The average IOP is thought to be about 15 mmHg.^2,5 Under normal conditions, IOP is distributed evenly throughout the eye; therefore, the perfusion pressure of the retina, choroid, and ciliary body must be greater than IOP before blood can flow through these structures. The intraocular tissue pressure of about 15 mmHg is higher than elsewhere in the body, where the average is about 5 mmHg.⁶

The distensible uveal tissue absorbs about 2 mmHg of the IOP. The potential space between the uvea and sclera, the suprachoroidal space, therefore has a pressure about 2 mmHg lower than the IOP.⁷ After glaucoma-filtering surgery, the IOP may become very low and the suprachoroidal space may fill with a plasma transudate (choroidal effusion) and cause detachment of the choroid and ciliary body.

The normal IOP is pulsatile, reflecting its vascular origin (Fig. 1).⁸ The pulses follow the arterial pulses, and a diagnosis of cardiac arrhythmia can actually be made from a continuous measurement of the IOP.⁹ The amplitude of the pulse is generally 2 to 3 mmHg, but may be higher if there is a large arterial pulse pressure, such as in hypertension or aortic regurgitation.⁸ Some have postulated that a low intraocular pulse amplitude is an indicator of reduced blood flow to the ciliary body.¹⁰ This can be most readily seen in carotid occlusive disease; whether a reduced IOP pulse amplitude is specific enough to truly indicate a reduced ocular blood flow remains to be demonstrated.¹¹

The IOP is a dynamic function like heart rate and blood pressure and is influenced by many factors. A single measurement of IOP does not necessarily reflect the average pressure in that hour, day, or week.

IOP in humans follows a diurnal rhythm.^4,8 Most commonly, the pressure is highest in the early morning (around 7 AM), and lowest in the evening (around 5 PM; Fig. 2), but considerable individual variation exists regarding the time of day or night when the peak and nadir occur.^12,13,14 The IOP usually varies <5 mmHg from peak to nadir, although differences as large as 15 mmHg have been found. Some people with elevated IOP are found to have large diurnal peaks and troughs¹⁵ and can show variations of as much as 8 mmHg from hour to hour.¹⁶ IOP rises in the supine position with larger increases in glaucoma patients; one study suggests that supine IOP predicts peak IOP better than any sitting measurement in the office.¹⁷ Nocturnal peaks of IOP occur more frequently with aging possibly related to the supine position.¹⁸ Irregular sleep patterns alter the usual diurnal pattern of IOP.¹⁹

The diurnal pattern of IOP has been correlated with circadian rhythms of other functions, such as blood pressure, body temperature, and adrenal corticosteroid secretion. In many subjects, the IOP rises several hours after an increase in plasma adrenal corticosteroids.^20,21 This pattern may be due to changes in both aqueous secretion and outflow resistance.^22,23

The existence of diurnal variation implies that a single random IOP measurement does not adequately represent average pressure over a 24-hour period. Peak IOP can only be obtained by around the clock measurements or with measurements taken at different times of the day. In glaucoma patients, normal IOPs recorded during office hours can give a false clinical impression of adequate pressure control.^24,25,26 Phelps et al. argued that a single office pressure measurement was likely, though not certain, to be representative of the peak diurnal pressure.²⁷ Zeimer, however, using data from Phelps et al., calculated that the 95% confidence interval for such a prediction was ± 6.6 mmHg, an uncertainty of more than 13 mmHg.¹⁴ Jonas et al. determined that a single in office IOP measurement had a 75% chance of missing the peak IOP.²⁸ Sequential IOP measurements in the office may be helpful in determining both the range and peaks of IOP.²⁹ A small (approximately 1.5 mmHg) seasonal variation in IOP has been described, with the highest pressures recorded in winter and the lowest in summer.^26,30

The IOP is subject to numerous short- and long-term influences (Tables 1 and 2). The IOP undergoes rhythmic oscillations other than those associated with the arterial pulse. It varies with the respiratory cycle, presumably through changes in venous pressure. Vasomotor variations are associated with waves having a periodicity of 3 to 8 per second (Traube-Hering waves). Although each of these variations produces changes of only 1 to 2 mmHg, the difference between the highest and lowest pressure over a 1-minute period can be as much as 8 mmHg.⁸

The IOP is relatively immune to physiologic changes in arterial blood pressure. Large swings in blood pressure cause the IOP to vary in the same direction, however.^31,32 Ligating one carotid artery causes a drop in IOP on that side, presumably due to a decrease in aqueous secretion, although the effect diminishes over several days.³³ External carotid compression has a similar result, and measurements of the magnitude of the pressure drop and the rate of recovery have been used to estimate carotid blood flow.³⁴ Interestingly, when one carotid artery is ligated or compressed, the IOP in the contralateral eye rises, possibly due to the increased blood flow and pressure in the contralateral carotid artery.³²

Obstruction of the venous return from the eye or head raises the venous pressure in the episcleral system and thus raises the IOP. The IOP rises about 0.8 mmHg for each 1-mmHg rise in episcleral venous pressure (EVP).³⁵ Conditions raising EVP include external pressure on the jugular vein, compression of the superior vena cava by a tumor, cavernous sinus thrombosis, arteriovenous fistula in the cavernous sinus (transmitting arterial pressure directly to the venous system), and any change in the orbital apex (e.g., neoplastic, inflammatory, dysthyroid) that compromises the venous drainage of the eye. A tight collar or necktie may also compress the jugular vein and raise the IOP.³⁶ However, this effect may be marked only in eyes with pre-existing glaucoma and may not last long.^37,38

The Valsalva maneuver, in which expiration is forced against a closed glottis producing no air flow, is a related condition that increases venous pressure and hence IOP.³⁹ Increased intrathoracic pressure collapses the superior vena cava, obstructing venous inflow from the head. Coughing and straining with defecation produce similar changes. Straining at weight lifting will raise the IOP, which is further increased by holding one’s breath at the same time.⁴⁰ Some evidence exists to implicate increased episcleral venous pressure as contributing to the pressure rise with weight lifting type exercise.⁴¹ Increased IOP has been associated with blowing a high-resistance musical wind instrument, such as a trumpet.^42,43 The Valsalva maneuver will also narrow the anterior chamber angle and thicken the ciliary body, which may precipitate angle closure in susceptible eyes.⁴⁴

Changes in position affect the IOP. There is a 2- to 4-mmHg increase in IOP when changing from the sitting or upright position to the supine position.^45,46,47 The elevation of IOP in the supine position explains some but not all of the nocturnal elevation seen in both healthy and glaucomatous eyes.^48,49 In glaucomatous eyes, the peak nocturnal IOP can be best estimated by the daytime supine IOP even though the supine position does not account for most of the nocturnal rise.⁵⁰ Light does not interfere with the nocturnal, sleep associated rise in IOP.⁵¹ Placing the head below the level of the heart in Trendelenburg position may cause a considerable temporary increase in the IOP.^52,53 Inverted posture may rapidly lead to IOPs of more than 30 mmHg.⁵⁴ These changes parallel an increase in the venous pressure in the head, but whether this is the mechanism for the increased IOP is not known. Some patients with glaucoma may have a much larger change in IOP with position than normal individuals.⁵⁵

External pressure on the eye increases the IOP, at least initially. The eye cannot expand significantly to accommodate the fluid displaced by indenting the globe and the IOP rises. The external pressure, however, accelerates the rate of aqueous outflow and the displaced volume eventually leaves the eye.¹ If the external pressure is released, the decreased intraocular volume yields an IOP that is lower than the initial IOP before applying external pressure. This sequence of events forms the basis by which repeated tonometry decreases IOP and is why some surgeons massage the eye before intraocular surgery.^56,57 Measurement of outflow facility in an eye during tonography is also based on the decrease in IOP after external pressure.

Forced eyelid closure is a form of external pressure on the eye. Blinking causes a pressure rise of 5 to 10 mmHg, and forced blinking has resulted in recorded IOPs as high as 90 mmHg.⁵⁸ “Squeezing the eyelids during either Goldmann tonometry or Tonopen readings can cause an average elevation of IOP of about 2 mmHg in normals and 4 mmHg in glaucoma eyes.^59,60 Some glaucoma eyes can have as much as an 8 mmHg rise.⁵⁴ Voluntary lid fissure widening, as is common during tonometry, is associated with an increased IOP of about 2 mmHg, whereas pressure on the eyelid caused by holding the eyelids open may result in much larger increases.⁶¹ Closed vitrectomy can subject an eye to high IOPs as well as wide fluctuations of the IOP.⁶²

Attempts to move the globe in a direction opposite to a mechanically restricted extraocular muscle raises the IOP. It is thought that this pressure rise is due to compression of the eye between the restricted muscle and the contracting muscle. This occurs, for example, when upgaze is attempted and the inferior rectus muscle is entrapped by an orbital floor fracture. With dysthyroid involvement of the inferior rectus muscle, the IOP on attempted upgaze may rise 3 to 10 mmHg.^63,64 IOP in normal individuals does not rise more than 2 mmHg with upgaze. Therefore, this phenomenon can be a helpful diagnostic sign when recognized. If unrecognized in a thyroid patient, it can cause an overestimation of resting IOP.

A similar increase in IOP is seen when the extraocular muscles co-contract, as in Duane’s syndrome, or after aberrant regeneration of a previously injured third nerve.⁴ IOP may increase after intravenous succinylcholine, a muscle-depolarizing agent commonly used by anesthesiologists to paralyze the skeletal muscles. Succinylcholine is generally thought to raise IOP by causing tonic extraocular muscle contraction; therefore, clinicians have avoided its use in patients with open eye injuries to avoid extrusion of global contents.^65,66,44,45 Kelly et al.,⁶⁷ however, have shown that succinylcholine raises IOP even when the extraocular muscles are detached from the globe. They attribute the ocular hypertensive effect of succinylcholine mainly to its cycloplegic action and to a lesser degree on its effect on EVP and choroidal blood volume. Nondepolarizing muscle relaxants, such as pancuronium or atracurium, do not raise the IOP.^68,69

Exercise can decrease the IOP, perhaps because of the acidosis produced by short-term physical exertion, although this mechanism has been disputed.^70,71 Even brief physical exertion can cause a mild lowering of IOP, possibly through sympathetic constriction of choroidal vessels and reduction in uveal volume.⁷² Continuous strenuous exercise can significantly reduce IOP, probably through increased plasma osmolarity.⁷³ Physical exertion of longer duration appears to have less effect on the IOP but exercise conditioning has been reported to lead to a small decrease in baseline IOP.⁷⁴ This effect may be more pronounced in patients with higher baseline IOPs.⁷⁵

Blunt ocular trauma usually has a biphasic effect on IOP: there is initially a transient rise, followed by a more prolonged decline until the injury resolves.¹ After trauma, inflammatory debris or swelling of the trabecular beams may obstruct aqueous outflow. Prostaglandins may also play a role. In rabbits, topical application of prostaglandin-E2 causes a rise in IOP, which is prevented by pretreatment with prostaglandin synthetase inhibitors such as aspirin and indomethacin.⁷⁶ The role of humoral factors is supported by the observation of consensual responses in the contralateral eye after ocular trauma and topical prostaglandin application.⁷⁷ The late, more prolonged decrease in IOP after trauma is probably due to the decrease in aqueous secretion usually seen in inflammatory conditions.

The level of accommodation has a small effect on the IOP. Accommodative effort decreases the IOP, whereas relaxation of accommodation returns the IOP to baseline values.^78,79 These changes parallel the larger effects of parasympathomimetic and parasympatholytic agents. Viscoelastic materials injected into the eye during surgery can also cause significant elevation of IOP.^80,81

The IOP is depressed by general anesthesia, irrespective of the type of anesthetic.^63,82 Possible mechanisms include muscle relaxation, decreased blood pressure, increased blood carbon dioxide levels, and a direct central effect of the anesthetic agent.^76,83 One important exception is ketamine, which may transiently raise IOP when given intravenously.⁶⁰ Retrobulbar anesthesia causes a considerable drop in IOP due to inhibition of the ciliary body and loss of extraocular muscle tone.¹ A large volume of anesthetic instilled into the retro- or peribulbar space may initially compress the globe and raise IOP, however. Similarly, a retrobulbar hemorrhage induced by the needle for retrobulbar anesthesia may compress the globe and raise IOP to fairly high levels.

Changes in plasma osmolality profoundly affect the IOP.⁴ Water passes freely across the blood-aqueous and blood-vitreous interfaces in either direction, but solute molecules such as ions exchange at much slower rates. If the total concentration of solute molecules in the blood exceeds the concentration in the aqueous and vitreous, water from the vitreous and probably aqueous is drawn into the plasma. This loss of water from the eye decreases the IOP. Interestingly, the empirically measured water loss is less than osmolality calculations predict, suggesting that there are limiting factors in the eye in addition to compensatory mechanisms.⁴ After several hours, the concentration of solute increases in the intraocular fluids, and the IOP returns toward baseline. It may even exceed baseline, resulting in a “rebound” phenomenon.⁸⁴

The ocular response to plasma hyperosmolality is used clinically in situations such as acute angle closure glaucoma, in which the IOP has risen to dangerous levels. Hyperosmolar agents are given to raise plasma osmolality and lower IOP. An effective hyperosmolar agent must penetrate the eye relatively slowly. If osmotic equilibrium is obtained too quickly, the IOP effect is short-lived.^5,61 Useful and relatively nontoxic agents include intravenous mannitol and oral glycerol and isosorbide. Oral ethanol can also raise plasma osmolality and reduce IOP indirectly by reducing the production of antidiuretic hormone.⁸⁵

Conversely, if the concentration of solute in the plasma is lower than that of the intraocular fluids, water enters the eye from the plasma and raises IOP.^4,86 This pressure increase may be considerable in glaucoma patients and forms the basis for the water-provocative test.⁵ In this test, a patient rapidly drinks a liter of water, lowering the plasma osmolality. Patients exhibiting an IOP increase of more than 8 mmHg were in the past thought to have glaucoma. The water provocative test, however, has a high false-positive rate and limited diagnostic value.⁵ Recent studies suggest that a positive water drinking test may identify patients whose glaucoma is at risk of progressing.⁸⁷ Nevertheless, the sensitivity of the IOP to hypo-osmolality in glaucoma patients should be considered, particularly when there are alterations in systemic fluids and electrolytes. IOP, for example, may increase significantly during hemodialysis. Whether or this effect is mediated by changes in plasma osmolality remains controversial.^88,89

A drop in body temperature causes a decrease in the IOP, probably by inhibition of aqueous secretion. A relatively large change in temperature (more than 1°) is necessary to produce significant pressure lowering, however; it is therefore unlikely that temperature plays a major role in physiologic variations of IOP.⁹⁰ A relatively rapid ascent to high altitude (>4,000 m) causes a reduction in IOP, which returns to pre-ascent levels after acclimatization has taken effect.⁹¹

Finally, blood pH affects IOP, with systemic acidosis lowering IOP. In addition to inhibiting carbonic anhydrase in the ciliary body, oral and parenteral carbonic anhydrase inhibitors lower IOP to some extent by producing a systemic metabolic acidosis.⁹²

Parasympathetic drugs, commonly known as miotics, cause constriction of the pupillary sphincter (miosis) and ciliary muscles. Contraction of the ciliary muscles, which insert on the scleral spur, causes a mechanical alteration in the trabecular meshwork, resulting in an increase in aqueous outflow facility and decrease in IOP.⁹³ The decrease in IOP is independent of miosis and seems to be greater when the baseline pressure is higher. Ciliary muscle contraction also results in a significant reduction of uveoscleral outflow.⁹⁴ In addition, miotics cause forward movement of the lens, anterior chamber shallowing, iris and ciliary body vasodilation, breakdown of the blood-aqueous barrier, and cataract formation.

The drugs in this group share the same qualitative effects; they differ mainly in their potency. Pilocarpine, the most commonly used miotic, acts directly on the ciliary muscle. Carbachol, which is more potent than pilocarpine, acts directly on the muscle and also inhibits acetylcholinesterase, the enzyme responsible for the catabolism of the neurotransmitter acetylcholine. Drugs acting as pure acetylcholinesterase inhibitors include physostigmine (eserine), echothiophate, demecarium bromide, and isoflurophate. The cholinesterase inhibitors are generally more potent than pilocarpine and carbachol.⁹⁵ In eyes with closed anterior chamber angles, miotics are ineffective in increasing outflow facility. They may even cause a paradoxical rise in IOP by decreasing uveoscleral outflow.

Parasympatholytic drugs have the opposite effect of their parasympathetic counterparts. Parasympatholytic agents inhibit ciliary muscle contraction, reduce trabecular outflow facility, and increase uveoscleral outflow. They are used to dilate the pupil for fundus examination, prevent accommodation, reduce inflammation, and prevent ciliary spasm. Drugs in this class include atropine, homatropine, scopolamine, cyclopentolate, and tropicamide. Some patients, including those with open-angle glaucoma, are more sensitive than others to the effects of parasympatholytic agents and may respond to such an agent with pressure rises that can exceed 8 mmHg.⁹⁶ These drugs are competitive inhibitors of the parasympathomimetics. If used concomitantly, these two types of drugs will usually cancel each other’s effects.⁹⁷ In eyes with narrow angles, parasympatholytic drugs may precipitate angle closure as part of their pupil dilation effect. This is an effect distinct from their brief effect on the ciliary muscle. Systemic agents with anticholinergic action, such as phenothiazines and antihistamines, can elevate IOP either by directly inhibiting aqueous outflow or by inducing angle closure.

The effects of adrenergic drugs on the IOP are complex and seemingly paradoxical. Topical adrenergic agonists such as epinephrine cause a decrease in IOP. Surprisingly, β-adrenergic blocking agents such as propranolol and timolol also reduce the IOP. Sympathomimetic pharmacology has not been fully elucidated, but the paradox may result from differing sites of action for each drug. The effect of epinephrine, an α- and β-agonist, is largely due to an increase in outflow facility, and is probably controlled by adrenergic receptors serving outflow pathways.⁹⁸ Some evidence suggests that the uveoscleral outflow pathway is primarily affected.⁹⁹ A study showed that dipivefrin, another α- and β-agonist, reduces blood flow in the ciliary body.¹⁰⁰ β-Blockers such as timolol appear to exert their hypotensive effect by reducing aqueous production, perhaps by inhibiting tonic β-adrenergic-controlled formation of aqueous; however, some evidence exists to implicate a direct action of β-blockers on ciliary epithelium.^101,102

Two kinds of α-adrenergic receptors exist: α1 and α2. Stimulation of ocular α1-receptors leads to elevation of IOP, mydriasis, eyelid retraction, and vasoconstriction. Ocular α2-receptors mediate a reduction in IOP, probably by inhibiting adenylate cyclase. This causes a decrease in cyclic adenosine monophosphate and subsequently a decrease in norepinephrine release and decrease in β2 stimulation, resulting in a reduction in aqueous production.¹⁰³ Clonidine, apraclonidine, and brimonidine are α-adrenergic agonists that lower IOP in humans.¹⁰⁴ Clonidine acts centrally on α-adrenergic receptors in the brainstem, reducing sympathetic outflow. This leads to decreased vascular resistance, hypotension, bradycardia, and sedation.¹⁰⁵ In the eye, clonidine causes decreased aqueous production and conjunctival vasoconstriction. Apraclonidine, a more polar analogue of clonidine, crosses the blood-brain barrier less readily and has fewer systemic effects than clonidine.⁹⁶ This drug decreases aqueous production, decreases EVP, and increases trabecular outflow facility.¹⁰⁶ Brimonidine is more selective for α2-receptors than apraclonidine.¹⁰⁷ Brimonidine has been shown to decrease aqueous production and increase uveoscleral outflow without affecting EVP.¹⁰⁸ Interestingly, brimonidine has been shown to have neuroprotective activity in an animal model of optic nerve injury.¹⁰⁹ Despite several studies confirming brimonidine’s neuroprotective activity in multiple in vitro and animal models, the clinical implications of this finding have remained elusive.

Carbonic anhydrase inhibitors are sulfonamide derivatives that compete for the active site of carbonic anhydrase. Inhibition of this enzyme leads to decreased bicarbonate production and sodium co-transport, thereby reducing aqueous production. Carbonic anhydrase inhibitors also induce ciliary body vasoconstriction and disrupt normal intraocular buffering systems.¹¹⁰ Orally administered agents (acetazolamide, methazolamide, ethoxzolamide, dichlorphenamide) cause a systemic acidosis, which contributes to decreased IOP. Dorzolamide, a topical carbonic anhydrase inhibitor, does not alter systemic acid-base balance and has somewhat less effect on lowering pressure compared to the systemic agents.¹¹¹ A similar effect can be seen with brinzolamide–another topical carbonic anhydrase inhibitor.¹¹² Both topical agents lower IOP by decreasing aqueous production.¹¹³

Prostaglandins are fatty acid derivatives produced throughout the body, including ocular tissue. Initial studies using rabbits showed that prostaglandins given intracamerally or topically caused conjunctival hyperemia, miosis, iris vasodilation, blood-aqueous barrier breakdown, and increased IOP.¹¹⁴ In contrast, subsequent experiments in other animals with lower dosages showed marked ocular hypotension.¹¹⁵ Prostaglandin compounds initially tested in humans showed significant external side effects. The phenyl-substituted prostaglandin-F2α analog PhXA41 (latanoprost) was found to have relatively few side effects while significantly lowering IOP.¹¹⁶

Latanoprost increases uveoscleral outflow with minimal effect on outflow facility and aqueous production.¹¹⁷ The mechanism by which latanoprost increases uveoscleral outflow may involve activation of enzymes that degrade ciliary muscle extracellular matrix.^118,119,120 Latanoprost has few systemic side effects but causes increased iris pigmentation by promoting increased melanin production in iris melanocytes. There appears to be little long-term significance to this unique ocular side effect. The prostaglandins also may increase periocular skin pigmentation and cause eye lashes to grow longer, darker and curlier.¹²¹ Travoprost is another prostaglandin agonist with effects similar to latanoprost.¹²² Bimatoprost, which may or may not be a prostaglandin analog, also lowers pressure by improving uveoscleral outflow; however, this agent may also increase trabecular outflow.¹²³

Urea and mannitol are intravenous osmotic agents used to raise plasma osmolality and reduce IOP relatively rapidly.^5,124 Glycerol and isosorbide can be given orally. Glycerol should be used with great caution in diabetic patients because it may precipitate ketoacidosis. Ethyl alcohol may be used when no other agents are available. All osmotic agents can cause significant hemodynamic alterations in patients with compromised cardiac and renal function.

Prolonged administration of topical and systemic corticosteroids can produce a significant IOP increase in susceptible individuals.^125,126 About 26% of the normal population have a modest increase of IOP of up to 8 mmHg after 4 to 6 weeks of topical use, whereas 4% have a >8-mmHg rise. More than 90% of primary open-angle glaucoma patients in one series had their IOP elevated by topical corticosteroids.¹²⁷ In some otherwise normal patients, a syndrome indistinguishable from primary open-angle glaucoma can be produced complete with optic nerve damage after prolonged use of topical corticosteroids.¹²⁸ Systemic corticosteroids take longer to raise IOP, probably because of less ocular penetration than topical preparations.¹²⁹

Studies by both Becker¹³⁰ and Armaly¹³¹ strongly suggest that the susceptibility to the IOP-raising effects of steroids is inherited and may be closely linked to the gene(s) for primary open-angle glaucoma. IOP response to steroids may be a risk factor for future development of primary open-angle glaucoma.¹³² Relatives of primary open-angle glaucoma patients have a higher percentage of steroid response than the general population.^133,134 Furthermore, the pituitary-adrenal axis, conjunctival fibroblasts, and peripheral blood lymphocytes of steroid responders were more sensitive to the effects of corticosteroids than those of nonresponders.¹³⁵ These studies suggest a genetically determined hypersensitivity to corticosteroids on the part of primary open-angle glaucoma patients, their relatives, and possibly some people with a genetic propensity for glaucoma, but no expressed manifestations of the disease. This hypothesis has been challenged by twin studies performed by Schwartz et al.¹³⁶

Studies have shown that the increased IOP induced by corticosteroids is due to a decreased outflow facility.¹³⁷ In rabbits, the decreased outflow may be due to a buildup of mucopolysaccharides in the trabecular meshwork. The exact mechanism for this pressure rise in humans is not known, however. The identification of mutations of the myocilin (trabecular meshwork inducible corticosteroid response [TIGR]) gene in a small but often severely affected percent of glaucoma patients has rekindled interest in the steroid response.^138,139

Glaucoma is a disorder usually associated with elevated IOP, in which the optic nerve undergoes a characteristic pattern of damage (cupping) leading to loss of visual function.

Not too long ago, all people with IOPs higher than 2 standard deviations above the mean (22 mmHg) were considered to have glaucoma. This definition has proved inadequate. Longitudinal studies by Armaly,¹⁸¹ Perkins,¹⁸² and, most recently, the Ocular Hypertension Treatment Study (OHTS)¹⁸³ have shown that only a small percentage of individuals with pressures >22 mmHg develop the full clinical picture of glaucoma, at least over a 7- to 10-year period. The OHTS study did confirm that the higher the IOP the greater the risk of developing glaucoma but IOP alone (at least between 24 and 32 mmHg) was a poor predictor of subsequent development of glaucoma. Furthermore, a significant proportion of patients with typical glaucomatous optic nerve damage have IOPs well below 22 mmHg, so-called “normal” or “low-tension” glaucoma. These observations imply that the level of IOP that damages the optic nerve differs between individuals. A cutoff of 21 mmHg for “normal” is arbitrary because it is a combination of optic nerve susceptibility and IOP level that produces glaucoma. Glaucoma is primarily an optic neuropathy, not an IOP abnormality.