Progress in Retinal and Eye Research 55 (2016) 108e148

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Progress in Retinal and Eye Research

journal homepage: www.elsevier.com/locate/prer

24-h monitoring devices and nyctohemeral rhythms of intraocular

pressure
Florent Aptel a, b, 1, Robert N. Weinreb c, 1, Christophe Chiquet a, b, 1, Kaweh Mansouri d, e, *, 1
a
Inserm U1042, Hypoxia and Physiopathology Laboratory, University Grenoble Alpes, Grenoble, France
b
Department of Ophthalmology, University Hospital, CHU Grenoble, Grenoble, France
c
Hamilton Glaucoma Center, Shiley Eye Center and Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA
d
Glaucoma Center, Montchoisi Clinic, Swiss Vision Network, Lausanne, Switzerland
e
Department of Ophthalmology, University of Colorado School of Medicine, Denver, CO, USA

a r t i c l e i n f o a b s t r a c t

Article history: Intraocular pressure (IOP) is not a fixed value and varies over both the short term and periods lasting
Received 22 April 2016 several months or years. In particular, IOP is known to vary throughout the 24-h period of a day, defined
Received in revised form as a nyctohemeral rhythm in humans. In clinical practice, it is crucial to evaluate the changes in IOP over
7 July 2016
24 h in several situations, including the diagnosis of ocular hypertension and glaucoma (IOP is often
Accepted 12 July 2016
Available online 28 July 2016
higher at night) and to optimize the therapeutic management of glaucoma. Until recently, all evaluations
of 24-h IOP rhythm were performed using repeated IOP measurements, requiring individuals to be
awakened for nocturnal measurements. This method may be imperfect, because it is not physiologic and
Keywords:
Intraocular pressure
disturbs the sleep architecture, and also because it provides a limited number of time point measure-
Nyctohemeral ments not sufficient to finely asses IOP changes. These limitations may have biased previous descriptions
Circadian of physiological IOP rhythm. Recently, extraocular and intraocular devices integrating a pressure sensor
Contact lens sensor for continuous IOP monitoring have been developed and are available for use in humans. The objective of
Glaucoma this article is to present the contributions of these new 24-h monitoring devices for the study of the
24-h monitoring nyctohemeral rhythms. In healthy subjects and untreated glaucoma subjects, a nyctohemeral rhythm is
consistently found and frequently characterized by a mean diurnal IOP lower than the mean nocturnal
IOP, with a diurnal bathyphase e usually in the middle or at the end of the afternoon e and a nocturnal
acrophase, usually in the middle or at the end of the night.
© 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction: intraocular pressure variations and nyctohemeral rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

1.1. Definition of intraocular pressure variations and fluctuations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
1.1.1. Definition of intraocular pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
1.1.2. Secretion and elimination of aqueous humour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
1.1.3. IOP measurement methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
1.1.4. Normal values and physiological variations in IOP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
1.2. The neuroanatomical and physiological bases of intraocular pressure nyctohemeral rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
1.2.1. The anatomic and functional organization of the circadian system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 112
1.2.2. Impact of the circadian system on the intraocular pressure rhythm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
1.3. Nyctohemeral rhythms of intraocular pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

* Corresponding author. Glaucoma Center, Montchoisi Clinic, Swiss Vision

Network, Lausanne, Switzerland.
E-mail address: kawehm@yahoo.com (K. Mansouri).
1
Percentage of work contributed by each author in the production of the
manuscript is as follows: Florent Aptel: 30%, Robert N. Weinreb: 20%, Christophe
Chiquet: 20%, Kaweh Mansouri: 30%.

http://dx.doi.org/10.1016/j.preteyeres.2016.07.002
1350-9462/© 2016 Elsevier Ltd. All rights reserved.
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148 109

1.3.1. Study methods (non-continuous measurements) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

1.3.2. Mathematical methods used to model rhythms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
1.3.3. Studies of nyctohemeral rhythms of intraocular pressure in healthy subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
1.3.4. Studies of nyctohemeral rhythms of intraocular pressure in subjects with glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
1.3.5. Studies of nyctohemeral rhythms of intraocular pressure in other conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
1.3.6. Limitations of the current tonometry methods in the study of the nyctohemeral rhythms of IOP measurements . . . . . . . . . . . . . . . . 129
2. Continuous monitoring of IOP with extraocular devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.1. Description and measurement principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2.2. Nyctohemeral rhythms of intraocular pressure in healthy subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
2.2.1. Description of rhythms and reproducibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
2.2.2. Influencing factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
2.3. Nyctohemeral rhythms of intraocular pressure in glaucoma patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
3. Continuous monitoring with intraocular devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
3.1. Description and measurement principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
3.1.1. Physical principles of pressure measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
3.1.2. External signal measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
3.1.3. First devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
3.1.4. Sensor integrated intraocular lenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
3.2. First clinical results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
4. Perspectives and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
4.1. Analysis and interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
4.2. Beyond absolute IOP e searching for inherent patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Financial support and sponsorship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

1. Introduction: intraocular pressure variations and and colourless media with a refractive index close to 1.33, is a
nyctohemeral rhythms fundamental element of the optical system formed by the eye,
allowing the propagation of light beams in the eye and the
1.1. Definition of intraocular pressure variations and fluctuations refraction of the light at the corneaeanterior chamber and anterior
chamberecrystalline lens interfaces. The permanent flow of
1.1.1. Definition of intraocular pressure aqueous humour brings various metabolic substrates and dissolved
Pressure is a force that is uniformly applied to the surface of an oxygen to the lens, the corneal endothelium and the trabecular
object per unit area over which that force is distributed. The eye is a meshwork, which are avascular structures, and allows the removal
space closed by a wall, similar to a surface. Pressure within the eye, of waste from the metabolism. Aqueous humour is also a vector for
called the intraocular pressure (IOP), is exerted on this wall and circulating components involved in paracrine communications and
being higher than atmospheric pressure, prevents the collapse of immune responses within the eye.
the eyeball. IOP results from the balance between the contents of
the globe (aqueous humour, lens, vitreous, uvea) and its container,
the corneoscleral wall. The corneoscleral wall is composed of 1.1.2. Secretion and elimination of aqueous humour
collagen and elastic fibres whose distension capacity is very low in Among the different contents of the eye, aqueous humour is the
adults, contrary to the capacity in children. Any increase in volume key determinant of IOP. The latter indeed depends on the variations
of the intraocular contents is immediately limited by the parietal in the balance between the production and elimination of aqueous
resistance or scleral rigidity, and results in an IOP increase. This humour, which can be summarized by Goldmann's equation:
scleral rigidity varies with age and with the subject's refractive
status. Since the distension of the corneoscleral wall is very limited, Po ¼ ðF  UÞ=C þ Pv
the IOP level depends largely on the secretion and elimination of
where Po is the IOP in millimeters of mercury (mmHg), F the rate of
aqueous humour, but other factors are also involved. The vitreous,
aqueous humour formation in microliters per minute (mL/min), U
which accounts for approximately two-thirds of the volume of the
the resorption of aqueous humour through the uveoscleral route
eye, can be subject to volumetric changes depending on its level of
(in mL/min), C is the facility of outflow in microliters per minute per
hydration, due to its high water content. These volumetric changes,
millimeter of mercury (mL/min/mmHg) and Pv the episcleral
constrained by the stiffness of the eye wall, also have an effect on
venous pressure in millimeters of mercury (mmHg).
IOP. The uvea transmits the changes in vascular volume and pres-
Aqueous humour is secreted by the anterior portion of ciliary
sure to IOP. A sudden increase in uveal blood volume causes a
epithelium lining the ciliary processes and enters the posterior
significant and immediate IOP elevation.
chamber. The various components of aqueous humour must tra-
The flow of aqueous humour within the eye has different major
verse the three tissues forming the ciliary processes e the capillary
functions. The steady state resulting from the balance between the
wall, stroma and epithelial bilayer e to reach the posterior cham-
production and elimination of aqueous humour generates a pres-
ber. The principal barrier to transport across these tissues is the cell
sure necessary for the development of the eye during embryonic
membrane and related junctional complexes of the non-pigmented
life and the maintenance of ocular structures in a state of perma-
epithelial layer (Hogan et al., 1971). In the ciliary epithelium, several
nent distension throughout life. Aqueous humour, a transparent
mechanisms will allow blood elements present in the stroma and
110 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
the intercellular spaces to cross cell membranes and the blood-
eaqueous barrier to produce the aqueous humour in the posterior
chamber. Some of the mechanisms are passive and do not require
metabolic energy, whereas others are active and therefore require
metabolic energy (Coca-Prados and Escribano, 2007; Freddo, 2013).
Diffusion occurs when solutes, especially fat-soluble substances,
are transported through the lipid portions of the tissue membrane
between the capillaries and the posterior chamber, proportional to
a concentration gradient across the membrane (Civan and
Macknight, 2004). Ultrafiltration is the flow of water and water-
soluble substances, limited by size and charge, across fenestrated
ciliary capillary endothelia into the ciliary stroma, in response to an
osmotic gradient or hydrostatic pressure. Diffusion and ultrafiltra-
tion are responsible for the accumulation of plasma ultrafiltrate in
the stroma, behind tight junctions of the non-pigmented epithe-
lium, from which the posterior chamber aqueous humour is
derived (Smith and Rudt, 1973; Uusitalo et al., 1973). Active secre-
tion requires a metabolic energy provided by enzymatic systems
(energy-dependent pumps hydrolyzing adenosine triphosphate
molecules to adenosine diphosphate molecules) in order to transfer
specific substances through the barrier, possibly across a gradient
concentration. Active transport takes place through selective
transcellular movement of anions, cations and other molecules
mediated by protein transporters distributed in the cellular mem-
brane. Active secretion is thought to be the major contributor to
aqueous formation, responsible for approximately 80e90% of the
total aqueous humour formation (Hogan et al., 1971; Mark, 2009).
Studies based on the measurement of decay over time of the
concentration of a tracer or dye injected into the anterior chamber
have estimated that about 1e1.5% of the volume of the anterior
chamber is renewed every minute (Bill, 1971; Freddo, 2001;
McLarren, 2009). The half-life of a water-soluble and low molecu-
lar weight dye is thus about 2e3 h. A study based on the fluo-
rophotometry technique found an aqueous secretion rate of
3.0 ± 0.8 mL/min between 8 a.m. and noon in 519 healthy subjects.
The distribution of this parameter in the population was approxi-
mately normal, with 95% of values between 1.5 and 4.5 mL/min
(Brubaker, 1991, 1998; Gabelt and Kaufman, 2003; Gabelt and
Kaufman, 2005).
A circadian rhythm of aqueous humour secretion was found,
with higher flow during the daytime and lower at night. Thus, the
flow estimated by fluorophotometry decreased to 2.7 ± 0.6 mL/min
between 2 p.m. and 6 p.m. (490 subjects) and 1.3 ± 0.4 mL/min
between midnight and 6 a.m. (Brubaker, 1991, 1998). The exact
mechanisms leading to the circadian pattern of aqueous humour
secretion are not exactly known. Nevertheless, it seems that the
diurnal activity of the sympathetic system is the major determinant
of these changes. Thus, the antagonists of beta-adrenergic re-
ceptors (beta-blockers) have little or no effect on the aqueous
secretion at night. In contrast, some non-selective adrenergic re-
ceptor agonists, such as epinephrine, significantly increase the
aqueous secretion when administered at night, but have little effect
during the daytime. One study found a 47% increase of aqueous
humour secretion following topical administration of epinephrine
at night, but only 19% after instillation of the same agent during the
day (Townsend and Brubaker, 1980). Comparable results but with
smaller differences are found after instillation of norepinephrine.
The factors influencing the aqueous humour secretion are sum-
marized in Table 1.
The aqueous humour exits the eye mainly via the trabecular
meshwork (conventional pathway) in adults and elderly subjects
and secondarily but significantly through the tissue of the iris
stroma and ciliary body to the supra-choroidal space (uveoscleral
or unconventional pathway).
The trabecular meshwork is a porous structure that consists of
connective tissue surrounded by endothelium. It acts as a filter. The
aqueous humour is then collected in a circular channel which fol-
lows the circumference of the eye behind the cornea called
Schlemm's canal and then flows in many small aqueous veins,
allowing the return of aqueous humour in the general blood cir-
culation. The trabecular pathway is responsible for 70e90% of the
outflow of aqueous humour; its proportion increases with age due
to the decline of the size of the uveoscleral pathway. In humans,
75% of the resistance to aqueous humour outflow is localized to the
trabecular mesh, and 25% occurs beyond Schlemm's canal (Grant,
1958). This route of elimination is dependent on the level of IOP
and an estimated flow of aqueous humour through this route
ranging from 0.22 to 0.30 mL/min/mmHg.
The nonconventional pathway consists in the passage of
aqueous humour through the iris root stroma e whose anterior side
is devoid of epithelium e and its passage through the muscular
bundles of the ciliary body to the supra-ciliary and the supra-
choroidal space. From there it crosses the sclera directly or
through the perivascular spaces, blood vessels and nerves. The
uveoscleral pathway is responsible for 10e30% of the elimination of
aqueous humour, the proportion of aqueous humour exiting the
eye via the uveoscleral pathway decreasing with age (Toris et al.,
1999). The uveoscleral outflow pathway is relatively independent
of the intraocular pressure.
1.1.3. IOP measurement methods
Indentation tonometry was the first quantitative method of IOP
measurement developed and is based on the simple principle that
we can submit the eye to an external force depressing the cornea,
and that the extent of depression induced by a given force is related
to IOP. The Shiøtz tonometer consists of a piston that deforms and
indents the cornea in a subject in the supine position due to its
weight and additional weights that can be added (Cridland, 1917).
The depth of the corneal depression produced by a given weight is
measured and the IOP is estimated from calibration tables. The
apparatus is shaped like a metal rod sliding along an axis. One
major limitation of indentation tonometry is that the indentation of
the cornea by a given force varies widely depending on the eye
wall's biomechanical properties. Changes in scleral rigidity in
subjects are therefore a major cause of error and explain the
gradual abandonment of the Shiøtz tonometer in clinical practice.
Since its development in 1950, Goldmann applanation tonom-
etry (GAT) has remained the gold standard method for measuring
IOP. No new technique has really supplanted GAT to measure IOP
even if classical applanation tonometry has limitations. In GAT
measurements, the cornea is flattened over a defined area
(3.06 mm in diameter) and the required applanation pressure is
used to estimate the IOP based on the Imbert-Fick law
(Force ¼ Pressure/Area) assuming that the eyeball is a perfect
sphere and the cornea a perfectly thin, elastic and flexible mem-
brane. GAT is therefore influenced by several ocular factors, such as
central corneal thickness, corneal biomechanical properties and
scleral rigidity (Ehlers et al., 1975; Liu and Roberts, 2005). Apart
from these biomechanical factors creating bias, GAT also suffers
from several operator biases (Whitacre and Stein, 1993). Moreover,
it implies sitting in front of a slit lamp, which is far from the
physiologic position during the nocturnal/sleep period.
Non-contact tonometers were developed beginning in the early
1970s and are now widely used in clinical routine. This variant of
the applanation tonometer uses a brief air puff for deforming the
cornea until it becomes concave, but via a phase in which the
flattened surface has the best reflection angle between a light
source and an optoelectronic sensor that is detected and regarded
as the measurement time. The time lapsed between the start of the
air jet and the maximum reflection on the cornea may be converted
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148 111

Table 1
Factors leading to aqueous humour secretion reduction.

Physiologic factors Age

Nocturnal period
Physical exercise
General factors Ocular blood flow reduction
Hypothermia
Acidosis
General anaesthesia
Local factors IOP elevation
Anterior uveitis
Scleritis
Retinal detachment
Choroidal detachment
Pharmacologic agents Beta-adrenergic receptor antagonists (beta-blockers)
Carbonic anhydrase inhibitors
Alpha-2-adrenerigc receptor agonists
Spironolactone
Opioid agonists
Hyperosmotic agents
Atrial natriuretic factor
Cannabinoids
Cyclic guanosine monophosphate
5-hydroxytryptamine1A receptor antagonists
Surgical procedures Cyclodestructive procedures (laser, ultrasound, cryotherapy)
Cyclodialysis
Cycloablation

to an IOP value.
More recently, new techniques have been developed to elimi-
nate a number of biases associated with traditional applanation
techniques and particularly to prevent corneal factors and analyse
the viscoelastic properties of the cornea, such as the Ocular
Response Analyser and the Pascal Dynamic Contour Tonometer.
They could allow a more comprehensive assessment of IOP. Studies
have shown that these methods are less influenced by corneal
thickness than GAT; however, they are not widely used in clinical
practice and have not replaced the GAT (Hager et al., 2008; Streho
et al., 2008).

1.1.4. Normal values and physiological variations in IOP

Several epidemiological studies have performed a one-time
measurement of IOP in large cohorts of healthy subjects to study
IOP distribution. In 1958, a study by Leydhecker et al. that measured
the IOP in 10,000 healthy subjects showed a roughly Gaussian
distribution curve of IOP within the population (Leydhecker et al.,
1958). Data from large epidemiological studies have confirmed Fig. 1. Normal values of intraocular pressure. Distribution of intraocular pressure in a
the Gaussian distribution, although it is slightly asymmetrical with population of 5220 eyes of healthy subjects (Framingham Eye Study) (Hiller et al.,
1999).
an overrepresentation of high pressures, mainly in individuals over
40 years of age (Colton and Ederer, 1980; Hiller et al., 1999) (Fig. 1).
They found a mean IOP of 15e16 mmHg with a standard deviation
in intrathoracic pressure results in a stretching of choroidal and
of about 2.5 mmHg. A statistically normal IOP was thus defined as
orbital veins, which instantly increases IOP.
the mean IOP ± 2 standard deviations, i.e. between 9 and 21 mmHg.
Accommodation: Prolonged accommodation induces a pro-
IOP is not a fixed value and varies over both the short term and
longed decrease in IOP, estimated at 2e3 mmHg for an accommo-
periods lasting several months or years (Aptel et al., 2014b).
dation of 4 diopters (Mauger et al., 1984). This effect is observed
At the short term (over seconds or minutes).
only for prolonged accommodative effort, exceeding 2e3 min,
Blood pressure and heart rate: Any change in systemic blood
which rarely occurs. The decrease in IOP after accommodation is
pressure directly changes IOP. A 10-mmHg increase in systolic
more pronounced in younger subjects.
blood pressure is accompanied physiologically by simultaneous
Eyelid blink: The immediate effect of a spontaneous eyelid blink
elevation in IOP of about 1 mmHg, possibly explaining the rela-
is an immediate elevation in IOP of 1e2 mmHg with a rapid return
tionship between the two conditions (Bulpitt et al., 1975). IOP varies
to the starting IOP at the end of the blink. A series of blinks (a series
synchronously with the heart pulse and increases by 1e2 mmHg
of 15 blinks lasting 2 s each) would lead to a drop in IOP up to
during systole responsible for intraocular blood flow.
2 mmHg due to a massage effect (Green and Luxenberg, 1979).
Breathing: Breathing also induces rhythmic oscillations of the
Pupillary size: Gloster and Poinoosawmy showed that mydriasis
IOP, the pressure rising slightly during inspiration and thereby
obtained by confinement in a dark room for 1 h induced an IOP
decreasing during expiration. Many subjects hold their breath
increase of 4 mmHg, with the return to the starting IOP taking place
during tonometry, which may increase lung pressure and the
in 10 min (Gloster and Poinoosawmy, 1973).
episcleral venous pressure by the Valsalva maneuver. The increase
112 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Eye movement: Forced sidelights cause a sudden and transient
IOP elevation with immediate return to baseline IOP (Cooper et al.,
1979). This can be exacerbated in certain pathological conditions
such as Graves' orbitopathy.
Central venous pressure: An increase in the central venous
pressure has an impact on the elimination of aqueous humour and
the drainage of venous blood from the eye. When the central
venous pressure increases by 1 mmHg, IOP rises by about
0.8 mmHg (Cooper et al., 1979). The Valsalva maneuver, which has a
direct action on the central venous pressure, thus causes an
elevation of IOP, as does coughing or straining.
Physical activity: Intense physical activity over a very short
duration leads to an immediate increase of IOP via elevation of the
systemic blood pressure. A sufficiently prolonged physical effort
leads to a reduction in IOP proportional to the intensity of the
physical effort (Hamilton-Maxwell and Feeney, 2012; Passo et al.,
1991). Metabolic changes involving the production of lactic acid,
an increased blood osmolality and a decrease in pH could explain
this phenomenon.
Postural factors: The transition from supine to a sitting or upright
posture causes a constant and immediate increase in IOP ranging
from 1.50 to 5 mmHg depending on the subject (Carlson et al., 1987;
Chiquet et al., 2003). An extended supine position results in a less
pronounced increase in IOP.
Ingestion of water and osmolarity: The rapid ingestion in less
than 5 min of an amount of water proportional to the weight of the
subject (10 mL/kg) is responsible for an increase of IOP observed in
the first hour after ingestion. The maximum average increase in IOP
varies according to the authors, up to 4.4 mmHg (Buckingham and
Young, 1986; Goldberg and Clement, 2010). The mechanism is not
fully understood. Conversely, dehydration conditions will induce a
decrease in IOP.
Hormonal factors: During pregnancy, there is an ocular hypo-
tensive effect with a return to baseline IOP during postpartum after
a period of 3 months. Progesterone may be responsible, acting by
decreasing the flow resistance of aqueous humour (Ziai et al., 1994).
By contrast, menopause induces an IOP elevation.
Ethyl alcohol, cannabis and its derivatives, heroin and some an-
aesthetics (ketamine, halogenated gases, and muscle relaxants)
have a hypotensive effect. In contrast, coffee, consumed in large
doses, may result in an increase in IOP which could reach up to
4 mmHg, with an effect extending up to 1.5 h (Buckingham and
Young, 1986).
At the long term (over several weeks or months):
Age: There is no clear consensus on the relationship between
IOP and age. A number of studies have found an increase in IOP with
age, which is linked to an increase in trabecular meshwork resis-
tance over time (Armaly, 1967; Colton and Ederer, 1980). Other
authors have found no difference in IOP depending on age in
Western populations (Bengtsson, 1972). In a study of 200,000
healthy subjects in Japan, Shiose found a decrease in IOP with age
(Shiose, 1990). He estimated that the increase in IOP with age in
Western populations could be related to factors such as body mass
index and high blood pressure.
Weight: Many studies have demonstrated a positive correlation
between IOP and the body mass index (Shiose, 1990).
Seasons: There is a circannual rhythm IOP in temperate coun-
tries. The highest is in winter and the lowest in summer, the
magnitude varying from 1 to 5 mmHg (Blumenthal et al., 1970).
Temperature: Recent exposure to high ambient temperature
causes IOP elevation, and the effect disappears after acclimatiza-
tion. This effect was related to an increase in body temperature.
Shapiro et al. have shown that a 0.6  C increase of in body tem-
perature caused a 2.5-mmHg elevation in IOP (Shapiro et al., 1981).
At the medium term (over 24-h periods):
Beginning in the mid-1990s, studies showed that IOP varies
throughout the 24-h period of a day, defined as a nyctohemeral
rhythm. This important point is not detailed here and the
description of the nyctohemeral rhythms of IOP will be addressed
below, including the recent findings with the new methods of
continuous IOP measurement.
1.2. The neuroanatomical and physiological bases of intraocular
pressure nyctohemeral rhythms
1.2.1. The anatomic and functional organization of the circadian
system
Circadian rhythms exist in all species, from single-cell organ-
isms to humans (Aschoff, 1984) and provide adaptive regulation of a
large number of internal functions (physiological, neuroendocrine
and behavioural) to external cycles of the environment (Morin,
1994). Most living organisms have developed an internal circa-
dian system that is capable not only of reacting to cyclic stimuli in
the environment, but also of anticipating these stimuli (Morin,
1994). In mammals, the temporal organization involves the sleep-
activity cycle, the synthesis of melatonin, thermal regulation, lo-
comotor activity, feeding behaviour, reproduction and osmotic
regulation (Morin, 1994).
1.2.1.1. Definition of circadian rhythm and nyctohemeral rhythm.
Biological rhythms are classified according to whether they occur
with a period equal to or near the Earth's rotation (24 h, circadian
rhythms) or the rotation of the Earth around the sun (365.25 days,
circannual rhythms), or a different period (ultradian rhythms). We
call biological rhythm the regular variation of a biological magni-
tude over time. A rhythm is characterized by different parameters:
- Period: the time interval separating the appearance of two
identical events (phase). The phase is a time marker that cor-
responds to a precise point on the curve. For example, the
minimum body temperature is used in humans as the marker
for the phase of circadian rhythm.
- Mean level (or mesor): the arithmetic mean of all the instan-
taneous values equidistant from a variable, obtained during a
period.
- Amplitude: the difference between the maximum and the mean
level.
- Acrophase: the maximum value of the variable studied in rela-
tion to time.
- Bathyphase: the opposite of acrophase, the minimum value of
the variable studied in relation to time.
The mathematical analysis of a rhythm (Halberg and Reinberg,
1967) is an approach designed to describe this rhythm, quantify it
and carry out statistical comparisons. The rhythms of daily activity,
or circadian rhythms (from the Latin circa, around, and dies, day),
present a period of approximately 24 h. A nyctohemeral rhythm is
defined as a rhythm expressed over a 24-h cycle influenced by light/
dark alternation. A nyctohemeral rhythm is only considered circa-
dian if its rhythmicity over 24 h is preserved when there is no
environmental influence (light or social activities). Experiments
reported in the literature have made it possible to define the IOP
rhythm as circadian in animals and nyctohemeral in humans. For
technical reasons, it would be necessary to keep healthy subjects or
glaucomatous patients in constant light for several days to prevent
any environmental information input (in a constant-routine para-
digm) to demonstrate that IOP rhythm is indeed circadian.
Circadian rhythms present two fundamental physiological
properties:
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148 113

- Circadian rhythms are generated by an endogenous clock
(located in the suprachiasmatic nucleus, SCN) and their period is
approximately 24 h. In absence of temporal factors from the
environment (light information), the rhythms follow their nat-
ural course, i.e. they express their own period, which is around
24 h (Czeisler et al., 1999).
- Circadian rhythms are synchronized over 24 h by light (24-h
light/dark cycles), considered the most important synchro-
nizer (zeitgeber, or giver of time) of the circadian system (Moore,
1992). The retina is the exclusive site of circadian photorecep-
tion in mammals. A fundamental function of the visual system is
to synchronize the biological endogenous clock in the SCN ac-
cording to the nyctohemeral and environmental photoperiodic
cycle. This light (or photic) information is transmitted to the SCN
via the retinohypothalamic (RHT) and geniculohypothalamic
(GHT) tracts. The photic entrainment induced by exposure to
light produces a lapse in the circadian clock depending on the
moment within the nyctohemeral cycle when light is presented.
1.2.1.2. The retinohypothalamic pathway. In mammals, the circa-
dian system comprises three basic components (see Fig. 2):
- A neurosensory input, made up of photoreceptors and retinal
neurons projecting to the SCN, synchronizing endogenous
rhythms to the external light/dark cycle.
- An internal clock, which generates oscillations close to 24 h. In
mammals, the SCN contains the internal clock and its period is
adjusted to light cycles through monosynaptic projections from
the retina, called RHT.
- The effector systems of the clock, which result in the temporal
regulation of the physiological and neuroendocrine rhythms.
The neurosensory input is composed of the RHT, allowing the
transmission of photic or nonvisual information (the non-image-
forming [NIF] system). Photic information is detected by the
retina and is characterized by changes in irradiance associated with
light and dark (Roenneberg and Foster, 1997), synchronizing the
endogenous clock. This information is then integrated over a rela-
tively long period of time in the SCN.
1.2.1.2.1. The retinohypothalamic pathway. The main pathway
entraining the circadian system - the RHT - transmits photic in-
formation from the retina to the hypothalamus, notably the SCN.
Several studies have shown that the RHT is necessary and sufficient
for photic entrainment of the SCN. Circadian photoreception is
exclusively ocular (Meijer et al., 1999). Bilateral enucleation
removes any possibility of photic regulation in rodents (Foster et al.,
1991) and in humans (Czeisler et al., 1995).
The data on circadian photoreception have evolved enormously
in the past 15 years. Initially, animal studies showed that circadian
photoreception only involved the classic photoreceptors such as
rods (502 nm) (Aggelopoulos and Meissl, 2000; Milette et al., 1990;
Provencio et al., 1994, 1998; Takahashi et al., 1984) or cones
(Aggelopoulos and Meissl, 2000; Calderone and Jacobs, 1995). The
studies conducted on transgenic mice without rods (Argamaso
et al., 1995; Lupi et al., 1999; Provencio et al., 1998) or middle-
wavelength-sensitive cones (Freedman et al., 1999) during devel-
opment suggested that rods or cones were not indispensable to
photic entrainment and that there was redundancy at the level of
circadian photoreception. Other studies conducted on double-
mutant rd/rd cl mice (C3H/He strain) or rdta cl mice (C57BL/6
strain), whose retina no longer presents any rods or cones (Lucas
et al., 1999), and in a vitamin A-deficient mouse model
(Thompson et al., 2001) showed that the normal response of the
circadian system to light was possible in absence of classic
photoreceptors.
This normal response of the circadian system in absence of
classic photoreceptors is explained by the presence of photosensi-
tive retinal ganglion cells (pRGCs) containing melanopsin, discov-
ered in 2000 (Berson et al., 2002; Hattar et al., 2002; Sekaran et al.,
2003). These pRGCs account for 0.2% of the RGCs (3000 RGCs/eye in
primates) and have been classified into five subtypes (M1eM5-type

Fig. 2. Schematic organization of the circadian system with a neurosensory input (retina), an internal clock (the suprachiasmatic nucleus) and effector systems of the clock, which
result in the temporal regulation of the physiological and neuroendocrine rhythms. Middle right: Immunolabelling of neurons of suprachiasmatic nucleus which receive projections
from retinal ganglion cells infected by the pseudorabic virus-Bartha in rodent (scale 200 mm). Middle left: Retinal ganglion cell which projects to the suprachiasmatic nucleus in a
rodent (cell infected by pseudorabic virus-Bartha) on a whole-mount retina preparation (scale 20 mm). (C. Chiquet and F. Aptel unpublished data). IGL: intergeniculate leaflet.
114 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
pRGCs). The M1 subtype is predominant with a large soma, the
largest quantity of melanopsin, and the most sensitive photo-
responses (compared to the other subtypes), long and scattered
dendrites that stratify in the external part of the inner plexiform
layer (Ecker et al., 2010). These RGCs are characterized by a strati-
fication of their dendrites in a specific sublamina of the inner
plexiform layer (Ecker et al., 2010; Hattar et al., 2006) as well as the
levels and isoforms of melanopsin which they express (Hughes
et al., 2012; Pires et al., 2009). The SCN is mainly innervated by
M1-type pRGCs (Baver et al., 2008; Ecker et al., 2010; Hattar et al.,
2006), and more incidentally by M2-type pRGCs (Baver et al., 2008).
Berson et al. (2002) noted that photosensitive ganglion cells
received rod/cone ON-type influxes (very transitory ON responses,
with very short latency and a lower threshold than from intrinsic
photosensitive responses). The electrophysiological responses of
ganglion cells containing melanopsin have a sensitivity peak at
480 nm, compatible with the action spectrum of photic entrain-
ment (Berson et al., 2002; Hattar et al., 2002). These pRGCs are less
sensitive than rods or cones because responses to single photons
are very slow with very prolonged integration times (20 times the
time needed for rods and 100 times the time needed for cones) and
they require greater light intensity and a longer duration (Díaz
et al., 2016). Stimulation of melanopsin leads to the activation of
a membrane-bound signalling cascade involving Gq/11-type G-
proteins, activation of PLCb4, and opening of downstream TRPC6
and TRPC7 ion channels, ultimately leading to Ca2þ influx and
cellular depolarization (Graham et al., 2008; Xue et al., 2011).
Current data therefore show that circadian photoreception is
mediated by cones, rods and pRGCs. The photic information
perceived by classic photoreceptors is transmitted to bipolar and
amacrine cells in contact with the pRGCs. Rod-, cone- and
melanopsin-driven signals are capable of driving entrainment and
are responsible for encoding different aspects of the light signal,
providing a robust and versatile measurement of daily light levels
(Lall et al., 2010; Lucas, 2013). More recent data even suggest that
the role played by pRGCs may not be limited to the non-imaging
forming pathway but that these RGCs may also modulate visual
perception because of their interaction with other retinal neurons
(such as dopaminergic amacrine cells) and their retina-recipient
visual areas including the dLGN and superior colliculus (Hankins
and Hughes, 2014; Lucas, 2013). Research is currently under way
on the mechanisms of the renewal cycle of melanopsin and on the
identification of other opsins in the retina such as OPN5 (neuro-
psin) and OPN3 (encephalopsin/panopsin).
1.2.1.2.2. Projections of RHT on the SCN. The first studies
showing the existence of retinal projections on the hypothalamus,
notably the SCN, date from 1972, using autoradiographic tracing
techniques (Hendrickson et al., 1972; Moore and Lenn, 1972). The
RHT pathway projects not only to the SCN but also other hypo-
thalamic structures such as the anterior hypothalamic area, the
retrochiasmatic area, the lateral hypothalamus and dorsal hypo-
thalamus, as well as structures such as the perifornical area (the
zona incerta), the lateral intergeniculate leaflets (IGLs), the pre-
tectum (pupillary light reflex), the amygdala complex and the
olfactive bulb (Cooper et al., 1989; Mick et al., 1993; Mikkelsen,
1992; Mikkelsen and Vrang, 1994).
In addition, axon collaterals forming the RHT and projecting to
the SCN continue in the optical pathway and terminate with dense,
bilateral projection of the IGL of the lateral geniculate complex
(Moore and Card, 1994; Pickard, 1985). The retina also projects to
other hypothalamic regions, other than the SCN, such as the medial
preoptic region (responsible for thermoregulation, drinking,
reproduction, maternal behaviour) and the lateral preoptic region,
the lateral hypothalamic region (feeding behaviour) and anterior
hypothalamic region (photoperiod), the supraoptic nucleus, the
retrochiasmatic region and the subparaventricular zone (Costa
et al., 1999).
1.2.1.2.3. RHT neurotransmitters. The two main RHT neuro-
transmitters are glutamate (GLU) and pituitary adenylate cyclase-
activating polypeptide (PACAP). Glutamate connects to the N-
methyl-D-aspartate (NMDA) and non-NMDA receptors at the SCN,
which modulates the function of the endogenous clock. PACAP is a
neuropeptide of the vasoactive intestinal peptide (VIP) family,
expressed in the peripheral and central nervous system. PACAP
presents in two active forms: PACAP-38 (with 38 amino acids) and
PACAP-27 (C-terminal truncated form). PACAP-38 is the dominant
form in tissue. Several functional studies have shown that PACAP,
alone or associated with GLU, is involved in the transfer of photic
information. More than 95% of RGCs projecting to the SCN are
PACAP-positive (Hannibal et al., 2001). PACAP modulates GLU ac-
tivity by amplifying the increase in intracellular calcium dependent
on GLU, through interaction with the AMPA/kainate signalling
pathway. In addition, PACAP reduces the increase in calcium via
metabotropic receptors.
Other neurotransmitters may be involved, such as N-acetylas-
partylglutamate (Moffett et al., 1991), substance P (Shibata et al.,
1992; Shirakawa and Moore, 1994) and VIP (Ibata et al., 1989).
1.2.1.2.4. The suprachiasmatic nucleus. By definition an endog-
enous internal clock (or circadian pacemaker) is a biological oscil-
lator that measures local time and regulates the temporal
organization of living organisms. A circadian pacemaker has three
fundamental properties: (1) endogenous oscillations, (2) adjust-
ment to environmental time (notably the light/dark cycle) and (3)
the production of an efferent signal that synchronizes all the os-
cillators present in the organism.
The SCN is a nucleus located in the dorsal part of the chiasma on
either side of the third ventricle (2.5 cm3). It has two anatomic
subdivisions: the ventrolateral part receiving retinal projections
and projections from the IGL and the dorsomedial part receiving
afferents from other cerebral regions. In humans, the hypothalamus
volume is approximately 4 cm3, 0.3% of the total volume of the
encephalon (twice as large as in the rat) (Hofman and Swaab, 1992).
RHT fibres are in contact with the neurons of the ventral part of the
SCN (Dai et al., 1998; Sadun et al., 1984), containing neurotensin or
VIP and sometimes vasopressin. The anatomic structures of the
circadian system in humans and primates differ from those of ro-
dents on essentially two points: the IGL is a component of the
lateral geniculate complex and the projections of the SCN are more
extensive than in rodents. The human circadian system differs from
that of rodents and other primates notably in the organization of
the SCN (a larger population of neuropeptide Y neurons, a large
population of neurotensin neurons) and efferent projections (more
extensive and denser on the paraventricular nucleus).
1.2.1.2.5. Molecular mechanisms of circadian oscillation genesis
and the effect of light on the circadian clock.
Electrophysiological analyses show that the majority of SCN neu-
rons present clock properties and that each of them oscillates at its
own rhythm (Welsh et al., 1995). To date ten genes, called clock
genes, have been identified: Per1, Per2, Per3, Clock, BMAL1, Cryl,
Cry2, Rev-erba and -b, and Casein kinase ε. Current research is
leading to a model of circadian rhythmicity founded on positive and
negative retrocontrols (transcriptionaletranslational feedback loop
(TTFL)). Both CLOCK and BMAL1 transcription factors activate the
transcription of target genes in the first feedback loop (Per1, Per2,
Cry1, Cry2) via E-box enhancer elements and in the accessory
feedback loop (Rev-erba and -b). The products of these clock genes
interact together and form transcriptional feedback loops (Buhr
and Takahashi, 2013).
Environmental irradiance synchronizes the circadian clock
depending on a succession of biochemical, cellular and molecular
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
events:
- Photon capture by retinal photoreceptors in mammals, followed
by transmission of photic information to the SCN by the RHT.
- Resulting in the release of GLU/PACAP in the axon projection
zones of axons of retinal ganglion cells mainly in the ventral part
of the SCN (Hastings et al., 1996).
- The pathway leading to induction or early genes in response to
light stimulation (King and Takahashi, 2000) brings into play
GLU release and its action on NMDA and non-NMDA receptors in
the SCN (Ebling, 1996). The simultaneous release of PACAP ac-
tivates PAC1 and VPAC2 receptors, increasing the concentration
of intracellular cAMP. This induces a cascade of intracellular
events, activation of kinase proteins, phosphorylation of Ca2þ/
cAMP response element binding protein leading to the induc-
tion of Per1 and -2 gene transcription (Gillette and Mitchell,
2002).
1.2.1.2.6. Circadian control of efferent systems. The main efferent
sites of the SCN are the hypothalamus (subparaventricular zone,
tuberal hypothalamus), the paraventricular thalamic nucleus and
the basal telencephalon, the pineal gland (via a multisynaptic
pathway), orthosympathetic projections in fat tissue, the thyroid
gland, the kidneys, the bladder, the adrenal gland and the spleen
(Bartness et al., 2001; Iuvone et al., 2005; Wiechmann and
Summers, 2008), parasympathetic innervation of the thyroid
gland, the liver, the pancreas and the submandibular gland
(Ueyama et al., 1999), cells containing thyrotropin-releasing hor-
mone (TRH) in the paraventricular nucleus (PVN) (Kalsbeek et al.,
2000).
A number of projections (rostral, periventricular, lateral [on the
IGL], posterior nerve projection) originate in the SCN to distribute
the circadian signal to the body and regulate various functions
(Miller et al., 1996): behavioural functions (sleep/wake cycle, eating
behaviour) and physiological functions (reproduction, thermal and
autonomic regulation, osmotic regulation, the hydroelectrolytic
balance, synthesis of melatonin, thyroid and adrenal hormones,
lymphocyte functions and cytokine production). Nearly 2e10% of
the genes are transcribed according to a circadian rhythm.
1.2.1.2.7. The geniculo-hypothalamic pathway. The GHT partici-
pates in the photic and non-photic entrainment of the SCN. Formed
based on a distinct layer of neurons of the geniculate complex (the
IGL), this pathway terminates in a region of the SCN shared with
RHT projections. The IGL belongs to the lateral geniculate complex
of the thalamus (dorsolateral geniculate [dLGN] and the ventro-
lateral geniculate [vLGN]) (Hickey and Spear, 1976). Retinal gan-
glion cells project bilaterally to the IGL and contralaterally for the
vLGN. Thus, the IGL neurons respond to photic stimulation in a
manner similar to SCN neurons (Moore, 1996). Nonphotic infor-
mation can come from locomotor activity, the availability of food, or
the ambient temperature. The IGL is an integral part of the circadian
system, participating in the entrainment of the SCN's internal clock.
1.2.2. Impact of the circadian system on the intraocular pressure
rhythm
The two main mechanisms of the circadian system's effect on
IOP rhythm involve ocular adrenergic innervation and the SCN.
1.2.2.1. Local clock in the ciliary body and rhythm of aqueous humour
secretion. Many studies have shown that aqueous humour pro-
duction by the ciliary epithelium presents a circadian rhythm
(Coca-Prados and Escribano, 2007; Smith and Gregory, 1989). The
circadian rhythm of the SCN communicates with the ciliary body by
numerous output signals such as norepinephrine, cAMP, arginine-
vasopressin, adenosine and dopamine (Coca-Prados and
115
Escribano, 2007). More recent data have suggested that a local
clock exists within the ciliary body, which expresses clock genes
such as Per, Clock, Cry, BMAL1 and Tim (Coca-Prados and Escribano,
2007) (Dalvin and Fautsch, 2015). Expression of Cry1 and Cry2
precede IOP variations in mice (Dalvin and Fautsch, 2015). These
data confirm an older study that had shown that cry-deficient mice
no longer presented circadian IOP variations (Maeda et al., 2006). In
animals, a circadian rhythm of adenylate cyclase activity exists,
partially mediated by beta-adrenergic receptors (Nii et al., 2001). In
humans, a nyctohemeral rhythm exists in aqueous humour secre-
tion, with greater flow during the diurnal period and less (50%)
flow during the nocturnal period (Liu et al., 2011). This reduction in
aqueous humour flow at night is apparently contradictory with the
nocturnal increase in IOP. Many factors may counterbalance this
reduction in aqueous humour, such as a reduction in outflow fa-
cility (Liu et al., 2011), uveoscleral outflow (Nau et al., 2013), and an
increase in episcleral venous pressure (Sit et al., 2008; Liu et al.,
2011).
It seems that the diurnal activity of the sympathetic system is
the major determinant in these aqueous humour variations. The
antagonists of beta-adrenergic-1 and -2 receptors (beta-blockers)
have little or no effect on the aqueous secretion at night (Dailey
et al., 1982; Schenker et al., 1981). The beta-1 selective antago-
nists (betaxolol) have the same effect (Brubaker, 1991; Vuori et al.,
1993). In contrast, certain nonselective agonists of adrenergic re-
ceptors, such as epinephrine, clearly increase aqueous humour
secretion when administered at night but have little effect during
the day. One study found a 47% increase in secretion after topical
administration of epinephrine at night, but only 19% after instilla-
tion of the same drug during the day (Townsend and Brubaker,
1980). Although with smaller differences, similar results were
found after instillation of norepinephrine. Beta-selective agonists
(isoproterenol, terbutaline, salbutamol) stimulate the production of
aqueous humour in monkeys under general anaesthesia and in
humans during sleep (Bill, 1970; Gharagozloo et al., 1988). In awake
humans, however, beta-agonists have no effect on aqueous humour
secretion (Shahidullah et al., 2005). It can therefore be assumed
that aqueous humour formation is at a base level at night, non-
stimulated, whereas it increases during the day through activa-
tion of beta-receptors secondary to an increase in the activity of the
sympathetic nervous system and/or to an increase in the circulating
catecholamine concentration.
1.2.2.2. Role of melatonin. The ciliary body contains melatonin
(MT) and its associated enzymes (Martin et al., 1992) and their
receptors (Osborne and Chidlow, 1994). IOP levels may be mediated
by the MT1 (Alcantara-Contreras et al., 2011; Tosini et al., 2013),
MT2 (Alarma-Estrany et al., 2008) and MT3 (Serle et al., 2004;
Pintor et al., 2001) receptors activity. MT2 receptor activity may
be modulated by noradrenaline. Reduction in the production of
aqueous humour by melatonin is mediated by the release of chlo-
ride parallel to the production of cAMP (Huete-Toral et al., 2015).
Agomelatine, a melatonin analogue, reduces IOP by 20% in rabbits


after topical application (Martínez-Aguila et al., 2013).
1.2.2.3. Mechanisms of action via innervation of ocular structures.
Nerve endings of the sympathetic and parasympathetic systems
innervate the ciliary body (Ruskell, 1971).
Fibres of the sympathetic system stem from the superior cer-
vical ganglion and terminate essentially in the immediate neigh-
bourhood of the ciliary vessels via the ciliary nerves. They are
present in the uveal blood vessels, the base and stroma of the ciliary
processes. Ciliary epithelium has a large number of receptors to the
sympathetic system mediators, but a priori these receptors are not
in contact with the sympathetic system's nerve fibres. In absence of
116 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
innervation of the ciliary epithelium, it is assumed that the cate-
cholaminergic neurotransmitters reach the corresponding re-
ceptors of the ciliary epithelium via paracrine diffusion. Stimulation
of the sympathetic system increases ciliary secretion.
In animal models, ocular sympathetic efferents play an impor-
tant role. The nocturnal increase in IOP is reduced in rabbits, either
after superior cervical ganglionectomy or after resection of the
cervical sympathetic trunk (Yoshitomi and Gregory, 1991). Intra-
cameral concentrations of noradrenaline and cyclic AMP (Liu, 1992;
Rowland et al., 1986; Yoshitomi et al., 1991) are higher at night. The
intracameral concentration of noradrenaline decreases by 25% after
resection of the cervical sympathetic trunk in the nocturnal period
compared to the contralateral eye (Liu, 1992). Furthermore, elec-
trical stimulation of the cervical sympathetic trunk at the end of the
diurnal phase produces an increase in IOP and an increase in
intracameral noradrenaline (Gallar and Liu, 1993). Liu et al. (1991)
suggested that the association of an increased resistance to
aqueous humour flow (mediated by a1-adrenergic receptors), and
an increase in aqueous humour secretion (mediated in part by b-
adrenergic receptors) contributes to the nocturnal IOP increase in
rabbits.
Adrenergic receptors are involved in the nocturnal IOP increase
in rabbits. Local instillation of an a1-adrenergic antagonist (pra-
zosin) attenuates the nocturnal increase in IOP in a dose-dependent
manner by increasing the resistance to aqueous humour flow,
whereas a postsynaptic a2-adrenergic antagonist (rauwolscine) has
no effect (Liu et al., 1991). Inversely, stimulation of presynaptic a2-
adrenergic receptors with apraclonidine produces a nocturnal
decrease in IOP, probably by inhibiting the release of noradrenaline
(Liu et al., 1991). During the night, instillation of a b-adrenergic
blocker has little or no effect on IOP (Liu et al., 1991; Gregory, 1990),
which suggests that the effect of catecholamines on the nocturnal
increase in IOP may only be partially mediated by b-adrenergic
receptors.
The fibres of the parasympathetic system stem from the
Edinger-Westphal nucleus, following the trajectory of the common
oculomotor nerve to the ciliary ganglion where the fibres take over,
before following the ciliary nerves. A second contingent of para-
sympathetic fibres follows the trajectory of the facial nerve arriving,
with the facial nerve, at the pterygopalatine ganglion where they
join before continuing toward the eye. These fibres terminate
essentially in the ciliary muscles. Acetylcholine produced by stim-
ulation of the parasympathetic system stimulates the cholinergic
receptors of the muscle fibres. Contraction of the ciliary muscle
thus increases elimination of AH, through both the trabecular and
uveoscleral pathways.
The SCNesympathetic pathwayseeye loop very probably ex-
plains the circadian control of the ocular sympathetic system
(Chiquet et al., 2001; Chiquet and Denis, 2004). A multisynaptic
projection exists between the SCN and the superior cervical gan-
glion via the preganglionic neurons and the cervicothoracic inter-
mediolateral cell column, releasing noradrenaline on the target
organs (pineal gland, eye). In addition, the superior cervical gan-
glion receives preganglionic parasympathetic fibres from the
Edinger-Westphal nucleus, itself controlled by the SCN. Thus,
sympathetic activity, resulting, for example, in the release of
intracameral catecholamines, is controlled by the SCN.
1.2.2.4. Role of the suprachiasmatic nucleus. Animal data: To study
the possible role played by the SCN in the circadian regulation of
IOP, Liu and Shieh (1995) made bilateral thermal lesions in the SCN
of rabbits. IOP fluctuations were significantly reduced for 2 weeks.
To study IOP circadian rhythm control by the SCN, one strategy
consists in analyzing the effects of light on the synchronization of
the rhythms. Light exposure at the beginning of night, when
melatonin is physiologically synthesized, results in physiological
inhibition of melatonin synthesis. This effect is mediated by the
retinohypothalamic pathway, the SCN and the multisynaptic
pathway, projecting to the pineal gland. Light inhibits the adren-
ergic innervation of the pineal gland and melatonin synthesis. In
rabbits, exposure to light during the nocturnal phase results in the
disappearance of the IOP's circadian rhythm (Lee et al., 1995),
suggesting a role of the SCN in the genesis of IOP circadian rhythm
in animals.
Circadian regulation of IOP via the SCN does not seem to involve
plasma melatonin. Indeed, unilateral resection of the cervical
sympathetic trunk leads to a significant effect on IOP by adrenergic
inhibition, without altering pineal synthesis of melatonin (Liu et al.,
1991).
Human data: The results in humans are less clearly established
for methodological reasons. In most published studies, human
subjects have been exposed to light to inhibit plasma melatonin
synthesis outside of the critical period for melatonin synthesis
(midnight to 2:00 a.m.). One study on aqueous humour flow
showed that light exposure (2500 lux, between 22:00 and 24:00)
during nocturnal sleep did not eliminate the nocturnal reduction of
aqueous humour flow (Koskela and Brubaker, 1991). In contrast,
another study (Wildsoet et al., 1993) reported that light exposure
(2500 lux, from 22:00 to 24:00) significantly reduced nocturnal IOP.
Therefore, the role of light exposure during the night on IOP and
aqueous humour flow need to be reassessed.
1.2.2.5. Dorsomedial/perifornical hypothalamus. This area of the
hypothalamus presents a large number of projections on the
sympathetic system (ter Horst and Luiten, 1986). A recent study
showed that stimulation of neurons within the dorsomedial hy-
pothalamus and the surrounding perifornical area (receiving direct
and indirect projections from the SCN) lead to an increase in
intraocular and intracranial pressure in rats (Samuels et al., 2012).
This increases the translaminar pressure gradient.
1.3. Nyctohemeral rhythms of intraocular pressure
1.3.1. Study methods (non-continuous measurements)
A biological rhythm is said to be circadian e the rhythm is
established in the absence of any environmental influence e or
nyctohemeral e the rhythm is established under the influence of
alternating light and dark e when the period is equal or close to
that of the rotation of the earth, i.e. close to 24 h. The identification
and characterization of a circadian rhythm therefore requires reg-
ular measurement of the parameter over a period of time at least
equal to the period of the rhythm, which is 24 h. Ideally, a study of
the parameter over a period of time equal to twice the period of the
biological rhythm provides a more precise characterization, but this
is rarely done in human studies for practical reasons (Czeisler et al.,
1999; Gronfier et al., 2007).
Mathematical methods used to model the evolution of the
parameter over time must be used to confirm that the parameter
has a rhythmic variation with a period close to 24 h and therefore to
define this rhythm as circadian. The main mathematical methods
available and used in the field of circadian research are detailed at
the end of this section. It should be noted that whatever method is
used the probability of identifying a circadian rhythm increases
when the measurement frequency of the parameter over time in-
creases (thus the number of measurements over 24 h) and vice-
versa (Brown and Czeisler, 1992). For parameters for which
continuous measurements are not possible, hourly measurements
providing 24 measurements over a 24-h period are often carried
out, allowing a relatively high probability of identifying an existent
circadian rhythm. By contrast, measurements made only every 2 or
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
3 h provide only a few measurement time points over a period of
24 h (12 and 8, respectively), and if the amplitude of the variations
of the parameter over 24 h is low the different mathematical
models available will have a relatively high probability of missing
an existing circadian rhythm, and thus falsely concluding in the
absence of a circadian rhythm (false conclusion of random varia-
tions over time). A high measurement frequency of the parameter
studied thus increases the probability of identifying a circadian
rhythm and increases the accuracy of the estimation of the main
quantitative parameters that describe this circadian rhythm.
The IOP curves over 24 h measured before the recent develop-
ment of continuous measurement methods were compiled from
discontinuous measurements. The IOP is a parameter influenced by
the body position, and in order to better describe the physiological
rhythm it is desirable to measure the IOP in conditions close to the
physiological conditions, that is in the orthostatic position during
the day and in the decubitus position during the night (Liu et al.,
2003a). In most studies, the measurements were taken in the
sitting position during the diurnal period and with subjects lying on
their back during the nocturnal period. Measurements were often
taken using Goldmann tonometers during the day and Perkins to-
nometers during the night, which has the advantage of using the
same reference method throughout the 24-h period. Measure-
ments using air puff tonometers or pneumotonometers were used
in some studies, with the use of portable tonometers that measures
the IOP in the supine position. Although it has been shown that
these tonometers could sometimes slightly overestimate the IOP
compared to Goldmann applanation tonometers, these tonometers
have the advantage of not requiring topical anaesthesia and allow
faster measurement with shorter arousal of the subjects during the
sleep period (Hubanova et al., 2015). The measurements are
therefore done in a state closer to the physiological conditions.
Moreover, since the aim of these studies is to look for a rhythm over
a period close to 24 h and to characterize the parameters of this
rhythm, the existence of a constant difference between the results
provided by the measurement method used and the GAT method is
not a crucial issue and does not alter the patterns found. In some
studies, the measurements were taken during the daytime with a
Goldmann tonometer and during the night with a non-contact
tonometer. This measurement method could introduce a bias in
the estimation of the 24-h rhythm as a difference between the
values measured during the daytime and night time due to the
different tonometers used may decrease or increase the probability
of showing a circadian rhythm, or even make a circadian rhythm
which actually exists disappear, or conversely, inducing an appar-
ently false circadian rhythm that does not actually exist.
The parameters used to describe the variations measured are
amplitude (difference between the maximum value and the mini-
mum value), the standard deviation, the time of the maximum
value and the time of the minimum value, and often the average of
Fig. 3. Characteristic parameters of a rhythmic function.
117
the daytime and night-time measurements. When a mathematical
method for modelling the rhythm is used (Cosinor, CircNOSA, etc.)
and confirms the circadian character of the rhythm, the pattern can
be characterized more precisely (Touitou and Haus, 1992) (see
Fig. 3).
1.3.2. Mathematical methods used to model rhythms
Graphical methods consisting in plotting the data as a function
of time can provide information on the obvious rhythmicity of the
parameters and its relative prominence as compared to noise may
be qualitatively (macroscopically) assessed. When sampling covers
several cycles, some measurement of the cycle-to-cycle variability
can be gained. The presence of any increasing or decreasing trends
can be observed, as is the existence of any outliers.
The cosinor method was developed for the analysis of time se-
ries in chronobiology focusing both on rhythm detection and
parameter estimation (Bourdon et al., 1995; Brown and Czeisler,
1992; Nelson et al., 1979). This method is based on a periodic
regression analysis; a cosine curve with a given period is fitted to
the measured values by least squares analysis. One must exercise
caution because the use of the cosinor method is based on the
assumption that the rhythm is sinusoidal and that the period of the
rhythm is closed to 24 h. Another limitation is that this type of
periodic regression is sensitive to outliers.
The single-component cosinor model is based on a single
monophasic regression model that can be written as:
YðtÞ ¼ M þ Acosð2pt=t þ fÞ þ eðtÞ
where M is the MESOR (a rhythm-adjusted mean), A is the ampli-
tude (a measurement of half the extent of predictable variation
within a cycle), f is the acrophase (a measurement of the time of
overall high values recurring in each cycle), t is the period (duration
of one cycle) and e(t) is the error term.
This approach consists of minimizing the sum of squared de-
viations between the data and the fitted cosine curve. The larger
this residual sum of squares is, the greater the uncertainty of the
estimated parameters. This is illustrated by the elliptical 95% con-
fidence region for the amplitudeeacrophase pair. When the error
ellipse does not cover the pole, the zero-amplitude (no-rhythm)
test is rejected and the alternative hypothesis holds that a rhythm
with the given period is present in the data.
The single-component cosinor can be extended to a multiple-
component model:
YðtÞ ¼ M þ A1 cosð2pt=t þ f1 Þ þ A2 cosð2pt=t þ f2 Þ þ …


þ Aj cos 2pt=t þ fj þ eðtÞ
Instead of solving a system of three equations in three un-
knowns, there are several normal equations that can be used to
estimate M and j pairs of (Aj, fj) when tj is assumed to be known,
where M is the MESOR (a rhythm-adjusted mean), A is amplitude (a
measurement of half the extent of predictable variation within a
cycle), f is the acrophase (a measurement of the time of overall
high values recurring in each cycle), t is the period (duration of one
cycle) and e(t) is the error term.
A multiple-component model is useful to obtain a better
approximation of the signal's waveform when it deviates from
sinusoidality with several different periods (polyphasic). It has the
advantage of being applicable to all sorts of rhythms and not
exclusively to monophasic rhythms, and does not assume a priori
that a rhythm is sinusoidal, in contrast with the cosinor technique
(Gronfier et al., 2007) (Fig. 4).
118 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Fig. 4. Mathematical methods used to model rhythms. Raw 24-h data obtained from a continuous intraocular pressure measurement device (grey) and modelled curve (black) with
a multiple-component model.
1.3.3. Studies of nyctohemeral rhythms of intraocular pressure in
healthy subjects
The studies of the nyctohemeral IOP rhythm in humans con-
ducted to date with non-continuous measurement methods are
summarized in Table 2.
The notion of an IOP rhythm was first raised at the beginning of
the 20th century. In 1904 Maslenikow was the first to describe IOP
variations during the day (Maslenikow, 1904). Duke-Elder subse-
quently confirmed the diurnal variations and described the pres-
ence of an early morning IOP peak followed by a decrease during
the rest of the diurnal period (Duke Elder, 1952). However, Henkind
et al. were the first to study the IOP variations over a 24-h period
and to talk about a characteristic IOP rhythm with a period close to
24 h (Henkind et al., 1973). Arriving at the same conclusions from
studies of IOP measurements over time, Kitazawa and Horie hy-
pothesized an individualized biological nyctohemeral rhythm IOP
(Kitazawa and Horie, 1975).
Many studies conducted since the late 1970s have unanimously
confirmed the existence of a nyctohemeral IOP rhythm. However,
they are not sufficient to confirm the circadian character of the 24-h
IOP rhythm because the circadian rhythm of a biological parameter
implies that it is generated by an internal biological clock (supra-
chiasmatic nucleus) in the absence of any influence of the envi-
ronment, including the light/dark alternation (Billiard et al., 1996;
Gronfier et al., 2007; Reinberg et al., 1985; Spiegel et al., 1999). To
date, no study has demonstrated a rhythm close to 24 h, without
any effect of day and night and thus performed in controlled and
constant low light conditions over several days to avoid the residual
effect of the powerful physiological synchronizers.
In healthy subjects, the circadian rhythm is characterized by a
mean diurnal IOP lower than the mean nocturnal IOP, with bath-
yphase during the day e usually in the middle or at the end of the
afternoon e and the acrophase during the night, usually the middle
€l
or end of the night period (Buguet et al., 1994; Liu et al., 1998; Noe
et al., 2001). The profile of the curve constructed from the 24-h
measurements in the healthy subject is shaped like a sine wave
with a trough during the day and dome during the night. Many
studies have evaluated the time of diurnal bathyphase and
nocturnal acrophase (Zeimzer, 1989). The results vary widely,
probably because of the disparity in study protocols, population
studies (ethnicity, age, sex ratio), seasons and countries in which
the study was conducted.
Studies in non-glaucomatous healthy elderly subjects have
found the same IOP variation patterns throughout 24-h periods as
in healthy young subjects with a comparable rhythmic profile
(Buguet et al., 1994). Some studies have shown a possible delay of
the phase timings of 24-h rhythms in elderly subjects, with
acrophase observed at the end of the night period or in the early
morning (Liu et al., 1999a).
In most studies, the differences between the mean IOP during
the nocturnal period and the mean IOP during the diurnal period
on healthy subjects ranged from 3 to 5 mmHg. The differences
between the peak and trough (maximum and minimum values
recorded) usually ranged from 5 to 10 mmHg. The amplitude of IOP
fluctuations over 24-h periods was highly variable from one indi-
vidual to another.
One study evaluated 24-h IOP in young healthy subjects un-
dergoing moderate illumination during the middle and the end of
the night period (Liu et al., 1999b). A nocturnal elevation of IOP was
still found despite light exposure. However, this does not formally
show that the IOP rhythm is fully endogenous and independent of
the environmental light synchronizer. For many biological circadian
rhythms, it has been shown that measurements should be taken in
controlled and constant low light conditions over several days to
avoid the residual effect of physiological synchronizers and to show
the primary endogenous rhythm (Gronfier et al., 2007).
Many studies have demonstrated that the transition from the
upright posture to a supine position causes a constant IOP elevation
varying from 1 to 4 mmHg (Wilson et al., 1993). One of the reasons
explaining this sudden and then sustained increase in IOP is the
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Table 2
Summary of the studies of the nyctohemeral rhythm of intraocular pressure in humans conducted with non-continuous measurement methods.
References Population Methods
Kitazawa and Horie, 1975. 12 normal individuals (24 eyes), 14 ocular IOP was measured with a Goldmann
hypertensives (28 eyes), and 14 patients (27 applanation tonometer in 12 normal
eyes) with primary open-angle glaucoma. individuals (24 eyes), 14 ocular
hypertensives (28 eyes), and 14 patients (27
eyes) with primary open-angle glaucoma
every hour for 24 h.
Frampton et al., 1987. 13 healthy subjects. IOP was recorded regularly over a 24-h
period in 13 normal subjects.
Brown et al., 1988a. 10 healthy subjects. Ten normal subjects slept over a series of
four nights for time periods of 30 min, 1, 2
and 4 h. IOP measurements were taken
using a non-contact tonometer before and
after sleep.
Brown et al., 1988b. Healthy subjects. IOP was measured immediately after
normal subjects were woken from at least
5 h of sleep. Measurements were taken at
approximately 15-s intervals for about
20 min.
Wildsoet et al., 1993. 5 groups of subjects: glaucoma, suspected The goal of the study was to investigate the
glaucoma, young high-normal IOP, elderly effects of sleep in five groups of subjects
high-normal IOP groups and an elderly (glaucoma, suspected glaucoma, young
control group. high-normal IOP, older high-normal IOP
groups and an elderly control group), the
effect of exposure to bright light (2500 lux)
during sleep on associated IOP changes, and
the relationship between changes in IOP
and plasma melatonin during sleep. For all
experiments IOP was measured before and
after sleep.
Buguet et al., 1994. 12 young (20.6 ± 0.3 years) and 12 older IOP was measured hourly over 24 h. An
(59.5 ± 1.6 years) healthy white adults. electronic tonometer (Tono-Pen) was used.
Nocturnal polysomnography was
measured. Wakefulness, light sleep (stages
1 and 2), slow-wave sleep (stages 3 and 4),
and rapid eye movement sleep were scored.
Follmann et al., 1997. 60 non-glaucomatous controls, 54 Daytime and nocturnal IOP values and
glaucoma patients with normal visual field, systemic blood pressure values were
and 46 glaucoma patients with visual field compared in 60 non-glaucomatous
loss. controls, 54 glaucoma patients with normal
visual field, and 46 glaucoma patients with
visual field loss. The daytime IOP was
measured with a Goldmann applanation
tonometer and the nocturnal IOP with a
Bio-Rad-Tono-Pen 2.
Liu et al., 1998. 33 healthy volunteers. Thirty-three volunteers were housed in a
sleep laboratory for 1 day under a strictly
controlled 16-h light and 8-h dark
environment. Sleep was encouraged in the
dark period. IOP was measured in each eye
every 2 h using a pneumatonometer.
Researchers used night-vision goggles to
take IOP measurements in the dark, while
the subject's light exposure was minimized.
In the first group of 12 subjects,
measurements were taken with subjects in
the sitting position during the light-wake
119
Results
In most subjects, pressure was highest
sometime during the day and pressure
elevation before rising was not
demonstrated. The lowest intraocular
pressure was most frequently observed
early in the morning, whether the patient
was normotensive or hypertensive.
Fourteen of 27 glaucomatous eyes had
intraocular pressure below 20 mmHg early
in the morning.
All subjects showed a significant rise in IOP
after sleep, ranging from 37 to 248%. In the
second experiment, IOP decreased when 15
subjects remained upright and awake
throughout the night. When sleep was not
permitted IOP was lowest at 3 a.m.; when
six of these subjects were permitted to
sleep from 6 to 8 a.m., they showed a rapid
and significant increase in IOP of up to 150%,
whereas the remaining 9 subjects showed
(posturally induced) increases of up to 38%.
The subjects showed a significant increase
in IOP of 3.4 mmHg after 30 min of sleep
and a further IOP increase thereafter to
6.4 mmHg above baseline.
The IOP of all 14 subjects was elevated after
sleep and returned to baseline levels with a
time course which was approximately
exponential; the longest time constant of
return of IOP to baseline was 1056.9 s and
the shortest 133.5 s. The mean time
constant of recovery was 404.8 s.
IOP increased significantly after sleep. There
was a significant difference between the
five groups with the old high-normal group
showing the greatest increase and the
young high-normal group showing the
smallest increase in IOP. The increase in IOP
after sleep was reduced when the same
subjects slept in bright light compared to
that recorded when subjects slept in the
dark. Plasma melatonin levels, as well as
IOP, increased after sleep in the dark,
although there was no correlation between
these changes for individual subjects.
IOP followed a circadian rhythm with a
nocturnal peak value (acrophase). The
variations in IOP were related to the stage of
sleep, being lowest during rapid eye
movement sleep and highest during slow-
wave sleep.
A tendency towards increasing IOP and
decreasing blood pressure was detected in
the non-glaucomatous controls, within
normal limits, and pathological changes of
IOP and blood pressure were observed with
a significantly high occurrence in the
glaucoma group with visual field loss.
Average IOP was significantly higher in the
dark period than in the light-wake period in
both groups. The lowest IOP occurred in the
last light-wake measurement, and the peak
IOP occurred in the last dark measurement.
The trough-peak difference in IOP was
8.2 ± 1.4 mmHg in the first group. IOP
changed sharply at the transitions between
light and dark. In the second group, the
trough-peak IOP difference was
3.8 ± 0.9 mmHg. IOP changed gradually
throughout the 24-h period. In comparison
(continued on next page)
120 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148

Table 2 (continued )

References Population Methods Results

Liu et al., 1999a. 21 healthy volunteers 50e69 years of age.
Liu et al., 1999b. 25 healthy volunteers, aged 18e25 years.
€l et al., 2001.
Noe 16 healthy African volunteers (age, 24.5 ± 1
years) and 11 African open-angle glaucoma
patients (age, 36.2 ± 3.3 years).
Liu et al., 2002. 19 young adults, aged 18e25 years, with
moderate to severe myopia (myopia group)
and 17 age-matched volunteers with
emmetropia or mild myopia (control
group).
Liu et al., 2003b.
period and supine during the dark period. In
the second group of 21 subjects, all IOP
measurements were taken with the
subjects supine.
Experimental conditions were strictly
controlled with a 16-h light period and an
8-h dark period. Sleep was encouraged in
the dark period. IOP was measured using a
pneumatonometer every 2 h (total of 12
times). Measurements were taken in both
the sitting position and the supine position
during the light/wake period but only in the
supine position during the dark period.
Subjects were housed overnight in a sleep
laboratory under a strictly controlled light-
dark environment. IOP was measured in the
supine position every 2 h, using a
pneumatonometer. An 8-h sleep period was
assigned to each volunteer according to
individual's accustomed sleep cycle. In the
early part of this assigned period, sleep was
encouraged with room lights off.
Researchers took IOP measurements at two
time points with the aid of night vision
goggles. In the middle to the late part of the
assigned period, lights were turned on
twice for a 1-h period. The light intensity
was the same as before bedtime. At the
ending of each light period, IOP was
measured under illumination.
IOP was measured hourly over 24 h with a
Modular One pneumatonometer. To
measure IOP at night, subjects were
awakened under polysomnography
(electroencephalogram, electromyogram,
electro-oculogram) recorded at night and
during a 90-min afternoon nap.
Hourly IOP values were analysed for
circadian rhythmicity with the cosinor
technique and in relation to the state of
wakefulness, light sleep (stages 1 and 2),
slow-wave sleep (stages 3 and 4), and rapid
eye movement sleep upon awakening.
Subjects were housed for 1 day in a sleep
laboratory. An 8-h accustomed sleep period
was assigned to each volunteer. Twelve
measurements of IOP, axial length, blood
pressure and heart rate were taken at 2-h
intervals. In the wake period, blood
pressure and heart rate were measured
after a 5-min bed rest. Axial length and IOP
were measured in supine volunteers.
Volunteers then sat for 5 min, after which
IOP was measured. In the sleep period,
measurements were taken in supine
volunteers in bed.
with the sitting IOP in the first group, the
supine IOP in the second group was
significantly higher during the light-wake
period.
When the sitting IOP data from the light/
wake period and the supine IOP data from
the dark period were considered, elevation
and reduction of IOP occurred around the
scheduled lights-off and lights-on
transitions, respectively. Mean IOP in the
dark period was significantly higher than
mean IOP in the light/wake period. The
trough appeared at the end of the light/
wake period, and the peak appeared at the
beginning of the dark period. The
magnitude of the trough-peak difference
was 8.6 ± 0.8 mmHg. Cosine fits of 24-h IOP
data showed a significant 24-h rhythm.
When IOP data from just the supine
position were analysed, the trough-peak
IOP difference was 3.4 ± 0.7 mmHg, with
similar clock times for the trough and the
peak. Cosine fits of supine IOP data showed
no statistically significant 24-h rhythm.
Average IOP was significantly higher in the
assigned sleep period versus outside the
period. The trough of mean IOP occurred
just before bedtime, and then IOP gradually
increased and peaked at the end of the 8-h
assigned sleep period. The difference
between the trough and peak IOP was
3.5 ± 0.7 mmHg (n ¼ 25). Within the
assigned sleep period, the average IOP
determined under illumination was
significantly higher than the average IOP
preceding the illumination.
Sleep patterns did not differ between
patients and healthy volunteers. As
expected, in the healthy subjects, IOP
followed a 24-h rhythm with a nocturnal
peak value (acrophase), and the variations
in IOP during sleep were related to sleep
structure, being lowest during rapid eye
movement sleep and highest during slow-
wave sleep. In the glaucoma patients,
however, the 24-h IOP rhythm was
reversed, with an afternoon acrophase and
an early morning trough.
In both the myopia and control groups, the
average supine IOP in the sleep period was
higher than the average sitting IOP in the
wake period. However, the magnitude of
this IOP elevation at night was significantly
less in the myopia group. In the sleep
period, IOP was lower in the myopia group
than in the control group. When only the
24-h supine IOP data were considered, the
trough occurred at 1:30 a.m., and the peak
occurred around noon in the myopia group.
In the control group, the trough was at 9:30
p.m., and the peak at 5:30 a.m. Least-square
cosine fits showed 24-h rhythms of supine
IOP in both groups, but their phase timings
differed. Axial length remained unchanged
throughout the day and night in both
groups. There was no difference in the 24-h
rhythms of mean blood pressure and heart
rate between the two groups.
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148 121

Table 2 (continued )

References Population Methods Results

24 untreated patients (age, 40e78 years)
with newly diagnosed abnormal optic discs
and/or abnormal visual fields and age-
matched control group of 24 individuals
with healthy eyes.
Orzalesi et al., 2003. 10 patients with POAG and 10 with OHT
were treated with latanoprost once a day,
brimonidine twice a day, and a fixed
combination of timolol and dorzolamide
twice a day for 1 month.
Liu et al., 2003a. 16 nonsmoking, healthy young volunteers
(age, 18e25 years).
Liu et al., 2003c. 16 healthy young adults (age, 18e25 years)
and 16 older adults (age, 47e74 years).
Mosaed et al., 2005. 33 younger healthy subjects (age, 18e25
years), 35 older healthy subjects (age, 40
e74 years), and 35 untreated older
glaucoma patients (age, 40e79 years).
Hara et al., 2006. 148 patients with untreated primary open-
angle glaucoma.
IOP, blood pressure and heart rate
measurements were taken every 2 h during
a 24-h period. In the 16-h diurnal awake
period, IOP was measured sitting and
supine, and blood pressure and heart rate
were measured supine. In the 8-h nocturnal
sleep period, all measurements were taken
in the supine position.
Four 24-h IOP curves were obtained for
each patient. With measurements at 3, 6
and 9 a.m., and at noon and 3, 6 and 9 p.m.,
and at midnight, using a handheld
electronic tonometer with the patient in
supine and sitting positions and a
Goldmann applanation tonometer with the
patient sitting at the slit lamp.
Subjects were housed in a sleep laboratory
for 24 h in a strictly controlled
environment. An 8-h nocturnal/sleep
period was assigned to each volunteer
according to the individual's accustomed
sleep cycle. IOP was measured every 2 h
with a pneumatonometer with the
volunteers in both sitting and supine
positions. The sitting and the supine IOP
data were compared for mean diurnal-to-
nocturnal IOP change and the cosine-fit 24-
h IOP rhythm.
Blood pressure and IOP measurements
were obtained every 2 h for 24 consecutive
hours. In the 16-h diurnal wake period,
blood pressure and IOP were measured
after a 5-min sitting rest. In the 8-h
nocturnal period, measurements were
taken with subjects in the supine position.
Sitting and supine ocular perfusion
pressures in the diurnal and nocturnal
periods were calculated, respectively, based
upon the blood pressure and IOP.
Subjects were housed in a sleep laboratory.
Measurements of IOP were taken every 2 h
using a pneumatonometer in the sitting and
supine positions during the diurnal/wake
period (7 a.m.e11 p.m.) and in the supine
position during the nocturnal/sleep period.
Correlations between average sitting or
supine IOP in the right eye between 9:30
a.m. and 3:30 p.m. (office hours) and peak
right eye IOP during the nocturnal hours
were analysed.
IOP was measured by non-contact
tonometry every 2 h from 6 a.m. to
midnight and every 3 h from midnight to 6
Mean diurnal IOP, either sitting or supine,
was significantly higher in the glaucoma
group than in the control group. For both
subject groups, nocturnal supine IOP was
higher than diurnal sitting IOP. However,
this diurnal-to-nocturnal increase in IOP
was significantly smaller in the glaucoma
group. When compared with the diurnal
supine IOP, the nocturnal supine IOP was
lower in the glaucoma group but higher in
the control group. Around normal
awakening time, the supine IOP increased
in the glaucoma group and did not change
in the control group. There was a diurnal-
to-nocturnal decrease in mean blood
pressure only in the glaucoma group.
All the drugs significantly reduced IOP
compared with the baseline at all times,
except for brimonidine at midnight, 3 a.m.
and 6 a.m. Latanoprost was more effective
than brimonidine in lowering IOP at 3 and 6
a.m. and at 3 p.m. (p ¼ 0.03), and the
combination of timolol and dorzolamide
was more effective than brimonidine at 3
and 9 a.m. (p ¼ 0.04) and at 3 and 6 p.m.
(p ¼ 0.05) and more effective than
latanoprost at 9 a.m. (p ¼ 0.05).
Mean IOP was significantly higher in the
nocturnal period than in the diurnal/wake
period for both the sitting and the supine
IOP. The 24-h IOP troughs appeared at the
end of the diurnal period, and the peaks
appeared at the end of the nocturnal period.
The difference between the trough and the
peak was 3.8 ± 0.6 mmHg in the sitting
position and 3.4 ± 0.6 mmHg in the supine
position. Cosine-fitting of 24-h IOP data
showed a synchronized 24-h rhythm of the
sitting and the supine IOPs for the group.
There was no difference in the phase timing
or the magnitude of variation between
these two 24-h rhythms of sitting and
supine IOPs.
Ocular perfusion pressure was found to be
higher in the older group than in the
younger group throughout the 24 h. The
peak of ocular perfusion pressure was in the
nocturnal period for both groups. Within
each subject group, the average nocturnal
ocular perfusion pressure in the supine
position was higher than the average
diurnal ocular perfusion pressure in the
sitting position. The diurnal-to-nocturnal
increase of ocular perfusion pressure was
larger in the older group than in the
younger group.
The average values of supine IOP during
office hours were found to have the
strongest correlation with peak nocturnal
IOP in older glaucoma subjects (r ¼ 0.713,
p < 0.001), whereas the correlation was less
in older healthy subjects (r ¼ 0.523,
p < 0.01) and was absent in younger healthy
subjects (r ¼ 0.224, p ¼ 0.21). The
correlation between average sitting IOP
values during office hours and peak
nocturnal IOP was also strong in older
glaucoma subjects (r ¼ 0.601, p < 0.001) and
moderate in older healthy subjects
(r ¼ 0.412, p < 0.05), but absent in younger
healthy subjects (r ¼ 0.077, p ¼ 0.672).
The peak of sitting diurnal IOP for 148
patients was 16.0 ± 2.7 mmHg, which was
significantly lower than the peak of supine
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122 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Table 2 (continued )
References Population Methods
a.m. with patients sitting and supine. IOP
was reproduced by designating the sitting
IOP as measurements taken when the
patient was awake and the supine IOP as
measurements taken when the patient was
asleep for each individual. The reproduced
diurnal IOP was composed of 12
measurements that included 2e4 IOP levels
measured with the patients supine and the
rest while they were sitting.
Barkana et al., 2006. 32 glaucoma patients (22 females and 10 We reviewed the records of all patients
males). with glaucoma who were admitted for 24-h
IOP monitoring over 3 years. Applanation
IOP was recorded in the sitting position
from 7 a.m. until midnight and in the supine
position at 6 a.m.
Konstas et al., 2006. 30 surgical patients and 30 medically IOP measurements were taken at 6 a.m., 10
treated patients with advanced glaucoma. a.m., 2 p.m., 6 p.m., 10 p.m. and 2 a.m.
Patients were matched by IOP ± 1 mmHg at
10 a.m.
Kida et al., 2008. 15 healthy young volunteers (age, 20e25 Subjects were housed for 1 day in a sleep
years). laboratory. Sitting and supine CCT were
measured every 2 h with an ultrasonic
pachymeter. Sitting IOP and corneal
hysteresis, an indicator of viscoelasticity,
were measured with a non-contact
tonometer.
Wozniak et al., 2006. 30 glaucoma patients on topical treatment IOP measurements were taken every 4 h for
and 50 healthy controls received IOP a 24-h period starting at 8 am. Additionally,
measurements every 4 h for a 24-h period blood pressure and heart rate were
starting at 8 am. measured and perfusion pressures were
calculated. At 12 pm IOP was initially
measured in a sitting position and then,
after 20 min, in the supine position. At
midnight this was carried out conversely. At
4 am IOP was measured in the supine
position; all other measurements were
taken in the sitting position. Measurements
in the sitting position were taken by
Goldmann and Perkins tonometry and in
the supine position by Perkins tonometry.
Sit et al., 2006a. 41 subjects (age, 40e78 years) with Subjects were housed in a sleep laboratory
untreated POAG. for 24 h. IOP of both eyes was measured
Results
IOP (18.9 ± 3.9 mmHg) or the reproduced
IOP (17.5 ± 3.6 mmHg). The average
reproduced IOP at each measurement time
peaked at 3 a.m. during sleep; with sitting
diurnal IOP or supine diurnal IOP, the peak
IOP was at noon. Twenty-nine patients
(20%) with an IOP less than 21 mmHg
during clinic hours had a reproduced IOP of
21 mmHg or greater while asleep,
compared with only 5 patients (3%) when
the patients were sitting only.
Mean 24-h IOP was 13.0 ± 2.2 mmHg. Mean
peak 24-h IOP (16.8 ± 3.2 mmHg) was
significantly higher than peak office IOP
(14.7 ± 3.2 mmHg). Peak IOP was recorded
outside of office hours in at least 1 eye in 22
patients (69%). Mean IOP fluctuation during
24-h monitoring (6.9 ± 2.9 mmHg) was
significantly greater than that during office
hours (3.8 ± 2.3 mmHg). Peak 24-h IOP was
higher than the peak IOP noted during
previous office visits in 40 eyes (62%).
Results of 24-h IOP monitoring led to
immediate treatment change in 23 eyes
(36%).
Surgical patients had a mean diurnal IOP of
12.1 ± 2.2 versus 13.5 ± 2.0 mmHg for
matched medically treated patients. The
average maximum IOP for the surgical
group was 13.4 ± 2.3 and 16.3 ± 3.2 mmHg
for the medical group. The 24-h range of IOP
for the surgical group was 2.3 ± 0.8 and
4.8 ± 2.3 mmHg for the medical group.
Except at 10 a.m., the surgical group had a
statistically lower IOP at each measured
time point. Eleven (37%) patients in the
medically treated group and none in the
surgically treated group had peak
IOPs  18 mmHg. The majority of peak IOPs
(10/11) occurred outside of normal office
hours.
There were consistent 24-h variations of
CCT and IOP for the group. Nocturnal mean
CCT and nocturnal mean IOP were
significantly higher than the diurnal mean
CCT and diurnal mean IOP, respectively. The
peak CCT occurred at 1:30e5:30 am and the
trough CCT at 1:30 pm. The peak IOP
occurred at 5:30 am and the trough IOP at
9:30 pm. Cosine fits of each subject's 24-h
CCT and IOP data showed synchronized
rhythms. The phase timing of 24-h CCT
rhythm was significantly earlier than the
phase timing of 24-h IOP rhythm. 24-h
variation of corneal hysteresis was
inconsistent and cosine fits of 24-h data of
corneal hysteresis did not display a 24-h
rhythm.
IOP was 1 mmHg lower in Perkins
tonometry measurements compared to
Goldmann tonometry. There was no
difference between the two patient groups.
In the supine position, IOP measured by
Perkins tonometry was higher than in the
upright position. At 12 am the difference
was 1.8 ± 2.7 mmHg in healthy subjects and
1.3 ± 2.7 mmHg in the POAG patients. At 12
pm the increase of IOP in the supine
position was even more pronounced with
2.4 ± 3.4 mmHg in healthy subjects and
5.6 ± 3.2 mmHg in the POAG patients. Blood
pressure and perfusion pressure were
lowest during night measurements.
No statistically significant difference was
found between mean, peak or trough IOPs
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148 123

Table 2 (continued )

References Population Methods Results

Orzalesi et al., 2006. 24 patients with POAG and 20 with OHT.
Lee et al., 2007. 18 POAG patients.
Perlman et al., 2007. Male army veterans, aged 22e81 years,
without a history of eye disease, were
studied around the clock from 1969 to
2003.
Kiekens et al., 2008. 21 patients with newly diagnosed
obstructive sleep apnea (OSA).
Kumar et al., 2008. 25 patients were recruited for the study, 16
males and 9 females. The mean age was
with a pneumatonometer every 2 h with
the patient in the sitting and supine
positions from 7 am to 11 pm and in the
supine position only from 11 pm to 7 am.
Mean, peak and trough IOPs were compared
in right versus left eyes. Strength of
association between IOPs of right and left
eyes, and residual values from linear
models of IOP.
Patients were treated with latanoprost,
travoprost and bimatoprost for 1 month.
The treatment sequence was randomized,
and washout lasted 30 days for each trial
drug. Four 24-h tonometric curves were
recorded for each patient: 1 at baseline and
1 after each treatment period.
Intraocular pressure was measured at 3, 6
and 9 am; noon; 3, 6 and 9 pm; and
midnight using a handheld electronic
tonometer with the patient in supine and
sitting positions and a Goldmann
applanation tonometer with the patient
sitting at the slit lamp. Supine systemic
blood pressure was recorded at the same
times.
Laser trabeculoplasty (180 ) was performed
on 28 eyes of 18 glaucoma patients. 24-h
IOP data were collected in a sleep laboratory
before and 45e80 days after the procedure.
Measurements of sitting and supine IOP
were taken during the 16-h diurnal/wake
period, and supine IOP measurements were
taken during the 8-h nocturnal/sleep period
at 2-h intervals.
Measurements of IOP (supine position),
blood pressure and heart rate (sitting
position), and collection of blood were
obtained every 3 h (8 readings/24 h) from 7
p.m. to 4 p.m. the next day. Individual time
series were analysed for circadian
characteristics by the least-squares fit of a
24- and 12-h cosine. After normalizing all
data to percent of mean to reduce inter-
subject variability in levels, grouped data
were analysed for time-effect by analysis of
variance and for circadian rhythm by
multiple component cosine fitting.
Individual 24-h averages were analysed by
simple and multiple regression for
relationships between IOP and systemic
variables, diabetic status and age.
IOP, blood pressure and pulse rate were
measured every 2 h during 24-h sessions. A
first series of measurements was taken
before CPAP therapy, and a second series 1
month after the initiation of CPAP therapy.
OPP was then calculated.
All subjects underwent daytime IOP
measurement by a single observer using a
of right and left eyes over a 24-h period. The
strength of association for mean IOP was
only moderate (R(2) ¼ 0.421e0.623).
Residual values of 3 mmHg were found in
14.0% ± 12.0% of IOP measurements for a
symmetric linear regression model, and
8.5% ± 10.6% of IOP measurements for a
best-fit linear regression model over 24 h.
All three drugs were highly effective in
reducing IOP when compared to baseline.
Mean IOP reductions were similar after the
three prostaglandin analogues, and none of
the differences among treatments reached
statistical significance. The drugs' effect was
significantly greater during the daytime (9
ame9 pm) than during the nighttime
(midnight to 6 am) with all prostaglandin
analogues. In 7/44 patients (16%), nocturnal
IOP was significantly higher than diurnal
IOP, both at baseline and under the three
prostaglandin analogues.
Compared with the baseline, changes in the
mean, peak and range of IOP were not
significant during the office-hour period
and during the diurnal period in either the
sitting or supine position. The mean, peak
and range of IOP were reduced significantly
during the nocturnal period in the supine
position. Mean and peak 24-h IOP values
were reduced significantly in the habitual
body positions (sitting during the diurnal
period and supine during the nocturnal
period). The reduction of mean 24-h IOP in
the supine position was also significant.
A significant circadian rhythm was found
for each variable. Circadian peaks
(orthophases) are located in the late
morning for right eye IOP (10:20) and left
eye IOP (10:52), and in the evening for heart
rate (18:52), systolic blood pressure (20:40)
and diastolic blood pressure (21:44). The
locations of individual circadian peaks for
IOP were found around the clock, but with a
significant predominance between 10 a.m.
and 4 p.m. (day type), and 04 a.m.e10 a.m.
(morning type).
Baseline measurements showed a
significant nyctohemeral fluctuation in the
average IOP, with the highest IOPs at night.
After 1 month of CPAP therapy, the average
IOP was significantly higher than baseline.
The increase in overnight IOP was also
significantly higher. A 24-h IOP fluctuation
of 8 mmHg was found in 7 patients at
baseline and in 12 patients during CPAP
therapy. The mean difference between
trough and peak IOP was 6.7 ± 1.5 mmHg at
baseline and 9.0 ± 2.0 mmHg during CPAP
therapy. Thirty minutes after CPAP
cessation a significant decrease in IOP was
recorded. There was a statistically
significant decrease in mean OPP during
CPAP therapy.
The mean peak IOP measured by diurnal
testing (15.52 ± 3.6 mmHg) was not
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124 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148

Table 2 (continued )

References Population Methods Results

68.8 ± 8.7 years (50e82 years), and 48% had
primary open-angle glaucoma.
Mosaed et al., 2008. 52 untreated glaucoma patients and 29 age-
matched normal control subjects.
Kida et al., 2008. 15 older volunteers with healthy eyes (age,
50e80 years)
15 healthy younger volunteers (age, 20e25
years).
Fogagnolo et al., 2009. 29 healthy subjects (10 young adults, 19
elderly) and 30 patients with untreated
glaucoma.
Deokule et al., 2009. 75 eyes of 45 POAG patients.
Renard et al., 2010. 27 patients with suspected NTG.
Goldmann Applanation Tonometer at 3-h
intervals. Subjects were then given 10 mL/
kg body weight of water to drink over
5 min; IOP was measured every 15 min for
1 h. Correlations between peak IOP and IOP
fluctuations as measured by the two
methods were analysed using Pearson's
correlation coefficient.
IOP measurements were obtained every 2 h
during a 24-h period from 52 untreated
glaucoma patients and 29 age-matched
normal control subjects housed in a sleep
laboratory. Habitual IOP measurements
were obtained using a pneumatonometer in
the sitting positions during the diurnal/
wake period (7 a.m.e11 p.m.) and in the
supine position during the nocturnal/sleep
period (11 p.m.e7 a.m.). CCT was measured
in all subjects using ultrasound pachymetry
once during office hours. The association
between IOP fluctuation (peak IOP-trough
IOP) during the 24-h period and the office-
hour CCT was assessed in both glaucoma
patients and healthy age-matched controls
using Spearman rank order correlation.
Subjects were housed for 1 day in a sleep
laboratory with a 16-h diurnal or wake
period and an 8-h nocturnal or sleep period.
Every 2 h, sitting corneal hysteresis, corneal
resistance factor and IOP were measured.
CCT was measured using an ultrasound
pachymeter. Data were compared with
previous observations in 15 healthy
younger volunteers (age range, 20e25
years).
Measurements were taken at 9 a.m.; 12, 3, 6
and 9 p.m.; and 12, 3 and 6 a.m., both in the
supine and sitting (Goldmann tonometer)
positions. Peak, mean and fluctuation of 24-
h IOP curves were compared with office-
hour measurements obtained in subjects in
the sitting position alone and with
combined pressures obtained in the sitting
and supine positions (four measurements in
each body position from 9 a.m. to 6 p.m.).
The percentage of subjects with estimates
of all IOP parameters within a cutoff of ±1
(peak and mean) and ±2 mmHg
(fluctuation) was calculated.
Patients underwent 24-h IOP assessment in
a sleep laboratory. The IOP measurements
were obtained with the subjects in the
supine and sitting positions during the
diurnal period and in the supine position
during the nocturnal period. The mean,
peak and trough IOP and IOP range (peak
through trough) were calculated for the
office-hour period (9 a.m.e4 p.m.), the
diurnal period (7 a.m.e11 p.m.), the
nocturnal period (11 p.m.e7 a.m.) and the
24-h period.
Subjects underwent 24-h monitoring of IOP
and blood pressure (BP), polysomnography,
and nailfold capillaropathy. The
nyctohemeral rhythms of IOP, BP and OPP
statistically different from that measured
with WDT (15.92 ± 3.2 mmHg) (p ¼ 0.7).
The mean fluctuation in IOP measured
during the day (2.32 ± 1.3 mmHg) was also
not significantly different from that
measured with WDT (2.24 ± 1.2 mmHg).
Although peak IOP measured during diurnal
testing showed a strong correlation with
peak IOP during WDT (r ¼ 0.876), IOP
fluctuation measured by the two tests
showed a poor correlation (r ¼ 0.0789).
There was no statistically significant
correlation between IOP fluctuation and
CCT in glaucomatous (p ¼ 0.405) and
normal subjects (p ¼ 0.456).
Variations in 24-h corneal hysteresis and
corneal resistance factor were not
significant in the older subjects, but there
were time-dependent variations in CCT and
IOP. The nocturnal CCT was thicker than the
diurnal CCT, but the IOP difference between
the diurnal and nocturnal periods was not
significant. Cosine-fits of CCT and IOP
showed synchronized 24-h rhythms. The
phase timing of CCT rhythm appeared
significantly earlier than the phase timing
of IOP rhythm. Compared with younger
subjects, older subjects had a lower mean
24-h corneal hysteresis and corneal
resistance factor, but not a lower CCT. Phase
timings of 24-h rhythms of CCT and IOP
were significantly delayed by aging.
Office-hour sitting measurements correctly
identified peak, mean and IOP fluctuation in
10% of the young adults, 32% of the elderly
control subjects and 20% of the patients
with glaucoma, whereas the combination of
supine and sitting measurements correctly
identified them in 30%, 85% and 46% of
cases, respectively. It is noteworthy that
office-hour measurements did not
characterize any 24-h parameter in 20% of
patients with glaucoma.
40 eyes were classified as having concentric
optic disc appearance and 35 eyes as having
nonconcentric optic disc appearance. The
mean nocturnal IOP was significantly
greater in the concentric group
(24.03 ± 0.8 mmHg) compared with the
nonconcentric group (21.9 ± 1.9 mmHg).
Most IOP peaks of patients with the
concentric optic disc appearance occurred
during the nocturnal period, as opposed to
the diurnal period of patients with the
nonconcentric optic disc appearance.
5 patients were excluded from the analysis
after the 24-h IOP curve (IOP > 21 mm
during nighttime [n ¼ 1] or daytime
[n ¼ 4]). Twenty-two (81%) patients
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148 125

Table 2 (continued )

References Population Methods Results

were modelled with a nonlinear least- received a diagnosis of NTG

Buys et al., 2010. 17 eyes of 17 patients with glaucoma with
controlled IOP and new disc haemorrhage.
Loewen et al., 2010. 9 healthy young adults with hyperopia, 32
age-matched subjects with emmetropia or
mild myopia (emmetropia group) and 34
subjects with moderate to severe myopia
(myopia group).
Fogagnolo et al., 2010. 40 glaucoma patients.
Lee et al., 2012. 72 men and 105 women with NTG in Korea.
squares, dual-harmonic regression
procedure, studying the mean value,
acrophase, nadir and amplitude of each
rhythm. Nonparametric tests were used to
study the relationship between the IOP
rhythm and vascular, sleep and visual field
parameters.
Patients were evaluated in a sleep
laboratory on two separate nights, the first
night lying flat and the second night in a 30-
degree head-up position. Intraocular
pressure and blood pressure were
measured every 2 h from 6 p.m. to 8 a.m. For
the 6 p.m., 8 p.m., 10 p.m. and 8 a.m.
measurements (awake period), the subjects
were sitting for both nights. For the
midnight, 2 a.m., 4 a.m. and 6 a.m.
measurements (sleep period), the subjects
were supine for the first night and 30 head
up for the second night.
24-h IOP data were collected in a sleep
laboratory. Every 2 h IOP measurements
were taken in the participants after 5 min in
the supine position and 5 min in the sitting
position during the 16-h diurnal/wake
period as well as when supine in bed during
the 8-h nocturnal/sleep period.
Patients underwent 24-h evaluation (8 p.m.,
midnight, 4 a.m., 8 a.m., noon and 4 p.m.) of
supine and sitting IOP, measured with
handheld Perkins and Goldmann
tonometer, respectively, and of CCT
measured using ultrasonic pachymeter. 30
patients were treated with timolol 0.5%
twice daily and latanoprost 0.005% once
daily; 10 patients were untreated.
Measurements were taken in both eyes, but
only one eye per patient was used for
analytical purposes. Three IOP curves were
drawn: sitting position, supine position and
habitual body position (diurnal sitting
measurements and nocturnal supine
measurements).
IOP was recorded at 8 a.m., 10 a.m., 12 p.m.,
2 p.m., 4 p.m., 6 p.m., 8 p.m., 10 p.m., 12
a.m., 3 a.m. and 6 a.m. using a hand-held
tonometer. The circadian pattern and peak
hours of habitual-position IOP and seated
IOP were analysed in all patients.
(IOP < 22 mmHg over 24 h). They exhibited
a diurnal acrophase (54.5%) or a nocturnal
acrophase (36.4%) of IOP. The remaining
patients (9.1%) with NTG had no
nyctohemeral rhythm. A significantly
higher proportion of patients with
capillaropathy and a higher nyctohemeral
fluctuation of IOP characterized the IOP
group with diurnal acrophase. An OPP
rhythm was found in all patients, (diurnal
[58%] or nocturnal [42%] acrophase) equally
distributed between the two IOP groups.
There were no significant differences
(p ¼ 0.68) between the two study visits in
IOP during the awake period (6 p.m., 8 p.m.,
10 p.m. and 8 a.m.) when patients were
sitting upright. During the sleep period
(midnight to 6 a.m.) the mean IOP was
3.2 mmHg lower in the 30-degree head-up
position compared with the flat position
(95% confidence interval, 0.25e6.1 mmHg).
16/17 patients (94.1%) had lower IOP in the
30-degree head-up position. The reduction
in IOP in the 30-degree head-up position
was 20% or more in 35% of patients (6/17).
There were no differences in blood pressure
or ocular perfusion pressure between the
two positions.
Average diurnal sitting IOP was lower in the
hyperopia group than in the other two
groups. The difference between the diurnal
sitting and diurnal supine IOP was greater
in the hyperopia group than in the myopia
group. In all three groups, the nocturnal
supine IOP was higher than the diurnal
sitting IOP. This elevation in habitual IOP
was most significant in the hyperopia
group. The hyperopia group also presented
a significant IOP elevation within the
nocturnal period. Simulated 24-h rhythms
of supine IOP were detected in all groups
with different phase timings, but simulated
24-h IOP variations were not different. The
24-h habitual IOP fluctuation (peak minus
trough) was inversely correlated to axial
length.
Untreated patients had higher IOP than the
treated group (habitual body position:
22.1 ± 5.1 mmHg vs. 16.0 ± 3.0 mmHg), but
no differences were found for IOP
fluctuations (habitual body position:
2.5 ± 1.2 mmHg vs. 2.3 ± 0.8 mmHg), mean
CCT (542 ± 38 mm vs. 534 ± 39 mm), and CCT
fluctuation (8.7 ± 5.6 mm vs. 6.5 ± 3.0 mm).
The correlation between IOP fluctuation
and mean CCT and its fluctuation was not
statistically significant in supine, sitting and
habitual body positions (p  0.07; R  0.20).
Analysis of the entire population indicated a
nocturnal peak (acrophase) for habitual-
position IOP. Subgroup analysis indicated
that 28 (15.8%) patients had diurnal
acrophase, 91 (51.4%) patients had
nocturnal acrophase and 58 (32.8%)
patients had no evident acrophase. There
were no correlations between various 24-h
habitual-position IOP parameters and VF
indices.
In the 177 NTG patients, there was a
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126 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Table 2 (continued )
References Population Methods
Mottet et al., 2012. 6 healthy young males. Subjects underwent six 24-h sessions of IOP
measurements over a 6-week period.
Subjects were housed in a sleep laboratory
in a constant controlled supine position and
in a strictly controlled environment. IOP
was measured hourly using a
pneumatonometer. A nonlinear least-
squares dual harmonic regression analysis
was used to model the 24-h IOP rhythm.
Mansouri et al., 2012c. 15 older volunteers with healthy eyes (age, Subjects were housed for 24 h in a sleep
53e71 years). laboratory. An 8-h accustomed sleep period
16 healthy younger subjects (age, 18e25 was assigned to each subject. Every 2 h, IOP
years). measurements were taken in the sitting and
supine positions. Simulated 24-h IOP
rhythms were determined using cosine
fitting of individual 24-h data. Sitting and
supine patterns of 24-h IOP were compared.
The average postural IOP effects during the
diurnal/wake period and the nocturnal/
sleep period were compared.
Grippo et al., 2013. 15 untreated patients with OHT (age, 41e77 IOP measurements were taken every 2 h
years). during a 24-h period. Measurements were
both sitting and supine (diurnal) and supine
only (nocturnal).
Liu and Weinreb, 2014. 38 younger healthy individuals, 53 older IOP was measured every 2 h sitting during
healthy individuals and 41 untreated older the day and supine at night using a
primary open-angle glaucoma patients. pneumatonometer. Rhythms of 24-h IOP in
the right eye and in the left eye were
estimated separately using cosinor
rhythmometry. Estimated 24-h IOP peak
timing (acrophase) and estimated 24-h IOP
variation (amplitude) were compared
between the paired eyes for each group.
CCT, central corneal thickness. CPAP, continuous positive airway pressure. IOP, intraocular pressure. NTG, normal tension glaucoma. POAG, primary open-angle glaucoma.
OHT, ocular hypertension. WDT, water drinking test.
Results
significant nighttime elevation of habitual-
position IOP, and nocturnal seated IOP was
significantly less than nocturnal habitual-
position IOP.
A significant nyctohemeral IOP rhythm was
noted in 30/36 (83%) sessions. Mean
nocturnal IOP was significantly higher than
diurnal IOP (20.1 ± 0.2 mmHg vs
18.8 ± 0.1 mmHg) in all subjects.
Amplitudes were not statistically different
among subjects. Intra-subject homogeneity
of distribution over time of the acrophase
and bathyphase was significant in 3/6 and
4/6 subjects, respectively. Intra-class
correlation coefficients of midline
estimating statistic of rhythm and IOP
values at 2, 3, 4, 10 and 11 a.m., and 2 p.m.
showed fair to good agreement among
sessions.
Within each age group, sitting and supine
patterns of 24-h IOP were similar and
parallel. Compared to the younger subjects,
the phase timing (simulated peak) of 24-h
IOP was significantly delayed for the older
subjects in both body positions. The
postural IOP effect for the older subjects
was 4.7 ± 0.8 and 4.8 ± 0.8 mmHg during
the diurnal and nocturnal periods,
respectively. These postural IOP effects
were not significantly different from the
postural effects in the younger subjects.
Mean sitting and supine IOPs were
significantly higher in the OHT group than
in the healthy control but not the glaucoma
group. Similar to the glaucoma group, the
OHT group demonstrated significant
differences from healthy controls in diurnal
IOP variation and IOP changes upon
awakening in habitual and supine positions.
The 24-h IOP curve acrophase and
amplitude for OHT were closer to those of
the glaucoma than the healthy control
group in the habitual position. 33% of OHT
subjects developed glaucoma during a
mean follow-up period of 4.3 ± 3.8 years.
Similar to findings in the glaucoma group,
habitual IOP curve phase delay, habitual IOP
variation, diurnal-to-nocturnal IOP changes
and IOP changes upon awakening of the
converters were significantly different from
those in healthy controls. There were no
differences between non-converters and
other groups.
The strength of association between the
paired 24-h rhythms of habitual IOP was
significantly weaker in glaucoma patients
than in healthy individuals.
Mean absolute time intervals between the
paired IOP peak timings were 1 h and
33 min in the younger healthy group and
1 h and 37 min in the older healthy group.
In the older glaucoma group, the mean
absolute time interval was 2 h and 30 min.
Coefficient of determination for the paired
24-h IOP variations in the older glaucoma
group was 0.343, significantly lower than
the coefficients of determination in the
younger healthy group (0.571) and the
older healthy group (0.646).
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
elevation of venous episcleral pressure. Some studies have evalu-
ated the 24-h IOP patterns in subjects resting in a constant supine
position over 24 h and have still found a 24-h rhythmic pattern with
lower IOP during the diurnal period and higher IOP during the
nocturnal period, but with lower amplitude than in subjects in the
upright position during the day and supine position during the
night (Buguet et al., 1994; Liu et al., 1998, 2003a; Noel et al., 2001).
In one of these studies, the difference between the highest value
and the lowest value was 8.2 ± 1.4 mmHg if the subjects adopted a
different body position at night than during the day, and
3.8 ± 0.9 mmHg when the subjects remained in a constant supine
position (Liu et al., 1998). This shows that the nyctohemeral rhythm
of IOP exists independently of body position change. A significant
portion of the nocturnal IOP elevation is caused by the postural
change from sitting to supine in the dark period but the postural
effect on IOP did not account for all nocturnal IOP elevation. It is
also interesting to note that with respect to the IOP values recorded
in the supine position, the passage in the left lateral decubitus
position causes a modest increase of IOP in the left eye and a
decrease of IOP in the right eye and vice-versa during the right
lateral decubitus transition (Noe €l et al., 2001).
Few studies conducted with non-continuous IOP measurement
devices have evaluated the relationship between sleep stages and
the IOP variations. Many physiologic parameters known to have an
impact on IOP levels and fluctuations vary across the different sleep
stages: blood pressure, central venous pressure, heart and respi-
ratory rate, body temperature, and sympathetic and para-
sympathetic nerve activity (Bakke et al., 2009; Castejon et al., 2010;
Cooper et al., 1979; Shapiro et al., 1981). All studies on sleep and
related 24-h or nocturnal IOP rhythms conducted with non-
continuous measurement devices require nocturnal awakenings,
thus potentially disturbing sleep structure, blood pressure dipping
status, and sympathetic activity. These repetitive arousals actually
prevented a continuously valid evaluation of the relationship be-
tween IOP variations and sleep micro- and macrostructure. In 1987,
Frampton et al. noted a sudden rise in IOP after subjects fell asleep
(Frampton et al., 1987). Later, in healthy subjects Brown found a
significant rise in IOP over the first 30 min of sleep, gradually
continuing during the night, and a decrease from waking and back
to its base value after about 20 min (Brown et al., 1988a, 1988b).
Furthermore, maintaining subjects awake during the night proved
to prevent the nocturnal IOP rise that occurred when the subject
was allowed to sleep in the morning (Frampton et al., 1987). More
recently, some studies seem to have found a relationship between
pressure changes and sleep stages, particularly with differences in
IOP levels and IOP variations during rapid eye movement sleep
stages compared to non-rapid eye movement stages (Buguet et al.,
1994; Noel et al., 2001).
Various studies have evaluated the reproducibility of the 24-h
IOP curves in the same individual. In a recent study six repeated
24-h sessions of IOP measurements were performed over a 6-week
period in a constant supine position in young heathy subjects
(Mottet et al., 2012). Intra-subject reproducibility of the acrophase,
bathyphase, amplitude and MESOR was fair to good in most sub-
jects. This could show that most subjects have a rather reproducible
24-h IOP pattern in the same condition and thus a single record of
IOP over a period of 24 h is sufficient to accurately characterize
nyctohemeral IOP variations in a given individual. The reproduc-
ibility of the 24-h IOP pattern in elderly subjects has not yet been
evaluated.
1.3.4. Studies of nyctohemeral rhythms of intraocular pressure in
subjects with glaucoma
As in healthy subjects, the IOP variations throughout a 24-h
period in patients with untreated primary open-angle glaucoma
127
seem to follow a nyctohemeral rhythm. It should be mentioned,
however, that studies of 24-h IOP rhythm in glaucoma subjects
conducted with non-continuous IOP measurements methods are
rare and that the results remain inconsistent. Some have found a
similar pattern to that seen in healthy subjects, with lower IOP
during the diurnal period and higher during the nocturnal period.
Other studies have suggested a phase delay in the periodic varia-
tions of IOP (þ4 to þ12 h) in subjects with glaucoma compared to
healthy subjects. In these studies, the acrophase was observed in a
significant proportion of the subjects during the day, usually in the
morning and sometimes in the afternoon. In some of the subjects,
the mean diurnal and nocturnal IOP levels were not significantly
different, whereas in others a higher diurnal IOP was found, in
contrast with studies conducted in healthy subjects that consis-
tently found a higher nocturnal IOP (Kitazawa and Horie, 1975;
Konstas et al., 1997; Noel et al., 2001).
The amplitude of the IOP variations over 24 h in glaucoma
compared to healthy subjects remains controversial. Some of the
studies that have evaluated the 24-h IOP variations in both healthy
subjects and untreated glaucomatous subjects with comparable age
and in the same methodological conditions have found higher
variations in glaucomatous subjects. For example, with sitting
measurements during the diurnal period and supine measure-
ments during the nocturnal period, Fogagnolo et al. measured a 24-
h IOP variation at 7.3 ± 3.2 in young healthy subjects,
7.5 ± 2.3 mmHg in elderly healthy subjects and 9.3 ± 3.2 mmHg in
elderly untreated glaucoma subjects (Fogagnolo et al., 2009). It
should be mentioned, however, that no study has compared the
relative 24-h IOP variations (amplitude divided by the mean IOP) in
healthy and glaucomatous subjects. Since the mean IOP level dur-
ing the 24-h period is usually higher, this could equalize the dif-
ferences found. It should also be mentioned that some studies did
not find higher 24-h IOP variations in subjects with glaucoma than
in healthy subjects. For example, with sitting measurements during
the diurnal period and supine measurements during the nocturnal
period, Liu and Weinreb measured an amplitude (half the distance
between the cosinor-fit maximum and minimum) of 3.12 ± 1.47
and 2.98 ± 1.54 mmHg in healthy elderly subjects e right and left
eye, respectively e and 2.29 ± 1.22 and 2.43 ± 1.43 mmHg in un-
treated elderly glaucoma subjects (Liu and Weinreb, 2014).
The other parameters describing the nyctohemeral IOP rhythm
(period, amplitude, intra- and inter-subject variability) were also
less clearly characterized in subjects with glaucoma than in healthy
subjects. The apparently higher variability of the IOP and IOP nyc-
tohemeral variations in glaucoma subjects particularly suggests the
value of the continuous recording methods that can provide several
measurements and thus characterize the IOP rhythm more accu-
rately in these subjects.
Similarly, the IOP nyctohemeral profile of subjects with normal-
tension glaucoma has been insufficiently studied to date, with
conflicting results. In a large study of 177 eyes of Asian subjects
with untreated normal-tension glaucoma, analysis of the entire
population indicated a nocturnal acrophase of habitual-position
IOP, with a peak at approximately 6 a.m. (Lee et al., 2012). Further
analysis of individual patients indicated that 28 (15.8%) patients
had a diurnal acrophase, 91 (51.4%) patients had a nocturnal
acrophase, and 58 (32.8%) patients had no evident acrophase. In a
recent study, 22 Caucasian patients with a diagnosis of NTG (un-
treated IOP < 22 mmHg over 24 h) were studied over a 24-h period
(Renard et al., 2010). They exhibited a diurnal acrophase (54.5%) or
a nocturnal acrophase (36.4%) of IOP (see Fig. 5). Other studies have
also reported higher diurnal IOP compared to nocturnal IOP in
normal-tension glaucoma subjects, but without any formal
modelling of the 24-h IOP (Nomura et al., 2010; Sakata et al., 2013).
Similarly, the pattern of 24-h IOP in subjects with ocular
128 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Fig. 5. Nyctohemeral intraocular pressure rhythm in subjects with normal-tension
glaucoma. From modelling, subjects were classified as subjects with a diurnal
rhythm, nocturnal rhythm or with no significant rhythm (Renard et al., 2010).
hypertension but without glaucomatous optic neuropathy has been
poorly characterized to date, with only one relevant study con-
ducted (Grippo et al., 2013). In 15 subjects with ocular hyperten-
sion, similar to healthy and glaucomatous subjects, IOP was found
to decrease progressively in the diurnal period with a bathyphase in
the late afternoon, while IOP increased during the nocturnal period
with an acrophase in the early morning (Fig. 6). In the habitual body
position (sitting during the day and supine during the night), the
IOP peak occurred between 1:30 a.m. and 3:30 a.m. in the subjects
with ocular hypertension (24.5 mmHg), but at 5:30 a.m. in both the
glaucoma and healthy control groups (22.6 and 22.5 mmHg,
respectively). The trough occurred at 9:30 p.m. for all three groups
(18.7, 17.8 and 14.9 mmHg for the ocular hypertension, glaucoma
and healthy control groups, respectively).
Many studies have evaluated the hypotensive effect of glaucoma
medications, laser or surgical procedures with multiple measure-
ments performed over 24-h periods, but very few studies have
modelled the effect of these treatments and procedures on the 24-h
IOP rhythm, and thus have stricto sensu evaluated the effect on the
24-h nyctohemeral patterns and the type of rhythm of treated
glaucoma patients (Konstas et al., 2015). The effect of the various
therapeutic classes, drugs and combinations on IOP is beyond the
scope of the present paper. Briefly, the studies conducted suggested
Fig. 6. 24-h intraocular pressure patterns of subjects with ocular hypertension (open
circles), healthy control (open triangles), and glaucoma (solid squares) groups. Mea-
surements were performed in the habitual position (diurnal sitting, nocturnal supine)
(Grippo et al., 2013).
that some therapeutic classes such as beta-blockers, carbonic
anhydrase inhibitors and alpha-agonists have a hypotensive effect
that predominates during the diurnal period and is less pro-
nounced or absent during the nocturnal period, whereas others
such as the prostaglandin analogues have a more homogenous
hypotensive effect over both the diurnal and nocturnal periods
(Konstas et al., 2015; Liu et al., 2004, 2009, 2010) (Fig. 7). Similarly,
very few studies have evaluated the effects of trabeculoplasty and
surgical procedures on the 24-h nyctohemeral rhythm. Some of the
studies currently available suggest that laser trabeculoplasty could
have a homogenous effect over 24 h and thus do not change the
pre-procedure IOP pattern (Tojo et al., 2014a). Others have found a
slightly higher IOP decrease during the nocturnal period than
during the diurnal period, flattening the 24-h IOP curve (Lee et al.,
2007, 2014). By contrast, studies conducted in patients undergoing
filtering surgery e trabeculectomy e show few or no differences in
IOP between the diurnal and nocturnal period, and even no dif-
ferences between the sitting and supine position, and thus suggest
a possible absence of 24-h IOP rhythm induced by the surgical
procedure (Konstas et al., 2006; Ross et al., 2011). These studies
suggest that the creation of an alternative and non-physiologic
pathway of aqueous humour drainage could be the cause of the
loss of the rhythmic character of IOP.
1.3.5. Studies of nyctohemeral rhythms of intraocular pressure in
other conditions
Ametropias: One study evaluated the effect of the refractive
status on the 24-h variation of IOP in young healthy subjects with
myopia, hyperopia and emmetropia (Loewen et al., 2010) (Fig. 8). In
all three groups, nocturnal supine IOP was higher than diurnal
sitting IOP. The nocturnal elevation of IOP in the habitual position
was greater in the hyperopia group than in the emmetropia group
and lower in the myopia group than in the emmetropia group. The
average IOP difference between the nocturnal and diurnal periods
was 7.5 ± 1.7 mmHg in hyperopic subjects, 5.0 ± 2.6 mmHg in
emmetropic subjects and 3.2 ± 2.5 mmHg in myopic subjects.
Sleep apnea syndrome: Obstructive sleep apnea (OSA) is a com-
mon medical condition characterized by repetitive partial or com-
plete obstruction of the upper airway causing repetitive nocturnal
oxygen desaturation, i.e. chronic intermittent hypoxia. A significant
association between OSA and glaucoma continues to be debated
Fig. 7. 24-h intraocular pressure patterns of glaucoma subjects without treatment
(open circles), with timolol (solid triangles), and latanoprost (solid squares) groups.
Measurements were performed in the habitual position (diurnal sitting, nocturnal
supine) (Liu et al., 2004).
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Fig. 8. Twenty-four-hour intraocular pressure profiles of hyperopia, emmetropia, and
myopia groups. Measurements were performed in habitual body positions, sitting
during the diurnal/wake period and supine during the nocturnal/sleep period (Loewen
et al., 2010).
(Aptel et al., 2014a). There are numerous factors capable of inducing
acute or chronic changes in IOP in patients with apnea such as
haemodynamic parameters, high sympathetic tone and vigilance
state. Obstructive respiratory events may be simulated by negative
inspiratory efforts that are associated with huge variations in cen-
tral venous pressure and thus in IOP. Finally, slow-wave sleep,
associated with changes in IOP in healthy subjects, is virtually
abolished in severe OSA. Nasal continuous positive airway pressure
(CPAP), the first-line therapy for OSA, suppresses abnormal respi-
ratory events to restore sleep quality and to partly or completely
reverse acute and chronic cardiovascular modifications associated
with the disease.
A few studies have evaluated the 24-h IOP rhythm in untreated
and CPAP-treated OSA subjects. One study conducted before and
after treatment initiation in 18 subjects found a nocturnal acrop-
hase in 28% of the subjects, a diurnal acrophase in 22% of the
subjects and absence of a 24-h rhythm in 50% of the subjects before
treatment (Pe
pin et al., 2010) (Fig. 9). After CPAP initiation, the
mean nocturnal IOP increased from 14.8 ± 0.8 mmHg to
18.3 ± 1.2 mmHg. In patients with initial abnormal IOP rhythm (i.e.
rhythm with diurnal acrophase or absence of rhythm), 67% shifted
to a normal 24-h IOP profile after treatment. Other studies have
found a significant increase in IOP during the nocturnal period in
OSA patients with CPAP compared to OSA patients without CPAP
(Kiekens et al., 2008).
1.3.6. Limitations of the current tonometry methods in the study of
the nyctohemeral rhythms of IOP measurements
All previous studies of 24-h IOP conducted to date have found a
significant nyctohemeral rhythm, in both healthy and glaucoma-
tous subjects and even in a constant supine or sitting position, with
usually higher IOP levels during the nocturnal period and lower IOP
levels during the diurnal period. However, when studying the
circadian rhythm of a biological parameter, a crucial point is not to
use a method that could disrupt the normal sleepewake cycle.
Studies have demonstrated that many biological endogenous
circadian rhythms may be perturbed by forced interruption of the
sleepewake cycle: melatonin secretion, body temperature, plasma
level of cortisol, blood pressure, heart rate, etc. (Dettoni et al., 1985;
Goichot et al., 1998; Redwine et al., 2000; Salin-Pascual et al., 1988;
Sasaki et al., 1993; von Treuer et al., 1996). Until now, all IOP
129
measurements methods e portable or not e required subjects to be
awakened for nocturnal measurements. We could therefore spec-
ulate that the results of the several studies conducted with hourly
or occasional awakening may have been biased or falsely induced
by stress-related artefacts or sleepewake cycle disorganization.
As mentioned above, another possible limitation of the studies
conducted with non-continuous measurement methods is that a
significant number of studies have used a relatively limited fre-
quency of IOP measurements to evaluate the 24-h IOP variations
and rhythms. Measurements taken only every 2 or 3 h provide only
a few time point measurements over a period of 24 h (12 and 8,
respectively), and if the amplitude of the variations of the param-
eter over 24 h is low the different mathematical models available
will have a relatively high probability of missing an existent
circadian rhythm, and thus falsely conclude in the absence of a
circadian rhythm (false conclusion of random variations over time).
A high frequency of measurement of the parameter studied thus
increases the probability of identifying a circadian rhythm and in-
creases the accuracy of the estimation of the main quantitative
parameters that describe this circadian rhythm.
2. Continuous monitoring of IOP with extraocular devices
2.1. Description and measurement principles
Temporary 24-h IOP monitoring is a noninvasive approach,
which offers potential advantages over permanent IOP monitoring,
mainly due to safety, tolerability, and ready reversibility. Further-
more, any individual is potentially eligible for this approach
because it does not require surgical intervention. However, in
contrast to implantable IOP sensors, temporary IOP monitoring via
contact lens approaches does not directly measure IOP (Mansouri
et al., 2015b).
The first steps in this direction were taken more than five de-
cades ago by Maurice (Maurice, 1958), who developed an auto-
mated recording indentation tonometer. Limited by the state of
technology at that time, the device was impractical and was not
pursued beyond the prototype stage. It nevertheless had the merit
of setting the stage for future attempts at 24-h monitoring that
could build on technological advances.
Cooper et al. (1979) described the use of radio telemetry for this
purpose. Their approach used a miniature guard ring applanating
transensor (AT), which was mounted in an acrylic haptic ring. The
sensor holder was modelled from a standard haptic whose central
optic was removed. Measurements were derived from applanating
the inferior sclera under the lower eyelid and were registered
through an automatic continual frequency monitor, which was
fixed to the head by elastic bands. The resonant frequency of the AT
was hypothesized to be directly proportional to IOP. These changes
were monitored in resonant frequency and transmitted to a remote
radio receiver, which converted its output to an analog signal. The
device was studied in anesthetized animals and conscious humans.
The investigators showed that measurements could be obtained for
up to 2 h and reflected physiological IOP changes such as ocular
pulsations and the effect of Valsalva maneuvers. They highlighted a
main limitation of the device, which was its strong dependency on
the individual's scleral rigidity and related factors. The device suf-
fered from several other shortcomings, chief among them the need
for customization to individual eyes, translating into high produc-
tion costs and precluding its wider use.
The 21st century heralded technological advances in telemetry
and micro-electromechanical systems, which enabled the devel-
opment of devices for ambulatory, continuous 24-h IOP measure-
ment (Akaishi et al., 2005; Mansouri and Weinreb, 2012a, 2012b;
Maurice, 1958; Schnell et al., 1996). The past 5 years in particular
130 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148

Fig. 9. Twenty-four-hour curves of intraocular pressure (IOP) before and during nasal continuous positive airway pressure treatment of patients with obstructive sleep apnea. Top:
at diagnosis, patients had normal IOP nyctohemeral rhythm (nocturnal acrophase); all 3 patients reassessed after treatment continued to have normal IOP rhythm. Middle: at
diagnosis, patients did not have IOP nyctohemeral rhythm; of 5 patients reassessed after treatment, 3 had normal IOP rhythm and 2 no IOP rhythm. Bottom: at diagnosis, patients
had IOP nyctohemeral rhythm and diurnal acrophase; of 4 patients reassessed after treatment, 3 had normalized rhythm (Pe
pin et al., 2010).

have witnessed the development of several noninvasive devices.
These contact lens-based approaches generally estimate IOP by
detecting corneal changes that are hypothesized to reflect IOP
changes.
Twa et al. (2010) embedded the piezoresistive sensor tip of the
dynamic contour tonometer (Pascal DCT, Ziemer Ophthalmic Sys-
tems AG, Port, Switzerland) into a hard contact lens. The sensor is
located in a contoured probe, which serves to minimize the effect of
corneal parameters on measurement errors. The authors demon-
strated that this approach could provide reliable IOP measurements
for the duration of 100 s, at a rate of 100 Hz. Hediger et al. (2009)
used the technology in 24 healthy subjects before and after Val-
salva maneuvers. They demonstrated the safety of the device and
its ability to detect IOP changes in a continuous manner. The major
advantage of this approach is the use of an already validated
technology (e.g., DCT). Although the reported measurements were
for a short duration, the technology could easily be expanded to
obtain 24-h measurements. Other limitations of this approach are
the use of a hard contact lens and the location of the sensor tip in
the center of the contact lens, negatively affecting central vision. To
the authors' best knowledge, and despite its promise, this tech-
nology has so far not been pursued any further.
Sa
nchez et al. (2011) described a flexible, nanocomposite, all-
organic bilayer sensor made of organic molecular metal (b-
(ET)2I3). The sensing bilayer membrane is incorporated into a rigid,
gas-permeable doughnut-shaped contact lens a with a 3-mm
central hole. The sensor is a polycarbonate film coated with a
polycrystalline layer of the highly piezoresistive molecular
conductor, capable of detecting deformations caused by pressure
changes of 1 mmHg. The investigators demonstrated proof of
principle in enucleated porcine eyes, in which electrical resistance
changes were highly correlated to manometrically modified IOP
levels. The authors also further described a custom-made contact
lens that was fitted to a healthy human eye. The sensor repeatedly
detected IOP changes secondary to eye blinks, saccades, and eye
rubbing. The organic material has the advantage of being up to ten
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
times more sensitive than inorganic metal-based gauges. Although
the sensing membrane is optically transparent for approximately
80% of the visible spectrum, its central positioning may cause visual
disturbances. Other practical challenges of this device are the need
for custom fitting as well as the rigid material, both of which pre-
clude widespread use in clinical practice.
A chipless soft contact lens with a resonance circuit was recently
described, in which a thin film capacitor is coupled with a sensing
coil to detect corneal curvature deformations (Chen et al., 2014). By
coupling the inductive coil with a capacitor to form a resonator,
changes in coil inductance can be detected wirelessly by an external
reader as changes in resonance. By establishing the correlation
between resonance and IOP, IOP can be estimated and monitored
by a wireless reader mounted near the eye. Eliminating the
embedded chip results in a significant reduction of contact lens
thickness (<150 mm instead of approximately 585 mm), thereby
reducing mechanical attenuation and improving strain sensitivity.
The feasibility of this IOP sensing concept was explored in a silicone
rubber eye model mimicking the usual human nyctohemeral IOP
range. The data showed that despite a pressure lag in the initial
cycle, the lag disappeared once the system had stabilized and that it
could closely track rapid and cyclical pressure changes. No human
data have been reported to date.
A different approach was taken by Margalit et al. (2014), who
proposed monitoring IOP by tracking secondary speckle pattern
trajectories produced by the reflection of an illuminating laser
beam from the iris or the sclera. This innovative technology had
previously been applied to remote monitoring of different biolog-
ical parameters such as heart rate and blood pulse pressure. The
underlying assumption for IOP estimation is that pressure changes
in retinal blood vessels are reflected in scleral and iris pulsations in
a way that is correlated to IOP. This assumption remains contro-
versial. They developed a speckle-based measurement system with
the ability to detect these movements at the nanometric scale. The
photonic device was tested in six rabbit eyes using two different
methods to modify IOP: via an infusion bag and via mechanical
pressure. In both cases, the eyes were stimulated with increasing
and decreasing steps of IOP. As IOP variations changed, the speckle
distributions reflected back from the eye. Data were recorded under
various optical configurations to define the experimental configu-
ration for the IOP extraction. They could demonstrate a high cor-
relation (R2 ¼ 0.98) between the device output and the reference
IOP. Despite interesting findings, numerous uncertainties remain:
the device does not measure iris/scleral movements directly and
the relationship between the photonic signal and IOP remains to be
Fig. 10. Principle of the Triggerfish Contact Lens Sensor measurement device. a. Principle of applanation tonometry: force (F) is applied to measure pressure (IOP) directly. b. The CLS
measures a composite of IOP, intraocular volume, and ocular biomechanical changes.
131
shown in human subjects. Importantly, this technology is unable to
obtain measurements during the crucial sleep period.
In summary, the above devices are currently at the experimental
stage and are not commercially available. Cost is a barrier for pro-
totype technologies moving from the laboratory setting to human
trials.
Leonardi et al. (2004) pioneered the field of temporary 24-h IOP
monitoring by developing the first “smart” contact lens at the Swiss
Federal School of Technology more than 10 years ago. They utilized
Hjortal and Jensen's theory that ocular dimensional changes
measured at the corneoscleral junction correspond to changes in
IOP (Hjortdal and Jensen, 1995) (Fig. 10). The device is based on a
disposable silicone contact lens that incorporates two (platinum-
titanium sensing-resistive) strain gauges that measure limbal strain
associated with changes in intraocular pressure and volume. Leo-
nardi's work led to the Triggerfish contact lens sensor (CLS; SEN-
SIMED Triggerfish®, Sensimed AG, Lausanne, Switzerland), which
obtained CE marking in 2009 and became the first commercially
available technology for 24-h IOP monitoring. FDA approval fol-
lowed in early 2016. The main value of the device is the ability to
record the IOP-related profile in a real-life setting for up to 24 h,
including during undisturbed sleep (Mansouri and Shaarawy,
2011).
The CLS monitors IOP-related changes near-continuously, as it
acquires a total of 288 data points over a 24-h period, each corre-
sponding to 30 s of continuous measurements, repeated every
5 min. The CLS is powered by inductive coupling through an
external antenna patched around the eye. The microprocessor
reads the contact lens strain gauges at a frequency of 10 Hz and
transmits data to the external antenna, which is connected to a
portable recorder unit worn around the patient's chest. Recorded
CLS profiles are visualized graphically on a computer interface
(Fig. 11). The output of the sensor is expressed in millivolt equiva-
lents (mVeq) corresponding to electric voltage changes and pre-
sented as arbitrary units (a.u.). At the beginning of each session,
measurements are normalized and start at 0 a.u. (Mansouri and
Weinreb, 2012a). Experimental data in enucleated porcine and
human eyes demonstrated high and reproducible correlations be-
tween IOP and CLS output (Leonardi et al., 2004, 2009).
In fact, measurements of the CLS do not reflect IOP directly but
rather a composite of intraocular pressure and volume changes as
well as the effect of ocular biomechanical properties on these pa-
rameters. The contribution of each of these three parameters to the
CLS signal is currently unknown. We therefore refer to its output as
“IOP-related patterns.” Although elevated IOP and IOP variations,
132 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148

which are directly related to the stress of eye tissues, have been
established as a major risk factor for glaucoma, intraocular volume
changes could also be of importance, because it is directly related to
the strain of the same tissues.
While tonometry measures IOP, the CLS is assumed to be
significantly influenced by intraocular volume changes, with the
relationship between the pressure and volume being curvilinear
(Silver and Geyer, 2000) (Fig. 10). Based on the model by Silver and
Geyer for the living human eye as an ellipsoid, a finite-element
nonlinear viscoelastic model of the human eye (corneoscleral
shell) was developed, which simulates the time-dependent vol-

Fig. 11. Example of 24-h monitoring with the Triggerfish Contact Lens Sensor. Shaded zones indicate absence of blinks, generally indicating periods of sleep.
umeepressure relationship (Leonardi and Mansouri, personal
communication). A trial-and-error method was used to define the
short-term (rate-independent part) nonlinear strainestress
behaviour of corneoscleral shell tissues seeking to match the short-
term volumeepressure relationship described by previous in-
vestigators. Experimental viscoelastic properties (rate-dependent
part) of corneoscleral shell tissues were then added to the finite-
element model to simulate the time-dependent volumeepressure
relationship. According to the model, following an instantaneous
pressure change (a creep-like response as in the case of a change in
body position) or a rapid volume change (a relaxation-like response
as in the case of intraocular fluid injection), very different time lags
occur before reaching the steady state where volume and pressure
are at equilibrium: simulations of typical loads show a creep time
constant tc of 40.3 min versus a relaxation time constant tc of
3.4 min. For volume changes at low rates that could correspond to a
physiological imbalance in the intraocular fluid inflow/outflow (0.5
and 0.1 mL/min), the model shows that the time lag between vol-
ume and pressure can be ignored. The model notably shows that,
depending on the load, there is a time lag in the volumeepressure
relationship that has to be taken into consideration when
describing this relationship. In practice, this signifies that CLS
measurements may vary from tonometry when studying different
IOP-changing events.
Furthermore, the CLS provides its measurements in arbitrary
units (corresponding to electrical units of voltage) instead of the
habitual mmHg unit. All the above factors have prevented direct
comparisons between the CLS and tonometry and have rendered
clinical interpretation of its readings challenging, providing a
source of controversy and misunderstanding (Faschinger and
Mossbock, 2013; Leonardi, 2014). This difficulty is further com-
pounded by the inability to use tonometry simultaneously on the
CLS-wearing eye. To address this limitation, 30 healthy subjects
were housed in a sleep laboratory (Liu et al., 2015). IOP was
measured every 2 h with a pneumatonometer in one randomly
selected eye in the habitual body position, while the fellow eye was
being monitored with the CLS. Using cosinor rhythmometry
modelling, simulated peak timing was 4:11 a.m. (tonometry) and
4:44 a.m. (CLS) (p ¼ 0.256). While these results indicated good
agreement between the two techniques for detection of peak IOP
timing, the simulated variations in the paired eyes were not
correlated.
Similar to our model, Flatau et al. (2016) also applied the Silver
and Geyer model to the CLS and proposed a simple calibration from
CLS to mmHg. They equated the increase in tonometer IOP from
sitting-to-lying to the corresponding rise in CLS values at the end of
the monitoring period. Their model has not been validated. When
applied to a database of over 500 subjects, it does not seem to
explain observed CLS/tonometry differences and, in some cases,
results in nonphysiological IOP amplitudes of over 70 mmHg over
the 24-h period (K. Mansouri, unpublished data). More research is
required to elucidate the complex relationship between the CLS
output and tonometry.
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
2.2. Nyctohemeral rhythms of intraocular pressure in healthy
subjects
2.2.1. Description of rhythms and reproducibility
The first study to evaluate the 24-h nyctohemeral rhythm of IOP
in healthy humans using the Triggerfish CLS was conducted in 2013
(Mottet et al., 2013). Participants underwent four 24-h sessions of
IOP measurements over a 6-month period. Two sessions with non-
contact tonometer (NCT) measurements in one eye and CLS mea-
surements in the fellow eye, one session with CLS measurements in
only one eye, and one session with NCT measurements in both eyes
were conducted. The goal of the study design was to evaluate both
the symmetry of the two eyes using the same tonometry method
(NCT) and the symmetry of the two eyes using two different
tonometry methods (NCT in one eye and CLS in the other eye) and
thus to compare the results of the two tonometry methods and
evaluate the convertibility of the electrical signal in pressure units.
This design also allowed us to evaluate the inter-session repro-
ducibility of the 24-h IOP rhythm measured with NCT and the CLS.
The protocol was strict. The subjects had to maintain a self-selected
constant sleepewake schedule (onset between 10 p.m. and 12 a.m.
and wake up between 7 and 8 a.m.) 2 weeks before and during the
study, checked by sleepewake diaries and ambulatory actigraphy
monitoring using a wrist accelerometer. Subjects unable to main-
tain a constant schedule were excluded. During the experimental
sessions, they were requested not to drink alcohol and caffeine-
containing beverages. Although the subjects were allowed to
have free activities between the NCT hourly IOP measurements,
participants were asked to go to bed after the IOP measurement at
10 p.m. and were asked to get up after the IOP measurement at 8
a.m. From raw IOP data over 24 h, a nonlinear least squares, dual-
harmonic regression analysis was used to model the 24-h IOP
rhythms.
Interestingly, a significant nyctohemeral IOP rhythm was found
in 31 of 36 sessions lasting 24 h (86%) using NCT and in all 24-h
sessions using CLS (100%). In all participants and throughout the
sessions, the mean nocturnal IOP was significantly higher than
diurnal IOP using NCT (15.6 ± 0.5 mmHg vs 13.9 ± 0.5 mmHg) or
CLS (14.0 ± 4.2 eqVm vs 0.2 ± 4.8 eqVm).
This was a crucial result, because it confirmed the results of the
studies conducted with the currently available non-continuous
tonometry methods, showing that the IOP nyctohemeral rhythm
was characterized by an acrophase in the late night/early morning
period. Given that sessions performed with CLS measurements
alone confirmed these earlier results, this demonstrates that the
IOP rhythm previously described in healthy humans with the
available tonometry methods is not an artefact due to nocturnal
awakening for IOP measurements and related sleep disorganiza-
tion. These results also showed that the CLS is a more sensitive
method than the NCT in detecting the 24-h IOP rhythm.
In all visits in which CLS and NCT were simultaneously used,
mean acrophase (3:05 a.m. ± 37 min vs 5:28 a.m. ± 41 min) and
bathyphase (3:14 p.m. ± 55 min vs 7:32 p.m. ± 57 min) were
significantly earlier in the eyes measured with CLS than in the eyes
measured with NCT. Using the same tonometry method (NCT),
mean acrophase (5:21 a.m. ± 51 min vs 5:49 a.m. ± 44 min) and
bathyphase (6:16 p.m. ± 65 min vs 7:49 p.m. ± 52 min) were not
significantly different. These results suggest that the differences
obtained by the two different techniques are related to the tech-
nical methods (number of IOP measurements) and not biological
variability (Fig. 12). This also confirmed that the CLS is a more
sensitive method than the non-continuous IOP measurements in
detecting and characterizing the 24-h IOP rhythm. The CLS allowed
better nonlinear dual-harmonic modelling of the 24-h IOP rhythm.
Thus, the CLS usually detects acrophase and bathyphase
133
significantly earlier (about 2 h) than NCT. One reason explaining the
greater ability of the CLS to detect and characterize the 24-h IOP
rhythm is likely the higher frequency of data acquisition, strongly
reducing the potential influence of outliers (24 time points over
24 h with NCT vs 288 time points with the CLS).
Among the sessions, the 24-h rhythm parameters found with
the same tonometry technique (NCT or CLS) in a given participant
and in a given eye were usually comparable. The most robust pa-
rameters among sessions were the MESOR and amplitude for NCT
and the acrophase and bathyphase for CLS. The most reproducible
IOP values were taken during the day (8 a.m.e10 p.m.) with NCT;
the most reproducible IOP changes were taken between 11 a.m. and
1 p.m. and between 6 p.m. and 8 p.m. with CLS (Fig. 13).
When taking NCT measurements in both eyes, most of the
subjects studied exhibited a significant correlation of simultaneous
hourly IOP values measured using NCT in their fellow eyes. When
taking NCT measurements in one eye and CLS measurements in the
contralateral eye, the IOP change at each point normalized from the
first measurement (9 a.m.) was not symmetric individually or
within the population. The CLS measures an electrical signal
expressed in millivolts. Measurements are normalized to the first
measurement of the session (in electric arbitrary units). The first
measurement of the recording session, just after activating the
device, is therefore arbitrarily set at 0 eqVm. The subsequent
measurements are the relative signal change. The unresolved
question about this device was whether these signal variations can
be used to estimate the variations in IOP expressed in millimeters of
mercury reached at each point using the IOP measured just before
contact lens equipment with NCT or GAT. Our results show that the
CLS cannot estimate the absolute value of IOP in millimeters of
mercury when using the pre- and post-CLS GAT measurements or
pre- and post-CLS NCT measurements (Fig. 14). When taking NCT
measurements in both eyes, IOP changes at each point compared
with the first measurement (9 a.m.) are usually symmetric in a
given participant or in the population. When taking NCT mea-
surements in one eye and CLS measurements in the fellow eye, IOP
changes at each point compared with the first measurement (9
a.m.) are not symmetric in a given participant or in the population,
and the difference varies inconsistently throughout the session or
among subjects. It is therefore not possible to use the relative
change in CLS signal multiplied by the IOP measured before CLS
equipment initiation to estimate the absolute IOP at each point of
the 24-h session.
Others later confirmed these findings. Agnifili et al. performed
one session of 24-h measurements in ten young healthy subjects
(Agnifili et al., 2015), who returned home after the device was
turned on and were advised to follow their normal daily activities
and were not controlled for sleep times and environmental factors.
No restriction of the subject's activity was required, and caffeine
and alcohol intake was possible. IOP was modelled as a linear,
quadratic or cubic function over time. IOP peaked during the night
(nocturnal acrophase) in 70% of healthy subjects, with a significant
cosinor pattern. The 24-h mean IOP curves showed the highest
peak during the night (mean peak hour at 4 a.m.), gradually
decreased during the morning (8e9 am) and reached the lowest
value in the early afternoon (4 p.m.). Tojo et al. conducted one
session of 24-h measurements in 11 healthy elderly subjects (mean
age, 70.2 ± 8.8 years) (Tojo et al., 2015). Contrary to the above-
mentioned studies, the measurement of continuous IOP with the
CLS started in the afternoon (approximately 3 p.m.). The patients
returned home with no restrictions in their posture and activity
during the measurement. The main characteristics of the 24-h
pattern were derived from the graphical curves (max, min, acrop-
hase, bathyphase), and the mean periodic CLS values were
compared (e.g., average signal during the nocturnal period
134 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148

Fig. 12. Non-contact tonometer and contact lens sensor raw and modelled data during two 24-h sessions performed in the same healthy subject (Mottet et al., 2013). Top: raw and
modelled data obtained from continuous measurement device. Bottom: hourly measurement in the fellow eye with portable non-contact tonometer.

Fig. 13. Contact lens sensor (a) and non-contact tonometer (c) 24-h measurement reproducibility over two 24-h sessions in young healthy subjects (Mottet et al., 2013).

Fig. 14. Symmetry of the non-contact tonometer (G) and contact lens sensor (F) 24-h measurements taken in the two eyes of young healthy subjects (Mottet et al., 2013).
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
compared to average signal during the diurnal period) to classify
the subjects into three pattern groups: diurnal, nocturnal and un-
classifiable. No mathematic modelling method was used. All eyes in
the healthy group were classified into the nocturnal type, with
significantly higher nocturnal CLS values than diurnal values.
In another study, the mathematically simulated peak timing and
the variation of 24-h CLS output signals in one eye was compared
with the simulated 24-h IOP rhythm in the contralateral eye in a
group of 30 healthy adults (Liu et al., 2015). Previous studies have
shown that in healthy adults, 24-h IOP rhythms in the paired eyes
are relatively symmetrical. The protocol was also strict. Before the
laboratory experiment, subjects were instructed to maintain an
accustomed 8-h sleep for 7 days. Subjects were given a wrist-
mounted device and a wake/sleep log to keep track of physical
activity and light exposure. They were also asked to abstain from
alcohol for 3 days and regular coffee for 1 day. The 24-h measure-
ments of continuous IOP with the CLS in one eye and the mea-
surement of the IOP with a pneumotonometer every 2 h in the
fellow eye started in the afternoon (approximately 3 p.m.) and were
performed in a sleep laboratory. Diurnal measurements were taken
in a sitting position (from 2 p.m. to 11 p.m. and from 7 a.m. to 1:30
p.m.) and the nocturnal measurement in a supine position (from 11
p.m. to 7 a.m.). Meal times and indoor activities were not regulated.
The 24-h rhythm in each of the paired eyes was estimated using the
least squares cosinor method.
The overall 24-h pattern of the CLS signal and of the IOP in the
contralateral eye was similar to those found in previous studies.
After the initiation of data collection at 2 p.m., there was a
continuous reduction in CLS output signals and a continuous IOP
reduction toward the transition from the diurnal/wake period to
the nocturnal/sleep period. The lowest CLS signal and the lowest
IOP occurred near the end of the diurnal/wake period. The mean
CLS signal and mean contralateral IOP value during the nocturnal/
sleep period were higher than the related values during the
diurnal/wake period. The highest values of the two 24-h data
profiles occurred during the nocturnal/sleep period. The peak
timings for the 24-h CLS data occurred at 4:44 a.m. ± 210 min and
for the IOP data in the contralateral eye at 4:11 a.m. ± 120 min. The
difference between the paired peak timings was not statistically
significant. The amplitude for the 24-h CLS rhythm was
99.8 ± 65.5 mV and the amplitude for the 24-h IOP rhythm was
3.1 ± 1.4 mmHg. Contrary to peak timing and in agreement with a
previous study, linear regression analysis showed no significant
correlation between these two data variations (r ¼ 0.043). These
results also have considerable importance. Since relatively sym-
metrical 24-h rhythms including the parameters of peak timing and
data variation are found with the same tonometry method in the
paired eyes of healthy individuals, the lack of correlation between
the amplitudes of simulated 24-h CLS output signals and 24-h IOP
in the contralateral eye confirmed the difficulty in the conversion of
CLS output signals to accurate IOP values using a general formula.
Estimated 24-h IOP rhythms using the two devices should not be
considered interchangeable.
2.2.2. Influencing factors
Age: As mentioned in Table 2, studies conducted in young,
middle-aged and elderly healthy subjects have consistently found
lower CLS and IOP values, higher CLS and IOP values during the
night, a diurnal bathyphase occurring in the late afternoon or early
evening and a nocturnal acrophase occurring in the middle or the
end of the nocturnal period.
Hourly awakening: In a recent study, two 24-h IOP measurement
sessions over a 2-month period in 12 young healthy subjects were
conducted (Aptel et al., 2014c, 2015). During one session, the IOP of
the first eye was continuously monitored using a CLS and the IOP of
135
the fellow eye was measured hourly using a portable non-contact
tonometer, with nocturnal hourly awakening for the IOP mea-
surement. During the other session, the IOP of the first eye was
continuously monitored using a CLS and the IOP of the fellow eye
was not measured, and therefore nocturnal awakening did not
occur. Overnight polysomnography was performed during the two
sessions to evaluate the sleep macrostructure. A nonlinear least
squares, dual-harmonic regression analysis was used to model the
24-h IOP rhythm from the CLS data. Comparisons of acrophase,
bathyphase, amplitude and MESOR were used to evaluate the effect
of hourly awakening on IOP rhythm. Comparisons of sleep structure
(absolute and relative total sleep time, non-rapid eye movement
[non-REM] sleep [N1, N2, N3], REM, sleep period and wake after
sleep onset [WASO]) were used to evaluate the effects of hourly
awakening on sleep architecture. A 24-h IOP rhythm with nocturnal
acrophase was found in all subjects for both the sessions with and
without awakening (Fig. 15). The present study identified few sleep
changes related to hourly nocturnal awakening for IOP measure-
ments. Hourly awakening for nocturnal IOP measurements
increased WASO but did not appear to change total sleep time, total
sleep period, sleep efficiency or slow wave and REM sleep stage
duration. Subjects seem to compensate for the multiple awaken-
ings imposed by increasing the duration of the total sleep period, so
that the total sleep time and the proportions of slow wave and REM
sleep stages in relation to total sleep time appear unchanged. Sleep
quality/fragmentation was also not altered by nocturnal IOP mea-
surements, with sleep efficiency and the micro-arousal index
remaining unchanged. Comparable 24-h IOP rhythms and
nocturnal IOP patterns evaluated with the CLS with and without
hourly nocturnal awakening for IOP measurements were also
found. An increase in CLS signal value variability throughout the
night was nevertheless observed when subjects were awakened.
These results are crucial, because they demonstrate that the 24-
h IOP rhythms appear to be unaffected by hourly nocturnal awak-
ening for IOP measurements in young healthy subjects. This study
therefore supports the validity of the data and conclusions pro-
vided by all the previous studies conducted with non-continuous
measurement methods and regular awakening having found that
IOP follows a nyctohemeral rhythm in healthy humans and patients
with glaucoma.
Sleep structure: In a later study, the relationships between
nocturnal IOP variations and sleep macrostructure were evaluated
(Aptel et al., 2015). One session of 24-h CLS measurement without
nocturnal awakening in young healthy subjects was conducted.
Overnight polysomnography was used to evaluate the sleep
macrostructure. The CLS measurement characteristics (mean,
maximum, minimum and amplitude) were evaluated across sleep
stages (non-rapid eye movement [non-REM] sleep [N1, N2, N3],
REM) to evaluate the effect of sleep stages on IOP values. The CLS
signal measurement changes during sleep stage changes were
calculated to evaluate the effects of sleep changes on IOP variations.
A 24-h IOP nyctohemeral rhythm was found in all subjects. During
the nocturnal period, IOP signal values were significantly lower
during wake stages than during REM and NREM N1, N2 and N3
sleep stages. IOP signal values were significantly higher during the
REM stage than during the NREM stages, and progressively
decreased as NREM sleep deepened. A positive relationship be-
tween the micro-arousal index and the nocturnal period CLS signal
standard deviation (r ¼ 0.76) was found, and a negative relation-
ship between sleep efficiency and the nocturnal period CLS signal
standard deviation (r ¼ 0.69). The results of this study thus show
that sleep micro- and macrostructure and nocturnal IOP variations
are closely related in young subjects without sleep disorders.
Across sleep stages, IOP is highest during REM sleep and progres-
sively decreases as NREM sleep deepens. Many ocular or systemic
136 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Fig. 15. Raw and modelled 24-h contact lens sensor signal rhythm without awakening (top) and with hourly awakening (bottom) during two sessions conducted in the same subject
(Aptel et al., 2015).
factors involved during the sleep stages could explain the higher
IOP levels during REM sleep and the wake state than during NREM
stages. Studies have shown that blinking and eye movements could
increase IOP (Campbell and Schertzer, 1995; Green and Luxenberg,
1979). Blinking and eye movements are frequent during the REM
sleep stages, micro-arousals and by contrast much less frequent
during the NREM sleep stages, particularly during the deep slow-
wave NREM sleep stages. Studies have found that compared to
wake and REM sleep, NREM sleep is characterized by a predomi-
nance of vagal parasympathetic activity, with a decline in sympa-
thetic activity that is most pronounced in slow-wave sleep
(Lombardi and Parati, 2000). Consequently, blood pressure, central
venous pressure, and the heart and respiratory rates decrease
throughout NREM sleep, particularly during slow-wave sleep. This
physiological context could explain that we found that IOP
continuously decreases with the progressive deepening of NREM
sleep. By contrast, studies have demonstrated that in REM sleep
sympathetic activity increases significantly and is highly variable
(Lombardi and Parati, 2000; Somers et al., 1993). Consequently,
blood pressure and heart rate are higher and highly changeable.
This could also explain that we found a significantly higher IOP
during REM sleep compared to NREM sleep.
The findings of the present study could also explain the physi-
ological 24-h rhythm of IOP. NREM sleep is prominent at the
beginning of the night, whereas the duration of the REM sleep in-
creases during the last sleep cycles. This could explain that the
acrophase of the IOP 24-h variation occurs in the second part of the
night or in the early morning just before awakening in a vast ma-
jority of healthy subjects.
Corneal thickness: The CLS is a soft hydrophilic contact lens,
containing passive and active (two platinumetitanium sensing-
resistive) strain gauges embedded in silicone to monitor fluctua-
tions in the diameter of the corneoscleral junction. A micropro-
cessor embedded in the contact lens sends an output signal
proportional to changes in the strain gauges. As IOP increases, the
circumference of the cornea increases and the strain gauge in the
lens detects the change. Silicone has an elevated oxygen perme-
ability and minimal water absorption (0.2% in weight), making it
insensitive to the hydration level at the ocular surface. The
transmissibility level, Dk/t, is 125. Corneal swelling has been re-
ported with most soft contact lenses after overnight wear. Since it
may change the corneal curvature and corneoscleral angle and thus
could impact the signal recorded, many studies have questioned
whether the CLS induces corneal swelling and related changes in
corneal and anterior segment curvature.
In 2014, the effect of overnight wear of the CLS on central
corneal thickness (CCT) was evaluated using anterior segment op-
tical coherence tomography (Hubanova et al., 2014) (see Fig. 16).
Twelve young healthy subjects were studied in a sleep laboratory.
Starting at 7 p.m., the CLS was fitted on one randomly selected eye.
Similar AS-OCT measurements were taken on both eyes every 2 h
from 8 p.m. to 8 a.m. The CLS was removed just after the 8 a.m.
measurement session. Measurements were repeated at 9 a.m. CCT
significantly increased during the night in both CLS and control
eyes. The maximum change was þ4.4 ± 1.7% in the CLS eyes
and þ2.9 ± 1.8% in the control eyes (p < 0.05). Throughout the night,
CCT significantly increased more in eyes with the CLS than in
control eyes. There were significantly more corneal curvature ir-
regularities after overnight wear of the CLS than in the control
eye: þ1.63 dioptre (D) versus þ0.02 D in the 3-mm central zone
and þ3.17 D versus þ0.01 D in the 5-mm central zone.
In another study, CCT was evaluated using ultrasound pachy-
metry the evening before CLS insertion and in the morning within
30 min after lens removal in patients with glaucoma (Freiberg et al.,
2012). A small increase in corneal thickness was found (þ2.7%), but
not significantly different from that found in the control eyes
(þ0.8%).
Whether or not corneal swelling at night affects the sensing
mechanism of CLS remains unclear. However, given that the
nocturnal corneal swelling is not major and the related change in
corneal curvature is very small or absent, and also given that
several studies have found a comparable 24-h rhythm pattern in
one eye with the CLS and in the contralateral eye measured with
the non-contact tonometry method, it seems unlikely that the 24-h
IOP rhythm usually found with the CLS in both healthy and glau-
comatous subjects is an artefact. In particular, it seems unlikely that
the nocturnal increase in IOP is due to or only due to corneal
swelling and related changes in the corneoscleral curvature.
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Fig. 16. Nocturnal change in CCT (%) with the CLS and in the fellow eye (Hubanova et al., 2014).
2.3. Nyctohemeral rhythms of intraocular pressure in glaucoma
patients
In 2009, a pilot study of the CLS in glaucoma patients was
conducted (Mansouri and Shaarawy, 2011). In a mixed glaucoma
group of 15 eyes, the CLS was shown to be well tolerated and
capable of obtaining 24-h measurements in an ambulatory setting.
One case of corneal erosion constituted the main adverse effect.
Other early reports provided similar results (Freiberg et al., 2012).
Follow-up studies using the second-generation CLS demonstrated
an improved safety profile and absence of corneal erosions,
including after repeated use (Mansouri and Weinreb, 2012b, 2015a;
Mottet et al., 2013). Using a visual analog scale for pain assessment,
glaucoma patients gave an average score of 27.2 mm and 23.8 mm
for first- and second-time CLS use, respectively, placing the comfort
score well below the generally accepted threshold of >54 mm for
“mild pain” (Collins et al., 1997). Device safety was also demon-
strated in patients with thyroid eye disease and ocular surface
disease (Parekh et al., 2014).
The CLS pilot study found that 69% of patients presented their
peak signal during the nocturnal period. This was the first time the
presence of a nocturnal acrophase in glaucoma patients was
demonstrated in an ambulatory setting, thus corroborating sleep
laboratory findings from a decade earlier (Liu et al., 2003b). Simi-
larly, in a small group of five untreated patients with normal-
tension glaucoma (NTG), all had a positive wake-to-sleep slope
(W/S slope), indicating a nocturnal IOP rise (Pajic et al., 2011). Once
these patients were on antiglaucoma treatment, only two out of
five still showed a positive W/S slope. It was posited that this
change may be due to treatment effect and may be potentially
beneficial to glaucoma prognosis.
However, before a putative treatment effect can be studied with
the CLS, and as with any new diagnostic technology, its reproduc-
ibility needs to be established. In this context, the highly dynamic
nature of IOP is a particular challenge, complicating the distinction
between its inherent variation and device variability. The repro-
ducibility of repeated 24-h CLS sessions in 40 treated glaucoma
patients at a 1-week interval was evaluated and fair to good overall
agreement was found (r ¼ 0.59) (Mansouri et al., 2012e). A cosinor
137
rhythmometry model was then developed, and showed improved
repeatability of r ¼ 0.76 in the same cohort (Mansouri et al., 2012d).
Similar results were found in healthy subjects (Mottet et al., 2013).
These findings demonstrated that most patients had repeatable
circadian IOP-related rhythms over weeks to months. Some eyes
presented highly characteristic and repeatable rhythms, resem-
bling an “IOP fingerprint.”
These studies laid the groundwork for therapeutic evaluation
studies using the CLS. The lack of a conversion factor for the CLS
output to the mmHg unit, however, is a major limitation to its
clinical interpretation. At present, the main value of CLS measure-
ments seems to be in documenting relative changes of IOP-related
events and their timing. It is known that glaucoma medications
mostly reduce daytime IOP in absolute terms with a small to
inexistent effect on modulating the 24-h IOP rhythm (Liu et al.,
2004, 2009, 2010). These changes may not be readily observable
with the CLS. In a prospective study conducted in nine patients
with ocular hypertension or glaucoma, two CLS curves were plotted
after wash-out of the glaucoma medications and a third CLS curve 3
months after initiation of a treatment with prostaglandin analogue
(PGA). Although the 24-h GAT IOP decreased significantly from
22.9 ± 5.1 to 18.2 ± 2.5 mmHg, the means and standard deviations
of the three CLS curves showed no significant difference (152.94,
142.35 and 132.98; and 133.51, 132.18 and 110.98, respectively)
(Hollo
et al., 2014). As the CLS output cannot be converted to the
mmHg unit, it has been suggested that the absolute data provided
by the CLS may be not useful to track changes due to medications or
positions, but instead relative normalized variations or modelled
data should be preferred (Mansouri and Weinreb, 2015).
In a prospective three-stage study, the effect of medications on
CLS parameters was evaluated in 23 glaucoma patients (Mansouri
et al., 2015b). An untreated baseline CLS monitoring session was
performed. Subsequently, patients were randomized to one of four
classes of antihypertensive drops and a second CLS session ob-
tained after 1 month of treatment. In the third stage, patients in the
three non-PGA groups were put on a PGA add-on before under-
going a third CLS monitoring session. While beta-blockers, alpha-
adrenergic agonists, and carbonic anhydrase inhibitors showed no
significant effect on 24-h IOP-related patterns, PGA treatment
138 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
seemed to decrease the nocturnal IOP rise, confirming earlier re-
sults from the sleep laboratory (Sit et al., 2006b). Although evi-
dence is scarce, it seems reasonable to assume that not all patients
exhibit the same circadian response to antihypertensive drops.
Therefore, the ability to study 24-h effects of glaucoma medications
is a prerequisite for personalized treatment of glaucoma. For
instance, an additional nocturnal IOP-lowering effect was observed
when a patient on PGA treatment and symptomatic nocturnal CLS
IOP peaks had a pilocarpine add-on (Mansouri et al., 2014). CLS
monitoring demonstrated a high nocturnal peak, whose timing
concurred with the patient's eye pain. Our group is currently
studying the effect of nighttime application of pilocarpine in
glaucoma patients with nocturnal IOP peaks.
The CLS has been used to investigate the effect of laser in-
terventions, surgery (Mansouri et al., 2014; Matsuoka et al., 2013),
and lifestyle (Mansouri et al., 2013a) on 24-h IOP-related patterns.
Previously, it had been shown that laser trabeculoplasty (LT) has a
significant effect on nocturnal IOP. Lee et al. (2007) studied the
effect of LT in 18 treated glaucoma patients who were housed in a
sleep laboratory for 24 h. They showed that mean and peak IOP
were significantly reduced during the nocturnal period in the
habitual body position, while there was no significant effect on
diurnal parameters. The reduction of mean 24-h IOP in the supine
position was also significant. Two studies investigated the effect of
selective laser trabeculoplasty (SLT) on 24-h IOP-related patterns
using the CLS. Tojo et al. (2014a) studied the effect of 360 SLT on
ten Japanese patients with NTG. Goldmann applanation tonometry
(GAT) IOP was reduced from 13.5 ± 2.5 mmHg to 11.3 ± 2.4 mmHg
(p ¼ 0.018) after 3 months. The range of IOP fluctuations over 24 h
was not significantly changed between before and after SLT treat-
ment (p ¼ 0.77). Although the range of IOP fluctuations during the
diurnal periods was not significantly changed between before and
after SLT treatment (p ¼ 0.92), the range of IOP fluctuations during
the nocturnal periods significantly decreased from 290 ± 86 mVEq
before SLT to 199 ± 31 mVEq after SLT treatment (p ¼ 0.014). Lee
Fig. 17. Repeated contact lens sensor monitoring of a patient before (A) and after (B) successful filtering surgery, demonstrating lower nocturnal than diurnal IOP-related patterns.
et al. (2014) obtained CLS curves before and after SLT in 18 pa-
tients with NTG. Cosine function was fitted to the CLS signal, as
described previously (Mansouri and Weinreb, 2012a). Treatment
success was defined as IOP reduction 20% and was obtained in
44% of eyes. In successful eyes, the CLS cosine amplitude was
reduced by 24.6%, while it increased by 19.2% in failed eyes. Results
from these studies indicate that SLT may reduce nocturnal IOP
fluctuations and result in nocturnal flattening of the IOP curve in
NTG patients.
Cataract surgery has in recent years been proposed as an IOP-
lowering intervention in glaucoma patients (Zetterstro € m et al.,
2015). A recent study using the CLS suggested that it may pro-
duce a lowering of IOP fluctuations during the nocturnal period in
patients with primary angle-closure glaucoma (Tojo et al., 2014b).
Evaluating ten patients with CLS measurements before and after
cataract surgery, they found that despite unchanged 24-h IOP-
related fluctuations, the mean range of nocturnal fluctuations was
significantly lowered from 246 ± 61 mVeq to 179 ± 64 mVeq after
the surgery (p ¼ 0.02).
Glaucoma surgery is assumed to be effective in halting or
slowing glaucoma progression by having a sustained nyctohemeral
IOP-lowering effect. Evidence for this assumption, however, is
scarce. Matsuoka et al. (2013) found that filtering surgery resulted
in a flattening of the nocturnal IOP curve. Other studies combining a
diurnal tension curve with a water-drink provocative test to esti-
mate IOP peaks showed that surgery was more effective than
medications in obtaining a more stable IOP curve (Medeiros et al.,
2002; Mansouri et al., 2008). However, the issue of whether IOP
fluctuations are an independent risk factor remains controversial
(Mansouri et al., 2013b). At present, no published data are available
on the effect of glaucoma surgery on CLS parameters. Outside a
study setting, we have observed that some patients with previous
trabeculectomy exhibited significantly more stable 24-h IOP curves
with dampening of nocturnal IOP on CLS monitoring (Fig. 17). In a
pilot study evaluating the safety and feasibility of CLS wear in
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148 139

patients after nonpenetrating deep sclerectomy, a significant

reduction of IOP-related fluctuations was observed after surgery
(Fig. 17; K. Mansouri, unpublished data). This is an important issue
and more research is eagerly awaited.
Given the cost and other practical constraints related to CLS
monitoring, the question arises as to whether data from one eye are
applicable to the fellow eye. The presence of inter-eye symmetry as
the underlying assumption of the monocular drug trial (King et al.,
2011) could not be demonstrated by several studies, however
(Bhorade et al., 2010; Realini, 2009). Scarce data are available on the
symmetry of 24-h IOP variations between fellow eyes of glaucoma
patients. Within the controlled environment of a sleep laboratory,

Fig. 18. Bilateral simultaneous contact lens sensor monitoring indicating strong inter-eye correlation. Blue line ¼ right eye; yellow line ¼ left eye.
fellow eyes of untreated patients with open-angle glaucoma (OAG)
demonstrated a moderate correlation (R2 ¼ 0.42e0.6) over a 24-h
period (Sit et al., 2006a). A recent study on bilateral simultaneous
IOP-related pattern monitoring with the CLS in untreated OAG
patients was conducted. Preliminary results in 20 patients show a
good correlation (R2 ¼ 0.75 ± 0.35) (Fig. 18. Mansouri et al., un-
published data). Improved IOP characterization via continuous 24-
h IOP monitoring may warrant revisiting the place of the monoc-
ular drug trial within the glaucoma diagnostic armamentarium.
Recently, De Moraes et al. (2016) evaluated the relationship
between the rate of visual field progression in subjects with glau-
coma and several parameters derived from the CLS measurements
(number of large peaks, mean peak ratio, wake-to-sleep slope,
amplitude and area under the cosine curve, and variability from the
mean). In mixed-effects linear model testing, the association be-
tween the parameter “mean peak ratio during sleep” was found to
be most important. They found that in terms of regression for each
additional peak during wake hours, the rate of progression accel-
erated by 0.14 dB/year, for every 10-unit increase in the mean
peak ratio while asleep, the rate of progression accelerated
by 0.20 dB/year, while for every10-unit increase in the W/S slope
it accelerated by 0.03 dB/year.

3. Continuous monitoring with intraocular devices

3.1. Description and measurement principles

Various characteristics are required for a sensor to be implanted

in the eye for IOP measurement (Mansouri and Weinreb, 2015; Yung
et al., 2014). The sensor must be accurate and sensitive to changes in
IOP. The signal measured by the sensor should be detected by an
antenna located outside the eye with no wire connection. The ma-
terials used to design the sensor and/or encapsulate the sensor
should be nontoxic and biocompatible. Finally, the sensor must be
small enough to be positioned in the intraocular space and must be
robust so as to operate for a long time.

3.1.1. Physical principles of pressure measurement

Various types of pressure sensors may be used (Kakaday et al.,
2009). The capacitive pressure sensors can meet the specifica-
tions of an IOP intraocular sensor and are frequently used. The
capacity represents the amount of electrical charge carried by a
driver for a given electric potential.
The capacitance between two parallel plates is calculated using
the equation

C ¼ e$A=d

where C refers to capacitance, A the area of the plates, d the dis-

tance between plates and e the dielectric constant of the medium
between the plates. In a capacitive pressure sensor, one plate is
rigid while the other usually features a thin membrane which de-
flects when subjected to pressure change. The deflected membrane
140 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
changes the distance between itself and the fixed plate, resulting in
a capacitance change. The change in capacitance is proportional to
the change in IOP and can be easily detected.
Capacitive-type pressure sensors can be integrated with an
inductor to form a resonant circuit. The change in capacitance is
correlated with the resonance frequency of the resonance circuit.
The resonant frequency changes in response to IOP can be tracked
remotely via inductive coupling by measuring either the imped-
ance or voltage spectrum across an external antenna.
3.1.2. External signal measurement
A wire connection is usually not used for practical reasons. The
telemetric systems used for the intraocular IOP sensor developed to
date can be divided into two categories: (1) those based on active
sensing devices and (2) those based on passive devices. In passive
telemetry, wireless monitoring of the IOP is achieved through
mutual inductance coupling between the inductor on the sensor
and the external loop antenna. In active telemetry a signal is sent by
a transponder and detected by an external antenna. The tran-
sponder includes a transducer, modulator, microprocessor and
transmitter. The microprocessor converts the analogue signals from
the pressure transducer to digital signals for transmission. A power
converter converts the electromagnetic energy from the external
interrogating device to a current signal to power the micropro-
cessor. The modulator is coupled with the microprocessor and
power converter for receiving digitized data from the micropro-
cessor and for modulating the interrogation signal in accordance
with the digital data.
3.1.3. First devices
Collins was one of the first to develop a device designed to be
implanted in the eye to continuously measure IOP (Collins, 1967a,
1967b). The device was mainly composed of a gas bubble encap-
sulated in a thin and flexible film. The film was surrounded by a
strain gauge consisting of a pair of parallel spiral coils which create
a circuit whose frequency changes with relative coil spacing.
Changes in IOP induce changes in gas bubble volume and thus in
spiral coil spacing. Repeated sweeping using an external detector
and monitoring the energy absorbed by the implanted device al-
lows continuous recordings of IOP results. Implantation of the de-
vice in rabbits demonstrated significant transient changes in IOP
during blinking, and continued functioning in 90% of cases after 6
months with the implanted device. Nevertheless, this device was
never adapted for humans.
Wolbarsht et al. developed an external device consisting of an
elastic band implanted in a circular manner at the equator of the
eyeball (Wolbarsht et al., 1980). Increases in IOP stretch the trans-
ducer and increase electrical resistance. Experimentation with
cannulated cadaveric human and animal eyes found reproducible
correlations between changes in the diameter of the eye and
changes in IOP. In vivo studies have demonstrated the device's poor
tolerability, with a high risk of periocular infections and sustained
inflammation. Moreover, it should be mentioned that the scleral
expansion associated with changes in the IOP is not the same for all
parts of the eye and not the same in different eyes, making the
relationship between its length and IOP nonlinear. The data
collected by the device were therefore hard to interpret and the
device was later abandoned.
Rizq et al. developed a subchoroidal implant (Rizq et al., 2001).
After a 2.5-mm-dimeter scleral trephination, the device was
implanted below the sclera, in the space between the sclera and the
choroid. The device was therefore able to detect the change in
choroid pressure. In vitro testing of the device in cannulated
cadaveric eyes revealed measurements that differed from anterior
chamber IOP values measured using manometry by 1.9e3.3 mmHg.
No in vivo evaluation of this device was performed in humans.
3.1.4. Sensor integrated intraocular lenses
Miniaturization of the electrical components has made it
possible to integrate an IOP sensor into intraocular lenses designed
to be used after cataract extraction. In 1992, Svedbergh et al. inte-
grated a gas bubble surrounded by spiral coils into an intraocular
lens (IOL) haptic, with an IOP measurement principle similar to the
device previously developed by Collins et al., as mentioned above
(Svedbergh et al., 1992). The signal related to the IOP values was
detected by an external detector that can be integrated into spec-
tacles. This detector scans resonant frequencies of the circuit, which
varies in a manner proportional to IOP. In vitro evaluations were
performed and reported, but no further animal or human studies
have been conducted.
Walter et al. also developed a miniaturized device with a
capacitive pressure sensor encapsulated in biocompatible silicone
that can be used to make an IOL (Walter et al., 2000). The sensor
was sufficiently small to be integrated into the haptics of the IOL.
This sensor was associated with an external readout device that can
be integrated into spectacles using magnetic high-frequency
transmission. In vitro studies were conducted in cannulated
enucleated porcine eyes and cannulated rabbit eyes. Good agree-
ment with pneumotonometry was found for large IOP changes. No
further in vivo or human studies have been conducted.
In 2001, Hille et al. also developed an IOP sensor integrated into
an IOL (Hille et al., 2001). The sensor was a silicon chip with a 1-mm-
thick membrane. The sensor was associated with an implanted
telemetry component that is responsible for signal processing and
alternating current power transmission. An extracorporal device
received the signal and demodulated it. The electric supply of the
intraocular system was achieved by external electromagnetic in-
duction. In vitro studies conducted in cannulated eyes demon-
strated that the telemetric transmission of IOP can be achieved with
an accuracy of ±1 mmHg and a frequency of registration of three
values per second. No further in vivo studies have been conducted
with this IOL sensor.
Recently, a German company (Implandata GmbH, Hannover,
Germany) has developed an implantable IOP sensor using micro-
plate capacitors, with thin diaphragms that deflect under pressure
(Paschalis et al., 2014; Todani et al., 2011). Similar to the above-
described and previously developed IOP sensors, this sensor mea-
sures the distance between two silicone electrodes, which varies
depending on the surrounding pressure. When the cell membrane
is mechanically deflected by pressure changes, the capacity of the
cell changes in accordance with the change in distance between the
“plates”. This results in an analogue signal that is proportional to
the absolute pressure within the eye.
The electronic components of the device are either biocom-
patible or inert. The integrated circuit is attached to a circular
microcoil antenna made of gold, and both of these components are
hermetically encapsulated in platinum-cured silicone. The magni-
tude of the capacitance change is measured digitally and trans-
mitted externally by radiofrequency. The IOP is tracked by the
external reader unit, which is electromagnetically coupled with the
sensor by bringing the reader close to the sensor and pressing a
button on the reader unit.
The outside diameter of the transponder disc is 11.3 mm, the
inside diameter is 7 mm, its thickness is 0.9 mm, and it weighs 0.1 g.
The metal (gold) and polyimide structure that forms the radio
frequency coil required for energy supply to the implant is
extremely thin (0.9 mm) and ductile and can be folded for im-
plantation; the encapsulation material that covers the implant is
very flexible and can be folded without delamination from the
structure (Fig. 19). The silicone chip where the actual sensor
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
Fig. 19. Intraocular implantable intraocular pressure sensor (http://implandata.com/
last access April 20, 2016).
module resides is rigid and does not need to be folded for
implantation.
This sensor can be implanted either in the sulcus between the
capsular bag and iris or placed in the capsular bag itself. This is
achieved through a corneoscleral tunnel similar to IOL implanta-
tion, and always occurs during cataract extraction or keratopros-
thesis procedures.
The implant does not require a battery. It is electrically passive
until powered externally by the proprietary reader device (Fig. 20).
The device is capable of providing ten IOP measurements per sec-
ond. In normal operation, to obtain an IOP reading, ten subse-
quently acquired samples are averaged. A “continuous mode” can
be activated acquiring a reading every 5 min. It is also possible to
acquire subsequent samples for longer periods of time (e.g. 100 s) in
a so-called online mode.
Two animal studies conducted with this device have been re-
ported to date. Todani et al. implanted the device in six rabbit eyes
after extracapsular lens extraction (Todani et al., 2011). During a 25-
month period, IOP was regularly measured with the implant, and
with pneumotonometry, contact tonometry and direct manometry.
The device appears to be well tolerated, with no evidence of sig-
nificant inflammation or scar formation by microscopic in vivo
examination. Histology of enucleated eyes did not reveal
Fig. 20. External reading device to be held no farther than 5 cm from the transducer. It
allows IOP measurement by radiofrequency (http://implandata.com/last access April
20, 2016).
141
intraocular inflammation or membrane formation. Repeated IOP
measurements with pneumotonometry, tonometry and the
implanted sensor resulted in standard deviations of 2.70 mmHg,
3.35 mmHg and 0.81 mmHg, respectively. The concordance be-
tween the sensor and direct manometry measurements was rather
high (the Pearson correlation coefficient values ranged from 0.984
to 0.999 for IOP variations between 10 mmHg and 50 mmHg). In
2014, Paschalis et al. presented the implantation of the device
within the ciliary sulcus of a normotensive rabbit eye after
extracapsular clear lens extraction (Paschalis et al., 2014). The
ability of the sensor to detect IOP changes resulting from the
administration of latanoprost 0.005% or dorzolamide 2% or vehicle,
each during a 2-week period. Both antiglaucoma medications
caused significant IOP reduction compared to baseline; latanoprost
reduced mean IOP by 10% (1.3 ± 3.54 mmHg; p, 0.001) and dor-
zolamide by 5% (0.62 ± 2.22 mmHg; p, 0.001). No difference was
found between mean baseline IOP (13.08 ± 2.2 mmHg) and mean
vehicle IOP (13.27 ± 2.1 mmHg).
3.2. First clinical results
A few preliminary clinical studies have been conducted with the
above-described Implantada system.
The sensor and the implant are similar to the device used in the
preliminary animal studies and are described above. The device
integrates pressure sensors, a temperature sensor, an identification
encoder, an analogue-to-digital encoder and a telemetry unit into a
single microelectromechanical integrated circuit. The integrated
circuit is attached to a circular microcoil antenna made of gold, and
both of these components are hermetically encapsulated in
platinum-cured silicone. The implant does not require a battery and
is electrically passive until powered externally by the proprietary
reader device. The reader unit is battery-powered and resembles a
television remote control. The same reader unit picks up the digital
data relayed by the transponder unit and subsequently displays the
IOP values on its light-emitting diode display. The reader and the
transponder unit need to be brought into close proximity of each
other (within 5 cm) before a button is pressed on the reader to
activate the electromagnetic coupling sequence.
In 2014, Melki et al. presented the preliminary results stemming
from an open-angle glaucoma patient who had the device
implanted in the ciliary sulcus following extracapsular cataract
extraction and in-the-bag intraocular lens implantation (Melki
et al., 2014). Phacoemulsification was performed through a 3.0-
mm incision located at the 12-o'clock position. A foldable plate-
haptic IOL was placed in the capsular bag. The device was then
folded with forceps and inserted into the sulcus.
The patient was monitored postoperatively for 18 months. The
primary objective of this study was to evaluate the safety and
tolerability of the device. There were no complications noted dur-
ing device insertion or postoperatively. No persistent intraocular
inflammation, pigment dispersion or angle narrowing was noted.
A minimum of three IOP measurements were obtained at all
visits by GAT and by the implanted sensor. It should be mentioned
that significant discordance between the two IOP measurements
was reported at some follow-up visits (up to 6.5 mmHg difference,
31.5 mmHg measured with the device and 25 mm Hg measured
with the GAT).
In 2015, Koutsonas et al. presented the implantation of the de-
vice in six patients with open-angle glaucoma and cataract with 1
year of follow-up (Koutsonas et al., 2015). The surgical procedure
was similar to that reported by Melki et al. The telemetric IOP
sensor was implanted at the end of cataract surgery, after intra-
capsular lens implantation, and it was implanted through a 5.5-mm
corneal incision in the ciliary sulcus. Viscoelastic injection was used
142 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
to widen the sulcus space. The sensor was then folded with forceps
and implanted in maximal mydriasis.
The IOP sensor was successfully implanted in each patient in the
ciliary sulcus; however, during implantation a significant pigment
dispersion occurred in three patients. In the initial postoperative
days, four of six patients developed significant sterile anterior
chamber inflammation, and two of these four patients showed a
hypopyon. Anterior chamber inflammation resolved completely
within 9 days after surgery with anti-inflammatory treatment. All
patients showed mild to moderate pupillary distortion and
pigment dispersion after surgery (Fig. 21). No significant endothe-
lial cell loss was found.
In five of six patients GAT measurements revealed higher IOP
values 6 months postoperatively than at baseline, which contra-
dicted the expected IOP lowering effect after cataract surgery. Mean
IOP values were 13.7 ± 63.3 mmHg, ranging from 9 to 19 mmHg at
baseline; and 15.8 ± 65.5 mmHg, ranging from 8 to 25 mmHg at the
ninth follow-up visit (6 months postoperatively).
Telemetric IOP values showed similar profiles compared to
those of Goldmann applanation tonometry in two of the six pa-
tients. Three patients showed a relevant IOP step during follow-up,
with a rather limited concordance between the Goldmann appla-
nation tonometry and telemetric IOP values, and in one patient,
negative telemetric values were obtained throughout the study.
4. Perspectives and future directions
With the anticipated introduction into clinical practice of 24-h
IOP monitoring devices, one of ophthalmology's long unmet
needs will finally have been addressed. This technological
achievement, however, creates new questions that need to be
answered before the availability of these devices can be translated
into improved diagnosis and management of glaucoma.
4.1. Analysis and interpretation
Implantable sensors provide direct IOP measurements in the
customary mmHg unit, whereas the CLS output is in relative units
and, therefore, not directly usable by clinicians. Given that simul-
taneous tonometry on a CLS eye is impossible, a conversion algo-
rithm is currently not available and is not expected in the near
Fig. 21. Transillumination of the peripheral iris resulting from intraoperative pigment
dispersion caused by the sulcus implantation (Koutsonas et al., 2015).
future. Definition of new parameters for analysis of CLS readings is
therefore needed. A basic and initial approach was the mathe-
matical modelling of the rhythmic nature of circadian IOP patterns,
using cosinor rhythmometry to study acrophase (e.g., timing of
peak IOP), bathyphase, and amplitude (Mansouri and Weinreb,
2012a). Our group further defined the wake-to-sleep and sleep-
to-wake slopes to reflect the nocturnal IOP rise and morning fall,
which is observed in a majority of healthy subjects and glaucoma
patients. We have derived approximately 30 different CLS param-
eters that characterize relative and absolute components of the CLS
signal. Some, such as “number of large peaks,” “mean peak ratio,”
etc., reflect the presence and nature of IOP peaks, while others
reflect the fluctuation aspect of the signal (e.g., “peak-to-trough
ratio”). It remains to be shown which of these variables are relevant
to glaucoma and the context within which they can be of clinical
use.
Despite the inherent advantage of implantable IOP sensors to
provide direct measurements in terms of analysis, the interpreta-
tion of the plethora of data obtained is a significant challenge. At
present, the correct way to deal with the “Big Data” aspects of these
devices is unknown, because there is no consensus on whether
mean or peak IOP is most relevant for glaucoma. Also, the role of
IOP fluctuations over the nyctohemeral period or over the long
term is controversial (Mansouri et al., 2013b). Crucially, no study
has properly addressed the significance of the nocturnal IOP rise, a
physiological event in healthy individuals, on glaucoma progres-
sion. There may be differences in the timing of IOP peaks and their
impact on glaucoma. This association has been described for
nocturnal blood pressure and cardiovascular disease (Boggia et al.,
2007). In fact, the assumption that nighttime IOP should be lowered
in patients with progressing disease is clinically driven and is
partially based on the observation that filtering surgery achieves
stable 24-h IOP curves, but this is, at present, not evidence-based.
Laboratory data from a rat glaucoma model show that the dark-
phase IOP increase is more detrimental to retinal ganglion cell
survival than its light-phase counterpart (Kwong et al., 2013). A
prospective longitudinal study in humans is needed to elucidate
the effect of nocturnal IOP on glaucoma pathogenesis and
progression.
It should be mentioned that certain valuable information about
the 24-h rhythm of IOP still cannot be obtained from the implanted
devices. Although very promising, these devices have been used to
date in very few human studies, with very preliminary and sparse
data.
As mentioned below, the Implantada IOP sensor e the only
implantable device used in humans to date e has been evaluated in
only two studies. In the first one (Melki et al., 2014), mainly
designed to study the usability and tolerability of the device, only
one subject with glaucoma was included and no 24-h measure-
ments were taken. In the second one (Koutsonas et al., 2015),
conducted on only six subjects with glaucoma undergoing cataract
surgery, the primary endpoints were also the safety and tolerability
of the device. Similarly, no 24-h measurements were taken, and
only one measurement was taken at each follow-up visit (usually in
the morning).
Although the implanted devices have not stricto sensu provided
new data on the nyctohemeral rhythm of IOP in humans to date, we
believe that they are a very promising means of studying IOP
rhythm more precisely in the future than existing devices.
4.2. Beyond absolute IOP e searching for inherent patterns
An important area of research will be the potential relationship
between 24-h IOP patterns and the risk of future glaucoma pro-
gression. There is evidence to suggest that at-risk individuals may
 F. Aptel et al. / Progress in Retinal and Eye Research 55 (2016) 108e148
exhibit inherent nyctohemeral IOP patterns. Grippo et al. (2013)
analysed 24-h sleep laboratory data of untreated ocular hyperten-
sive patients who converted to glaucoma after a mean of 4.4 years.
They found several IOP parameters that distinguished these pa-
tients from healthy controls. These included 24-h IOP acrophases
and amplitudes, habitual IOP curve phase delay, habitual IOP
variation, diurnal-to-nocturnal IOP changes, and IOP changes upon
awakening. None of the parameters alone, however, could distin-
guish future converters from non-converters. Patients who later
converted were closer to the characteristics of glaucoma patients
than to non-converters. These results suggest the existence of
distinct IOP parameters that, independent of IOP level, may be
predictive of future disease onset.
Further exploring the possibility of disease-inherent nycto-
hemeral IOP patterns, Agnifili et al. (2015) assessed 24-h IOP-
related patterns between healthy subjects and patients with NTG
and primary open-angle glaucoma (POAG) using the CLS. They
found that CLS parameters were able to distinguish the three
groups. Both POAG and NTG exhibited more prolonged peaks and
higher fluctuation than healthy subjects during the 24-h period.
Using simple sine modelling, there were significant CLS parameter
differences between the two glaucoma subgroups with respect to
morning vs. evening/night periods. In a Japanese population, it was
shown that patients with pseudo-exfoliative glaucoma had larger
24-h IOP fluctuations and an earlier acrophase than healthy sub-
jects (Tojo et al., 2015). All healthy eyes had their maximum CLS
value during the nocturnal period, compared to only seven of the 11
glaucoma eyes (64%).
Recently, De Moraes et al. (2016) tested the hypothesis that 24-h
CLS parameters correlate to the rate of visual field progression in
glaucoma patients. They included 40 patients who had shown
different rates of progression in the past and who had a minimum
of eight visual field exams. In mixed-effects linear model testing,
the association between CLS, the parameter “mean peak ratio
during sleep” retained the greatest importance. They found that in
terms of regression for each additional peak during wake hours, the
rate of progression accelerated by 0.14 dB/year, for every 10-unit
increase in the mean peak ratio while asleep, the rate of progression
accelerated by 0.20 dB/year, while for every10-unit increase in the
W/S slope it accelerated by 0.03 dB/year. This further showed that
CLS parameters explained a greater proportion of the variance of
rates of progression than tonometry parameters such as mean,
peak, and fluctuation. In the future, clinical studies designed to
determine long-term effects of 24-h IOP patterns should identify
which CLS parameters best correlate with glaucoma progression.
The above studies point to the possibility that the CLS provides
valuable data beyond mere continuous IOP measurements. Since its
signal is derived from changes in pressure, volume, and ocular
elasticity, CLS parameters have the potential to provide indirect
information about IOP-mediated stress on the connective tissues of
the optic nerve head, the putative site of glaucoma injury
(Burgoyne et al., 2005). Gisler et al. (2015) showed that automated
analysis of CLS recordings can accurately quantify eye blinks, which
could partially reflect the elasticity of ocular tissues. The impor-
tance of evaluating the CLS signal as a surrogate for the biome-
chanical integrity of the eye was further highlighted by Flatau et al.
(2016). They measured the CLS signal change in glaucoma and
healthy eyes during contact with a pillow in the face-down position
during simulated sleep. They found that this position was associ-
ated with an increase of the CLS signal in glaucoma eyes (p ¼ 0.03)
but not in healthy eyes (p ¼ 0.33). These changes were reproduc-
ible. Interestingly, eyes with past visual field progression had a
greater change of the CLS signal than stable glaucoma eyes. These
results indicate that it may be possible to develop preventive
strategies in at-risk patients using provocative testing and CLS
143
measurements.
It should be mentioned that the role of the nocturnal e and
mainly positional e increase in IOP in the occurrence or progres-
sion of glaucoma neuropathy has not been demonstrated to date.
Several theories explaining the death of retinal ganglion cells in
subjects with glaucoma have been proposed, including a mechan-
ical displacement of the lamina cribrosa due to a gradient between
IOP and the cerebrospinal fluid (CSF) pressure. If considering this
hypothesis, it could be possible that the increased CSF pressure in
the supine position for hydrostatic reasons counteracts the
nocturnal increase in IOP (Hayreh, 2016; Jonas et al., 2015; Wostyn
et al., 2014). Many studies have demonstrated increased CSF pres-
sure in the supine position (leading to a nyctohemeral rhythm of
CSF pressure roughly comparable to the nyctohemeral rhythm of
the IOP) (Hayreh, 2016). The relative nocturnal to diurnal increase
in CSF pressure and/or intracranial pressure seems to be compa-
rable to the relative increase in IOP. By contrast, we do not now
know whether the body position-related changes in IOP and in CSF
pressure occur simultaneously or with a time-lag between them.
Similarly, it should be mentioned that the role of vascular factors
has been put forward to explain the pathogenesis of glaucoma.
Even this theory remains controversial, several papers have found
reduced ocular perfusion pressure or reduced optic nerve head
blood flow in subjects with glaucoma compared to controls (Mottet
et al., 2015). Similarly, because of the positional factor and hydro-
static pressure, the supine position could reduce the nocturnal
decrease in ocular perfusion pressure.
5. Conclusions
At present, the CLS is the only approved and commercially
available device that provides 24-h IOP-related data. Other ap-
proaches and devices will become available in the near future.
Current decision-making processes in glaucoma generally rely
on single IOP measurements. The integration of 24-h IOP data in
treatment concepts may challenge current views, wherein medi-
cations and dosing schedules aim to achieve constant 24-h steady-
state drug levels. Ultimately, the routine availability of 24-h IOP
data may lead to chronotherapy for glaucoma, individualization of
treatment regimens, and improved treatment outcomes.
Financial support and sponsorship
Supported in part by a grant of the Association de Recherche et
de Formation en Ophtalmologie (ARFO) and the Fondation de
l'Avenir ETO (F. Aptel and C. Chiquet). Supported in part by core
grant P30EY022589 from the National Eye Institute and an unre-
stricted grant from Research to Prevent Blindness, New York, NY.
(R.N. Weinreb). The funding sources have no role in the writing of
this paper.
Financial disclosure
F. Aptel, None; R.N. Weinreb, Research support from Sensimed
AG; C. Chiquet None; K. Mansouri, Research and financial support
from Sensimed AG.
Acknowledgments
None.
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