While elevated intraocular pressure (IOP) is the most commonly recognized risk factor for glaucoma, the role of IOP fluctuation throughout the day has also been shown to be a risk factor in glaucoma disease development and progression.1-7 These findings are especially significant in light of studies that have established that nocturnal IOP is higher than diurnal IOP in young and aging patients both with and without glaucoma.8-10

In addition, disturbed blood flow during periods of nocturnal hypotension has been shown to be a risk factor for glaucoma development and progression, indicating a vascular pathophysiology in these individuals.11-12 So, higher mean nocturnal IOP levels coupled with nocturnal drops in blood pressure can lead to low ocular perfusion and ischemic damage to the optic nerve.

If your patient’s disease progresses despite well-controlled IOPs (as measured in the office) and excellent medication compliance, consider the possibility of nocturnal influences on blood pressure and IOP.

IOP Monitoring Around-the-clock
If getting accurate and timely intraocular pressure monitoring is the problem (especially during sleep), then around-the-clock pressure monitoring could be the answer. Here are two upcoming devices:

• Triggerfish. Available in Europe, the Triggerfish (Sensimed AG) is comprised of a two-part system: a “smart” contact lens and a small receiver worn around the patient’s neck. The lens is a soft hydrophilic silicone single-use contact lens that monitors fluctuations in the diameter of the corneoscleral junction, which are directly correlated to fluctuations in intraocular pressure. A telemetric chip and a micro-loop antenna are also embedded into the lens for the wireless reception of power and return of data. The patient also wears a flexible adhesive antenna around the eye, which is connected to the portable recorder. The patient wears the Triggerfish up to 24 hours (the lens doesn’t interfere with vision) and assumes normal activities, including sleep. When the patient returns to the doctor, the data is transferred from the recorder to the practitioner’s computer via Bluetooth for immediate analysis. Triggerfish has CE approval in Europe, but is not yet FDA approved in the U.S.

• One-millimeter computer. A recently developed computer, only 1 cubic millimeter in size (about as big as this letter “A”), is at the heart of a prototype intraocular pressure monitor designed by electrical engineers at the University of Michigan. The system includes an ultra low-power microprocessor, a pressure sensor, memory, a thin-film battery, a solar cell and a wireless radio with an antenna that can transmit data to an external reader device that would be held near the eye. “This is the first true millimeter-scale complete computing system,” the researchers said. The device is expected to be commercially available in just a few years.
What Are You Measuring?

In clinical practice, almost all practitioners primarily rely on sporadic and occasional measurements of IOP obtained during office hours and predominantly in the sitting position, to make glaucoma treatment and management decisions. While doctors may schedule their patients for serial tonometry or IOP measurements at different times of the day to try and assess diurnal fluctuation, this likely does not provide as accurate a clinical picture as one may hope. Although in-office IOP measurements may meet treatment targets, exercise caution when extrapolating data and making treatment decisions based on a few in-office IOP readings.

For example, one study found that the peak IOP in 69% of glaucoma patients was recorded outside of office hours. Also, 24-hour IOP monitoring showed that the mean peak 24-hour IOP was higher than the peak office IOP (16.8mm Hg vs. 14.7mm Hg). Similarly, the mean IOP fluctuation during 24-hour monitoring was significantly higher than IOP fluctuation acquired during office hours (6.9 mm Hg vs. 3.8mm Hg). This is an indication that we may not be getting the full picture when it comes to our patients’ pressure.

Even if we tell ourselves that seeing glaucoma patients periodically at different times of day and different days of the year will paint a proper clinical picture, this may not necessarily be the case. The same study found that in 62% of eyes, the peak 24-hour IOP was higher than any IOP noted and recorded during previous office visits.13

Another study also found wider IOP fluctuation outside office hours than with in-office measurements.14 The mean peak 24-hour IOP averaged 4.9mm Hg higher than mean peak IOP measured in office, which warranted additional medical treatment in 59% of patients.

The evidence suggests that in the majority of glaucoma patients, the highest pressure readings tend to be at a time during which IOP measurements are not routinely obtained.

Take it Lying Down
Whether causative or additive to increases in nocturnal IOP, sleep position and posture also appear to affect IOP levels. Specifically, IOP has been shown to increase by 3mm Hg to 4mm Hg when a patient is lying flat (supine) in both normal and in untreated glaucomatous eyes, regardless of time of day.10,15,16 One possible explanation is that there is a redistribution of body fluid in the supine position, which leads to choroidal vascular congestion and a subsequent rise in episcleral venous pressure.

However, this theory does not fully explain the nocturnal elevation of IOP that was observed, even when all IOP measurements were performed around the clock in the supine position.17 The implication is that there must be more than just the positional redistribution of fluid and episcleral venous pressure accounting for the preferential rise in IOP overnight.

Direct pressure on the globe during sleep may play a further role in nocturnal IOP increases. One study found a 78% agreement between the eye with the larger cup-to-disc ratio and the preferred side for sleeping.18 Although all patients appear to be affected by this change in posture, studies indicate that glaucoma patients are more likely to have greater IOP rise after changing from an upright position to a horizontal position when compared to healthy individuals.19-21 In addition, there have been observations made that the greatest posture-induced IOP variation occurred in eyes with more advanced disease.21 This may indicate that more diseased glaucomatous eyes are less capable of absorbing large fluctuations in IOP and higher IOP levels.

However, even patients with ocular hypertension (and no glaucoma diagnosis) experience greater IOP changes with posture changes compared to normals, and some researchers have suggested that horizontal IOP measurements should be included when managing these patients as well.22 In regard to disease progression, worsening of visual field damage in normal tension glaucoma has been shown to be associated with IOP measured in the supine position and the magnitude of IOP elevation that accompanies postural changes.23

Ocular Perfusion
Although mechanical damage to retinal ganglion cells through elevated IOP remains the most recognizable cause of glaucoma and the target of treatment, not all patients with glaucomatous damage have elevated IOP.24 During sleep, most people experience a decrease in sympathetic nervous system activity, which results in an approximately 10% to 20% decrease in systolic and diastolic blood pressure.25 In glaucoma patients, disturbed blood flow during periods of nocturnal hypotension has been shown to be a risk factor for glaucoma development and progression, indicating a vascular pathophysiology in these individuals.11,12

Nocturnal hypotension can lead to poor ocular perfusion, which itself is another important risk factor to consider, especially in glaucoma patients whose disease progresses despite controlled IOP.24 Not only has there been a greater prevalence of low blood pressure and nocturnal over-dipping reported in low-tension and primary open-angle glaucoma patients, but also these factors have been shown to increase the likelihood of visual field deterioration in glaucoma patients with well-controlled IOPs.25,26

Ocular perfusion pressure is defined as the difference between arterial blood flow and IOP.27 The Barbados Eye Study, Rotterdam Eye Study and the Baltimore Eye Study all identified diastolic perfusion pressure (DPP)—defined as the difference between the diastolic blood pressure and IOP—as an important risk factor for glaucoma development and progression.28-30

When DPP dropped below the 50mm Hg to 55mm Hg range in those studies, investigators reported a higher prevalence of glaucoma. The Barbados Eye Study found a mean DPP of 63.2mm Hg in healthy subjects compared with 53.8mm Hg in subjects with glaucoma (during sleep periods). This contributed to a three-fold increased risk of developing open-angle glaucoma after four years of follow-up in subjects with low ocular perfusion pressure.29 Similarly, the Rotterdam Eye Study found a 4.68 times greater chance of developing glaucoma in patients with low DPP (less than 50mm Hg).30

Likewise, the Baltimore Eye Study found that patients with DPP below 30mm Hg overnight had age-race adjusted risk of glaucoma six times greater than those with perfusion pressure greater than 50mm Hg. The study investigators proposed that the autoregulation of retinal blood velocity and blood flow is compromised at certain threshold limits, which leads to poor perfusion and ischemia of the optic nerve.28 So, nocturnal hypotension coupled with increases in IOP can cause hazardous deficiencies in ocular perfusion pressure and lead to glaucomatous damage.

Vascular Dysregulation
Vascular dysregulation, manifesting as inappropriate vasospasm or inadequate compensatory dilation in the eye, has also been shown to also be a distinct risk factor for glaucoma.31,32 The regulation of ocular blood flow involves changing metabolic needs during various visual tasks, compensating for fluctuations in perfusion pressure, and maintaining a constant temperature in the back of the eye.33 In people with defective ocular autoregulation and elevated nocturnal IOP, blood vessels are unable to respond adequately to fluctuations in blood flow and low perfusion, which can result in an unstable oxygen supply, ischemia and optic nerve damage.34

While nocturnal over-dipping has been established as a risk factor for glaucoma, some studies have also observed nocturnal nondippers as being at higher risk for glaucoma.35,36 These studies indicate that an underlying vascular dysregulation, and not just nocturnal hypotension, may be responsible for glaucomatous changes.

Glaucoma in cases of vascular dysregulation may not be linked to a stable reduction in ocular blood flow, but rather unstable blood flow through perfusion pressure fluctuation or disturbed autoregulation.37 This leads to repeated reperfusion injury to the optic nerve and glaucomatous changes. Systemically, these individuals are prone to cold hands, low blood pressure, migraine, and reduced feeling of thirst.38

Blood Pressure Changes
While the lowering of blood pressure is an important step to reduce risk for cardiovascular morbidity and mortality, hypotension is not ideal or healthy for patients and can lead to serious systemic problems as well. Lowering blood pressure to a hypotensive level is not done on purpose, although overtreatment does occur. Some individuals may suffer from “white coat syndrome” and will have increased blood pressure measurements in the presence of doctors.25 This could potentially lead to over-medicating patients in attempts to lower their measured blood pressure and thus lead to even lower nocturnal blood pressures.39,40

In the Rotterdam Eye Study, an association between low DPP and high-tension glaucoma was detected only in patients on antihypertensive treatment. Treatment of high blood pressure reduces the diastolic blood pressure, which when combined with increased nocturnal IOP, leads to nocturnal dipping of diastolic perfusion pressure.30 Another study recently found that nocturnal dippers and extreme dippers had reduced thickness of nerve fiber layer and greater visual field deterioration compared to non-dippers.41 Study investigators suggested avoiding excessive lowering of blood pressure in these groups.

The Rotterdam Eye Study also found an increased risk of glaucoma in users of calcium channel blockers. While beta-blockers decrease both diastolic pressure and IOP and tend to influence diastolic perfusion pressure less, calcium channel blockers decrease blood pressure without affecting IOP. The results suggest that these agents should be used with caution in glaucoma patients vulnerable to low perfusion pressure.42 Consider consulting with the primary care doctor about switching from a calcium channel blocker to an alternative systemic hypotensive medication in susceptible glaucoma patients.

While most practitioners to some degree subscribe to the theory that hypotension can have negative effects on glaucoma, others say there is insufficient evidence to support increasing a patient’s blood pressure as therapy for glaucoma.25 By eliminating the nocturnal dip in blood pressure, patients could be put at a greater risk of cardiovascular events.

While we do not advocate an increase in blood pressure, we do routinely ask our glaucoma patients what time they take their hypertension medications. If the patient takes them in the evening, we will consult with the primary care provider to see if there is any medical reason that would prevent the patient from taking blood pressure medication during the day.

Intraocular pressure measurements during the night are higher than during the day in both young and old patients, and those with and without glaucoma.16
In addition to changing blood pressure medication dosage times, one easy and less controversial recommendation that optometrists can give their glaucoma patients is to encourage them to sleep with a pillow placed underneath their head. In one study, initial IOP increases after changing to supine position were neutralized by adopting a semi-reclined position that raised the head.43 Given that one-third to one-fourth of the day is spent in the horizontal position, it may be reasonable to advise glaucoma patients to sleep with their heads slightly elevated.44

Practitioners must also consider the role of sleep apnea in perfusion pressure and in nocturnal IOP fluctuation. One mechanism by which sleep apnea may lead to glaucoma is by hypoxic injury to the nerve. This may be caused by disrupted autoregulation of blood flow to the nerve from periods of hypoxia and/or hypercapnia, excessive carbon dioxide in the blood, or by disruption of blood flow from periods of hypotension during apneas.45

In addition to ischemic changes, individuals on continuous positive airway pressure (CPAP) therapy experience significant 24-hour IOP fluctuations and higher mean IOP values at night compared to baseline pre-CPAP therapy measurements.46 This has significant implications for glaucoma management, so a thorough medical history should be performed.

Management After Midnight
IOP lowering medications have shown varying efficacy in combating nocturnal IOP increases. Several studies have found that beta-blockers have limited efficacy in lowering IOP at night, while prostaglandin analogues have shown a sustained 24-hour IOP lowering effect.47,48 Another study compared 24-hour IOP lowering effects of 1% brinzolamide t.i.d. with 0.5% timolol q.a.m. in patients who are already taking latanoprost. During the diurnal period, both medications lowered IOP significantly; however, only 1% brinzolamide was found to significantly lower IOP during the nocturnal period.49 Due in part to changes in circulating catecholamines, there is a natural decrease of aqueous humor flow at night by about 50%, which would render a drop that targets aqueous production (i.e., beta-blocker) less efficacious.50,51

With regard to laser treatment, a recent study suggested that even individuals who have responded poorly to laser trabeculoplasty during office-hour IOP measurements showed benefit in nocturnal IOP measurements.52 When patients with moderate to advanced glaucoma were treated with medications vs. those controlled with trabeculectomy were compared, the mean 24-hour IOP, peak IOP and range of IOP measured were significantly lower in the surgical group.53 In our opinion, this supports consideration of surgery to level out the pressure in those patients currently progressing despite what appears to be controlled ocular pressure.    
Glaucoma patients whose disease progresses despite meeting target IOP during in-office measurements pose difficult challenges for the managing doctor. Numerous studies have found that in the majority of patients, the highest IOP in a 24-hour period occurs at night.

Yet, IOP measurement during the evening and nighttime requires admitting patients into a hospital setting, which causes obstacles such as patient inconvenience, high cost, and the need for a trained individual capable of accurately measuring IOP.13 It is much more practical to have a high index of suspicion for other causes of glaucoma development and progression.

Eye care practitioners should also take caution and remember that their in-office IOP measurements only provide a small glimpse of their patient’s overall IOP curve.

Drs. Chu and Hamp both practice at W. G. Hefner VA Medical Center, in Salisbury, N.C.

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