Daytime IOP measurements are not enough for complete glaucoma care.
Elevated intraocular pressure (IOP) is a major, and currently the only, modifiable risk factor that has been shown to reduce the risk of glaucoma onset and progression.
Diurnal measurements of IOP, usually during office hours, are commonly used for the assessment of IOP variation and the relative success of medical, laser, or surgical IOP-lowering interventions.
Such measurements, however, fail to capture variation in IOP over the day/night cycle, which may be influenced by factors such as body position.
IOP is regulated by aqueous humor which is maintained by the anterior chamber angle and ciliary body of the posterior chamber and flows out via trabecular meshwork or canal of Schlemm.
The aqueous humor flow is imbalanced when the resistance exists in its outflow pathway, which leads to an increase of IOP. The elevated IOP causes damage to the optic nerve head, resulting in irreversible blindness eventually.
Although numerous factors determine glaucoma such as age, family history, high myopia, IOP, and so on, the IOP is proved to be the only modifiable risk factor for glaucoma. Currently, the only available therapeutic approach for glaucoma is lowering the elevated IOP via medication, laser, or surgery.
The progression of glaucoma will occur less frequently or stop when the elevated IOP is lowered by 30–50% with medicine. Therefore, accurate and reliable IOP measurements will provide strong support for effective intervention in the progression of glaucoma.
The effectiveness of a single IOP measurement versus 24 hours IOP monitoring has been debated on numerous occasions. On the basis of the influence of diurnal and nocturnal variations, many ophthalmologists believe in conducting IOP measurements for 24 hours.
However, this is less practical and inconvenient to the patients. Thus, there are recommendations to conduct multiple measurements during office hours (diurnal) in a clinic setting. There is supportive evidence to suggest that daytime serial IOP is similar to the night-time measurement.
Moodie et al. found that 24 hours measurement did not confer any extra advantage as compared to daytime IOP measurement in patients with evidence of glaucoma progression. Daytime measurement was similar to night-time measurement.
However, Hughes et al. found that there was no significant difference in the mean IOP at daytime and 24 hours measurement, but the ability to identify peak IOP was significantly higher with 24 hours measurement.
Most ophthalmologists have treated glaucoma patients whose disease progresses, despite seemingly well controlled intraocular pressure (IOP) measured in the clinic during office hours. Normal-tension glaucoma (NTG) patients especially exhibit this trend.
Although other unknown factors may play a role in progressive optic nerve head injury, elevated IOP is the only proven treatable risk factor. However, the IOP data collected in the clinic paint a small picture of the optic nerve head environment throughout the 24-hour period.
The effects of nocturnal IOP patterns are often overlooked, despite patients spending a significant portion of their lives in a sleep state. A better understanding of the 24-hour variations in the optic nerve head environment and how these variations may be affecting patients’ disease is crucial to mitigating glaucoma progression.
Over the past 2 decades, extensive research has been dedicated to studying the normal IOP pattern in humans. Intraocular pressure typically follows a nychthemeral rhythm, meaning that IOP fluctuates from day to night following light–stimulus patterns.
These patterns are based on input from the retinal melanopsin-expressing ganglion cells to the suprachiasmatic nucleus in the hypothalamus. In healthy subjects of all ages, IOP tends to peak at night and dip during the day.
Aqueous production decreases overnight, so elevated nighttime IOP is thought to be primarily due to increases in episcleral venous pressure and choroidal congestion that occur with horizontal positioning. However, a few studies have shown that IOP remains higher in sleep states regardless of positioning.
Thus, when measuring IOP during the day, it is likely at one of its lowest values for the 24-hour period. In patients who have glaucoma, 24-hour IOP patterns are more varied.
While most studies have continued to show nighttime peaks in glaucoma, these peaks tend to occur later in the night or early morning, and some patients do have peaks during the day.
Also, patients with glaucoma seem to have higher amplitudes of variation in IOP from day to night, indicating larger swings in IOP compared to normal.
Some researchers have proposed that these variation patterns are related to circadian rhythm disruption in glaucoma patients who already have injury to their retinal ganglion cells.
A link between sleep disturbances and glaucoma has been repeatedly established. More recent studies have used a contact lens sensor (CLS) to measure IOP-related corneoscleral changes continuously for 24-hour periods in healthy subjects and in patients with glaucoma.
These studies have confirmed the normal nychthemeral IOP pattern in humans and have also allowed for analysis of the relationship between 24-hour IOP-related changes and visual field progression.
The CLS studies have collectively suggested that higher day-to-night IOP fluctuations and nighttime IOP spikes are associated with faster visual field progression. There may be a few explanations for why nocturnal IOP values tend to be more volatile in patients with glaucoma.
As mentioned above, IOP elevates at night primarily due to increased episcleral venous pressure and choroidal vascular congestion. This normal elevation, related to reduced venous outflow, may be exacerbated in glaucoma patients who already have impaired trabecular outflow.
Further, changes in IOP associated with horizontal or sleep positioning seem to be more dramatic and longer lived in patients who have glaucoma than in patients who do not have glaucoma, suggesting that normal vascular autoregulatory mechanisms may be dysfunctional at baseline in glaucoma patients.
Also, daytime glaucoma medications can preferentially lower daytime IOP levels while not effectively lowering IOP overnight.
Indeed, certain classes of drug are more effective overnight than others. Prostaglandins are the most consistently efficacious at reducing IOP throughout the 24-hour period, with an average 24% to 29% IOP lowering from baseline IOP at all time points measured.
However, it should be noted that nighttime IOP values follow the normal nychthemeral pattern and remain higher than daytime values, even with these medications.
Carbonic anhydrase inhibitors, brimonidine, and beta-blockers have shown varied efficacies in the nocturnal period compared to daytime, but again these have not been shown to decrease nocturnal IOP to daytime levels.
Aqueous suppressant drugs appear to have the least effect overnight due to the already reduced physiologic production of aqueous at night.
Of note, topical beta-blockers may be contraindicated for nighttime dosing, because this drug class can systemically lower blood pressure and reduce ocular perfusion pressure, potentially exacerbating glaucomatous injury overnight.
The nighttime effectiveness of Rho-kinase inhibitors has not yet been reported, but it is thought to be similar to that of prostaglandins. In summary, although topical medications lower the average 24-hour IOP, no medication has been shown to flatten the patterned rise of IOP overnight.
Results of the LiGHT trial have led to the use of selective laser trabeculoplasty (SLT) as a first-line therapy for the treatment of ocular hypertension and open angle glaucoma. The multicenter trial showed that SLT is not only noninferior to topical medication as initial therapy, but may even be slightly superior.
The study mentioned that both reduced reliance on patient drop compliance and more effective 24-hour IOP lowering may be responsible for this finding. A CLS study performed in 2015 supported the IOP-lowering benefits of SLT with reduced average IOP over 24 hours.
However, the study also showed that the nychthemeral pattern of IOP persisted, with IOP peaks occurring at night and with amplitudes similar to pre-SLT treatment.
To date, the only glaucoma treatment that has been shown to completely flatten the 24-hour IOP curve is trabeculectomy surgery.
The reduction in IOP variation and nighttime spikes is likely the primary reason that disease progression slows down in patients post-trabeculectomy. Currently, there are no studies assessing the 24-hour effects of tube shunts or minimally invasive glaucoma surgeries (MIGS).
There is an established relationship between nocturnal dips in systemic blood pressure and glaucoma progression, especially in NTG patients.
One group studied nighttime blood pressure patterns in newly diagnosed glaucoma patients on prostaglandin analogues with normal IOP during office hours and found that nocturnal hypotension was associated with worse visual field progression.
Likewise, in 2019, Kwon et al found that lower nighttime diastolic blood pressure levels were significant predictors of visual field loss in NTG patients.
Ocular perfusion pressure, the difference between mean arterial pressure and intraocular pressure, is decreased in glaucoma patients by the combination of both nocturnal hypotension and elevated nighttime IOP peaks.
In patients who show progression despite controlled daytime IOP values, it is imperative to assess for potential drops in nighttime blood pressure and to work with the patient’s medical team to reduce these events.
Systemic antihypertensives should be avoided before bedtime, if possible, as should other medications that cause vascular compromise (eg, phosphodiesterase inhibitors).
Further, these patients should be assessed for sleep-disordered breathing patterns, such as sleep apnea, which are known causes of nocturnal hypoxia and hemodynamic instability. The role of head and sleep position has also been considered as a contributor to glaucoma progression.
Multiple studies have shown that IOP elevates more from sitting to supine to inverted, and one study found that the lateral decubitus sleeping position was significantly associated with worsening visual fields in the dependent eyes of NTG patients.
However, the data surrounding the effects of head and sleep position in glaucoma are inconsistent, making the recommendations towards optimal sleep positions for glaucoma patients unclear.
Despite the strong evidence that lowering nocturnal IOP would minimize IOP elevations throughout the 24-hour period and help slow visual field progression in glaucoma patients, therapies that specifically target nocturnal IOP are limited.
A pair of negativepressure eye goggles that locally reduce IOP while worn overnight is being developed with some early publications showing an IOP lowering of 35% compared to controls overnight.
Lowering IOP with this technology should also improve ocular perfusion pressure. Other technologies and therapies are moving away from drop therapy to reduce medication burden and to curb inconsistencies in IOP through the 24-hour period.
Allergan (now AbbVie) recently released the bimatoprost intraocular implant, Durysta, which provides a more direct and continuous IOP-lowering effect inside the eye. The continuous drug elution may be more effective overnight than its topical counterparts, but this has not been studied.
Also, MIGS procedures are gaining popularity due to their ability to reduce drop burden and provide more consistent IOP lowering, though these procedures come with their own individual surgical risks and limitations, and studies are needed to understand the effect different MIGS have on nocturnal IOP patterns.
The future of glaucoma therapy must take into consideration the many factors and systemic patterns affecting the optic nerve head throughout the day as well as the night. To slow progression of disease, it is no longer sufficient to focus solely on daytime IOP measurements that are conveniently obtained in clinic.
Those interested in improving outcomes for patients who have glaucoma must find ways to target the multiple physiologic environments affecting the optic nerve.
Individualized continuous IOP measurements, further studies of the role of intracranial pressure changes in glaucoma, and the development of treatments aimed at better 24-hour and nocturnal IOP control are a few places to start.