Circadian IOP Rhythms in Glaucoma

How does this impact our treatment decisions?

By Angelo P. Tanna, MD

For decades, it had been thought that intraocular pressure is highest during the early morning hours in most individuals. A series of methodically conducted studies performed in the sleep laboratory at the Hamilton Glaucoma Center of the University of California at San Diego has substantially changed our understanding of the pattern of circadian IOP variation. Here, I will discuss some of the newest findings in this area and their potential impact on treatment decisions and medication choices for our glaucoma patients.

What is Known About the Pattern of IOP Fluctuation?

When IOP is measured in the habitual position — that is, in the sitting position during the daytime or diurnal period and in the supine position during the nocturnal period — the highest observed IOPs occur during the nocturnal period. This is true both for most control subjects and most patients with glaucoma.

Although postural position clearly has an important impact on IOP, resulting in a higher IOP due at least in part to elevation of the episcleral venous pressure during the nocturnal period, other factors must be at play because diurnal IOP is not as high as nocturnal pressure (among normals, but not glaucoma patients) even if the diurnal measurements are performed with subjects awake in the supine position. In normals, supine nocturnal IOP is higher than supine diurnal IOP. However, in glaucoma patients, supine diurnal IOP is actually higher than supine nocturnal IOP.

All of this may be surprising, since it is known that the rate of production of aqueous humor is lowest during the nocturnal period (see Table 1). Other than episcleral venous pressure, the factors at play that result in higher-than-expected nocturnal pressures in normal subjects are not yet known, but may include the effect of endogenous corticosteroids on trabecular meshwork outflow facility.

An immediate clinical implication of this newly discovered knowledge pertains to the efficacy of our currently available ocular hypotensive therapies during the nocturnal period. In order to understand whether medications are likely to lower IOP during the nocturnal period, we must first review the basics of aqueous humor production.

The Role of Aqueous Flow

The adrenergic system plays an important role in the regulation of the rate of aqueous flow. Specifically, higher levels of the concentration of cyclic adenosine monophosphate (cAMP) in the non-pigmented ciliary epithelium result in increased rates of aqueous flow. By interacting with receptors associated with different types of G-proteins (activating and inhibitory), beta-adrenergic antagonists (beta-blockers) and alpha-adrenergic agonists influence the level of intracellular cAMP in the non-pigmented ciliary epithelium.

Landmark published studies demonstrated that during the nocturnal period, there is a reduction in the rate of production of aqueous humor and that this reduction in aqueous flow is in part a result of a reduction in adrenergic stimulation. These studies also showed that timolol does not reduce the rate of aqueous flow below its already low rate during sleep. Subsequent studies have verified that both timolol and brimonidine, both medicines that primarily lower IOP by reducing aqueous production by reducing cAMP concentrations in the ciliary epithelium, do not lower nocturnal IOP in patients when measured in the habitual position.

Conversely, the component of aqueous flow driven by the carbonic anhydrase system is constitutively active and can be inhibited by systemic and topical carbonic anhydrase inhibitors during both the diurnal and nocturnal periods. Published evidence shows that carbonic anhydrase inhibitors lower both diurnal and nocturnal IOP. Prostaglandin analogs increase uveoscleral outflow and lower IOP during the entire circadian period. Laser trabeculoplasty improves conventional outflow and has been shown to be efficacious in lowering nocturnal IOP, as does trabeculectomy.

Medication Selection

Adrenergic activity drives the production of aqueous humor only during the diurnal period; therefore, adrenergic agents such as topical beta-blockers and the topical alpha2-selective adrenergic agonist, brimonidine, are not effective at lowering nocturnal IOP. The apparent paradox here is that despite the fact that the adrenergic drive for aqueous production is inactive during the nocturnal period, and the rate of aqueous production is accordingly reduced during the nocturnal period, IOP is highest at night, when IOP is measured in the habitual position. Again, the reasons for this higher IOP at night in the face of reduced aqueous production are incompletely understood, but partly the result of increased EVP. The adrenergic system is, therefore, not a meaningful target for IOP-lowering therapy during the nocturnal period.

Although recent studies show that beta-blockers and alpha2-selective adrenergic agonists have no nocturnal ocular hypotensive efficacy when pressure is measured in the habitual position, this is in contradiction to previous studies that have demonstrated nocturnal IOP-lowering efficacy of these classes of agents; however, those studies were performed in patients who were awakened at various intervals and transported to a slit lamp with IOP measured with a Goldmann tonometer in the sitting position.

Basic Questions About IOP

Although it seems obvious that lowering nocturnal IOP must be beneficial in the setting of glaucoma, in reality there is no evidence that has shown this to be true. Is it possible that nocturnal IOP reduction may be less important? Perhaps. We must ask the question, “How does higher IOP cause glaucoma damage?” We do not yet have the answers to this question; however, there are two possibilities to consider in the context of the importance of nocturnal IOP.

First, there is a line of evidence that suggests the trans-lamina cribrosa pressure gradient (see Figure 1) may be the important biomechanical factor with respect to the development of glaucomatous optic nerve damage. The relevant pressure gradient is the IOP minus the CSF pressure in the region posterior to the lamina cribrosa. Since intracranial pressure is higher in the supine position than in the sitting or standing positions, a higher IOP in the supine position may be balanced to some degree by a higher CSF pressure.

Figure 1. The trans-lamina cribrosa pressure gradient is the IOP minus the CSF pressure. ILLUSTRATION BY MARK ERICKSON/JIREHDESIGN.COM

Second, there is ample evidence from population-based studies that lower ocular perfusion pressure (blood pressure minus IOP) is a major risk factor for the prevalence of glaucoma and the incident development of glaucoma. The lower the BP or the higher the IOP, the lower the ocular perfusion pressure. Blood pressure is generally lower during the nocturnal period; however, there are various potential factors that may mitigate the adverse effect of this drop in blood pressure on true ocular perfusion. Remember, the ocular perfusion pressure formula above is just a gross estimate. It is conceivable that variations in systemic vascular resistance, patterns of blood flow and patterns of oxygen and energy utilization during the nocturnal period may maintain true ocular perfusion despite the presence of lower systemic blood pressures.

Guidance for the Clinician

Given some of the uncertainty regarding the importance of nocturnal IOP lowering, how should the clinician proceed? My approach is to preferentially use agents that lower diurnal and nocturnal IOP, when possible. In patients who progress despite seemingly well-controlled IOPs, it may be all the more important to consider nocturnal IOP control. In such patients, careful consideration should be given to advancing to laser trabeculoplasty or incisional glaucoma surgery. As new evidence becomes available and once continuous IOP measurement techniques evolve, there is little doubt that nocturnal IOP control will gain importance in everyday glaucoma management. OM

References

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