenever in the real circadian cycle it occurs. However, short bursts of moderate light during the dark cycle had no effect on the nocturnal pressure elevation.234 Aging subjects also seem to have a relative elevation of IOP toward the

end of the dark cycle although most of it may be related to the supine recumbent position.235

Most of the diurnal pressure variation is caused by fluctuations in the rate of aqueous humor formation. There has been controversy about whether there are also diurnal variations in the facil-

ity of aqueous humor outflow, but recent studies indicate that this effect is small at most.224,229,236–240 The rate of aqueous formation

falls to low levels during sleep and increases during the day, most likely in response to circulating catecholamines.241,242 The decrease in aqueous flow during sleep is not as pronounced in untreated primary open-angle glaucoma patients as in normal controls, but the magnitude of the difference is so small that clinical relevance is unlikely.243 A few investigators have postulated that the diurnal IOP variation follows the diurnal glucocorticoid cycle, with IOP peaking about 3–4 hours after plasma cortisol.244

The diurnal variation in IOP has extremely important clinical implications for glaucoma patients. Asrani et al have shown that large diurnal variation in IOP is a risk factor for progression of glaucoma.245 Others have shown that the diurnal IOP curve is altered in glaucoma patients compared to normal subjects.246

The fact that the pressure can vary dramatically during a given day makes it unreasonable to assume that a single pressure taken at a specific time is representative of the average pressure the patient experiences over time. It is quite possible that this single pressure

represents a high or low point, and that the patient’s average pressures are substantially different.223,247 This is of particular concern

in patients with normal-tension glaucoma, in whom it may be

important to know whether the pressures are always in the low/ normal range, or if they sail into the 20 s every evening.248,249 A full

24-hour diurnal curve measurement is often prohibitively difficult to arrange in today’s climate of cost containment.A modified diurnal curve is much more practical, while still providing useful information. It is often fairly easy to measure an ‘office diurnal curve,’ which generally means checking the pressure every 1 or 2 hours from about 8 a.m. to 6 p.m. Pressure swings of 6 or 8 mmHg are not uncommon.222 Knowing the patient’s daily pressure excursions allows the physician to tailor therapy toward blunting peaks in pressure, as well as controlling the average pressure during a certain time of day.250 Jonas and co-workers estimated that a single a.m. in-office IOP measurement has about a 75% chance of missing the diurnal IOP maximum, and they recommend that the patient’s fol- low-up visits can be scheduled at differing times of the day to try and capture the maximum.251 This group has also suggested that it is the level of IOP itself, not the magnitude of fluctuations, that actually is responsible for continued optic nerve damage.252

Home tonometry has been suggested as a method of following patients’ pressures away from the office. It is unclear whether this method is practical in large populations, although it has been a successful adjunct in certain circumstances.253

Seasonal variation

A seasonal variation of IOP has been reported, with higher IOPs in the winter months.196,228,254–256 This phenomenon has been attrib-

uted to changes in the number of hours of light and to alterations of atmospheric pressure.255

Cardiovascular factors

A number of studies have shown a correlation between IOP and systemic blood pressure.194,196,197,206,214,257,258 The relationship is

such that large changes in blood pressure are accompanied by small changes in IOP. For example, Bulpitt and co-workers have estimated that systemic blood pressure must rise by 100 mmHg to increase IOP by 2 mmHg.206 Normally, IOP fluctuates 1–3 mmHg as arte-

rial pressure varies with each cardiac cycle.259 The magnitude of this IOP fluctuation is related to the height of the ocular pressure259,260

and to the variation of arterial pressure. Systemic hypertension and glaucoma show only a modest association, and the bulk of the effect is attributable to perfusion pressure or other vascular effects, rather than increased IOP.261 Slower changes in IOP are seen with the Traube-Hering waves. A few researchers believe that IOP also correlates with pulse rate and hemoglobin concentration.197

Elevations of episcleral venous pressure, whether from local or systemic conditions, are associated with increased IOP. The rise in IOP is usually in the same range as the rise in episcleral venous pressure.

Alterations in serum osmolality produce changes in IOP. This is

best exemplified by the marked changes in IOP that occur during hemodialysis.262–264 Hyperosmotic drugs such as glycerine, urea,

and mannitol are administered systemically to reduce IOP during acute episodes of glaucoma.

Exercise

Strenuous exercise produces a transient reduction of IOP.265–270

This phenomenon is at least in part caused by acidosis and alterations in serum osmolality.266,270 In one study, a program of condi-

tioning reduced baseline IOP in normal volunteers.271 In general, those who are more physically fit are more likely to have a lower resting IOP.272 However, in extremely heavy exercise involving straining, such as weight lifting, IOP can be elevated significantly, perhaps due to valsalva or even increased intracranial pressure that is transmitted to the periocular venous system.273 In addition, holding one’s breath during weight lifting further increases the IOP.274

Wind instrument playing

Playing a wind instrument can raise the IOP, even in ophthalmologically normal individuals.275 The rise in IOP is higher with high-resistance instruments.276 Those musicians with large numbers of playing hours on high-resistance wind instruments are more likely to have optic nerve damage or visual field loss than their low-resistance colleagues.276

Lifestyle

Increased IOP was associated with increasing body mass index, increasing alcohol consumption and increasing cigarette consumption in one Japanese study.277 The Blue Mountain Eye Study also showed a modest correlation between smoking and IOP.278 Another result of the Blue Mountain Eye Study is that there is a positive correlation between caffeine consumption and level of IOP.279 In the Barbados Eye Study, systemic hypertension and diabetes were associated with increasing IOP with age.280 The Tanjong Eye Study suggested that lower socioeconomic status is associated with increasing IOP.281

Postural changes

When normal individuals go from the sitting to the supine position, IOP rises by as much as 6 mmHg.282–289 An even greater response

is seen in patients with open-angle glaucoma or normal-tension glaucoma.282,285–287,290,291 When normal volunteers are placed in

an inverted position, IOP increases markedly – that is, from an average of 16.8 mmHg to 32.9 mmHg in one study.292 Once again, the rise is greater in glaucomatous eyes.293 The increase in IOP occurs very rapidly and probably reflects changes in arterial and venous pressure.283 The episcleral venous pressure does increase in the supine position, at least partly accounting for the increase in IOP when lying down.294 However, postural changes in venous pressure cannot explain all of the IOP change since there is a difference between supine and prone IOPs.295 Brief elevations of IOP are unlikely to be dangerous in normal individuals, but they may be harmful in patients with advanced glaucoma.289

Postural changes in IOP become a problem when one depends on an examination under anesthesia to determine IOP in children or those developmentally challenged. The anesthesia reduces IOP (see below) but the act of placing the patient supine increases the IOP. Furthermore, positioning on the table, straight,Trendelenburg or reverse Trendelenburg will affect the IOP – with Trendelenburg causing an increase in IOP and the reverse Trendelenburg a decrease. All these factors have to be melded into interpreting the measurement.

Neural factors

A number of investigators have postulated that IOP is under neural control. As of yet there is no proof for this hypothesis, although some interesting observations have been made. Sympathectomy

produces a transient reduction in IOP and an increase in outflow facility from a release of catecholamines.296,297 In a similar fashion,

adrenergic agonists and cyclic adenosine monophosphate are capable of reducing IOP. 298–300

Other investigators have explored neural control of IOP by the parasympathetic system. Stimulation of the third cranial nerve reduces IOP.301 Cholinergic drugs lower IOP by increasing outflow facility. Conversely, ganglionic blocking drugs increase IOP.302 Finally, other investigators have sought central nervous system centers that might control IOP. Some researchers have found that

stimulation of specific diencephalic areas in experimental animals alters IOP, whereas other researchers303,304 believed these effects

were non-specific in nature. The third ventricle is close to the hypothalamus and other diencephalic centers. Infusion of a number of substances – including calcium, prostaglandins, arachidonic acid,

cyclic nucleotides, hyperosmotic solutions, and hypo-osmotic solutions – alters IOP.305–307

Changes in IOP seem to mirror changes in intracranial and cerebrospinal fluid pressure and some have suggested that IOP could be used as a marker for increased or decreased intracranial pressure in patients with known intracranial pathology.308

Psychiatric disorders

Ocular self-mutilation is a rare finding in psychotic and other severely disturbed patients.309–313 The authors have seen one

young man who pressed and rubbed his fists against his eyes continually unless he was heavily medicated or physically restrained. At the time of our examination his vision was 20/200 in his better eye, with no light perception in the worse eye. Both eyes showed extensive cupping typical of glaucomatous damage, although his pressures were entirely normal and he exhibited no other risk factors for glaucoma.

Hormonal factors

As mentioned previously, the diurnal intraocular fluctuation may follow the glucocorticoid cycle.244 Administration of corticosteroids topically, periocularly, and systemically raises IOP.

Some researchers have questioned whether sex hormones have

an influence on IOP. It has been noted that IOP varies with the menstrual cycle314–316 and is low in the third trimester of pregnancy.314,316,317 However, other studies have not found good cor-

relations between IOP and serum levels of progesterone and estrogen.318,319 Pharmacologic doses of progesterones and estrogens reduced IOP in experimental animals and man.316 Hormone replacement therapy in women has no effect on IOP;320 however, esterified estrogens with methyltestosterone therapy does raise IOP.321

Diabetic individuals have higher IOPs than the general population.The reason for this association is unclear.A careful populationbased study found that diabetic patients did not have an increased prevalence of glaucoma when selection bias was ruled out.322

Other hormones, including growth hormone, thyroxine (levothyroxine), aldosterone, vasopressin, and melanocyte-stimulating hormone, may influence IOP physiologically or when administered in pharmacologic doses.323

Refractive error

A number of studies have reported higher IOPs in myopic individuals.214,324,325 Intraocular pressure also correlates with axial

length.326 This has been reported in several studies involving pedi-

atric patients, with some investigators suggesting that the increased pressure leads to the increase in axial length.327–329 However, not

all studies in children are able to confirm this association.330

Foods and drugs

A variety of foods and drugs can alter IOP transiently (Table 4 4). Topical cycloplegic agents as well as systemic agents that have cholinergic effects can raise the IOP.339 Occasionally, longer acting cycloplegics like cyclopentolate can cause prolonged and serious

pressure rises in glaucoma patients; such significant pressure rises

are quite rare in eyes free from glaucoma.340 Anesthetic and sedative agents will lower IOP.341,342 The effect of general anesthesia is com-

pounded by the fact that IOP is elevated during the excitatory phase and becomes progressively lower as the anesthesia lasts longer and phases of anesthesia become deeper. Therefore, timing of measurement following induction of general anesthesia is important. If one measures too early, you may be in the excitatory phase and erroneously read a pressure that is higher than resting pressure. If one measures later, the IOP may be lower than resting IOP due to the effects of deeper anesthesia plane or longer duration of anesthesia.

Miscellaneous

Significant spontaneous asymmetric fluctuations do occur among both normal subjects and glaucoma patients; such fluctuations may cause trouble in interpreting one-eyed studies as well as interpreting therapeutic interventions.343 Forced eyelid closure can cause a significant increase in IOP and attempted squeezing of the eyelids

during tonometry can be a significant source of error with either the Goldmann tonometer or the Tono-Pen.344,345 Just the place-

ment of an eyelid speculum, even in a child fully induced with general anesthesia, can raise the IOP by about 4 mmHg.346 A tight

necktie can significantly raise IOP in glaucoma patients and possibly in normal subjects;347,348 this can have some important impli-

cations for glaucoma management, although prolonged use of a tight necktie may produce adaptive reflexes that return the eye to its pre-tight necktie level.349 Nevertheless, it seems reasonable to caution glaucoma patients not to wear tight neckties.

The Blue Mountain Eye Study showed a small but significant correlation between increasing iris pigmentation and IOP level.350 Intraocular pressure is reduced at extremely high altitudes and returns to resting levels upon descent.351

Eye movements

If the eye moves against mechanical resistance, IOP can rise substantially.352–355

Table 4-4  Food and drugs influencing intraocular pressure

Eyelid closure

Forcible eyelid closure raises IOP by 10–90 mmHg.356 Repeated eyelid squeezing reduces IOP.357 Widening of the lid fissure

increases IOP by approximately 2 mmHg.358 Conversely, with Bell’s palsy, IOP is slightly reduced.359,360

Inflammation

Intraocular pressure is usually reduced when the eye is inflamed because aqueous humor formation is reduced. However, if the outflow channels are more affected than the ciliary body, IOP can be elevated.

Surgery

In most cases, IOP is reduced after ocular surgery. However, if the outflow channels are affected by inflammation or by the surgery itself (e.g., by viscoelastic substances or by an incision that reduces support for the trabecular meshwork), IOP can be elevated.361 Trabeculectomy seems more effective at controlling IOP over the 24-hour period than maximal medical therapy.362