Nocturnal intraocular pressure (IOP) elevation has been
implicated in the progression of open-angle glaucoma (OAG) and its subtypes,
including normal-tension glaucoma (NTG). Published work has highlighted the
importance of decreasing nocturnal IOP to limit glaucomatous progression,
particularly in more vulnerable patients such as those with NTG. NTG is a
subtype of OAG that is difficult to treat with standard options like drops,
laser trabeculoplasty, and minimally invasive glaucoma surgery (MIGS) because
of a lower baseline IOP. The importance of lowering nocturnal IOP and its
impact on disease progression has been reinforced by studies evaluating 24-hour
IOP data.
The measurement of IOP over a 24-hour time frame has shown
that peak (acrophase) IOP primarily occurs at night, particularly in patients
with glaucoma. Nocturnal IOP elevation is influenced by a multitude of factors
including circadian rhythm and body position. The circadian rhythm of IOP is
regulated by the suprachiasmatic nucleus (SCN) with both glucocorticoids and
the sympathetic nervous system potentially playing significant roles. A number
of approaches have been utilized to explore 24-hour IOP profiles including the
use of overnight measurements in sleep labs, a contact-lens sensor (SENSIMED
Triggerfish®, SENSIMED AG, Lausanne, Switzerland), and now implantable IOP
sensors (EyeMate®, Implandata Ophthalmic Products, Hannover, Germany). Further,
multiple 24-hour IOP sensors are under development with some achieving FDA
breakthrough designation, highlighting the importance of recognizing and treating
elevated IOP, 24-hours a day. Data from studies evaluating 24-hour IOP profiles
have consistently demonstrated that nocturnal IOP elevation is more common in
glaucoma patients and leads to glaucomatous progression in OAG patients,
including those with NTG.
The Early Manifest Glaucoma Trial demonstrated that every 1
mmHg decrease in IOP is associated with a 10% decrease in glaucomatous
progression. Studies have also shown that decreasing the total IOP burden, the
area under the curve, slows glaucomatous progression. Thus, strategies
targeting IOP reduction remain the foundation of glaucoma treatment. Although
there have been considerable advances in treatment options over the past
decade, there remains a need for improved 24-hour IOP control and monitoring.
A recent joint paper23 by the American Glaucoma Society
(AGS) and American Society of Cataract and Refractive Surgeons (ASCRS)
emphasized this notion by stating that: (a) 24-hour IOP monitoring/control, and
(b) non-invasive therapeutics that lower IOP and improve ocular blood flow were
unmet needs, “especially in challenging patients who do not adequately respond
to current therapies or those in whom IOP is already within the normal range”.
In this report, authors reviewed:
● The impact of nocturnal IOP elevation on glaucomatous
progression
● The importance of decreasing nocturnal IOP on slowing
glaucomatous progression
● The rationale for why lowering nocturnal IOP elevation is
beneficial
● Potential future therapies for improved management of nocturnal
IOP elevation
Impact of Nocturnal IOP Elevation on Glaucomatous
Progression
In the treatment of glaucoma, IOP reduction remains the only
clinically-validated modifiable risk factor. Clinicians nearly always rely on
daytime (in-office) IOP measurements to guide treatment decisions. These
measurements, however, only provide a partial snapshot of a patient’s 24-hour
IOP profile. It is well documented that daytime measurements often miss IOP
peaks, leading to disease progression for patients whose IOP is seemingly
controlled based on clinic visit measurements.
There is significant heterogeneity in methodological
approach, body position, and the tools used. Some performed measurements over a
full 24-hours while others separated diurnal and nocturnal periods over
different days since IOP can vary day-to-day and hour-to-hour. Newer tools that
measure IOP as the subjects went about their regular lives have also been
created. A contact lens IOP sensor (SENSIMED Triggerfish®, SENSIMED AG,
Lausanne, Switzerland) showed that 70% of healthy subjects and 90% of glaucoma
patients had elevated nocturnal IOP. Implantable devices (EyeMate®, Implandata
Ophthalmic Products, Hannover, Germany) attempt to more accurately capture true
IOP through continuous monitoring that bypass biases attributed to measurements
using the cornea. Several studies have confirmed their safety and accuracy
compared to Goldmann applanation and can confirm nocturnal IOP elevations
without disturbing sleep. Insurance coverage for these devices and therapies
that can lower nocturnal IOP would allow more equitable access to quality data
and improved treatment for the benefit of patients.
The introduction of continuous 24-hour IOP monitoring
techniques has supported IOP’s expected nyctohemeral rhythm and pattern of
nocturnal peaks. Compared to that of healthy subjects, the nocturnal IOP
elevation in glaucoma patients is not only higher, but also longer. 24-hour IOP
profiles in patients with glaucoma are more volatile, with larger amplitudes of
nocturnal elevation. A multitude of recent studies evaluating 24-hour IOP
profiles have demonstrated a relationship between nocturnal IOP elevation,
especially nighttime spikes, and glaucomatous disease progression.
De Moraes confirmed the pattern of peak IOP occurring at
night and found that the mean peak ratio and magnitude of elevation predicted
faster progression and visual field change. The mean peak ratio findings in
this study imply that those patients with a higher nocturnal elevation are at
greater risk. An additional recent study by Yang found that increased elevation
in nocturnal IOP correlated with faster rates of visual field loss.
Furthermore, a recent study in treated glaucoma, including NTG patients, found
that 79% of patients with progressive glaucoma, despite an apparent controlled
daytime IOP, had elevated nocturnal IOP, despite an apparent controlled daytime
IOP, suggesting a strong association between nocturnal IOP spikes and disease
progression. In this study, mean daytime IOP was similar between progressors
and non-progressors, respectively (13.57 mmHg ± 2.16 and 13.04 mmHg ± 2.06).
However, 65% of patients with progression had nocturnal IOP elevations while
only 24% of those without progression did. Collectively, these studies
highlight the importance of nocturnal IOP elevation and its likely impact on
glaucoma progression despite a seemingly “controlled” daytime IOP.
Another implication of nocturnal IOP elevation is ocular
perfusion pressure (OPP), defined as the difference between mean arterial
pressure (MAP) and IOP at any given time. OPP is reduced when blood pressure is
low or IOP is high. Multiple large-scale studies have shown a link between low
OPP and glaucomatous disease progression, including the Baltimore Eye Survey,
which demonstrated a 6-fold increase in glaucoma risk in patients with reduced
diastolic perfusion pressure. A study of 24-hour IOP and blood pressure
patterns in patients with NTG reported that patients with a ≥20% reduction in
nocturnal BP had a higher rate (>3-fold increase) of visual field
progression. An additional study in newly-diagnosed NTG patients revealed that
lower nocturnal diastolic BP was significantly predictive of visual field
progression. Overall, these studies highlight the importance of OPP in the
development and progression of glaucoma while supporting the need for treatment
options that lower IOP at night, a time when patients are likely most
vulnerable to glaucomatous damage.
The decrease in nocturnal OPP is compounded by the vascular
dysregulation present in glaucoma. Typically, physiologic ocular blood flow is
autoregulated to meet and maintain metabolic needs. Normal autoregulation
involves appropriate changes to local vascular resistance in response to OPP
fluctuations, such as vascular dilation to offset low OPP. Vascular
dysregulation in glaucoma, however, may mean that vessels stay constricted
despite low OPP, further causing insufficient blood flow of the optic nerve
head (ONH) tissue. Prior studies using laser doppler flowmetry have demonstrated
that reducing IOP can stimulate autoregulatory responses. Studies have also
demonstrated that reducing IOP leads to an increase in blood flow at the ONH.
Since autoregulation and OPP is impaired in patients with glaucoma, lowering
nocturnal IOP improves OPP and subsequently increases blood flow, which has
been demonstrated to be protective of retinal ganglion cells in model systems.
The Importance of Decreasing Nocturnal IOP to Slow
Glaucomatous Progression
It is well established that IOP peaks at night, likely due
to circadian rhythm and increased episcleral venous pressure inherent to the
recumbent position. However, it remains unclear why there are larger degrees of
elevation in patients with glaucoma. It is possible that impaired trabecular
outflow compounds the increased episcleral venous pressure observed at night.
Prior work has also shown that changes in IOP associated with positioning of
the body (for example, horizontal position) are more significant in patients
with glaucoma. It is therefore unsurprising that studies have linked extended
sleep duration to glaucoma progression. A study in >6000 patients
demonstrated that longer sleep duration is associated with a 3-fold greater
risk of progression in patients who slept ≥10 hours per night. Regardless of
the mechanism, these findings highlight the importance of decreasing the
duration or magnitude nocturnal IOP could slow glaucomatous progression.
A number of studies have investigated the nocturnal
IOP-lowering efficacy of treatments for glaucoma. Despite the growing body of
evidence supporting the role and importance of nocturnal IOP in glaucoma
management, therapies that specifically target nocturnal IOP reduction are
limited. At night, topical agents have reduced IOP lowering efficacy; the
untreated high nocturnal IOP can dramatically decrease nocturnal OPP especially
in the setting of low nighttime blood pressures.4 Since IOP is increased by
episcleral venous pressure (EVP), which is elevated at night in the horizontal
position, it is no surprise that treatments like MIGS, laser trabeculoplasty,
and topical medications are less effective at lowering nocturnal IOP because
they do not impact EVP, except for rho-kinase inhibitors. Thus, there remains a
need for better treatment options that safely and effectively lower nocturnal
IOP.
Commonly prescribed topical IOP-lowering agents such as
beta-blockers (timolol), alpha-agonists (brimonidine) and carbonic anhydrase
inhibitors (dorzolamide) have proven daytime efficacy but have minimal effect
on nocturnal IOP. The only medication class to consistently demonstrate a
benefit of nocturnal IOP reduction are prostaglandin analogues; however, the
magnitude of IOP reduction at night is reduced in comparison with daytime efficacy.
A prior study by Liu investigated the nocturnal effects of timolol or
latanoprost as compared with no treatment in glaucoma patients. While both
agents were effective at lowering daytime IOP, timolol’s nighttime efficacy was
no different than the absence of treatment. Both the timolol and latanoprost
groups still exhibited nocturnal IOP peaks, showing reduced efficacy at night.
An additional study by Liu demonstrated a benefit of adding brinzolamide to
latanoprost for reducing nocturnal IOP, but the difference was minimal, with
all groups still demonstrating a nocturnal IOP peak.
Although prostaglandin analogues are known to lower both
daytime and to a lesser degree nocturnal IOP2, the necessity of a daily drop
implies that the effect is cyclical. It is therefore plausible that sustained
drug delivery systems like the bimatoprost intracameral implant (Durysta®,
AbbVie, Chicago, IL, USA) and the travoprost intracameral implant (iDose® TR,
Glaukos, Aliso Viejo, CA, USA) might provide an incremental benefit over the
drop form. A recent study on Durysta shows that unlike the bimatoprost drop,
which lowers daytime IOP twice as much as nocturnal IOP, the Durysta implant
was able to lower both diurnal and nocturnal IOP by similar amounts. Although
the nighttime IOP was still overall higher than daytime, this study suggests
that implantable drug delivery systems may provide better 24-hour coverage.
There is yet no nocturnal data on the iDose due to the recent arrival on the
market.
The recently published LiGHT trial demonstrated that
although post selective laser trabeculoplasty IOP had a lower 24-hour average,
its 24-hour rhythm and nocturnal peaks were similar to that of pre-treatment
measurements. Because no studies to date have investigated the 24-hour IOP profile
after MIGs surgeries, it is unknown if MIGs can actually lower nocturnal IOP.
Most of these MIGs target the conventional pathway, which is undermined by
increased nocturnal EVP. It is possible that supraciliary shunts, which bypass
EVP via the unconventional pathway, may effectively lower nocturnal IOP;
however there have been no 24-hour IOP studies on supraciliary shunts.
The only incisional surgical treatment shown to provide
24-hour control is trabeculectomy, which has also demonstrated the best efficacy
of slowing glaucoma progression in progressive glaucoma with elevated or normal
IOP. Multiple studies have been published supporting the benefit of
trabeculectomy in reducing nocturnal IOP elevation, including work highlighting
the superior 24-hour IOP control offered by trabeculectomy versus maximal
medical management. The minimization of nocturnal IOP elevation conferred by
trabeculectomy may be one of the key reasons trabeculectomy leads to slowed
disease progression. While trabeculectomy may provide nocturnal control in
patients at greatest risk for profound vision loss, the morbidity associated
with filtration surgery suggests that a safer method to lower IOP at night
remains a significant unmet need in glaucoma management.
Therapies That Lower Nocturnal IOP
The evidence supporting the importance of lowering nocturnal
IOP and minimizing IOP elevations throughout the 24- hour period is robust.
However, the current landscape shows a very limited number of interventions
that successfully minimize nocturnal IOP elevations in patients with glaucoma.
Until recently, only trabeculectomies have been shown to lower reliably lower
nocturnal IOP.
The Ocular Pressure Adjusting Pump (Balance Ophthalmics,
Sioux Falls, SD, USA), is the only FDA-approved device that has been shown to
lower nocturnal IOP. While the device is worn, it lowers IOP by applying
negative pressure independently to each periorbital region using a
pressure-modulating pump and a pair of pressure-sensing goggles. The
IOP-lowering effect of the device has been demonstrated in multiple studies,
including a study by Goldberg in which mean nocturnal IOP was reduced by 35%
during device usage. Additional studies have demonstrated the benefits of
device use on ocular blood flow. Computational modeling demonstrated a
significant reduction in biomechanical strain at the ONH, supporting the
biomechanical benefit of employing negative periocular pressure to lower IOP.
The IOP lowering effect of the device was independent of baseline IOP or
additional treatment.
Reduction of IOP during both day and night clearly provides
a therapeutic benefit in slowing the progression of OAG, especially the
difficult-to-treat NTG. This paper summarizes the findings of recent research
to highlight the importance of nocturnal IOP control and the likely benefit of
periodic IOP reduction in slowing the progression of glaucoma. The Ocular Pressure
Adjusting Pump may be the first safe and effective method for reducing
nocturnal IOP, especially for patients with NTG.
Source: Huang et al; Clinical Ophthalmology 2024:18
https://doi.org/10.2147/OPTH.S494949
