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REVIEW ARTICLE Personalizing Intraocular Pressure: Target Intraocular Pressure in the Setting of 24-Hour Intraocular Pressure Monitoring Arthur J. Sit, MD, and Christopher M. Pruet, MD Abstract: Determining target intraocular pressure (IOP) in glaucoma patients is multifaceted, requiring attention to many different factors such as glaucoma type, severity of disease, age, race, family history, corneal thickness and hysteresis, and initial IOP. Even with all these variables accounted for, there are still patients who have progression of the disease despite achieving target IOP. Intraocular pressure variability has been identified as a potential independent risk factor for glaucoma progression but is currently difficult to quantify in individual patients. New technologies enabling measurement of both diurnal and nocturnal IOP may necessitate modifying our concept of target pressure. Key Words: 24-hour intraocular pressure, target intraocular pressure (Asia Pac J Ophthalmol 2016;5: 17–22) G laucoma is a characteristic optic neuropathy affected by multiple factors, but reduction of intraocular pressure (IOP) is currently the only therapy demonstrated to be effective at reducing the risk of disease progression. When evaluating a patient, a balance needs to be achieved between the benefits of lowering IOP and the burdens of the therapy. Most practitioners determine a target IOP after evaluating the risk factors of the individual patient, tailor their therapies toward achieving the target IOP, and then modify their therapy or target IOP if the patient shows progression. Multiple variables contribute to the determination of target IOP. INITIAL FACTORS INFLUENCING TARGET IOP Maximum IOP and Percentage Reduction Large multicenter clinical trials have clearly demonstrated that reduction of IOP decreases the risk of developing glaucoma or disease progression. However, by design, clinical trials have an IOP target based on a fixed percentage reduction. Reviewing the various IOP targets used in clinical trials can provide some guidance on optimal target IOP selection. The Ocular Hypertension Treatment Study found that a 20% reduction in IOP in patients with a baseline IOP of 24 to 31 mm Hg in 1 eye and 21 to 31 mm Hg in the fellow eye reduced the rate of developing glaucoma at 5 years from 9.5% to 4.5%.1 A follow-up study from the same cohort of patients showed that those initially randomized to observation had delayed treatment by a mean of 7.5 years before being placed on ocular antihypertensive therapy. As a result, the 13-year rate of developing glaucoma after initial randomization to observation was 22% in the observation group From the Department of Ophthalmology, Mayo Clinic, Rochester, MN. Received for publication September 20, 2015; accepted December 14, 2015. A.J.S. is consultant to AcuMEMS Inc, Allergan Inc, and Sensimed AG and received research support from Aerie Pharmaceuticals Inc and Glaukos Corp. C.M.P. has no funding or conflicts of interest to declare. All sources of support are processed through the Mayo Clinic and do not go directly to either A.J.S. or C.M.P. Reprints: Arthur J. Sit, MD, 200 1st St. SW, Rochester, MN 55905. E-mail: sit. [email protected]. Copyright © 2016 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000178 compared with 16% in the initial treatment group. The IOP target was set as a 20% reduction from baseline or an IOP less than 24 mm Hg, whichever was lower.2 The Early Manifest Glaucoma Trial (EMGT) compared treatment of patients with newly diagnosed glaucoma with a standardized protocol of argon laser trabeculoplasty and betaxolol (which resulted in a 25% IOP reduction) with observation and no therapy. The study found that the 25% reduction of IOP was associated with a 45% rate of progression over 5 years as compared with a 62% rate of progression in patients who received no therapy.3 The Collaborative Initial Glaucoma Treatment Study (CIGTS) randomized patients with newly diagnosed glaucoma to medical treatment or trabeculectomy. After initiating treatment, the mean IOP in the medical group was 17 to 18 mm Hg (roughly 35% reduction) and 14 to 15 mm Hg in the surgical group (roughly 40% reduction). Overall, there was no significant difference in the progression rates between the medically and surgically treated groups. This suggests that initial IOP reductions greater than 35% may have a limited effect on progression in this patient population, but generalizability to other groups is uncertain, particularly in patients with advanced disease. Level of Disease On subgroup analysis of the CIGTS study, 1 group in particular seemed to benefit from initial surgery. Patients who presented with advanced disease, defined as a mean deviation of less than −10 dB on Humphrey Visual Field testing, had decreased rates of progression (defined as a decrease in mean deviation of ≥3 dB) 7 years after randomization to surgery compared with medically treated patients.4 This suggests a benefit to having lower target IOP in the setting of advanced disease, although the decreased progression in this group may also be related to a decrease in IOP variability with trabeculectomy as compared with topical medications.5 A similar benefit of aggressive IOP reduction was reported in the results of the Advanced Glaucoma Intervention Study. Patients with advanced disease (defined as glaucomatous visual field defects and IOP > 18 mm Hg despite maximally tolerated medical therapy) were less likely to progress if their average IOP was less than 14 mm Hg over 6 to 18 months after argon laser trabeculoplasty or trabeculectomy.6 In contrast to the groups that had higher average IOPs, this subgroup also consistently had IOP of 18 mm Hg or less during this time frame, suggesting more stable IOP as well. It remains unclear whether the decreased rate of progression is due to lower IOP, lower IOP variability, or a combination of the two. Glaucoma Type Some types of glaucoma may have elevated risk of progression and warrant more aggressive target IOPs. When recruiting for the EMGT trial, many patients with ocular hypertension and without visual field deficits were enrolled. In a subgroup analysis, ocular hypertensive patients (IOP 24–31 mm Hg) with pseudoexfoliation were age, sex, and IOP matched with patients without pseudoexfoliation. At a mean of 8.7 years, 28% of the control subjects and 55% of the pseudoexfoliation patients had developed Asia-Pacific Journal of Ophthalmology • Volume 5, Number 1, January/February 2016 www.apjo.org Copyright © 2016 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited. 17 Asia-Pacific Journal of Ophthalmology • Volume 5, Number 1, January/February 2016 Sit and Pruet glaucoma, indicating that pseudoexfoliation patents have a higher risk of progression.7 Other Predictors of Progression Numerous other risk factors for glaucoma have been identified in clinical trials.8 Decreased central corneal thickness is an established risk factor for glaucomatous progression in both openangle and angle-closure glaucomas,9,10 as is older age, especially in the setting of normal IOP.11 African ancestry is a risk factor for both the development and progression of disease.12 Family history also puts a patient at risk of developing glaucoma.13 Low corneal hysteresis has also been associated with glaucomatous progression.14 Tissue biomechanical properties, such as scleral elasticity, are likely risk factors for progression but cannot be easily measured at present.15 However, unlike IOP, these risk factors (as well as others) currently cannot be, or are very difficult to, modify. IOP VARIABILITY With an impressively large number of factors contributing to whether a patient will lose vision from glaucoma, setting the target IOP is complex and must be individualized. Once a target IOP (or range of IOPs) is set and therapy is initiated and stabilized, follow-up visits are typically focused on determining if patients are at their target pressure, if they are exhibiting progression of the disease, and if their target IOP needs to be adjusted. As multiple IOP measurements are performed over extended periods, it may be possible to determine another potential risk factor for glaucomatous progression: IOP variability. Long-term Variability The importance of long-term IOP variability over years is difficult to study. However, post hoc analyses of clinical trial data have suggested that at least some patient populations may be susceptible to IOP variations. Nouri-Mahdavi et al16 performed a retrospective analysis of the Advanced Glaucoma Intervention Study data and found that IOP variation over years of follow-up was a significant risk factor for progression. A problem with this particular study was that the data included IOP measurements taken after therapy was modified for visual field progression, resulting in a higher IOP variability in patients with progression. Caprioli and Coleman17 performed an analysis on the same cohort, this time analyzing data only before visual field progression and excluding patients with multiple surgeries. They found that high variability in the lowest tertile of mean IOP was linked to glaucomatous progression, whereas it was not linked to progression in the highest tertile of mean IOP.17 In contrast, patients with early glaucoma were analyzed using the EMGT data, which did not show a link between IOP variability and glaucomatous progression. Instead, only elevated mean IOP was found to be related to disease progression.18 Retrospective analysis of the CIGTS data by Musch et al19 found no association between IOP variability and progression in patients randomized to the trabeculectomy arm of the study. However, for patients randomized to medical therapy, maximum IOP, IOP range, and IOP SD were all associated with visual field progression. The Ocular Hypertension Treatment Study data also indicated that IOP variability in the medically treated group was linked to higher rates of developing glaucoma. However, this association was not seen in the ocular hypertensive patients randomized to observation.20 A possible reason why only certain groups seem to be affected by IOP variability was suggested by Caprioli:21 mean IOP is the predominant risk factor for patients with elevated IOP, whereas when IOP is lower, its variability has a stronger influence on 18 www.apjo.org progression. Concerning the apparent susceptibility of medically treated patients to IOP variations, treatments that suppress aqueous production do not stabilize IOP throughout a 24-hour period, in contrast to treatments that improve outflow facility. This may lead to an increase in IOP variability that is not easily captured in single measurements recorded during the diurnal period.22 Diurnal Variability Variation of IOP over the course of the day, instead of over years, may also be a risk factor for glaucoma. Jonas et al23 obtained diurnal tension curves on control subjects and patients with primary open-angle glaucoma (POAG) and secondary open-angle glaucoma (pigmentary and pseudoexfoliation). They reported that patients with secondary open-angle glaucoma had a diurnal IOP peak in the afternoon, in contrast to both control subjects and POAG patients who had a morning peak with a gradual decrease in IOP throughout the day. This study also reported that patients with secondary open-angle glaucoma tended to have greater IOP variability compared with control subjects and POAG patients. Bergeå et al24 obtained diurnal tension curves on patients every 2 months for 2 years in a group of patients with POAG and pseudoexfoliation glaucoma. Their findings showed that POAG patients tended to have lower pressures than pseudoexfoliation glaucoma patients, and neither their mean IOP nor IOP variation was clearly associated with progression. However, the number of patients with POAG was small. In contrast, both mean IOP and IOP variation were associated with visual field progression in pseudoexfoliation glaucoma patients. Asrani et al studied a group of patients with open-angle glaucoma who measured their own IOP 5 times a day over 5 days using a specially designed home applanation tonometer that required topical anesthetic. In this group of patients, with a maximum inclinic IOP of 24 mm Hg and a maximum in-clinic variability of 8 mm Hg, self-measured IOP variability was found to be a risk factor for progression after 1 year.25 Controversy exists regarding the repeatability of diurnal IOP patterns. Realini et al26 found that, in treated POAG patients, the agreement between serial diurnal curves was uniformly poor with intraclass correlation coefficients ranging from −0.1 to 0.4. In contrast, Mottet et al27 performed 6 diurnal curves on 6 healthy patients and found that 80% of measurements demonstrated a nyctohemeral rhythm. However, intrasubject and intersubject variability of rhythmic parameters and IOP values was relatively high. Short-term Variability There is currently a lack of evidence to conclude whether short-term IOP variations, lasting seconds to minutes, may contribute to glaucoma.28 However, it is clear that there are a wide range of normal behaviors that can influence IOP. McLaren et al29 demonstrated, by using a continuous pressure monitoring system in rabbits, that IOP undergoes nearly constant change and is affected by breathing, lid position, eye position, pulse pressure, tonometer application, and physical activity. Downs et al30 similarly used an implanted aqueous transducer (allowing for unrestricted activity) in 3 female primates and documented IOP fluctuations of up to 10 mm Hg on an hourly basis. Other studies have demonstrated changes in IOP due to blinking, head position, body position, eye position, blood pressure (BP), and accommodation. Caffeine consumption, excessive water intake, wearing a tight necktie, and playing a wind instrument affect IOP as well.31 The mechanism of short-term IOP variations is unclear but does not appear to be related to systemic venous pressure.32 In addition to the intrinsic fluctuation of IOP, measurements can vary because of operator error and patient factors. © 2016 Asia Pacific Academy of Ophthalmology Copyright © 2016 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited. Asia-Pacific Journal of Ophthalmology • Volume 5, Number 1, January/February 2016 One area of particular interest is the effect of body positioning on IOP. Malihi and Sit33 found that in healthy patients, when sitting with the neck in a neutral position, IOP is roughly 1.6 mm Hg lower than in neck extension, 5.0 mm Hg less than in neck flexion, and 2.5 mm Hg lower than in the supine position. Thus, IOP measurements in the clinic are typically performed with the body positioned to give the lowest possible readings. Further investigations are required to decide if IOP variability in other body positions is increased in glaucoma patients and to determine the role (if any) of body position–induced IOP changes in glaucoma pathogenesis. Circadian Variations Intraocular pressure fluctuates with a circadian pattern, and this pattern seems to be altered in glaucoma. In a series of studies, Liu et al34 measured IOP every 2 hours in the sitting and supine positions during the waking period and in the supine position during the sleeping period throughout a 24-hour period in patients with newly diagnosed glaucoma and healthy control subjects. They determined that, when in physiologic positions (sitting during the diurnal phase, supine in the nocturnal phase), IOP was highest in the nocturnal period for most patients, including both control and glaucomatous patients. However, when IOP was measured in the supine position, glaucomatous patients were found to have a nocturnal decrease in supine IOP, in contrast to healthy control subjects who had an increase in nocturnal supine IOP compared with diurnal supine IOP. The potential clinical significance of the circadian IOP pattern is based on the circadian variation of ocular perfusion pressure (OPP), which is directly related to IOP and BP. Like IOP, BP can vary significantly with a 24-hour cycle, but the magnitudes of the changes (in mm Hg) tend to be much larger than the variations in IOP.35 In another study, Liu et al36 measured the diurnal (sitting) to nocturnal (supine) IOP change in healthy younger and older adults. They found that nocturnal IOP increased by 5.1 mm Hg compared with diurnal IOP in young adults and by 4.5 mm Hg in older adults. This nocturnal increase in IOP, coupled with a decrease in mean arterial pressure from 95 to 83 mm Hg in young adults and 107 to 99 mm Hg in older adults, suggests a decrease in OPP at night. However, this may be more than compensated for by the local positional arterial BP changes experienced by the eye in the supine position. Liu et al36 took this into account and calculated that OPP may actually be increased during the nocturnal period, by 3.6 mm Hg in young adults and 10.1 mm Hg in older adults without glaucoma. However, in glaucoma patients, these beneficial changes may be altered by vascular dysregulation and systemic hypotension. Graham and Drance37 reported that patients with relative nocturnal systemic hypotension had significantly greater glaucoma progression rates than did patients with higher nocturnal BP. Also highlighting the importance of optic nerve perfusion, Sung et al35 found that, in patients with normal-tension glaucoma (NTG), circadian variation in OPP was the strongest prognostic factor for progression, even more important than mean OPP. Further complicating the issue of OPP in glaucoma is the finding that circadian IOP patterns in glaucoma may be variable. In a study by Renard et al of 22 NTG patients, a variety of IOP patterns were detected, suggesting the loss of normal circadian rhythms in this population.38 Fifty-eight percent of their patients exhibited a diurnal acrophase (IOP highest during the day), which was opposite to subjects without glaucoma described by Liu et al, whereas only 42% exhibited a nocturnal acrophase (IOP highest at night). Although there was no significant difference in OPP between these 2 groups, the diurnal acrophase pattern was associated with capillopathy confirmed by nailed capillaroscopy, suggesting abnormal vascular regulation. © 2016 Asia Pacific Academy of Ophthalmology Personalizing Intraocular Pressure Methods of Measuring IOP Over 24 Hours Until recently, the only clinically available method for obtaining a 24-hour IOP curve was admission to the hospital where a series of trained technicians or nurses would measure IOP at predetermined intervals using handheld or slit-lamp tonometry. Although this approach is reasonable for research purposes, it is not a viable strategy for routine clinical use. It is inherently time consuming and disturbing for the patient to obtain IOP measurements throughout the day and night, and the financial costs for hospital admission and staffing with trained personnel are prohibitive. Diurnal curves can be performed during clinic hours, but these cannot capture the nocturnal period where OPP may be at a minimum. Self-tonometry has the potential to decrease the cost and increase the convenience of 24-hour IOP monitoring, as it would be performed by the patients themselves outside the clinic or hospital. However, self-tonometry devices have met with limited success. The Proview Eye Pressure Monitor (Bausch & Lomb Incorporated, Bridgewater, NJ) functions by having the patient look inferotemporally and then press the instrument tip onto the closed eyelid in the superonasal position with increasing force until a phosphene is generated because of mechanical stimulation of the retina. The force applied at the subjective phosphene initiation is then recorded. This method has been found to be less accurate and less repeatable than Goldmann applanation tonometry.39 It detected pressures of greater than 21 mm Hg in only 18% (4/22) of patients40 and had a discrepancy of 6.6 ± 3.6 mm Hg in patients with pressures of more than 20 or less than 10 mm Hg.41 The Ocuton-S (EPSa Elektronik & Praezisionsbau, Saalfeid, Germany) selfapplanator is similar to a Goldmann applanator, requiring corneal anesthetic. In addition to its poor reproducibility compared with the Goldmann, the additional risks of abrasion and infection have limited its acceptance.42 The Icare (Icare Finland, Helsinki, Finland) is a rebound contact tonometer that does not require corneal anesthesia. Its clinical use is already widespread. However, its use as a self-tonometry device has met with limitations: nonperpendicular and off-center measuring limit the reproducibility of its readings.43 In addition, any self-applied tonometer requires the patient to be disturbed during sleep for measurements in the nocturnal period if 24-hour pressures are desired. In response to the need to measure ambulatory 24-hour IOP in a patient-independent manner, multiple devices have been proposed and developed in the past decade. The first device that was available for routine clinical use was the SENSIMED Triggerfish (Sensimed AG, Lausanne, Switzerland), which is available in many countries around the world but is not yet approved by the US Food and Drug Administration. The Triggerfish is a disposable contact lens sensor (CLS) that measures minute corneal curvature changes, which occur with changes in IOP.44 These readings are wirelessly transmitted to a sensor placed over the patient’s ocular rim. The CLS records the voltage from an internal sensor 10 times a second for 30 seconds, transmits its data, then repeats the process 5 minutes later. One important limitation is that the output of the sensor is in millivolts, not in actual IOP, highlighting that this device is designed to monitor a profile of IOP, not IOP itself. The validation of the relationship between millivolt and IOP is difficult, given that Goldmann tonometry cannot be reliably performed on a patient wearing the CLS. In addition, controversy exists regarding the correlation of changes in CLS measurements with IOP. Mottet et al45 studied 12 healthy volunteers over three 24-hour periods (performing noncontact tonometry during 2 sessions and CLS in 2 sessions) and found a significant correlation between acrophase and bathyphase in all intrapatient sessions, but the CLS data were not symmetric to noncontact tonometry either individually or within the study population. In 1 report, www.apjo.org Copyright © 2016 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited. 19 Sit and Pruet Asia-Pacific Journal of Ophthalmology • Volume 5, Number 1, January/February 2016 the millivolt profile for positional changes did not match the IOP changes obtained from the fellow eyes in 5 subjects, and a 5–mm Hg increase over 30 minutes in an enucleated human eye was poorly reflected in the millivolt profile as well.46 Nevertheless, multiple studies have used data from the CLS to infer IOP patterns. Lee et al47 recorded 24-hour Triggerfish data in 18 NTG patients, half of whom were on prostaglandin therapy, and found that the diurnal output voltage variability was higher than nocturnal voltage variability, that there were more voltage spikes in the diurnal period than in the nocturnal period, and that the voltage changed more rapidly moving from the diurnal to nocturnal than from the nocturnal to diurnal period.47 There was no significant difference between the prostaglandin- and non–prostaglandin-treated groups. Lee et al48 also reported Triggerfish results in 18 NTG patients who underwent selective laser trabeculoplasty. Patients with a 20% or greater reduction in IOP by Goldmann tonometry at 1 month had a 24.6% reduction of the amplitude of their 24-hour cosine-wave-fitted Triggerfish output, whereas patients who did not achieve a 20% decrease in IOP experienced a 19.2% increase in the amplitude of their Triggerfish cosine-fit voltage profile and had an increase in 24-hour millivolt variability. Mansouri et al49 evaluated 21 healthy and 19 POAG patients with 2 Triggerfish sessions; correlation coefficients between the sessions were 0.51 for patients not on glaucoma medication and 0.63 for those using glaucoma medication, but these correlations did not reach statistical significance. Positive linear slopes from waking to 2 hours into sleep were detected in both sessions for the no-glaucoma medication group but not for the glaucoma medication group. This could mean that the diurnal pattern in POAG is disrupted by either medication use or the pathology of POAG itself.49 All of the aforementioned methods of measuring IOP are external and noninvasive and rely on the response of the cornea to pressure. Because of the invasive nature of direct IOP measurement via manometry, this is typically performed only for research purposes during unrelated surgery and in the laboratory setting with animal models. However, attempts to develop an implantable IOP monitoring device have continued for decades, and the first devices appear to be nearing clinical availability. The Wireless IOP Transducer (WIT; Implandata Ophthalmic Products GmbH) is an implant designed to provide IOP measurements through direct access to the posterior chamber. The WIT is a silicone-based sulcus implant with 8 individual pressure transducers that measure IOP in the sulcus, then transmit the processed average measured IOP to a radiofrequency receiver placed in front of the orbital rim. Todani et al6 implanted 6 WITs in rabbits directly after either open sky or manual extracapsular cataract extraction. These sensors were noted to have good correlation with manometry in sedated rabbits and were more precise than pneumotonometry or the Tono-Pen (Reichert, Depew, NY). Two of the 6 implants exhibited a drift in their readings necessitating recalibration to manometry: one at a rate of 2 mm Hg per month that started after 1 year of implantation, and the other was an abrupt drop at 1.5 years. Neither device showed further drift after recalibration. No ocular toxicities or inflammation were noted in the implanted rabbits over the 25-month study.6 The WIT has also been implanted in 1 human patient after phacoemulsification through a 3-mm superior clear corneal incision. Corneal edema and iritis resolved within 1 month, and final best corrected visual acuity was 20/25 after posterior YAG capsulotomy; the angle remained open except for peripheral anterior synechiae at the surgery wound. The IOP measured by the WIT differed by as much as 6.5 mm Hg and exhibited a drift to a lower pressure after 36 weeks. The patient had an unexplained rise in IOP to 25 mm Hg by Goldmann applanation tonometry at 31 weeks after surgery, which resolved after a month’s course of latanoprost 20 www.apjo.org and did not recur after discontinuation of latanoprost.50 Although these problems highlight the difficulties with long-term implantable pressure sensors, this approach shows promise as a tool to enable 24-hour IOP monitoring and evaluation of IOP variation in glaucoma patients. MINIMIZING VARIATIONS Appropriate selection of IOP-lowering therapy can help to minimize IOP variations. The rationale for this comes from an understanding of the aqueous humor dynamics of normal IOP variations and the mechanisms of action of glaucoma therapies. During the nocturnal period, the production of aqueous humor decreases roughly 50%, compensated by a small decrease in outflow facility and a large decrease in uveoscleral outflow, to produce a relatively stable IOP (when measured in the same body position as in the diurnal period).51 Aqueous suppressants seem to have minimal effect in the nocturnal phase, likely due to aqueous humor production being at a basal level during sleep. In contrast, prostaglandin analogs seem to maintain efficacy during the nocturnal phase (albeit at a lower level than during the diurnal phase), likely due to their effect on improving uveoscleral outflow, which is reduced at night. In comparison, both aqueous suppressants and prostaglandin analogs have good efficacy during the diurnal phase.52 Prostaglandin analogs would be the medication class of choice for patients who had nocturnal IOP rises thought to be contributing to progression. Typically, procedures that increase outflow facility tend to lower IOP variations more than those that lower aqueous production.22 Laser trabeculoplasty has been shown to increase outflow facility and also to decrease IOP rise in the nocturnal period.53 Awell-functioning trabeculectomy in patients with advanced glaucoma has also been shown to lower IOP in both the diurnal and nocturnal periods and reduce pressure variations compared with medical therapy.5 DETERMINING TARGET IOP IN THE SETTING OF 24-HOUR MONITORING In conclusion, some patients will continue to progress despite an apparently adequate IOP when measured in a clinic setting. In patients such as these, diurnal curve measurements or 24-hour IOP monitoring may identify IOP variability as a potential cause of disease progression. As discussed in IOP VARIABILITY, this would be of particular importance in patients with low mean IOPs (eg, in the range of 10–12 mm Hg) and worsening glaucoma. In addition, detection of an IOP rise during the nocturnal phase could indicate the need to advance therapy to decrease IOP variability at night (as discussed in MINIMIZING VARIATIONS). Finally, the role of IOP variability in glaucoma cannot be separated from variability in OPP. Blood pressure variations are much larger than IOP variations, and the effect on mean arterial pressure at the optic nerve head is unclear. However, in patients with disease progression despite seemingly wellcontrolled IOP, an assessment of 24-hour BP and vascular instability may be warranted. In particular, NTG patients may benefit from these additional investigations, which could help to stabilize their disease. REFERENCES 1. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–713; discussion 829–830. © 2016 Asia Pacific Academy of Ophthalmology Copyright © 2016 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited. Asia-Pacific Journal of Ophthalmology • Volume 5, Number 1, January/February 2016 2. Kass MA, Gordon MO, Gao F, et al. Delaying treatment of ocular hypertension: the Ocular Hypertension Treatment Study. Arch Ophthalmol. 2010;128:276–287. 3. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268–1279. 4. Musch DC, Gillespie BW, Lichter PR, et al. Visual field progression in the Collaborative Initial Glaucoma Treatment Study: the impact of treatment and other baseline factors. Ophthalmology. 2009;116: 200–207. 5. 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Effect of laser trabeculoplasty on nocturnal intraocular pressure in medically treated glaucoma patients. Ophthalmology. 2007;114:666–670. It is only with the heart that one can see rightly; what is essential is invisible to the eye. — Antoine de Saint Exupéry 22 www.apjo.org © 2016 Asia Pacific Academy of Ophthalmology Copyright © 2016 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.