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Intraocular Pressure Phasing and Glaucoma

2T in Australia | 0.5CD in New Zealand | 1 June 2018

 

By Jessie Huang and Dr. Barbara Zangerl

Obtaining the intraocular pressure measurements of patients with, or at risk of glaucoma, while in their habitual environment and across the day, can provide insights that will potentially influence their management.

LEARNING OBJECTIVES

1. Recognise the implications of intraocular pressure (IOP) fluctuations on glaucoma diagnosis and management
2. Identify physiological factors that influence IOP
3. Discuss different methods for measuring and phasing intraocular pressure

Approximately 3 per cent of Australians aged 50 years and over have glaucoma and approximately half are currently undiagnosed.1,2 Glaucoma is a multifactorial disease, with aetiology and pathophysiology remaining largely unknown. The only proven treatments for delaying or slowing its progression focus on the reduction of intraocular pressure (IOP), even in patients with normal tension glaucoma who have historically low intraocular pressures. Additionally, the risk of glaucoma in patients with ocular hypertension can be decreased with IOP lowering treatment. Due to its asymptomatic nature in early disease, detection of  glaucoma relies on opportunistic case finding by eye health practitioners.3

An essential element of a glaucoma examination is the measurement of intraocular pressure. Developed in the 1950s, Goldmann applanation tonometry is widely accepted as the gold standard for clinical IOP measurement and has been used in many large, multicentre, randomised clinical trials. From these studies, we understand that elevated IOP is a major risk factor for glaucoma conversion and progression, although the underpinning mechanism is unclear.4,5 The association of IOP fluctuations with glaucoma has also been studied extensively, but has not produced conclusive evidence. These studies, however, have resulted in two broad definitions of IOP fluctuations commonly referred to in scientific literature; namely long and short term fluctuations.

Long term fluctuation relates to the variability of measurements, expressed as standard deviation, over a given period of time, typically over several years. Effectively, this equates to the variability of IOP  measurements recorded once at each three to six monthly visit, across the follow up period of a clinical trial. In the Advanced Glaucoma Intervention Study,6 comprising an investigation of 509 eyes in 401 patients over an average of seven years, larger IOP fluctuation was associated with visual field progression in some patients. Patients included in this study had open angle glaucoma, which was no longer controlled by topical treatment and were randomised to either argon laser trabeculoplasty, trabeculectomy or both as part of the trial. On the other hand, the Early Manifest Glaucoma Trial,7 focusing on 255 patients with newly diagnosed glaucoma, did not find any association between long term IOP fluctuation and disease progression. These patients had either primary open angle including normal tension or pseudoexfoliative glaucoma. It is possible that differences in the patient populations with respect to stage of disease and also subtypes have impacted on the resultant findings.

Other studies have investigated short term IOP fluctuation, which is generally defined as the variability of IOP over a 24 hour period or less. This can be expressed by calculating the amplitude i.e. subtracting the lowest IOP from the highest IOP or the standard deviation of measurements within a 24 hour period. In studies that examine diurnal IOP during waking hours, many patients demonstrate their highest IOP in the morning, which tends to decrease throughout the rest of the day, although significant individual variation does exist. In 24 hour studies, which also examined IOP throughout the night, nocturnal IOP tended to be higher than diurnal IOP. Some studies have shown that patients suffering from glaucoma display a greater amount of diurnal fluctuation compared to normal subjects,8 suggesting that larger short term fluctuations may be associated with glaucoma progression.9

PHYSIOLOGICAL DETERMINANTS OF INTRAOCULAR PRESSURE

Intraocular pressure is defined as the force exerted by the contents of the eye (aqueous humour, lens, vitreous and uvea) on its container, the corneoscleral wall.10 As the corneoscleral wall is relatively rigid, any increase in the intraocular volume contents will result in an elevation of the IOP. Among the eye’s contents, the dynamics of aqueous humour is the key determinant of IOP.

Aqueous humour is produced by the ciliary processes and flows from the posterior chamber to the anterior chamber via the pupil, providing oxygen and nutrients to avascular structures of the eye that include the lens, corneal endothelium and trabecular meshwork. The outflow of aqueous humour facilitates removal of metabolic waste products and occurs via either the conventional pathway (through the trabecular meshwork into Schlemm’s canal) or uveoscleral pathway (unconventional pathway). Normal regulation of the IOP is achieved by a balance between the production and outflow of aqueous humour. Consequently, any condition leading to an increase in production or inhibition of outflow will result in an increase of the IOP. Therefore, pharmacological treatments for glaucoma to reduce IOP are designed to have the opposite effect. The mechanism of action of the beta-adrenergic blockers and carbonic anhydrase inhibitors is to reduce aqueous humour production, whereas prostaglandin analogues cause increased drainage of aqueous humour and it has been shown that alpha-adrenergic agonists can effect both actions.

A range of other factors can cause transient changes to IOP and some of these may be encountered in the consulting room. Prolonged accommodation can result in small decreases in IOP while physiological mydriasis, after being in a dark room, can slightly increase IOP. Straining, coughing and holding of breath cause increased central venous pressure and subsequent IOP elevation. Hence, overestimation of IOP can occur in patients who are anxious about tonometry and hold their breath during measurements. Systemic hypertension is associated with an increase in IOP and pregnancy is reported to have a hypotensive effect. IOP can even vary with the seasons, typically higher in the winter compared to summer time.

METHODS FOR MEASURING INTRAOCULAR PRESSURE

As mentioned earlier, Goldmann applanation tonometry is currently widely accepted as the gold standard for clinical IOP measurement. However, there is currently a multitude of devices for measuring IOP available for clinical use, all of which have relative advantages and disadvantages.

Goldmann applanation tonometry uses the Imbert-Fick principle (Force = Pressure/Area) to estimate intraocular pressure by measuring the force required to flatten the cornea over a fixed area (7.35mm2 or a circle with a diameter of 3.06mm). To estimate IOP, the Imbert-Fick principle assumes that the eye is a sphere filled with liquid and that the corneoscleral wall is an infinitely thin membrane. Measurements made with applanation tonometry cannot fully account for differences in corneal and scleral biomechanical properties between individuals. Clinically, IOP is underestimated in individuals with thin corneas and conversely, overestimated with thick corneas. Therefore, applanation IOP measurements should be evaluated in the context of central corneal thickness measurements. Practical disadvantages of Goldmann tonometry include its lack of portability and need for sterilisation, however due to expert consensus; it is still the gold standard for clinical practice and has been used in numerous large clinical trials for glaucoma.

In 1972, Grolman11 described a new tonometer system which, in contrast to Goldmann tonometry, required no mechanical contact with the eye, no topical anaesthesia and provided objective measurements of IOP. The non-contact tonometer projects a column of air of increasing force on the cornea, gradually achieving applanation (flattening) then also indentation of the cornea, whereby the cornea assumes a concave shape. At this point, the intensity of the air is reduced to allow the cornea to return to its normal shape, while passing through the state of applanation once more. Hence, the pressure required to flatten the cornea is used to estimate the intraocular pressure. A recent iteration of the non-contact tonometer is the Ocular Response Analyser (Reichert, Rochester, NY), which also provides additional measurements believed to be related to the biomechanical properties of the cornea. One of these measurements is named corneal hysteresis. More recently, it has been suggested that lower corneal hysteresis might also be associated with glaucoma progression, however whether this effect will be borne out by other ongoing studies remains to be seen.12

The principles of rebound tonometry were first described in 1931 by Obbink but did not become commercially realised until the 2000s with Icare instruments (Helsinki, Finland). In rebound tonometry, IOP is estimated from the motion characteristics of a probe that is bounced off the cornea, with a faster rebound equating to a higher IOP and conversely, a slower rebound indicating lower IOP. The end of the probe that contacts the patient’s cornea for a matter of microseconds consists of a small, rounded plastic tip. The other end consists of a gold-plated metallic wire that is manipulated by a magnetic field within the handheld, battery-operated instrument. The deceleration of the probe after contacting the cornea, and also the time that the probe is in contact with the cornea, is used to estimate IOP. Measurements with Icare rebound tonometry have on average demonstrated good agreement with Goldmann applanation tonometry.13-15 However, there is a tendency for the differences between the two modalities to increase with lower or higher IOPs, as well as when central corneal thickness is thinner than 500 microns or thicker than 600 microns.13 In comparison to GAT, the advantages of rebound tonometry include its portability, ease of use and no need for anaesthesia to obtain measurements.

Other methods for obtaining IOP measurements include indentation tonometry and dynamic contour tonometry. In 1905, the Schiötz tonometer was one of the first instruments designed for quantitative IOP measurement.16 In indentation tonometry, the underlying principle is that the amount of depression exhibited by the eye in response to the application of an external force is proportional to the intraocular pressure. Practically, the depth of corneal depression measured in response to weights applied to the eye provides an estimate of intraocular pressure. In contrast, a relatively new concept is dynamic contour tonometry, which was designed to measure IOP independent of corneal properties such as thickness. The design of the tonometer tip, instead of being flat (as with Goldmann tonometry) is curved to mimic the contour of the cornea, with a cup-like appearance. The principle behind this design is that of contour matching, whereby the pressure inside a sphere is equal to that exerted by a tight fitting cover on the surface of the sphere. Hence, an estimate of the IOP can be obtained once the probe is aligned to the cornea.

DEVICES FOR IOP PHASING

To gain a better understanding of a patient’s diurnal or short term IOP fluctuations, in-office phasing could be employed with any of the aforementioned methods. IOP phasing can help the clinician appreciate the profile of the IOP across the day to determine the amplitude of changes as well as detect potential IOP spikes. Regardless of the chosen technique however, such measurements are typically limited to the availability of the clinician, which often omits information on IOP changes outside normal office hours.

IOP typically displays a cyclical pattern with the amplitude of IOP variation and the timing of the peak IOP demonstrating considerable inter-individual variability. With up to 69 per cent17 of patients exhibiting their peak IOP outside office hours, 24-hour monitoring would provide a more comprehensive picture of these fluctuations. However, practically, this process can be time and labour intensive for clinicians and also inconvenient for patients, as it requires several visits. Additionally, obtaining 24-hour measurements would require an overnight stay in a hospital sleep laboratory. To overcome these challenges, automated and patient-administered instruments are continuing to be developed to monitor IOP.

Continuous 24 hour monitoring with implantable intraocular devices are currently under investigation for use in humans. This technique was originally developed in rabbits and consists of a wireless, telemetric IOP sensor encapsulated in silicone. The sensor has so far been implanted in the ciliary sulcus of six glaucoma patients, at the same time as planned cataract extraction and intracapsular lens implantation were performed.18 The implant consists of eight pressure sensors and antennae, which transmit IOP measurements to an external unit when held in front of the eye. IOP is calculated as the differential between the measurement of pressure within the eye and outside the eye. Patients followed for one year showed no major adverse responses although all patients did show mild to moderate pupillary distortion and pigment dispersion following surgery. One of the early outcomes of this trial was that the device would benefit from alterations in its size and shape to minimise pupillary distortion and contact with the iris. A potential limitation for future clinical use is the required implantation, which likely would only be considered for patients scheduled for planned surgical intervention. It also remains unclear how these measurements relate to applanation tonometry measurements and further studies are required to demonstrate how these measurements could be used clinically.

Another continuous IOP monitoring device currently being investigated is a contact lens sensor, commonly known as the Sensimed Triggerfish (Lausanne, Switzerland). The Triggerfish consists of a microstrain gauge embedded on a silicone contact lens, which measures small changes in ocular dimensions at the limbus, which are believed to representative of IOP changes. The device may be worn for 24 hours and every five minutes, an electrical output, measured in millivolt (mV) units is collected. Consistent with previous studies, the Triggerfish demonstrated higher measurements at night compared to during the day across a 24 hour period. One current limitation of the Triggerfish for clinical use is that the measurements are recorded in arbitrary units (corresponding to electrical units of voltage) which are not directly translatable to mmHg. Despite this, in a study of 40 patients, some IOP parameters measured by the contact lens sensor were found to be associated with the rate of visual field progression in treated glaucomatous eyes.19 Further research in this device is warranted before it can be adopted into standard clinical practice.

Using the principle of rebound tonometry, a new instrument for phasing of IOP has become available to clinicians in recent years. The Icare HOME (Helsinki, Finland) allows patients to measure their own IOP in their habitual environment (Figure 1). One advantage of this method is that long term monitoring would be possible, however the measurements would generally be limited to waking hours. Nevertheless, self-tonometry by patients can still provide additional information to eye care practitioners and help us to better understand the relationship between diurnal IOP and glaucoma.

Figure 1. Icare HOME rebound self-tonometry being performed

One of the key utilities of patient self-monitoring is IOP phasing in glaucoma patients and suspects. In a clinical trial at the Centre for Eye Health, it was demonstrated that after one week of Icare HOME phasing, the pattern of IOP variation could be robustly estimated.20 This is important because previous studies have shown that diurnal IOP patterns can vary from day to day, hence IOP phasing for one day may not sufficiently represent the true pattern of variation.21,22

In the study, glaucoma patients and suspects who successfully completed Icare HOME training and certification (about 30 minutes) were asked to self-monitor their IOP over several (minimum of four) weeks. Training included orientation of the different components of the instrument and instruction on measurement procedure including insertion of a disposable probe, correct positioning at the central cornea, checking that measurements were taken and disposal of the probe upon conclusion. Certification was achieved if patients were able to independently obtain three reliable measurements that satisfied a predefined criterion specified by the manufacturers.

To establish a diurnal curve, patients were instructed to take measurements four times a day: upon waking, at lunchtime, dinnertime and before bed. The results showed that on average, across both the glaucoma patient and suspect groups during waking hours, IOP was highest during the day and decreased in the evening. Although, there was considerable interindividual variation, two main patterns of IOP variation were observed. Almost half of the group obtained their peak (highest) IOP around midday (lunchtime) with many others showing a peak in the morning (upon waking). For patients who were able to obtain measurements for both eyes, 88 per cent revealed consistent patterns between the eyes. An example of this is shown in Figure 2, of a patient’s IOP measurements showing similar measurements between the two eyes over several days.

Figure 2. Diurnal IOP measurements, plotted in Icare Clinic Software, show the cyclical pattern of IOP over three days, for a patient attending the Centre for Eye Health. Measurements obtained three to four times per day, demonstrating amplitudes of 7mmHg in the right eye and 8mmHg in the left eye. The IOP was generally symmetrical between the eyes and during waking hours appeared higher during the day than at night.

The study also found that there was variability in the amplitude of diurnal IOP, ranging from two to 11mmHg across the participants. The median IOP amplitude was 4.9mmHg for the glaucoma group and 3.3mmHg for the glaucoma suspects, however this was not statistically significant. Peak IOP was not predictive of the amount of IOP fluctuation, as demonstrated by the IOP curves of two patients as shown in Figure 3. These patients have similar peak IOPs during the day but their amplitudes differed by several mmHg.

Figure 3. Diurnal IOP measurements for two patients attending the Centre for Eye Health demonstrate the cyclical pattern of IOP over a 72 hour period. Measurements obtained three to four times per day revealed differences in amplitudes (Patient 1: 7mmHg and Patient 2: 4mmHg) despite having similar peak IOPs.

From the patient’s perspective, study participants rated the instrument as generally easy to use. The instrument has a simple design and is straightforward to operate, however occasional difficulties were expressed in obtaining measurements. This may be related to issues with handeye dominance, with right-handed subjects reporting more difficulty in obtaining left eye measurements. Additionally, subjects reported uncertainty in correct positioning of the instrument during measurements, which should be centred on the cornea. Although acceptable to most patients, using the Icare HOME may not be appropriate for all, as about 20 per cent of patients are not able to complete the training and certification process.14,20 For patients that are able to use the instrument, IOP phasing with the Icare HOME can help to uncover clinically significant findings that inform ongoing patient management.

During the study, two patients, identified as glaucoma suspects, were found to demonstrate large diurnal IOP fluctuations with self-monitoring. In Figure 4, we can appreciate that peak IOP was around 25mmHg for both patients however the timing of these peaks differed by several hours. For Suspect One, peak IOP was observed in the early morning and their IOP decreased into the normal range to approximately 19mmHg in the afternoon. Conversely, Suspect Two showed an increase from about 19mmHg in the morning to 25mmHg in the afternoon. Assuming clinical working hours of 9am-5pm, Suspect Two’s peak IOP would be detected during an eye examination, however Suspect One’s peak IOP would remain undetected. Hence, self-monitoring of IOP can help to reveal clinically significant IOP changes occurring outside normal office hours.

Figure 4. Diurnal IOP measured with Icare HOME for two glaucoma suspects (Suspect 1 and Suspect 2) demonstrating similar peak IOPs but different patterns of fluctuation throughout the day.

Current clinical practice generally relies on single IOP measurements obtained during office hours. With advancements in technology, it is now possible to obtain IOP measurements in a patient’s habitual environment across the day. As highlighted in this article, this data can provide clinicians with insights into IOP fluctuations and potentially influence management of patients with glaucoma or at-risk of glaucoma. It and should be considered as part of clinical management for patients at risk of developing or being treated for glaucoma.

 

       Jessie Huang BOptom (Hons), GradCertOcTher is a Senior Staff Optometrist at Centre For Eye Health. With a strong interest in research, particularly in glaucoma management, she is currently undertaking studies towards a doctorate degree at UNSW. Ms. Huang has practiced in rural and metropolitan clinics across Australia and been involved in teaching across clinical and tertiary institutions in Australia and Vietnam 
 
Dr. Barbara Zangerl, DVM, PhD is an internationally recognised researcher investigating various aspects of inherited and complex blinding disorders. Her current work at the Centre for Eye Health strongly focuses on chronic, progressive disorders, specifically glaucoma and diabetic retinopathy to develop clinical markers for early detection, and optimise patient management through both implementation of advanced testing modalities and improved health care models.


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' With advancements in technology, it is now possible to obtain IOP measurements in a patient’s habitual environment across the day... '