![In vivo confocal microscopic images depicting: Left: dendritiform cells with long dendrites found in the bulbar conjunctival epithelium (400 μm × 400 μm image captured at depth of ~20 μm from the epithelial surface in the temporal quadrant), Right: dendritiform cells in the sub-basal epithelium of mid-peripheral cornea (1 mm × 1 mm montage) [190].](https://www.researchgate.net/profile/Helmer-Schweizer/publication/350398362/figure/fig1/AS:1014662732734464@1618925855163/n-vivo-confocal-microscopic-images-depicting-Left-dendritiform-cells-with-long_Q320.jpg)
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Contact Lens and Anterior Eye 44 (2021) 192–219
1367-0484/© 2021 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
CLEAR - Effect of contact lens materials and designs on the anatomy and
physiology of the eye
Philip B. Morgan
a
,
*, Paul J. Murphy
b
, Kate L. Gifford
c
, Paul Gifford
d
, Blanka Golebiowski
d
,
Leah Johnson
e
, Dimitra Makrynioti
f
, Amir M. Moezzi
g
, Kurt Moody
h
,
Maria Navascues-Cornago
a
, Helmer Schweizer
i
, Kasandra Swiderska
a
, Graeme Young
j
,
Mark Willcox
d
a
Eurolens Research, Division of Pharmacy and Optometry, University of Manchester, UK
b
University of Waterloo, School of Optometry and Vision Science, Waterloo, Canada
c
School of Optometry and Vision Science, Queensland University of Technology, Brisbane, Australia
d
School of Optometry and Vision Science, UNSW Sydney, Australia
e
CooperVision Specialty EyeCare, Gilbert, AZ, United States
f
School of Health Rehabilitation Sciences, University of Patras (Aigio), Greece
g
Centre for Ocular Research and Education, University of Waterloo, Canada
h
Johnson & Johnson Vision Care, Jacksonville, FL, United States
i
Alcon Vision Care, IMG, Vernier-Geneva, Switzerland
j
Visioncare Research Ltd, Farnham, UK
ARTICLE INFO
Keywords:
Contact lens evidence-based academic reports
(CLEAR)
Eyelid
Cornea
Conjunctiva
Myopia control
Inammation
ABSTRACT
This paper outlines changes to the ocular surface caused by contact lenses and their degree of clinical signi-
cance. Substantial research and development to improve oxygen permeability of rigid and soft contact lenses has
meant that in many countries the issues caused by hypoxia to the ocular surface have largely been negated. The
ability of contact lenses to change the axial growth characteristics of the globe is being utilised to help reduce the
myopia pandemic and several studies and meta-analyses have shown that wearing orthokeratology lenses or soft
multifocal contact lenses can reduce axial length growth (and hence myopia).
However, effects on blinking, ptosis, the function of Meibomian glands, uorescein and lissamine green
staining of the conjunctiva and cornea, production of lid-parallel conjunctival folds and lid wiper epitheliopathy
have received less research attention. Contact lens wear produces a subclinical inammatory response man-
ifested by increases in the number of dendritiform cells in the conjunctiva, cornea and limbus. Papillary
conjunctivitis is also a complication of all types of contact lenses. Changes to wear schedule (daily disposable
from overnight wear) or lens materials (hydrogel from SiHy) can reduce papillary conjunctivitis, but the effect of
such changes on dendritic cell migration needs further study. These changes may be associated with decreased
comfort but conrmatory studies are needed. Contact lenses can affect the sensitivity of the ocular surface to
mechanical stimulation, but whether these changes affect comfort requires further investigation.
In conclusion, there have been changes to lens materials, design and wear schedules over the past 20+years
that have improved their safety and seen the development of lenses that can reduce the myopia development.
However, several changes to the ocular surface still occur and warrant further research effort in order to optimise
the lens wearing experience.
1. Introduction
Contact lenses are medical devices worn to offer refractive correction
or a medical solution to a clinical problem at the ocular surface. In all
circumstances, a key aim is for a contact lens to achieve its desired
performance whilst either (a) leaving the anatomy and physiology of the
eye unaffected or (b) altering ocular characteristics only as intended (e.
g. the programmed, structural change of the eye during in myopia
control with contact lenses). Given the complexity of the anatomical
* Corresponding author.
E-mail address: philip.morgan@manchester.ac.uk (P.B. Morgan).
Contents lists available at ScienceDirect
Contact Lens and Anterior Eye
journal homepage: www.elsevier.com/locate/clae
https://doi.org/10.1016/j.clae.2021.02.006
Contact Lens and Anterior Eye 44 (2021) 192–219
193
structures and physiological processes with which a contact lens in-
teracts, this has proven to be a high threshold and one not yet fully met
by modern lenses despite signicant improvements in designs and ma-
terials, especially over the past 50 years.
This paper outlines the various changes caused by contact lens wear,
how these alter with different contact lens types and their degree of
clinical signicance. The information is provided on a structure-by-
structure basis and broadly follows the order in which an eye care
practitioner might examine the integrity of the eye during a contact lens
examination. This paper aims to review information which is different to
the CLEAR Complications Report [1] which features as a sister paper in
the CLEAR initiative. In general terms, the CLEAR Complications Report
[1] describes changes to the eye which require clinical intervention. The
current paper covers physiological and anatomical alterations which do
not require such intervention either because this is not considered to be
helpful for patient care, or because the described ocular change has only
recently been described and/or the appropriate clinical management is
not yet established. Inevitably there is modest overlap in these papers
but due to the deliberately different approaches taken (this paper takes
an anatomy-based approach whereas the CLEAR Complications Report
[1] adopts an aetiology-based structure), where this occurs it is relevant,
helpful and additive.
2. The eyelids and adnexa
2.1. Blinking
Blinking is an important ocular surface physiological mechanism,
maintaining physiology and providing good optics [2]. It involves both
the upper and lower eyelids: the upper lid moves in the vertical and
inward, whereas the lower lid moves in a temporal-to-nasal direction
[3]. Blinking is either voluntary (a conscious and deliberate blink), re-
ex (elicited by external tactile, light, sound or electrical stimulation),
or spontaneous (an unconscious blink in the absence of deliberate
stimuli), with the latter the most common and most relevant to contact
lens wear. The spontaneous blink-rate varies between 8 and 21 blinks
per minute (in primary gaze) [4], has a duration of about 300 ms and an
upper blink excursion of 7−10 mm [5,6].
These key blink variables can be inuenced by various factors. For
example, both dry eye disease (DED) and contact lens wear cause an
increase in blink-rate [7–9]. Substantial variability in spontaneous blink
rate has been reported in the literature, which may be attributed to a
number of factors including methodology employed [10], task per-
formed during blink assessment [7,11–14], gaze direction [12,15,16],
cognitive and emotional factors [17] and inter-participant variability
[18,19]. The exact nature of the stimulus responsible for the increase in
blink-rate during contact lens wear is not clear, but tear lm instability,
visual disturbance and symptoms of ocular irritation may provide
stimulation for blinking [7,20]. One report has noted an association
between greater subjective dryness and increased blink-rate [21]. There
appears to be little difference between the sexes [22,23] and although
blink-rate increases with age, this may be due to age-related dry eye
disease issues [9].
Increased blink-rate and unaltered blink completeness has been re-
ported in the early stages of hard and rigid corneal lens wear [11,24,25],
whereas no difference in overall blink-rate was found between long-term
rigid corneal lens wearers and non-wearers [26]. However, long-term
rigid corneal lens wearers showed fewer complete blinks and more
blink attempts than non-wearers. In addition, rigid corneal lens wearers
with 3- and 9-o’clock staining showed more incomplete blinks and more
blink attempts than wearers with minimal staining and non-wearers
[26]. A trend toward an increased blink-rate was also shown in neo-
phytes tted with soft lenses [27,28], as well as in adapted soft contact
lens wearers [7,29,30]. There was no clear effect of soft contact lens
wear on blink completeness [27–29], which appeared to be more
inuenced by the task performed during the assessment [7].
There is limited evidence of the effect of different soft lens materials
and designs on blink characteristics. A shorter inter-blink interval (i.e.
increased blink-rate) was reported after 10 min of soft contact lens wear,
particularly for toric lenses (a periballast design and a double slab-off
design), although none of the changes were statistically signicant
[25]. An increased blink-rate was found in subjects wearing a hydrogel
contact lens (etalcon A) after exposure to controlled adverse environ-
mental conditions, whilst no change was observed in subjects wearing a
SiHy lens (naralcon A) [31]. The authors suggested that the higher
blink frequency was ‘a compensation mechanism to alleviate the rela-
tively higher dryness over the lens surface.’ A higher blink-rate for SiHy
lens wear (comlcon A), compared with hydrogel lens wear (omalcon
A), was seen during exposure to controlled standard and adverse envi-
ronmental conditions [32]. According to the authors, the higher dehy-
dration observed for the SiHy lens in the study could be the reason for
the rise in blink-rate ‘in an attempt to refresh the tear lm more
frequently’, although other work has found dehydration to be greater
with conventional hydrogels [33,34]. Contrary to these studies, other
investigators found no signicant difference in the increment of blink
rate after two months of lens wear between hydrogel (hilalcon B) and
silicone hydrogel (lotralcon B) materials [28]. The effects of contact
lens wear on other aspects of blink dynamics, such as velocity and
duration, have not yet been studied.
The notion of incomplete blinking may be relevant to contact lens
wear as incomplete blinking accounts for a two-fold increase in the risk
of DED, meibomian gland atrophy and poor tear lm stability [3].
Incomplete blinking might be more problematic for patients with low
blink-rates, as this combination of effects will increase the exposure of
the inferior ocular surface. This means that potential contact lens pa-
tients who are more predisposed to incomplete blinking, those who are
using computers or ‘digital devices’ [9] or some ethnic groups (e.g.
Asian patients [35]), may require closer clinical attention prior to tting
and during the aftercare process.
The measurement of blink characteristics has been challenging and
complex using traditional methods [17,36]. However, the increased
availability and accessibility of technologies such as high-speed digital
cameras [10,37,38] and mobile phones [39] have facilitated the inves-
tigation of human blinking. Additionally, commercially available in-
struments designed for tear lm analysis, such as the LipiView II
interferometer or the IDRA ocular surface analyser, have the capability
to measure some aspects of blink dynamics, allowing eye care practi-
tioners (ECPs) to assess blink characteristics in the clinical setting.
2.2. Ptosis
Eyelid ptosis is the prolapse of the upper eyelid below its normal
position [40]. Blepharoptosis is the more specic term for this
ophthalmic condition and it can be either congenital or acquired [41].
Ptosis related to contact lens use is described.
Typically, the distance between the upper lid margin and the eyelid
Abbreviations
CEDC corneal endothelial dendritic cells
CI condence interval
ECP eye care practitioner
LIPCOF lid parallel conjunctival folds
LWE lid wiper epitheliopathy
Ortho-k orthokeratology
PMMA poly methyl methacrylate
SICS solution-induced corneal staining
SiHy silicone hydrogel
P.B. Morgan et al.
Contact Lens and Anterior Eye 44 (2021) 192–219
194
fold is minimal, but in contact lens induced ptosis this is enlarged, which
may be of cosmetic concern [3]. Since the vast majority of patients wear
contact lenses bilaterally, this condition may not be noticeable and so its
prevalence may be higher than that reported in clinical practice. A
systematic review has suggested that there is an increased risk of ptosis
in rigid corneal (OR 17.4x) and soft contact (OR 8.1x) lens wearers
compared to non-wearers [42]. Previous studies have highlighted the
association of prolonged rigid corneal lens wear with acquired ptosis
[43–50]. Although the exact mechanism remains unknown, most au-
thors agree that excessive physical manipulation of the eyelids during
insertion and removal of rigid corneal lenses may be responsible for
inducing damage to the levator aponeurosis [43,46,48,51]. Other pro-
posed mechanisms include eyelid oedema or inammation [44] and
contact lens-induced irritation [46,49]. There are fewer reports of con-
tact lens induced ptosis in soft contact lens wearers [49,52]. Contact lens
application and removal and contact lens induced-irritation may play a
role in the pathogenesis of ptosis in soft contact lens wearers [47,49,52].
The vertical palpebral aperture size of rigid corneal lens wearers is
signicantly smaller than non-wearers, but this phenomenon does not
occur with soft lens use [51]. This observation has been conrmed in
long-term adapted rigid corneal and soft lens wearers, when compared
to non-lens wearers. The palpebral aperture size of the rigid corneal lens,
soft lens and non-lens wearer groups were: 9.76 ±0.99 mm, 10.25 ±
0.94 mm and 10.10 ±1.11 mm, respectively [53]. Ptosis is a feature of
the upper eyelid and rigid corneal lenses cause a reduction in palpebral
aperture size of about 0.5 mm [51,53].
Subjects tted on an overnight wear basis with a rigid corneal lens in
one eye and a soft lens in the other eye for 13 weeks had a maximal
reduction in palpebral aperture size of 12 % with the rigid corneal lens at
the 4–6 week time point versus 3 % for the soft lens eye [41]. At 13
weeks, the rigid corneal lens wearing eye had demonstrated a 3 %
reduction in palpebral aperture size compared to a 7 % increase for the
soft lens eye. These results suggest there may be an adaptation for many
patients wearing contact lenses, with an initial reaction that may
diminish over time, although the rigid corneal lens/soft lens contralat-
eral nature of the study design may have inuenced the ndings. Most
cases of ptosis can be managed by retting into an alternative lens type
or discontinuing lens wear, although surgery is an option in extreme
cases where ptosis does not resolve after discontinuation of contact lens
wear [3].
2.3. Meibomian gland changes
Meibomian glands are large sebaceous glands located in the upper
and lower eyelids just posterior to the tarsal plate. They contribute most
of the tear lm lipid layer which protects the aqueous phase from
evaporating too quickly and also stabilises the tear lm by lowering
surface tension. Any abnormalities in Meibomian gland function and/or
anatomy lead to reduced meibum secretion and/or altered lipid
composition which in turn disrupt the ocular surface integrity and in-
uence contact lens success [54–56].
There is no consensus on the impact of contact lenses on Meibomian
glands (see Table 1). However, most recent data suggest that contact
lens wear is not associated with Meibomian gland atrophy although it
may affect Meibomian gland function [57–61]. Early ndings on the
relationship between contact lens wear and Meibomian glands showed
that meibum in contact lens wearers has a 3 ◦C higher melting point than
in non-wearers, with no difference between the three types of contact
lenses (polymethyl methacrylate [PMMA] corneal, soft or rigid gas
permeable corneal) [62]. Another study examined the relationship be-
tween various ocular factors and self-reported contact lens-associated
dry eye. The data did not show correlation between Meibomian gland
dropout (i.e. apparent atrophy or loss of Meibomian glands when
imaged) and dry eye in contact lens wearers suggesting that structural
changes do not lead to altered or reduced meibum secretion. Further-
more, most patients (both contact lens wearers and non-wearers) had no
signs of Meibomian gland dropout or had dropout of less than 25 %.
However, the pre-lens lipid layer thickness was strongly associated with
dry eye status [57].
A 2009 cross-sectional study found greater Meibomian gland
dropout in 121 contact lens wearers than in 137 non-contact lens
wearers, with the upper eyelid more affected than the lower. This work
also noted that Meibomian gland dropout started not from the orifice
side but from the distal side in contact lens wearers [63]. Another
outcome of this study was the signicant correlation between the
duration of contact lens wear and Meibomian gland dropout [63]. The
study results were compared to the earlier ndings of age-related
changes of the Meibomian glands in a normal population where the
authors found that aging increases the severity of Meibomian gland
dropout. On average the Meibomian gland changes in contact lens
wearers (mean age =31.8 ±8.0 years) from this study could be
observed in a 60- to 69-year-old age group of non-contact lens wearers
from the previous study [64]. There was no signicant difference in
average Meibomian gland dropout between rigid corneal lens wearers
and hydrogel lens wearers [63]. Another, more recent study which also
evaluated the effect of contact lens wear on Meibomian glands in an
Asian population supports these ndings in that contact lens wear
negatively affects Meibomian glands and, furthermore, the structural
changes worsen with years of wear [65]. Other researchers have also
reported apparent changes to Meibomian glands related to contact lens
wear [66,67]. However, the methodology used (Meibomian gland acini
reflectivity and acinar unit diameter measured by in vivo laser scanning
confocal microscopy) is now considered to not image the Meibomian
glands but rete ridges present at the dermal-epidermal junction [68].
Furthermore, there is no association between rete ridges parameters
measured by laser scanning confocal microscopy and actual Meibomian
glands seen in meibography images [69].
The relationship between contact lens-related allergic conjunctivitis
and morphological changes in the Meibomian glands has been investi-
gated. It has been shown that allergic reaction, rather than contact lens
wear, causes Meibomian gland distortion in patients with contact lens-
related allergic conjunctivitis. However, contact lens wearers both
with and without contact lens-related allergic conjunctivitis showed
higher Meibomian gland dropout in contrast to non-wearers even
though it was (marginally) not signicant (p =0.051). There was no
signicant difference between the mean Meibomian gland distortion
between rigid corneal and hydrogel lens wearers [58].
Other workers have found no association between changes in the
Meibomian gland morphology (both in Meibomian gland distortion and
dropout level) and contact lens use. Here, contact lens wearers had
signicantly worse meibum quality and orifice plugging and further-
more, abnormal meibum quality was strongly correlated to the duration
of contact lens wear [59]. This group challenged previous ndings [58]
suggesting that contact lens replacement schedule and wearing time
should be considered when assessing the effect of contact lens wear on
Meibomian gland morphology [59]. Other studies have also failed to
show that contact lens use affects Meibomian gland structure and
function [60,70].
The aforementioned ndings suggesting that the duration of contact
lens wear correlates with characteristics of the Meibomian glands stand
in contrast to another study that did not nd that correlation [71]. Ac-
cording to these authors, functional and structural Meibomian gland
changes in soft contact lens wearers occur within the rst two years of
wear but do not worsen thereafter; however, the changes seem to be
permanent as contact lens dropouts did not show signs of improvement
[71]. These results are consistent with other ndings that found Mei-
bomian gland characteristics in SiHy contact lens wearers worsen sig-
nificantly after three years of contact lens wear but remain stable after
seven years of wear [72]. The earliest change that can be observed in
Meibomian gland appearance caused by contact lens wear is thickening
of the upper eyelid glands [72].
A detailed analysis of various characteristics of Meibomian glands,
P.B. Morgan et al.
Contact Lens and Anterior Eye 44 (2021) 192–219
195
such as area of dropout, number of glands, Meibomian gland length,
Meibomian gland width and Meibomian gland irregularity has been
provided [73]. This showed that experienced contact lens wearers had
larger areas of dropout and shorter glands when compared to
non-contact lens wearers, but those changes were not correlated to years
of wear. However, neophytes tted with daily disposable soft contact
lenses did not show any structural changes in Meibomian glands within
the rst 12 months of wear suggesting that changes happen later in time.
Differences between contact lens materials were also examined. Here,
hydrogel contact lens wearers showed some signicant variations in the
total number of glands and the area of gland atrophy in contrast to SiHy
wearers. Non-invasive tear film breakup time also appeared to be
dependent on the lens material. Furthermore, the changes in the per-
centage area of gland atrophy correlated with the uorescein tear lm
breakup time in SiHy contact lens wearers. Moreover, the preferred
habitual lens modality (monthly/fortnightly) seems to have an impact
on the area of gland atrophy and gland width, although this relationship
was not clearly explained by the authors [73]. Meibomian gland width is
a characteristic that does not seem to be affected by contact lens wear.
Two studies found no correlation between this particular Meibomian
gland characteristic and contact lens wear when successful contact lens
wearers were compared to both contact lens dropouts and non-wearers
[73,74].
Larger areas of Meibomian gland dropout are associated with shorter
uorescein tear lm breakup time [75]. A moderate negative correlation
has been reported between daily lens wear duration and FBUT [76]. No
signicant change in non-invasive tear film breakup time has been found
after six months of SiHy contact lens wear, a similar nding to other
studies in hydrogel contact lens wearers, but in contrast to one other
study that reported reduced non-invasive tear film breakup time in
neophytes after being tted with hydrogel contact lenses [77–80].
The relation between subjective symptoms in contact lens wear and
Meibomian glands is also ambiguous. One study found that disturbed
Meibomian gland function characteristics (foam at Meibomian gland
orices, expressibility, meibum quality, lipid layer thickness, uorescein
tear lm breakup time and evaporation rate) were associated with
symptoms of discomfort among the symptomatic contact lens wearers
[67] whereas another did not nd a difference in lipid layer patterns
between asymptomatic and symptomatic contact lens wearers [81]. In
addition, there was no difference in pre-lens tear break-up time between
symptomatic or asymptomatic groups [82]. Many other studies have
shown that subjective symptoms are related to contact lens wear [57,61,
65,66,72] but on the other hand, there are also some that did not
observe this relation [59,60,71,83,84].
The inuence of overnight orthokeratology (ortho-k) on Meibomian
glands has also received some attention in the literature. No significant
differences in Meibomian gland appearance and uorescein tear lm
breakup time after 3 years of ortho-k wear in children and adolescents
have been reported [61]. These ndings are supported by another study
that did not nd signicant changes in non-invasive tear film breakup
time, orice plugging, meibum quality, difculty of meibum excretion
and Meibomian gland dropout level when comparing time points prior
to and 2 years after the ortho-k wear in teenagers [83]. These outcomes
are contrary to that one study that found that Meibomian gland
appearance in the upper eyelid got gradually worse and non-invasive
tear film breakup time signicantly decreased within 12 months of
ortho-k wear [84].
Overall, then, the mechanism for Meibomian gland loss in contact
lens wear is not fully understood. Possible explanations involve me-
chanical trauma, chronic irritation and aggregation of desquamated
epithelial cells at the orifices of the glands [62,63,85].
Table 1
Effect of contact lenses on Meibomian glands. The blank spaces indicate that either evaluation was not performed, or it was not possible to make a clear judgement
whether results were relevant and appropriate. *Orthokeratology study. See also [86]. NIBUT =non-invasive breakup time; FBUT =uorescein tear lm breakup time;
LLT =lipid layer thickness; MG =meibomian gland; CL =contact lens.
Study Subjects Symptoms Plugging,
obstruction
Meibum quality also
expressibility
NIBUT,
FBUT
LLT Evaporation
rate
MG
appearance
Ong and Larke (1990) [62] CL wearers 70 yes
Non-wearers 70
Nichols and Sinnott (2006) [57] CL wearers 360 yes yes no
Arita et al. (2009) [63] CL wearers 121 yes yes
Non-wearers 137
Villani et al. (2011) [66] CL wearers 20 yes yes yes
Non-wearers 20
Arita et al. (2012) [58] CL wearers 64 +77 no yes no
Non-wearers 55 +47
Michalinska et al. (2015) [59] CL wearers 41 no yes yes (quality) / no
(expressibility) no no
Non-wearers 31
Pucker et al. (2015) [60] CL wearers 70 no no no no
Non-wearers 70
Alghmandi et al. (2016) [71] CL wearers 60
no yes yes yes no no yes Non-wearers 20
CL dropouts 20
Na et al. (2016) [61]* CL wearers 58 yes no no
Ucakhan et al. (2018) [72] CL wearers 87 (173
eyes) yes yes yes yes
Non-wearers 55 (103
eyes)
Wang et al. (2019) [83]* CL wearers 59 no no no no
Pucker et al. (2019) [74] CL wearers 56 no no
CL dropouts 56
Gu et al. (2020) [65] CL wearers 85 yes yes yes
Non-wearers 63
Yang et al. (2020) [84]* CL wearers 60 no yes yes
Non-wearers 60
Llorens-Quintana et al. (2020) [73] CL wearers 33 yes
CL dropouts 8
P.B. Morgan et al.
Contact Lens and Anterior Eye 44 (2021) 192–219
196
3. Conjunctiva
3.1. Bulbar and limbal conjunctiva
3.1.1. Hyperaemia
Hyperaemia is a visible response to the wearing of a contact lens (or
to some other irritating or inammatory factor) that is expressed as
dilation of the conjunctival blood vessels [87]. This dilation changes the
appearance of the exposed sclera and overlying bulbar and limbal con-
junctiva within the palpebral aperture from a quiescent ‘white’ to a
provoked ‘red’. The shift in hyperaemia is a sign that some underlying
factor has altered the homeostatic conjunctival blood ow balance. No
eye is ever perfectly ‘white’ as the conjunctiva contains visible blood
vessels. There is a normal range in the hyperaemia appearance for the
general population, reecting physiological variation between in-
dividuals and non-irritative inuences on the homeostatic balance
[88–90]. It is therefore important, when assessing change in hyperaemia
with contact lens wear, to establish the non-lens wear baseline for each
patient and to compare future change to that baseline.
The hyperaemia is produced by increased dilation of the arterioles in
the limbal corneal arcades and/or the bulbar conjunctival arteries [91].
The arteriolar walls are encircled by smooth muscle cells that control the
diameter of the arteriole and thus blood ow through the arteriole.
When stimulated, the smooth muscle relaxes leading to an increase in
the arteriole diameter [91]. This changes the ratio between the hyper-
aemia of the blood vessels to the whiteness of the scleral background and
the eye appears redder. The smooth muscle cells are innervated by
sympathetic nerves [92], which provide central autonomic control over
the arteriole diameter. The muscle cells are also affected by local factors.
These locally-derived factors are moderated by chemical agents, such as
prostaglandins or cytokines, that form part of the inammatory response
[90,93,94].
Increased dilation of the arterioles can be caused by mechanical
irritation, hypoxia, hypercapnia, acidic shift (increase in lactic and
carbonic acids), increased osmolarity, increased potassium, toxic re-
actions to a noxious agent, (e.g. preservatives, hydrogen peroxide), or as
part of the inammatory response to allergens or infection [95–97].
Many of these factors can be present in contact lens wear and can be
acute or chronic in their expression.
Hyperaemia is such a common response to contact lens wear [93,
98–101] that it is easy to forget that hyperaemia can be a sign the eye is
experiencing stress [90,102,103]. It is therefore important to include
questions about any reported or observed ocular hyperaemia as part of
the patient’s lens wear history during a clinical examination [104]. The
clinician should identify the potential causes for the hyperaemia and
make suitable changes to the lens specications, wear schedule, or lens
care solution to prevent the condition becoming chronic. The clinician
can use visual scales to grade hyperaemia severity and to monitor
treatment effect [105]. Signicant efforts have been made to develop
standardised grading scales that are easy to use by the clinician or that
rely on computer analysis [106–112].
The main areas identied as possible causes for bulbar and limbal
hyperaemia in contact lens wear are: lens surface/ocular surface me-
chanical interactions, pre-lens surface deposits, post-lens hypoxia,
altered tear lm, lens care solutions and ocular hygiene. All of these
produce some form of inammatory response from the ocular surface.
● Mechanical interactions can be produced by both tight-tting and
loose-tting lenses, with a particular effect on the limbal arcades
producing limbal hyperaemia [113,114]. Lens edge design can have
a particular effect on lens movement and on limbus/lens interaction
[115]. Movement of the lens over the limbal area is the primary
source of the mechanical interaction [116] and can be visibly
observed as limbal hyperaemia and increased staining in the peril-
imbal area [117]. Treatment is by modication of lens specications
to improve the t, with close attention to lens edge design [118].
●Pre-lens surface deposits are a feature of all contact lens wear mo-
dalities, including daily disposable, although with this modality the
clinical consequences of deposits are negligible. Deposit formation
occurs as a result of chemical interactions between the lens material
and the tear lm [119]. The deposits produce an allergic-type in-
ammatory reaction [120,121]. Treatment is by initiating or
increasing the frequency of the surface cleaning regime, or by
changing lens wear modality.
● Post-lens hypoxia is produced by insufcient gas-exchange through
the lens, principally due to low lens Dk [122]. Hypoxia was a
particular feature of early low Dk soft lens materials [93]. Silicone
hydrogel (SiHy) lens materials have effectively removed hypoxia
(and thus hypercapnia) as a source for limbal and bulbar hyperaemia
[123,124]. Post-lens hypoxia is treated by choosing a lens material
with a higher Dk [125,126]. Hypoxia is still an issue for scler-
al/overnight medical wear due to the effect of the post-lens uid
reservoir [127,128].
● A less stable tear lm can be produced in contact lens wear, which
induces increased tear evaporation [129–131], leading to partial
dehydration of the lens material [132,133]. This may produce me-
chanical effects from a tighter lens t or increased friction from the
lens surface [131,134]. Treatment is by changing the lens material,
lens wear modality, environmental conditions (if possible) and other
lens wearer adaptations.
● Lens care solutions can produce limbal and bulbar hyperaemia
[135–138]. This may be a direct effect from a biologically incom-
patible reaction between solution component and ocular surface, or
indirectly through a failure of the product to work effectively, e.g. an
ineffective protein cleaner. Treatment is by changing lens care so-
lution modality or by lens wear modality.
● Lid-related infections, such as blepharitis or meibomian gland
dysfunction, can be related to poor lid hygiene [139]. For these
cases, improved lid hygiene can produce a signicant improvement
in ocular hyperaemia.
3.1.2. Sodium uorescein, lissamine green and rose bengal staining
Two types of dye, sodium uorescein and lissamine green, are
currently used to examine the conjunctiva as part of contact lens pre-
tting and aftercare examinations [140]. Experimentally, uorescein
is actively taken up by healthy cells in cell culture [141,142]. Clinically,
it is thought to permeate the cytoplasm of living but damaged cells,
whereas lissamine green stains the cell membrane of dead or damaged
cells. The presence of lissamine green staining is thus highly specic for
dry eye disease [143]. Both stains are enhanced by the use of lters: a
yellow lter with blue light in the case of uorescein and a red lter with
white light for lissamine green. Lissamine green has largely replaced
rose bengal, which is toxic, even in relatively low concentrations and
uncomfortable, if not painful, for the patient [144].
Two main types of conjunctival staining are noted in soft contact lens
wearers: i) dryness-related staining, primarily located on the nasal and
temporal bulbar conjunctiva and ii) circumlimbal mechanical staining
from contact lens edges.
Conjunctival uorescein staining is commonly seen in non-contact
lens wearers, but typically at lower levels than in contact lens
wearers. Some conjunctival staining was seen in 98 % of a mixed group
of contact lens wearers and non-wearers; however the proportion of
subjects showing greater than Grade 1 staining (0–4 scale) was much
higher in the contact lens group: 62 % versus 12 % [145]. Another study
found conjunctival uorescein staining in approximately half (53 %) of
non-wearers versus 63 % of lens wearers [146]. With both groups, the
incidence of staining was signicantly higher for those classied as
symptomatic.
Lissamine green conjunctival staining is less common than uores-
cein staining in both contact lens wearers and non-wearers. However,
lissamine green staining (outside of the limbal area normally covered by
the lens edge) is more discriminating in identifying symptomatic
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patients, particularly contact lens wearers [146]. The authors hypoth-
esised that reduced blinking in soft lens wearers results in greater
evaporation and poorer conjunctival lubrication which, in turn, leads to
increased friction during the blink and tissue damage.
There has been little research on the effect of soft lens wear on
conjunctival staining. However, two studies have thrown useful light on
the signicance of edge design [117,147]. Soft lens edge proles broadly
t into three categories: rounded, knife and chisel edge designs. Edge
design was the primary factor in controlling circumlimbal uorescein
staining for SiHy lenses [117]. A rounded edge produced the least cir-
cumlimbal staining, while a thin knife edge design produced the most,
with an inverse association between staining and comfort. Comfort was
poorest with the rounded design and highest with the knife edge (72 vs.
87 out of 100) [117]. The study also noted lens rigidity as a secondary
factor, nding that a lens of higher modulus generated more circum-
limbal staining than a similar design of low modulus. Another study
found broadly similar results with a wider range of lens types [147].
With both chisel and knife edge designs, the higher modulus SiHy de-
signs showed signicantly more conjunctival staining than their
hydrogel counterparts.
Conjunctival staining induced by the lens edge is rarely symptomatic
or accompanied by hyperaemia and, therefore, does not necessarily
require a change of lens. An exception might be instances of signicant
conjunctival indentation which has been imaged by optical coherence
tomography in soft lens wearers [148–151]. Clinically, this is revealed
by pooling of uorescein in circumlimbal indentations corresponding to
the positioning of the lens edge. In one study of nine different soft lens
types, conjunctival indentation was associated with poorer comfort
[152]. This can be alleviated by switching to a lens of thinner edge
design and/or lower modulus.
3.1.3. Lid-parallel conjunctival folds
Lid-parallel conjunctival folds (LIPCOF) are observed as small folds
on the bulbar conjunctival surface, close to the lower lid margin and
near to the limbus. They occur in both the lower temporal and nasal
bulbar conjunctival areas (at around 4 and 8-o’clock of the corneal
location), while the patient is looking in the primary gaze [118,153].
The term lid-parallel conjunctival fold was rst introduced in 1995
[154] and the feature has been the subject of research by others sub-
sequently [82,153,155,156].
LIPCOF are thought to be caused by increased shearing forces during
blinking, as a result of increased friction between the ocular surface and
the lids, which, in turn, has been caused by reduced lubrication due to a
decient tear lm [157]. These causal factors are particularly found in
dry eye disease and studies have shown that LIPCOF is highly correlated
with dry eye disease and associated symptoms [153,156–159]. The
movement of the eyelids on the conjunctiva causes it to wrinkle into the
folds. The model proposes that the greater the friction, the greater the
size or extent of the LIPCOF. The folds are not permanent, but are
maintained by the position of the eyelid. If the lower lid is retracted, the
LIPCOF will disappear, but will reappear after normal blinking [157].
LIPCOF can also occur in subjects showing no other signs or symptoms of
dry eye disease [160].
LIPCOF are classied in two ways: by assessing the height of the folds
[154] or by counting the number of folds [161–163]. The number of
folds approach has been adopted for both slit-lamp biomicroscopy and
optical coherence tomography assessment [153,155,164].
LIPCOF interfere with tear meniscus assessment, either of the tear
meniscus radius [165], height [165,166] volume [167,168], curvature,
depth or cross-sectional area [162]. LIPCOF may affect tear lm mixing,
spreading and thus ocular surface lubrication, although the precise
mechanism for this is unclear [169].
‘Contact lens discomfort’ is an adverse clinical response to contact
lens wear, characterised by the wearer reporting symptoms of discom-
fort and possible reduced lens wear time. Symptoms are not always
associated with clinical signs. LIPCOF has been proposed as a feature of
contact lens discomfort [82,161,170–172].
The aetiology of LIPCOF in contact lens wear is thought to be similar
to that in dry eye disease - increased friction between the moving eyelid
and the ocular surface. The presence of the contact lens in the eye alters
the normal spreading and stability of the tear lm over the ocular sur-
face and the normal apposition of the eyelid against the bulbar
conjunctival surface. These changes lead to an increase in friction at the
ocular surface between the eyelid and conjunctiva during blinking,
particularly in the 4 and 8 o’clock area where the shear forces are
thought to be greatest [170,173]. Within this model, improving the
wettability of the lens surface and thus the distribution of the tear lm
over the lens and exposed conjunctiva, should also reduce friction and
the incidence of LIPCOF. However, it should be noted that a clear
relationship between the coefcient of friction and LIPCOF is yet to be
proven [118].
There is a limited literature on the effects of different contact lens
types, materials and designs on LIPCOF. Most studies report a positive
correlation between the presence of LIPCOF and discomfort symptoms
or with the extent of lens wear experience. In a series of studies on
subjects experiencing discomfort when using low to medium water
content (24–62 %) monthly disposable hydrogel contact lenses, LIPCOF
was strongly positively correlated to discomfort symptoms, older age, lid
wiper epitheliopathy (LWE) and to a lower mucin production [82,171,
174].
The effect is also seen with neophyte lens wearers. One study re-
ported that the main discriminators for contact lens-induced dry eye in
neophyte contact lens wearers wearing vilcon A hydrogel contact lens
and senolcon A SiHy contact lenses was LIPCOF [160]. Similarly,
neophytes who wore SiHy lenses full time for six months showed an
increase in LIPCOF [80]. The extent of lens wear experience is also a
factor in the development of LIPCOF. Using the term ‘con-
junctivochalasis’, but using the Hoh LIPCOF scale to describe conjunc-
tival changes (suggesting LIPCOF might have actually been reported), an
increase in LIPCOF with lens wear experience and with lens wearer age
has been reported [175]. Also, a positive correlation between LIPCOF
and duration of contact lens wear (with LIPCOF ndings higher after at
least a year of SiHy usage) has been found [176].
There is one contrasting report that found no relationship between
LIPCOF and contact lens materials (hydrogel contact lens and SiHy
contact lenses) or lens wear modality (yearly disposable contact lens and
monthly disposable contact lens) [155], although this could be due to
the small number of study subjects in this work.
It has been proposed that LIPCOF should be incorporated into the
clinical assessment of lens wearers to identify those wearers at greater
risk of developing contact lens discomfort symptoms. This is based on
the nding that ocular dryness symptoms are strongly linked to a
combination of LIPCOF and non-invasive tear film breakup time [156].
However, even though the specicity and sensitivity of LIPCOF ‘sum’
scores (a combination of nasal and temporal score) has proved to be
excellent [160], the repeatability of LIPCOF is limited, although prob-
ably better than other measures that may be associated with contact lens
discomfort such as tear break-up time, Schirmer test, tear meniscus
height or phenol red thread test [177].
It is important to note that, clinically, LIPCOF should not be mistaken
for conjunctivochalasis or conjunctival aps. LIPCOF refers to small
conjunctival folds of about 0.08 mm height [162,178], visible under
white light (slit-lamp magnication >18x) [179,180] and caused by
friction forces during blinking [181]. Conjunctivochalasis may partly
share the same aetiology as LIPCOF, but it is also age-related and can be
located anywhere on the bulbar surface [157,181–183]. ‘Conjunctival
aps’ are epithelial sheets, containing goblet cells, which are detached
from the conjunctiva, are sized of 0.01 mm height, can be located
anywhere on the bulbar surface in irregular directions and are mainly
reported after SiHy contact lens wear [157,184–187].
The management of LIPCOF in contact lens wearers has been aimed
at reducing the amount of friction between the lids and the contact lens,
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either by recommending the use of articial tears or by changing to a
contact lens with improved lens surface wettability (see CLEAR Main-
tenance and Biochemistry Report [188] for discussion on contact lens
wettability). A recent study demonstrated that moving experienced
monthly replacement daily contact lens wearers to senolcon A
two-weekly replacement lenses, or to spectacle wear, signicantly
improved LIPCOF after three months [173]. However, a clear frame-
work for such intervention is yet to be formulated [180].
3.1.4. Sub-clinical inammatory response
The inammatory response to contact lens wear, which occurs in
response to a myriad of factors including mechanical interactions be-
tween the lens and ocular surface, hypoxia, tear lm alterations, de-
posits on the lens surface, lens care solutions and hygiene, is observed
clinically as hyperaemia at the conjunctiva as discussed above. Sub-
clinical biomarkers, such as dendritiform cells which may initiate and
modulate the immune response by stimulation of T and B cells (see also
review [189]), can be imaged using in vivo confocal microscopy [190]
(Fig. 1). Although the effects of contact lens wear and ocular surface
conditions on dendritiform cells in the corneal epithelium have been
studied (see Section 4.1.5) [190,191], less is known about any impact on
dendritic cells within the conjunctiva and limbus.
The density of dendritiform cells in the temporal bulbar conjunctiva
was increased following one week daily wear of SiHy and hydrogel
reusable lenses (disinfected with hydrogen peroxide), but not of the
same hydrogel lenses replaced daily [192]. This increase was of similar
magnitude to that observed at the lid margin (Section 3.2.3) and central
cornea (Section 4.1.5) in the same study. Increased numbers of immune
cells in the bulbar conjunctiva were conrmed using impression
cytology and ow cytometry [192]. In contrast, another report
demonstrated that one week wear of daily disposable hydrogel lenses
resulted in a rise in the number of dendritiform cells in the nasal con-
junctiva [193]. This difference may be attributed to lens type or to
methodological differences as dendritic cell numbers are shown to differ
across bulbar conjunctival regions; here, cell numbers were reduced
after four weeks and returned to similar numbers to pre-lens wear levels
at six months of lens wear [194]. There was no difference in the number
of conjunctival dendritiform cells between experienced wearers of
reusable hydrogel lenses (with a mean of 10 years wear experience) and
non-contact lens wearers [194].
Upregulation of the immune response may be more likely to occur
when contact lenses are re-worn and proteins and lipids on the lens
surface [195] or microbial contamination of the lens storage case may
play a role in initiating such a response. Lens material or lens design
cannot be excluded and the role of these factors in upregulation of
conjunctival inammation requires further investigation; as does the
impact of rigid corneal lenses. Nevertheless, the return towards pre-lens
levels [194] suggests the immune response is transient and adaptation
occurs.
In the normal cornea, the highest density of dendritiform cells at the
ocular surface is found at the limbus [191]. In this region, dendritiform
cells are activated to mature and migrate via the lymphatic vessels be-
tween the cornea and lymph node [196]. They are also nearby the limbal
blood vessels, enabling travel in the circulation to further facilitate the
immune responses. They also have a role in intravascular surveillance
within the limbal vessels [197]. The impact of contact lenses and spe-
cically materials and edge design on limbal dendritic cells has not yet
been studied, but this area is worthy of research given the essential role
these cells play in ocular surface defence.
3.1.5. Sensitivity changes
Before considering conjunctival sensitivity, it is helpful to differen-
tiate the neural architecture in the conjunctiva, which consists of
epithelial free nerve endings and specialised receptor bodies [92], from
the cornea, which consists of epithelial free nerve endings [198–201].
The density of sensory nerve bres in the cornea is the highest in the
body. These nerve bres are arranged in large overlapping receptive
elds, providing an extremely high level of sensitivity [202,203]. The
conjunctival neural density is much less than the cornea and provides a
reduced sensitivity as a result [204]. It is also helpful to dene the limits
of bulbar and limbal conjunctiva. For this review, bulbar is considered to
begin 2 mm from the visible limbal/cornea junction and the limbal
conjunctiva to be contained within a 2 mm annular zone around the
visible junction [205]. A soft contact lens can be expected to cover and
move over the limbal area during wear [114].
3.1.5.1. Bulbar sensitivity changes. There is a limited literature on
bulbar and limbal conjunctiva sensitivity changes with contact lens wear
and the results are mixed. Early studies showed a reduction in bulbar
sensitivity with PMMA corneal, rigid gas permeable corneal and low Dk
soft hydrogel lens wear [206,207]. In contrast, both an increase [208]
and no change [209] in sensitivity with contact lenses have also been
reported. An increase in sensitivity in lens wearers who discontinued
wear due to discomfort has been reported [206]. No studies have re-
ported on bulbar sensitivity changes with scleral lens wear.
A convincing mechanism to explain the process that produces an
Fig. 1. In vivo confocal microscopic images depicting: Left: dendritiform cells with long dendrites found in the bulbar conjunctival epithelium (400
μ
m ×400
μ
m
image captured at depth of ~20
μ
m from the epithelial surface in the temporal quadrant), Right: dendritiform cells in the sub-basal epithelium of mid-peripheral
cornea (1 mm ×1 mm montage) [190].
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Contact Lens and Anterior Eye 44 (2021) 192–219
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altered bulbar sensitivity is lacking for both rigid and soft lens wear. This
may be due to the large overlapping receptive elds of the ocular surface
receptors and the imprecision of current sensitivity measurement tech-
niques. The conjunctival blood supply facilitates gas exchange and en-
sures a normal metabolism for the bulbar conjunctiva and since the lens
is not physically present, a mechanical interaction does not occur. A
possible effect from conjunctival drying, associated with 3 and 9 o’clock
staining or with insufcient blinking during lens wear [210] affecting
conjunctival epithelial nerve bre endings is possible, but this has not
been tested. The lack of an obvious mechanism for sensitivity loss in the
bulbar conjunctiva, in combination with the current results, suggests
that sensitivity is not signicantly changed in bulbar conjunctiva for any
modern lens wear type.
3.1.5.2. Limbal conjunctiva sensitivity changes. The general evidence for
the limbal conjunctiva is that short-term and long-term wear of soft
hydrogel and SiHy lenses produces an increased limbal conjunctival
sensitivity [116,211]. An increase in sensitivity was also found in pre-
vious lens wearers who discontinued wear due to discomfort [211]. In
contrast, other studies have found no change in inferior limbal
conjunctival sensitivity for both low Dk soft hydrogel and SiHy lens
wearers [212,213].
The presence and movement of the soft lens edge over the limbal
conjunctival zone during lens wear suggests a mechanical interaction
between the lens and the limbal conjunctival sensory nerves [214].
Evidence for this mechanical interaction on the limbal zone has been
observed as circumlimbal staining following SiHy lens wear [117].
However, in contrast to the reduced sensitivity produced by adaptation
to a mechanical stimulus as reported for the corneal nerves (Section
4.1.6), the mechanical interaction with the limbal zone increases
sensitivity. This suggests that the mechanical interaction has a different
form which promotes an increased neural response or that the neuro-
receptors respond differently [201,215]. Moreover, the neural archi-
tecture is different in this area, possessing specialised pressure sensors
[201,216,217]. It is unclear whether this difference has a role in the
altered neural response.
Increased limbal sensitivity may lead to symptoms of discomfort by
the lens wearer and so form part of the contact lens discomfort model
[218]. The form that this symptomatic limbal zone/lens interaction
takes is unclear, but lens edge design, lens modulus and lens thickness
might all inuence the strength of the mechanical interaction [117].
Signicantly, these factors have also been linked to lens wear discomfort
[118,137,219].
The alternative mechanism for how the lens could affect limbal
conjunctival sensitivity (hypoxia) can be rejected since this would lead
to a depression in neural activity [220] rather than the observed in-
crease. An alteration in corneal or conjunctival metabolism is, in any
case, unlikely with the presence of the extensive blood supply through
the limbal arcades [205].
3.2. Palpebral and marginal conjunctiva
3.2.1. Papillary hyperaemia and roughness
The palpebral conjunctiva forms the back surface of both eyelids
[221]. It is a key part of the ocular lubricating system, in conjunction
with the tear lm, that assists with eyeball and eyelid movement [222].
It is formed into an epithelial layer, containing mucin secreting cells
(goblet cells) and a stromal layer that contains the blood supply, derived
from the episcleral arteries and some inammatory cells. The normal
appearance of the palpebral conjunctiva is satin or smooth in 14 % of
people, containing small uniformly sized ‘micropapillae’ (<0.3 mm
diameter) in 85 % of people, or containing non-uniform papillae (up to
0.5 mm diameter) in <1 % of people [120]. Palpebral hyperaemia and
roughness can be graded using visual grading scales [105]. Similarly to
bulbar and limbal hyperaemia, there is considerable inter-participant
variation [223] and a normal baseline should be obtained for each pa-
tient before lens wear to allow comparison with subsequent lens wear.
Assessment should only be made across the central area of the everted
lid as other areas of the conjunctiva can be affected by non-contact
lens-related effects or by the lid eversion process, which can distort
the lid along the lid margin [224].
Changes to the papillary conjunctiva are a signicant complication
of all types of contact lens wear and are caused by the interaction be-
tween the front surface of the contact lens and the back surface of the
eyelid [101,120]. The interactions can be mechanical or allergic in na-
ture, producing an inammatory response that alters the homeostatic
balance in the conjunctival blood vessel diameter (hyperaemia) [91]
and an inammatory cell response that produces localised swelling in
the conjunctival epithelium and stroma (roughness) [94,224]. The me-
chanical interaction is produced by increased friction between the
palpebral conjunctiva and lens surface, due to lens dehydration or lens
surface deposition [170,225]. A papillary reaction can also be caused by
surface deposits or by chronic leakage of lens care solution ingredients
(e.g. PHMB) from the lens during wear [136]. These clinical signs and
their cause are characteristic of contact lens-induced papillary
conjunctivitis [226]. Differential diagnosis should also be made for
allergic, atopic and vernal conjunctivitis, which can show similar clin-
ical appearance and symptomatology [227].
The appearance of contact lens-induced papillary conjunctivitis can
vary with time from onset, lens wear type or modality and inammation
severity [228]. Onset can be within a few weeks (from initial lens wear)
for soft contact lenses, or up to 14 months in rigid corneal lens wear
[224]. Studies indicate that 6–12 % of soft hydrogel lens wearers will
present with contact lens-induced papillary conjunctivitis at some stage
in their lens wear lifetime [229–233], that overnight lens wear increases
the incidence rate (up to 18 %) [234,235] and that daily disposable lens
wear reduces the rate (as low as 2 %) [236]. Silicone hydrogel lens wear
produces a slightly higher incidence rate than soft lens wear [100,235].
A contact lens-induced papillary conjunctivitis incidence rate of 2 % has
been reported in overnight rigid corneal lens wear [229].
Contact lens-induced papillary conjunctivitis presents as both
increased hyperaemia, which appears rst, and increased lid roughness.
In soft hydrogel lens wear, papillae are more numerous than in rigid
corneal lens wear, are located towards the upper tarsal plate and the
apex of the papillae has a rounded, atter form [120,224]. In rigid
corneal lens wear, the papillae are crater-like and are located towards
the eyelid margin [120,224]. In severe cases, papillae can develop up to
1 mm in diameter and extend over a wide area of the conjunctiva. Here,
patients can complain of discomfort/itching (which may be sufcient to
cause the patient to stop lens wear) and blurred vision from increased
mucin production. Treatment may involve stopping lens wear for a
period of time, along with the use of anti-inammatory therapy, a
change in lens wear type/modality and/or lens care solution [224,228].
3.2.2. Lid wiper epitheliopathy
The lid wiper is the portion of the eyelid marginal conjunctiva that is
in contact with the globe and wipes the ocular or contact lens surface
during blinking. Lid wiper epitheliopathy (LWE) is a clinical condition
observed through the staining of the lid wiper region with uorescein,
lissamine green or rose bengal [237], which extends beyond the physi-
ological staining of Marx’s line [238]. Lid wiper epitheliopathy is
observed in both upper and lower eyelid and has been shown to occur in
contact lens wearers as well as in non-wearers [209,237,239–247]. The
severity of lid wiper staining is most commonly graded subjectively
based on the horizontal and vertical extent of lid margin staining [248],
although objective/automated techniques have also been used [249,
250].
Although the exact aetiology of LWE remains unclear, the primary
hypothesis is that LWE results from increased friction between the lid
wiper and the ocular or contact lens surface during blinking in the
absence of adequate lubrication [237]. LWE is likely to be a
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multifactorial condition with different underlying causes [134],
including decient tear lm [251], altered mucin production [171],
increased tear osmolarity [252–254], inammation [134], incomplete
blinking [255] and eyelid pressure [256,257]. A recent study further
supports the primary hypothesis that inadequate lubrication causes
friction factors and results in LWE [258]. Upper LWE may have a
different aetiology to lower LWE [239,253]. During contact lens wear,
the frictional properties of contact lenses may contribute to the aetiology
of LWE [170].
Lid wiper staining was observed in 25 % of patients presenting to an
eye clinic, including contact lens wearers and non-wearers [259]. Some
reports suggest a greater prevalence and grade of LWE staining in con-
tact lens wearers (52 %–84 %) compared with non-wearers (13 %–40 %)
[239,241,244], whilst others have found no difference [242,243,245,
246]. Studies investigating longitudinal changes in LWE have shown
increased upper lid wiper staining with lens wear [80,160,254,260].
Upper LWE staining signicantly increased in neophytes after four
weeks of hydrogel contact lens wear [160]. Similarly, increased upper
LWE grades were found in neophytes following six months of SiHy
contact lens wear [80]. Increased upper lid wiper staining was reported
after 10 days of SiHy lens wear, compared to spectacle wear at baseline,
whilst no change was found for the lower lid [254]. Regarding diurnal
variation, upper lid wiper staining signicantly increased throughout
the day in contact lens wearers, whilst no change was observed in
non-wearers [261]. An increased area of lower lid wiper staining has
been reported after 12 h of soft contact lens wear, whilst no change was
found in non-wearers [209].
There is limited evidence of the effect of different contact lens ma-
terials and designs on LWE. Greater LWE prevalence and grade in rigid
corneal lens wearers compared with soft contact lens wearers was re-
ported for the upper lid, whilst lower LWE was similar between groups
[239]. Similarly, rigid corneal lens wear was associated with greater
LWE grades compared with soft contact lens wear, particularly at the
upper lid margin [262]. These ndings would suggest a mechanical ef-
fect possibly related to lens-related factors such as modulus, edge design,
movement. Conversely, a study on daily wearers of hydrogel, SiHy or
rigid corneal contact lenses failed to demonstrate an effect of lens type
on upper lid wiper staining [263]. In addition, a number of studies
showed no signicant differences in LWE grades or patterns between
SiHy lens types [254,260,264]. In contrast, in a study of a large sample
of soft contact lens wearers, habitual senolcon A wearers were found to
have the lowest LWE grades. However, according to the authors, the
clinical signicance of the differences observed was unclear [265]. To
date, no studies have demonstrated a link between contact lens coef-
cient of friction and LWE.
A limited number of studies have investigated the impact of contact
lens wear on the lid wiper at a cellular level using impression cytology
techniques. No differences were found in the appearance of epithelial
cells and density of goblet cells of the upper marginal epithelium be-
tween contact lens wearers and non-wearers [245]. Expression of
keratinization-related proteins (laggrin, transglutaminase-1 and cyto-
keratin 1/10) was demonstrated in the lid margin epithelium, which
may indicate that a pathological process occurs at the lid wiper. In
contrast, soft contact lens wearers with short and moderate experience
had altered cytoplasmic and nuclear characteristics, as well as reduced
goblet cell density in the upper lid wiper compared with non-wearers
[246]. Interestingly, the lid wiper epithelium of previous contact lens
wearers was similar to that of non-wearers suggesting that changes
during contact lens wear might be reversible to some extent. Rigid
corneal contact lens wear has been associated with a wider, more ker-
atinised, lid wiper conjunctiva compared with soft contact lens wearers
and non-wearers, both at the upper and the lower lid margin [262].
These ndings lend support to the proposed mechanical or frictional
nature of LWE.
The relationship between vital staining of the lid wiper and the
specic underlying morphological changes remains unclear. Although,
in some instances, histological widths of the lid wiper conjunctiva were
signicantly correlated with lissamine green staining grades [262], no
correlation was found between lissamine green staining and morpho-
logical changes in the lid wiper epithelium [246].
Only two studies have investigated the vascular response of the lid
wiper to contact lens wear. Redness of the upper and lower lid wiper (as
an analogue of vascular response) in soft contact lens wearers and non-
wearers did not signicantly change through the day or following ≥6 h
of lens wear [244]. In contrast, increased microvascular network density
has been reported in the upper lid wiper after 6 h of SiHy lens wear in
neophytes, whilst no change was observed through a day of no lens wear
[266].
While LWE has been established as a diagnostic marker for dry eye
disease [162], the relationship between LWE and contact lens discom-
fort is not clear. Several studies have reported greater LWE prevalence
and grade in symptomatic contact lens wearers (67 % and 90 %,
respectively) compared with asymptomatic lens wearers (13%–32%),
primarily for the upper lid wiper [67,82,171,237,240–243]. In contrast,
an approximately similar number of studies have been unable to show a
relationship between LWE staining and contact lens associated dry-
ness/discomfort [80,134,209,244,247,254,262]. This could be partly
due to differences in methodology, population characteristics and clas-
sication criteria for contact lens discomfort. Histological widths of the
lid wiper conjunctiva have not been associated with contact lens comfort
[262]. No association was also observed between lid wiper hyperaemia
and subjective comfort [244]. On the other hand, increased microvas-
cular density in the lid wiper was signicantly correlated with decreased
contact lens comfort [266]. Recently, a study investigating the use of
uorescein-labelled wheat germ agglutinin as a marker for ocular sur-
face mucins found that symptomatic lens wearers showed reduced
wheat germ agglutinin uorescence in the lid wiper, which may suggest
altered density and/or structure of mucins [267].
Contradictory results in the literature may be partly due to discrep-
ancies in staining protocol and grading technique. Lid wiper staining has
been shown to be inuenced by dye concentration [250,268], instilled
volume [250], frequency of lid eversion [268,269], sequential instilla-
tion and timing of assessment [270], which highlights the need for a
standardised methodology. The limited repeatability of subjective
grading of LWE staining [177,271] and variations between brands [272]
may have also contributed to inconsistencies in the literature.
Whether LWE really represents a pathological process and its clinical
signicance are still under debate. Nonetheless, subjects showing severe
lid wiper staining may benet from treatments aimed at increasing
lubrication during contact lens wear [241]. Management strategies
could include altering lens type and wearing modalities, improving
blinking behaviour [255] and the use of lubricant eye drops [263,273,
274].
3.2.3. Sub-clinical inammatory response
Given the nature of the interaction between the tissues of the
palpebral conjunctiva and lid margin with the contact lens edge and
surface, it would be reasonable to speculate that recruitment of immune
cells would be seen in these tissues.
The density of dendritic cells at the lid margin was increased
following one week of daily SiHy and hydrogel reusable lens wear, but
not in daily disposable wear of the same hydrogel lenses [192]. This
increase was of similar magnitude to that observed on the bulbar con-
junctiva and central cornea in the same study. The rise in number of
dendritic cells was supported by a rise in leukocytes shown with
impression cytology and ow cytometry and suggests an upregulation in
inammation occurs at the lid margin with the wear of reusable lenses,
but not when these lenses are replaced daily. It is hypothesised that
degraded proteins and lipids on the lens surface or microbial contami-
nation of the lens storage case and then transfer of microbial product to
the lens may play a role in initiating such an inammatory response
[195].
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Interestingly, another study of daily disposable hydrogel lens wear
reported elevated density of dendritic cells at the lid margin after 6
months of wear in patients with symptoms of contact lens discomfort,
but not in asymptomatic wearers [275]. Pre-lens wear dendritic cell
density was not measured, so it is impossible to surmise whether the
recruitment of immune cells into the lid margin was a response to the
presence of the lens itself or a subclinical inammation due to contact
lens dry eye. No relationship was found between lid margin dendritic
cells and lens comfort [192]. Nevertheless, the demonstrated relation-
ship between contact lens-induced discomfort and higher numbers of
dendritic cells at the lid margin is worthy of further study.
Immune cells on the palpebral conjunctiva have not been observed in
the context of contact lens wear. Examination of the palpebral con-
junctiva conducted in normal patients and in those with severe allergy
(vernal keratoconjunctivitis) has suggested that dendritic cells can be
observed on the palpebral conjunctiva using in vivo confocal microscopy
[276,277]. It is not clear whether the reported cells were observed in the
thin 2–3 layer epithelium of the palpebral conjunctiva or in deeper tissue
[277]. A study which examined the palpebral conjunctiva in normal
eyes and in trachoma showed no association between the number of
dendritiform cells viewed in vivo in the palpebral conjunctiva and the
number of cells labelled as dendritic cells in an immunohistochemical
examination of biopsy specimens from the same patients [278] sug-
gesting that the dendritiform cells may not all be true dendritic cells.
3.2.4. Sensitivity changes
There is a very limited literature on changes in the palpebral and lid
margin conjunctiva sensitivity in contact lens wear. In part, this may be
due to difculties in measurement of this area - for example, lid
manipulation and exposure of the tissue under measurement may
impact on the values obtained. In general, studies indicate that soft
contact lens wear produces a reduction in upper lid palpebral conjunc-
tival sensitivity, but a possible increase in sensitivity in symptomatic
lens wearers. A reduction in palpebral conjunctiva sensitivity in rigid
corneal lens wearers and in low Dk soft lens wearers has been reported
[279]. A decrease in palpebral sensitivity with soft contact lens wear,
but an increase in sensitivity in symptomatic soft lens wearers has also
been reported [280]. There was an increase in palpebral sensitivity for
soft lens wearers compared to non-lens wearers [281]. One study re-
ported reduction in upper lid palpebral sensitivity in soft lens wearers,
but an increase in lower lid palpebral sensitivity in the morning [209].
The mechanism for these effects appears to be the mechanical interac-
tion between the anterior lens surface and the overlying palpebral
conjunctiva during eyelid blinking producing an adaptation in the
neural response to the repeated stimulation. The increase in sensitivity
in symptomatic lens wearers suggests a possible effect on lens wear
discomfort from this route [280].
Lid margin sensitivity is the highest of all the conjunctival areas
[282–284]. It is generally considered to be reduced in both rigid corneal
and soft lens wear [209,279,281,282,285,286]. The mechanism for this
effect is thought to be linked to a neural adaptation from the mechanical
interaction between the eyelid margin and the edge of the contact lens
during blinking.
4. Cornea
4.1. Epithelium
4.1.1. Fluorescein staining
Fluorescein is versatile enough to reveal most disruptions to the
ocular surface and is helpful in detecting a wide range of contact lens-
related stress factors, including: desiccation, trauma, infection, allergic
and toxic effects. As well as differentiating various corneal disorders
through the pattern of staining (Fig. 2), it indicates the severity through
the depth and extent of staining and, therefore, is an invaluable pointer
towards management.
Despite its long history of use in ophthalmology, the mechanisms of
corneal staining are not fully understood [287,288], although recent
research has expanded this. Sodium uorescein is water soluble and is
more accurately described as a dye rather than a stain. Early theories
suggested that punctate staining represented an accumulation of uo-
rescein in intercellular spaces or pooling in sites of missing cells. How-
ever, these have been largely discredited. Several observations point
towards the fact that uorescein enters the epithelial cells themselves: i)
rinsing with saline fails to eliminate punctate staining [289], ii) punctate
staining matches the size and shape of epithelial cells [290], iii) cells
shed by apoptosis show uorescein staining and iv) even healthy
epithelial cells uoresce, albeit at a much lower level than damaged cells
[291]. In the case of deeper corneal damage, uorescein can diffuse in
the stroma and show a background glow [292].
An extensive study of contact lens wearers (91.5 % soft, 8.5 % rigid
corneal) noted corneal staining in 54 % of patients [293]. Factors related
to increased corneal staining included: increased daily wearing times,
lissamine green conjunctival staining, contact lens deposition, increased
tear meniscus height, decreased hydrogel nominal water content and
lower nancial income. The wearing of SiHy (as opposed to hydrogels)
gave lower levels of corneal staining.
4.1.1.1. Desiccation. With both rigid corneal and soft contact lenses,
desiccation induced staining is the most commonly encountered type of
corneal staining. Desiccation staining occurs in locations where the tear
lm is thinnest and/or least stable. Soft lens smile-shaped staining oc-
curs parallel and adjacent to the lower lid. Not surprisingly, desiccation
staining is more common with partial blinking and often marks the
lowest extent of the upper lid during the blink. Desiccation staining can
also coincide with the edge of the lower tear meniscus due to a thin band
in the tear lm from surface tension [29].
Low levels of desiccation staining can be tolerated since this can
often be present in the normal non-lens wearing eye [294]. Low to
moderate levels of corneal desiccation staining can be mitigated by
improved blinking, the use of wetting drops, reduced wearing time, or
the use of dehydration-resistant lens materials [295].
Rigid lens 3 & 9 o’clock staining is also a type of desiccation staining
but occurring through instability of the pre-corneal rather than pre-lens
tear lm. The characteristic triangular shape of 3 & 9 o’clock staining
can be explained in terms of poor corneal wetting during the blink due to
vaulting of the lid between the lens edge and ocular surface. The largest
gap occurs when the lid crosses the widest part of the lens. Less wide-
spread 3 & 9 o’clock staining, closer to the lens edge can be explained by
localised tear lm thinning adjacent to the tear meniscus surrounding
the lens. Both types of staining are best mitigated by modifying the lens
design to improve corneal wetting, i.e. decreasing edge clearance,
decreasing edge thickness, decreasing diameter, or increasing diameter
[296].
4.1.1.2. Trauma. The simplest example of corneal trauma is foreign
body abrasion caused by dust or an eyelash being trapped beneath the
lens. Epithelial abrasions can heal at more than one square millimetre
per hour, depending on the initial wound size; larger wounds healing
faster [297]. Based on the results of animal studies [292], a temporary
discontinuation of lens wear has been proposed based on the depth and
extent of corneal staining: 24 h if slight stromal diffusion, two to three
days if moderate stromal diffusion.
Superior arcuate corneal staining (also termed Superior Arcuate
Epithelial Lesion) was relatively common with early hydrogel designs
and perplexed ECPs for some time, partly due to its similarity to superior
limbic keratitis. However, it became clear that Superior Arcuate
Epithelial Lesions are due to trauma from relatively stiff soft lenses
[298]. Superior Arcuate Epithelial Lesions are typically located on the
cornea under the upper lid approximately a millimetre from the limbus.
Lenses of high modulus or thick lenses of any modulus that fail to align
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Contact Lens and Anterior Eye 44 (2021) 192–219
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with the corneal shape can result in pressure points. Additional pressure
from the upper lid and lens motion during the blink produce an abrasion
which is invariably severe enough to warrant a change of lens design.
The edges of both rigid corneal and soft lenses, when in contact with
the corneal surface, can cause corneal staining of varying degrees. Rigid
lenses with inadequate edge clearance can produce arcuate staining
close to the limbus. This can be confused with 3 & 9 o’clock desiccation
staining but is differentiated by examining the peripheral lens t. When
the lens is moved close to the limbus, the uorescein t should show
some peripheral clearance, even if only minimal. Soft lenses whose
edges encroach onto the peripheral cornea can also result in mild
staining. In aligning with the ocular surface, soft lenses show the
greatest deformation at the edge, which typically stretches about 4 %
causing a band of pressure [299]. In both cases, the remedy is to modify
the lens t to avoid corneal contact with the lens edge.
4.1.1.3. Toxicity. Solution-induced corneal staining (SICS) is a common
side effect of soft lens multipurpose disinfection systems. Unlike other
types of staining, SICS is usually evident in three or more peripheral
corneal sectors. Often the punctate staining follows a circular pattern
but, in more severe cases, can involve the whole of the cornea. Gener-
ally, the level of corneal staining in SICS is low grade, although more
severe cases may be associated with reduced comfort [300–302] and an
increased incidence of inltrative events [303]. The phenomenon of
SICS shows a number of interesting features. First, the severity varies
greatly according to the lens-solution combination [304]. Group 2
hydrogel lenses in conjunction with polyhexamethylene biguanide
(PHMB) solutions induce the greatest level of staining. This can be
explained in terms of the preservative uptake-release characteristics;
being highly temperature sensitive, Group 2 materials discharge a
relatively high proportion of solution into the post-lens tear lm, thus
increasing the dosage. Second, the staining usually reaches a maximum
two hours after insertion but then disappears after a further two hours
[305]. This is at least partly explained by an associated increase in
shedding of corneal cells with SICS, suggesting a temporary increase in
epithelial apoptosis [306]. SICS may be related to an increase of
dynamin-mediated uptake of uorescein into cells which in turn is due
to the presence of Tetronic 1107, a block co-polymer included in a
number of multi-purpose solutions [142].
4.1.2. Hypoxia-related responses: microcysts and epithelial oedema
Contact lens-induced hypoxia has inspired a large body of research
and led to many insights into corneal physiology [122,307,308]. In
relation to the corneal epithelium, hypoxia leads to: decreased epithelial
metabolic rate [309,310], reduced basal cell mitosis [311,312],
epithelial cell enlargement and increased cell life [313], epithelial
thinning [309,314,315], lactate accumulation, acidic shift and increased
bacterial binding [316,317]. The main clinical manifestations of this
include: epithelial microcysts, compromise in junctional integrity, neo-
vascularisation and decreased corneal sensation (Section 4.1.6).
Soft contact lens wear has been reported to suppress corneal basal
epithelial cell mitosis in rabbits [312]. Subsequent work showed a cor-
relation between reduced oxygen supply and reduced exfoliation of
epithelial cells with both rigid corneal and soft lens wear [318–320]. A
correlation with the ability of Pseudomonas aeruginosa to bind to exfo-
liated epithelial cells was reported that was hypothesised, but not
proven, to be a factor in increased risk of corneal infection [321].
Binding of P. aeruginosa to corneal cells was greater with hydrogel lenses
than SiHy lenses [319] but, by contrast, hyper-oxygen permeable rigid
corneal lenses did not increase P. aeruginosa binding. However, a sub-
sequent study has shown a reversal of this effect over a longer period
(6–12 months) of wear [322].
There is no evidence for corneal epithelial swelling due to anoxia
[323,324] or hypoxia [325,326]. Corneal epithelial oedema is a rare
manifestation of contact lens wear, usually arising from signicant
trauma or being exposed to a hypotonic environment. Fluid accumulates
in the intercellular spaces rather than within cells. Increased lactate
production during hypoxia may accumulate between basal cells and
draws water out of the cells by osmosis [327]. Light scattering from
these vacuoles of lower refractive index can result in cloudy vision and
coloured haloes. Visual phenomena with epithelial oedema are similar
to those experienced with stromal oedema but occur much earlier, i.e.
with relatively low levels of oedema. With high levels of epithelial
oedema, vacuoles may be visible on slit lamp examination and are
distinguished from epithelial microcysts by marginal retro illumination;
vacuoles show unreversed illumination [328].
Epithelial microcysts are an indicator of disordered epithelial
metabolism and in contact lens wearers, occurs as a delayed response to
high levels of chronic hypoxia [329]. Since they are associated with
overnight wear or contact lenses of low oxygen transmissibility, they are
rarely seen with daily wear of current SiHy lenses.
Epithelial microcysts are translucent, typically 15–50
μ
m in diameter
and show reversed illumination, indicating a higher refractive index
than surrounding tissue [328]. They form in the basal layers, gradually
moving to the corneal surface, at which point they may stain with
uorescein. Non-contact lens wearers can show small numbers (<10) of
microcyst but, in lens wearers, larger numbers, even hundreds, may be
present. They are usually asymptomatic and, except in severe cases,
Fig. 2. Schematic representation of various patterns of corneal uorescein
staining. A. ‘Smile’ desiccation staining; B. Desiccation staining; C. 3 & 9
o’clock staining; D. Foreign body tracks; E. Superior arcuate staining (SEAL); F.
Inferior staining from soft lens edge; G. Limbal staining and follicles from
thimerosal hypersensitivity; H. Solution-induced corneal staining (SICS); I. Se-
vere SICS; J. Microbial keratitis (MK); K. Adenovirus/Epidemic Keratocon-
junctivitis; L. Epithelial microcysts breaking the corneal surface.
P.B. Morgan et al.
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203
have no effect on vision. There is an inverse relation between lens ox-
ygen transmissibility and the number of microcysts [329]. Hydrogel
lenses are associated with a greater number of microcysts compared to
rigid corneal lenses with similar Dk/t [329].
Their aetiology and morphology is not fully understood but micro-
cysts are believed to represent degenerated (apoptotic) cells [330] due
to altered mitosis of the basal epithelial cells [329]. A curious feature of
microcysts is their time-course; their onset is slow, reaching a peak after
several months and, when lens wear is ceased, rst increase in number
before disappearing over a period of 2–3 months. The return of basal cell
mitosis to normal levels may accelerate the process of bringing cellular
debris to the surface [309].
4.1.3. Corneal wrinkling
Corneal Wrinkling is a rare but notable complication of thin hydrogel
lenses [331,332]. The prevalence has been estimated to be 1.7 % in
wearers of disposable hydrogel overnight wear lenses [233], whereas
others have argued that it is limited to those using mis-designed custom
lenses and may be unfamiliar to the contemporary contact lens practi-
tioner [333].
Wrinkles in the thin central zone of these lenses are temporarily
transferred to the corneal surface through lid pressure and so wrinkling
is generally considered to have a mechanical aetiology, although an
osmotic cause has also been suggested [334]. Clinically, wrinkling can
result in a reduction in visual acuity and is evident from pooling of
uorescein and deformation of keratoscope images.
4.1.4. Corneal warpage
Throughout the history of contact lenses, there have been many re-
ports of corneal warpage, however, these have tended to relate to non-
standard lenses, such as rigid corneal PMMA, opaque tinted, toric and
overnight wear contact lenses. Corneal warpage can manifest as: i) an
increase in corneal astigmatism, ii) central irregular astigmatism, iii)
loss of radial symmetry and iv) change from normal corneal asphericity.
A review of early case reports (1965–1988) noted that, out of 473 cases,
343 (72.5 %) were associated with rigid corneal lenses and 130 (27.5 %)
with hydrogel lenses [335]. Another report found corneal warpage was
associated with the t of rigid corneal lenses [336]. Several reports
discussed corneal warpage with early examples of opaque tinted lenses
[337,338]. In a more recent study of prospective refractive surgery pa-
tients [339], contact lens wearers were required to cease lens wear for 5
days to 3 weeks depending on lens type; 6.7 % (11/165) patients showed
signicant corneal warpage. The recovery rates varied with lens type,
soft overnight wearing eyes taking the longest (11.6 ±8.5 weeks) and
rigid corneal lenses the shortest (8.8 ±6.8 weeks).
Corneal warpage is a rare occurrence with contemporary high Dk
contact lenses, but remains a possibility with low Dk lenses. Notably,
there is one report of keratoconus being wrongly diagnosed in the case of
corneal warpage due to soft lens wear [340] and the correct discrimi-
nation of these two conditions is still a subject of study [341].
4.1.5. Sub-clinical inammatory response
Clinically observed corneal inltrates and inammatory events occur
in up to 10 % of all soft contact lens wearers per year [342]. However,
sub-clinical inammation is much more common and possibly ubiqui-
tous when contact lens wear is rst commenced (see Section 3.1.4).
Changes in the density, morphology and distribution (e.g. migration into
the corneal centre) of corneal epithelial dendritic cells (CEDC) are
considered pathognomonic of activation of the corneal immune
response [343] and have been observed in the presence of corneal
infection, ocular surface disease including dry eye and allergy and
during contact lens wear.
in vivo confocal microscopy investigations have shown elevated
CEDC density in the central cornea in soft contact lens wearers [192,193,
344–347], suggesting these cells migrate into the centre in response to
an inammatory stimulus, perhaps due to the presence of the contact
lens, as has been shown in animal models of lens wear [348,349]. A
summary of studies which have to date examined the effects of contact
lens wear on corneal dendritic cell density presented in Table 2 illus-
trates much variability in cell numbers reported by different in-
vestigators who may have used differing methodologies and criteria.
However, from the available evidence, it can be surmised that CEDC
numbers increase during lens wear, that this increase is temporary and
that there is an effect of lens type.
The corneal CEDC response occurs as quickly as after 2 h of hydrogel
lens wear in non-wearers [350]. These rapid changes are perhaps not
surprising as measurements of DC kinetics in mice show track speeds of
the order of 3
μ
m/min [351]. CEDC in the central cornea returned to
baseline levels after 6 months of wear [193], which agrees with ndings
of other investigators who found central CEDC density not to be elevated
in experienced lens wearers compared to non-wearers [190,346].
In contrast, another report found that CEDC density was not signif-
icantly higher than baseline until 4 weeks wear of hydrogel lenses and
had not returned to baseline by 6 months [347]. Only two studies have
quantied the distribution of CEDC away from the corneal centre. One
report showed an increased density of CEDC in the peripheral cornea
after 1 week of reusable hydrogel lenses, which had not returned to
baseline at 6 months [347]. Another report showed CEDC density in the
mid-peripheral cornea to be increased in lens wearers [190].
These differences between studies are likely to be due to the lens
type, replacement schedule and use of disinfecting solution, as well as
contact-lens dry eye status. When considering only asymptomatic lens
wearers, only a small (not signicant) rise in CEDC was found [193].
Daily replacement of lenses also reduces the CEDC response – no
elevation of CEDC occurred at 1 week of wear when hydrogel lenses
were replaced daily, but CEDC density increased when the same lens was
reused and disinfected [192]. The effect of lens material and oxygen
transmissibility remain unclear, with higher, lower and no differences
reported between SiHy and hydrogel lenses [192,345,346].
4.1.6. Sensitivity and nerve changes
Since the earliest introduction of contact lenses, changes in corneal
sensation have been a feature of contact lens wear. Although an optical
benet is produced by lens wear, the mechanical interaction of the
contact lens with the cornea and eyelids can produce a strong foreign
body sensation, particularly in rigid corneal lens wear. Thus adaptation
to the presence of the lens is a desired side-effect for successful rigid
corneal lens wear [21,282,286,352–354]. Adaptation to soft lens wear is
not needed to the same extent, but discomfort from soft lens wear raises
a different question about how the corneal nerves respond to lens wear
and whether a lack of adaptation may be contributing to discomfort
[21].
Wearing PMMA or rigid corneal lenses will produce a marked
reduction in corneal sensitivity in the wearer, with the magnitude of the
effect depending on the length of lens wear, both in the short-term (over
a period of a day) and in the long-term (over a prolonged period of daily
lens wear), up to a maximum effect for that wearer [355–362]. There is
also reduced sensitivity in wearers of reverse geometry ortho-k lenses
[363]. A total loss of sensitivity does not occur, although sensitivity may
be sufciently reduced to increase the risk of an undetected foreign body
[357,359]. Peripheral corneal sensitivity, not covered by the lens, is
unaltered [364]. Recovery of sensation after lens wear follows a similar
effect - a shorter period of lens wear allows for an earlier recovery, with
full recovery appearing to occur [355,365]. No signicant morpholog-
ical changes in corneal nerve structure have been noted with high Dk
rigid corneal lens wear [366].
Ortho-k lenses, by virtue of being rigid, and also of being worn
overnight, produce a reduction in sensitivity, with similar changes
related to duration of wear as those seen in standard rigid corneal lenses.
Central sensitivity is reduced by approximately 50 % and recovers to
pre-lens wear levels after cessation of lens wear [367–369]. Corneal
nerve morphology is affected by ortho-k, with a reduction in nerve bre
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Contact Lens and Anterior Eye 44 (2021) 192–219
204
density and re-organisation of the nerve bre orientation [368–372].
The nerve bre changes also resolve with cessation of ortho-k lens wear,
in sync with the recovery in sensitivity [369,372]. These features
strongly indicate a direct link between sensitivity loss and the me-
chanical effect of the ortho-k lens on the corneal epithelium during
overnight lens wear [367]. A metabolic effect from hypoxia under the
lens is not considered to be a factor, since very high Dk lens materials are
used and no corneal oedema is observed.
No studies have reported on corneal sensitivity change in scleral lens
wear, but the vaulting of the lens over the cornea, combined with good
Dk lens materials and an appropriate post-lens uid reservoir thickness,
suggests that no change in sensitivity is likely. This is supported by ev-
idence that corneal neural structures are unchanged with scleral lens
wear [366,373]. However, scleral lens materials with an insufcient Dk
[374], or with an excessive post-lens tear reservoir [127,128] will pro-
duce oedema, suggesting that either scenario may produce a reduced
sensitivity.
For low Dk soft hydrogel lenses, both a mild reduction in sensitivity
[116,362,375,376] and no change in sensitivity has been reported [211,
377,378]. For studies that reported a reduction, a full recovery to
pre-lens wear levels occurs when lens wear is stopped [375,376]. The
duration of wear does not appear to produce an increase in effect beyond
Table 2
Summary of studies reporting corneal epithelial dendritic cell density in contact lens wearers. HCL =hard (PMMA) contact lenses; SCL =soft contact lenses; Hy =soft
hydrogel contact lenses; SiHy =silicone hydrogel contact lenses; DD =daily disposable contact lenses; w =week.
Study Subjects Corneal epithelial dendritic cell density (cells/mm
2
)
Centre Periphery
Zhivov et al 2007 [344] Contact lens HCL: 36 ±22 HCL: 189 ±34
wearers SCL: 114 ±41 SCL: 228 ±35
(n=54)
Non-wearers 34 ±3 98 ±8
(n=70)
Sindt et al 2012 [345] Contact lens All: 64 ±71
–
wearers signicantly higher than non-wearers
(n=53)
Hy: 47 ±44
SiHy DD: 69 ±77
no signicant difference between lens types
Non-wearers 29 ±23 –
(n=10)
Lop´
ez-De La Rosa et al 2018 [346] Contact lens Hy: 132 ±83
–
wearers signicantly higher than SiHy & no wear
(n=40)
SiHy: 68 ±77
not signicantly different to no wear
Non-wearers 58 ±20 –
(n=20)
Alzahrani et al 2017 [193] Contact lens 1w Hy DD: 47 ±25
–
wearers signicantly higher than no wear
(n=60)
24w Hy DD: 32 ±29
not signicantly different to no wear
Non-wearers 27 ±19 –
(n=23)
Golebiowski et al 2020 [190] Contact lens 20.1 ±26.3 15.8 ±13.6
wearers not signicantly different to no wear
(n=20)
Non-wearers 18.6 ±23.9 12.3 ±10.8
(n=20)
Saliman et al 2020 [192] Contact lens 1w Hy DD: 15.2 ±7.1
–
wearers not signicantly different to BL
(n=20)
1w Hy: 24.1 ±11.1
1w SiHy: 22.7 ±7.8
signicantly higher than BL
Baseline 14 ±7.5
– (n=20)
(experienced wearers)
Liu et al 2020 [347] Contact lens 1w Hy: 32.29 ±5.47 1w Hy: 53.54 ±6.84
wearers 4w Hy: 60.52 ±12.29 4w Hy: 90.42 ±8.80
(n=20) 12w Hy: 62.71 ±13.25 12w Hy: 57.81 ±6.40
[data reported as mean ±SE] 24w Hy: 55.94 ±10.63 24w Hy: 47.40 ±4.35
4-24w signicantly higher than no wear all signicantly higher than no wear
Non-wearers 16.25 ±2.58
(n=20) 19.06 ±2.53
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Contact Lens and Anterior Eye 44 (2021) 192–219
205
the maximum effect for the wearer [362]. Depending on the water
content of the lens and the duration of wearing, some loss in sensitivity is
likely.
For high Dk soft hydrogel, daily disposable and SiHy lenses, no sig-
nicant loss in sensitivity has been noted using any type of instrument
[211–213,379], although differences in sensory processing have been
noted [379,380]. The consequences for this latter nding are unclear,
but may have a role in contact lens discomfort. No signicant changes in
corneal neural architecture have been noted with soft contact lens wear
in the central or mid-peripheral cornea, although the changes may be
more subtle than those visible with confocal microscopy [213,366,
381–383].
The different patterns of effect with each lens type illustrate the two
main mechanisms proposed to explain sensitivity loss: sub-lens corneal
hypoxia and mechanical pressure or rubbing [201,214,384,385]. The
importance of gas exchange through the lens material is demonstrated
by the reduction in sensitivity loss with increasing lens Dk and/or tear
exchange [214]. This matches with experimental studies that demon-
strate a reduced corneal sensitivity with a reduced pre-corneal oxygen
concentration (compared to normal) [386,387]. The exact mechanism
for this reduction has not been established, but has been linked to an
altered corneal metabolism, i.e. the change in gas exchange rate leads to
an altered metabolic level within the cornea that produces a new
sensitivity baseline. This change may be moderated by hypoxia and/or
hypercapnia [220], as well as altered stromal pH [220], neurotrans-
mitter [213,388,389] and acetylcholine transferase activity [386,390,
391]. Evidence for a hypoxia-related mechanism is shown by the re-
covery in corneal sensitivity in PMMA lens wearers retted into rigid
corneal lenses [392] and in low-Dk soft lens wearers retted into SiHy
lenses [208,212].
The mechanical effect is revealed by the different ndings between
the rigid and soft lens material, each of which delivers signicantly
different stimulation to the corneal nerves. The mechanical interaction
of the lens with the corneal surface produces a sustained response from
the corneal nerves (and thus symptoms of discomfort in the lens wearer),
which gradually reduces with neural adaptation [393]. This adaptation
may be at the receptor level or at a higher level [393].
4.2. Stroma
4.2.1. Neovascularisation
The limbal vasculature does not provide the required nutrition and
oxygen for corneal metabolism [394]. The cornea receives the required
oxygen for its respiration from the anterior surface through diffusion of
atmospheric oxygen that is dissolved in the tear lm. The required
nutrition (e.g. glucose and amino acids) for the avascular cornea diffuse
from the aqueous humour across the leaky corneal endothelium [395,
396].
Peripheral corneal oxygen deprivation by contact lens wear may lead
to limbal hyperaemia that is inversely related to peripheral lens oxygen
transmissibility (Dk/t) [123,397]. The increased limbal hyperaemia by
contact lens wear could be a precursor to corneal neovascularisation.
However, a direct link between limbal hyperaemia and the neovascular
ingrowth has not been established [307]. The absence of vessels in the
cornea is a major factor in maintaining its transparency. The loss of
corneal transparency by progressive growth of invading new vessels in
the cornea could be sight threatening [398]. A suggested mechanism for
maintaining corneal avascularity is through an active balance between
corneal angiogenic and antiangiogenic factors [399]. Peripheral corneal
swelling can facilitate limbal vessel penetration into the cornea but the
presence of stromal swelling by itself is not a sufcient trigger to the
growth of new vessels. Contact lens-induced corneal neovascularisation
may be triggered by corneal hypoxia through down-regulating anti--
angiogenic factors and up-regulating angiogenic factors [399,400].
However, corneal hypoxia may affect the balance between corneal
angiogenic and antiangiogenic factors through two different
mechanisms [401]:
● Hypoxic route: the hypoxia itself may trigger the release of vascular
endothelial growth factor in an attempt to rescue the oxygen-thriving
epithelial and endothelial cells.
● Hypoxia mediated inammatory route: hypoxia-induced corneal
inammation may signal the release of inammatory vaso-
stimulating factors in the stroma.
Corneal limbal vasculature has an insignicant role in corneal
oxygenation. The vascular arcade does not penetrate the normal clear
cornea due to barrier function of limbal stem cells among other things.
However, as a result of the imbalance from hypoxia the limbal vessels
may penetrate and continue to encroach the stroma towards the corneal
apex. The depth of corneal vascularisation may depend on the location
of the angiogenic site in the cornea hence deeper stromal vascularisation
could be expected with higher degrees of corneal hypoxia. The posterior
oxygen supply to the peripheral endothelial cells from the aqueous
could, at least in part, explain the uncommonness of contact lens-
induced deep stromal vascularisation. Deeper stromal vascularisation
could pose a higher risk of corneal opacication from leaking lipid into
the stroma [399], plus the additional risk of intracorneal haemorrhage
[402].
Clinically, the state of corneal oxygenation can be gauged from its
inverse relation with contact lens-induced corneal swelling. Hypoxia-
induced corneal vascularisation may rarely occur with rigid corneal
overnight wear lenses, or with PMMA daily wear. This is attributed to
the smaller diameter of hard lenses hence greater exposure of peripheral
cornea to oxygen. The risk of corneal vascularisation is increased with
overnight wear, compared to daily wear, of conventional hydrogel
lenses [99,403]. The same is true with SiHy lenses. Although, on
average, the risk of corneal vascularisation has been minimised with
greater oxygen availability in SiHy lenses [125,404,405], a cautious
approach to identify and monitor high-swellers is still suggested
[406–408]. This is to prevent potentially sight-threatening outcomes
from silent vessel ingrowth, as well as to lower the risk of possible in-
ammatory events associated with vascularisation in these patients
[409]. This is particularly important in lenses with higher minus power,
thicker lens edge prole and especially in SiHy overnight wear [407,
408,410].
4.2.2. Hypoxia-related responses: swelling, striae, folds, haze
Hypoxia-induced corneal swelling mainly occurs in the stroma which
accounts for around 90 % of corneal thickness [411]. The stroma plays
an important role in maintaining corneal transparency because of its
uniquely organised lamella structure of collagen brils [412] with
anterior stromal keratocytes contain a crystalline protein to minimise
backscattering of the light [413]. Collagen brils in the anterior stroma
are more tightly packed than the posterior stroma to provide adequate
rigidity and strength for maintaining the anterior corneal curvature and
shape against the stress from stromal swelling [414].
In open-eye conditions at sea level the bare cornea is exposed to the
atmospheric partial oxygen pressure (PO
2
) of 155 mmHg [415]. The PO
2
is reduced to one third or ~55 mmHg that is largely supplied by the
palpebral conjunctival blood vessels in closed eye conditions [415]. A
contact lens barrier will reduce the available PO
2
leading to increased
anaerobic metabolism of glucose [416,417] in corneal epithelial cells.
Lactic acid, the product of the anaerobic metabolism, diffuses posteri-
orly into the stroma. The increased osmotic pressure caused by elevated
levels of lactic acid production from anaerobic corneal metabolism leads
to stromal swelling [418–420]. This is because the hydrophilic compo-
nents of the stromal ground substance will expand by diffusion of
additional water from the anterior chamber, across the leaky corneal
endothelium by osmosis [421]. This phenomenon can physiologically
occur when eyelids are closed during sleep (overnight corneal swelling)
and is in the range of 3–4 % of corneal thickening [422–424]. Typically,
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the cornea is at its maximum thickness upon waking in the morning and
it gradually recovers to its daytime thickness within a few hours after
eye opening [422,423,425–429]. A contact lens barrier can also induce
corneal swelling. There is a direct linear relationship between corneal
hydration and thickness [430,431]. Therefore, corneal swelling is often
used to determine the level of oxygen supply through a contact lens
[407,432].
Assuming an average of 4 % overnight central corneal swelling
without lens wear in their original study, a minimum Dk/t criterion of
87 Dk/t units was established to avoid lens-induced overnight corneal
swelling in overnight wear [433]. Although a higher lens trans-
missibility requirement of at least 125 Dk/t units was reported after
updating the assumption of no-lens overnight swelling to 3 % [434].
However, based on clinical studies with SiHy lenses, even at higher lens
Dk/t levels of 175 [428] and 211 [410] Dk/t units, closed-eye lens-in-
duced corneal swelling could not be eliminated.
It was also suggested that 24 Dk/t units was needed to prevent
average central corneal swelling in daily wear [433]. This criterion was
re-evaluated in a more recent study and determined to be 19.8 and 32.6
Dk/t units, respectively, to avoid average central and peripheral corneal
swelling in soft lens daily wear [435]. The results of current short-term
studies suggest expecting an average minimal ocular physiological
impact in open-eye wear with a minimum central Dk/t ~25 units and
peripheral Dk/t of ~11 units [436,437]. It is noteworthy that the sug-
gested minimum Dk/t values for closed or open-eye lens wear can only
predict the population average corneal swelling values and are inher-
ently incapable of reecting individual Dk/t requirements in practice
[408].
There is a greater degree of swelling in the posterior cornea [438]
compared to its anterior region [439]. Differential corneal swelling is
supported by the relevant physiological [440,441], physical [439,442,
443] and ultrastructural [414,444–446] differences between stromal
anterior and posterior properties. This is in line with the reported [438]
higher water content of the mammalian posterior than anterior stroma
[447] attributed to higher ratio [448] of keratan sulphate, a more hy-
drophilic glycosaminoglycan [449], in the posterior stroma compared to
higher ratio of dermatan sulphate, a less hydrophilic glycosaminoglycan
in the anterior stroma. In this process, stromal collagen brils do not
have the capability to absorb water. They are only being more separated
because of the expansion of their surrounding ground substance in direct
relation to the hypoxia. This can lead to increased light scattering that
may affect corneal transparency.
Corneal transparency depends on the precise ultrastructure of the
corneal stroma, which remains steady under aerobic conditions [446,
450]. In the presence of sufcient oxygen, the corneal stroma can stay at
a constant level of 78 % hydration (deturgescence), ensuring trans-
parency [451,452]. Stromal light scatter occurs because of increased
distances and decreased uniformity of the collagen brils in the
oedematous stroma [412]. Intense light scattering was reported with
slight swelling of the anterior stroma, but relatively slight light scat-
tering has been observed with a higher degree of posterior stromal
swelling [442]. The stromal haze may occur as a result of an increased
amount of back scattered light from the anterior stroma [453]. There-
fore, the haze is more likely to occur with higher levels of corneal
swelling (>15 %), for example after closed-eye wear of a low Dk/t lens
and/or in high-swellers. However, haze is more commonly seen in
corneal pathological conditions (e.g. Fuchs’ dystrophy). Corneal haze
can clinically be measured with customised slit-lamp biomicroscopy,
confocal microscopy or using a Scheimpflug device [453].
Stromal striae and folds are two important short-term clinical indices
of corneal swelling that are more commonly seen with low Dk/t
hydrogel lenses and especially after closed-eye lens wear [454,455].
Striae and folds are reported at swelling levels as low as ~4 and ~7 %,
respectively [456]. A useful clinical tool for estimating the magnitude of
corneal swelling was devised using the correlation between the number
of striae or folds to the level of the observed corneal swelling in the study
[457]. Striae and folds gradually disappear as a result of stromal
deswelling after removal of hypoxic stress. Striae are clinically seen as
vertical lines in the posterior stroma because of increased uid separa-
tion of the posterior stromal brils due to posterior stromal swelling.
Folds are seen in the posterior corneal surface as a result of buckling/-
attening of the posterior limiting lamina from further increase in the
posterior stromal swelling as the stroma cannot expand laterally. Striae
and folds of the swollen posterior stroma are reported to be visible in
different angular directions, including horizontally, using confocal mi-
croscopy [458]. Results from a clinical study suggested signicantly less
attening of the posterior corneal surface with a SiHy lens (lotralcon A)
compared to a hydrogel lens (etalcon A) after one week of overnight
wear [459]. There was less posterior corneal attening with the
hydrogel lens in their study compared to an initial report from another
group who examined 3 h closed-eye wear of a thick hydrogel and a
PMMA contact lens, respectively [460]. This is in line with lower levels
of corneal swelling in their study because they used lenses of higher Dk/t
in overnight wear and examined corneal swelling and posterior curva-
ture later in the day (instead of immediately after eye opening in the
initial 3 h closed-eye study). Although a more recent open-eye study
[461] measured posterior corneal steepening with a hydrogel toric lens
in daily wear this was attributed to the regional pattern of corneal
swelling in this study showing higher swelling in the corneal periphery
than the centre because of lower oxygen transmissibility in the thicker
peripheral stabilization zones of the lens. Stromal striae and folds are
less frequently expected with daily wear of hydrogel or with overnight
wear of SiHy lenses. However, they can still occur in those with high
levels of swelling [408]. Stromal striae were 4 times less frequent with
overnight wear of a SiHy lens (balalcon A) compared to overnight wear
of a hydrogel lens (etalcon A) in a 12-month study [462].
4.2.3. Thinning
Early studies revealed an asymptomatic progressive corneal thinning
phenomenon with overnight wear of hydrogel lenses [463,464]. A
landmark 5-year study [309] of unilateral soft lens overnight wear
showed that, 7 days after the discontinuation of lens wear (recovery
period of the chronic swelling), the average stroma was ~11 microns or
2.3 % thinner than the baseline (~2 microns thinning/year). This
nding was attributed to the possible effects of the chronic stromal
swelling on morphology and/or the function of stromal keratocytes
thereby reducing their ability for synthesis of the stromal components
and/or to the possible effects of hypoxia-induced acidosis on breaking
down the components of the stromal grand substance [309]. However,
similar progressive thinning effects were also reported in daily wear of
hydrogel and rigid corneal lenses, as well as in overnight wear of SiHy
lenses [465,466].
A novel study [467] using confocal microscopy investigated the ef-
fect of 6-month overnight wear on the stromal keratocyte density in
neophytes where subjects wore a hydrogel lens (etalcon A) in one eye
and a SiHy lens (balalcon A) in the other eye. They found that the
posterior stromal keratocyte density was reduced in both eyes equally,
independent of lens oxygen transmissibility [467]. Therefore, they
concluded that the reduction of the keratocyte density in overnight wear
was not dependent on lens-induced hypoxia and/or swelling [467].
Based on these results they suggested a mechanical aetiology for the loss
of keratocytes from the physical presence of the lens on the cornea
[467].
In a further investigation in this regard, a study [468] found that, in a
group of neophyte subjects, keratocyte densities were lower in the SiHy
and rigid corneal lens-wearing eyes compared to their contralateral
controls, despite similar levels of anoxia-induced corneal swelling for 2 h
in the lens-wearing and control eyes. They also found higher levels of
tear inammatory markers after rubbing the no-lens eyes compared to
their contralateral controls in the nal part of their experiment. These
ndings led them to hypothesise that “the mechanical stimulation of the
corneal surface, due to the physical presence of a contact lens, induces
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207
the release of inammatory mediators that cause keratocyte dysgenesis
or apoptosis” [468].
A 12-month study of 30 days of overnight wear [469] found no
signicant differences in corneal thickness and in overall stromal kera-
tocyte density among the SiHy group, the rigid corneal group and
non-wearers. However, some inammatory markers in the tear lm of
the lens-wearing groups were higher than in the control group; specif-
ically, higher concentrations of epidermal growth factor were found in
wearers of both SiHy and rigid corneal lens wearers compared to
non-wearing controls whereas interleukin-8 was shown to be increased
in rigid corneal lens wearers only.
A more recent 6-month daily wear study found a greater decrease in
the overall keratocyte density in hydrogel than in rigid corneal lens
wearers [470]. Also, the decrease found in each group was higher than
their neophyte counterparts. They attributed the higher loss of kerato-
cytes in the hydrogel group to a contribution from higher stromal hyp-
oxic stress in hydrogel compared to rigid corneal lens wear. However,
they found no changes in the corneal thickness of the neophyte
lens-wearing groups during the 6- month study period.
Current knowledge on the aetiology and mechanisms of the stromal
thinning is still inconclusive and requires further research. Contact lens-
induced stromal thinning may affect the integrity of the cornea in
extreme cases. Also, progressive loss of corneal thickness in long-term
contact lens wearers could be a point of concern for suitability for
future refractive surgery.
4.3. Endothelium
4.3.1. Polymegethism and pleomorphism
The endothelium is the most posterior layer of the cornea and is
formed by a monolayer of differentiated epithelial cells. The primary
role of the endothelium is as part of the homeostatic mechanism of
maintaining a balanced water content in the corneal stroma, which
ensures corneal transparency [205]. Metabolic ion pumps within the
cells promote a shift in solute concentration between the corneal stroma
and the anterior chamber and water moves along the concentration
gradient in response and out of the stroma [471].
At birth, the cells are evenly distributed across the posterior corneal
surface and take a polyhedral shape that is most efcient in achieving
full coverage [205]. This produces a typical hexagonal cell shape, which
is found in 70–80 % of cells. Endothelial cell density averages 3100
(2700–3500) cells/mm
2
in children and reduces with age to approxi-
mately 2200 (1000–3000) cells/mm
2
by the age of 80 years (a reduction
rate of c.0.25 % / year) [472–475]. A minimum endothelial cell density
of 400–700 cells/mm
2
is thought to be necessary to maintain adequate
endothelial function and corneal transparency, but an endothelial cell
density between 1000–2000 cells/mm
2
is susceptible to corneal
decompensation [476]. The gradual reduction in endothelial cell density
is due to physiological attrition in the cell numbers and to the absence of
cell replication, an effect thought to be due to contact inhibition be-
tween the cells [477,478]. This contact inhibition also encourages cells
to spread to maintain contact with neighbouring cells, especially
following death of a neighbouring cell. It is important to compare any
changes observed from contact lens wear with these physiological
changes that occur with age.
As the cells decrease in number, the remaining cells spread out to
cover the gaps. Polymegethism describes the appearance of the corneal
endothelium where the usual consistency of cell size is lost. At the same
time, the cells lose their hexagonal regularity. This is called pleomor-
phism, which describes the increase in cell shape variation [479]. Both
phenomena have been shown to increase with age [480].
As a metabolically-active cell layer, the endothelium is affected by
any reduction in available oxygen supplied through the cornea from the
atmosphere [415,481]. This happens physiologically with eye closure
during sleep, resulting in a small amount of overnight corneal swelling
(oedema) due to the impaired oxygen supply to the endothelium [429].
The swelling rapidly decreases upon eye opening. In contact lens wear,
this physiological effect can be articially-induced with both rigid
corneal and soft contact lenses of low Dk/t, producing central corneal
oedema [482–485]. The low Dk/t also creates hypoxic stress to the
endothelial cells, promoting increased cell death as a result of the
chronic reduction in oxygen supply to the endothelium, in combination
with the effect of contact lens-induced pH changes [486]. The cell death
leads to a reduced endothelial cell density and increased polymegethism
and pleomorphism [487,488]. An increased effect is observed with
increasing lens wear experience [489]; a short lens wear experience does
not produce a signicant effect.
With modern lens materials of higher Dk/t, these effects are no
longer a common feature of contact lens wear [490–493]. However,
when low Dk/t lenses must be used, careful monitoring of the corneal
endothelium should be made.
4.3.2. Bedewing
Clusters of oedematous droplets or leucocytes deposited on the sur-
face of the corneal endothelium were rst reported in chronically
intolerant PMMA contact lens wearers in 1979 [494]. They proposed
that the droplets were composed of inammatory cells whose release
was stimulated by hypoxic stress caused by over-wear of low Dk/t len-
ses. The ‘precipitates’ were observed on the endothelium in the area of
the inferior pupil margin at high magnication and the phenomenon
was termed ‘endothelial bedewing’. The authors noted that management
with low Dk/t soft lenses had mixed results. However, endothelial
bedewing has been reported in 20 % of 70 non-contact lens wearers,
which supports much earlier work that bedewing is a physiological
feature [495]. The authors argued that the need to use slit-lamp mar-
ginal retro-illumination to view the bedewing (indicating that the
droplets had a higher refractive index than the surrounding aqueous
humour) supported the theory that the droplets contained inammatory
cells.
Bedewing is certainly a physiological phenomenon in a non-lens
wearing eye and may be associated with hypoxic stress in low Dk/t
lens wear. The main associated symptom is fogging of vision, which may
be sufcient to reduce lens wear time or cease lens wear. Best treatment
when observed in low Dk/t lens wearers is to re-t with a high Dk/t
contact lens material to avoid hypoxic stress, should that be the causa-
tive factor. However, even so, symptoms and endothelial bedewing may
continue.
The presence of inammatory cells in the anterior chamber is always
a sign of possible inammation, which may be of much more severe
aetiology and consequence. Contact lens ECPs should take care to
investigate and exclude other causes for the presence of inammatory
cells [496].
4.3.3. Blebs
The term endothelial blebs is used to describe apparent holes
observed in the regular mosaic of the corneal endothelium. They were
rst described in 1977 [497] and further explained by the confocal
microscopy work of Efron. The authors proposed that the apparent
absence of endothelial cells was due to oedematous swelling of the cell
causing light, reected from the ‘bulging’ posterior surface of the
affected endothelial cell, to be directed along a divergent path and away
from the axis of observation [498]. They can occur on any area of the
cornea covered by the contact lens [499].
Blebs are visible within minutes of contact lens application, with
their numbers peaking after 30 min and diminishing over the following
hours [487,497,500,501]. The phenomenon has been linked to localised
areas of endothelial swelling from acidosis caused by hypercapnia
(increased carbon dioxide) and hypoxia (reduced oxygen supply),
resulting from altered gas diffusion through the cornea [502]. This
impaired diffusion is particularly a feature of low Dk/t contact lens wear
[500,501] and can be provoked by exposing the corneal surface to a
reduced O
2
partial pressure to simulate hypercapnia or anoxia [502].
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208
Scleral lens wearers tted with a large post-lens tear reservoir (400
μ
m
vs 200
μ
m) also develop blebs, due to hypoxia at the corneal surface
[503]. Even with moderate to high Dk/t SiHy lenses, endothelial blebs
can form after one hour of eye closure [504]. In a closed eye situation,
the bleb response has been reported as being greater in Asian vs.
non-Asian eyes when wearing a low Dk/t soft contact lens [505].
Endothelial blebs should not be confused with endothelial guttae,
which are generally larger, are found at the central cornea and can be
associated with corneal disease, such as Fuchs’ dystrophy [478,506,
507]. Nor should they be confused with Hassall-Henle Bodies, which,
although benign, are found in the corneal periphery and are associated
with aging [205,507].
Endothelial bleb formation may be occurring more frequently than
expected, particularly in new contact lens wearers. Experienced lens
wearers do not show the same incidence level, but with additional
interference in oxygen supply, perhaps with prolonged eyelid closure,
bleb formation may be promoted. However, there is no known clinical
signicance and no lasting negative consequence to corneal health
[508]. The best clinical treatment is to use higher Dk/t materials and to
encourage lens wearers to avoid sleeping in their lenses.
4.4. Intentional changes to corneal thickness with orthokeratology
In modern ortho-k, rigid contact lenses are tted to deliberately alter
corneal curvature by a targeted amount during sleep to correct ame-
tropia on lens removal. The anterior corneal surface attens in response
to wear of ortho-k lenses designed to correct myopia [509–511] and
steepens in response to wear of ortho-k lenses designed to correct hy-
peropia [512,513]. While small change to posterior corneal curvature
[514] and asphericity [515] have been reported over the short term in
response to ortho-k for correcting myopia, over the longer term posterior
corneal curvature has been shown to remain unchanged [516,517].
Instead the corneal thickness prole alters to compensate the change to
anterior corneal curvature, with the central cornea thinning and para-
central cornea thickening in myopic ortho-k and the opposite prole of
central thickening and paracentral thinning in hyperopic ortho-k [518].
The changes to corneal thickness prole from myopic ortho-k, when
applied to Munnerlyn’s formula [519] used to calculate ablation depth
in laser refractive surgery, accounts for the degree of refractive change
that is achieved [510,520] and closely to that reported for hyperopic
ortho-k [518]. This afrms evidence that ortho-k lens wear only in-
uences anterior corneal curvature rather than bending the overall
cornea.
Using the optical pachometer, one study [521] reported an increase
to central stromal thickness immediately after lens removal following
overnight wear of both standard rigid corneal lenses and ortho-k,
consistent with that expected from closed eye wear contact lens
induced hypoxia [433]. Less central thickening was reported in the
ortho-k lens compared to standard rigid corneal lens wearing eyes,
however, leading the authors to suggest that myopic ortho-k suppresses
the central corneal oedema response from overnight rigid corneal lens
wear. Once overnight oedema has subsided there is general agreement
that the central corneal thinning response from myopic ortho-k is pre-
dominantly due to thinning of the central corneal epithelium [520,522,
523], however there is disagreement on which structure inuences the
reported paracentral thickening from myopic ortho-k lens wear, possibly
due to limitations of the instrument being used. Whilst one study [520]
reported paracentral stromal thickening alone using an optical pach-
ometer, another report [522] instead paracentral epithelial thickening
using time-domain optical coherence tomography. Another study [523]
reported thickening of both the paracentral stroma and epithelium using
spectral-domain optical coherence tomography. Central and paracentral
corneal thickness returns to baseline values within 3 days of dis-
continuing myopic ortho-k lens wear [522].
Only short-term changes to corneal thickness have been reported for
hyperopic ortho-k. One study [524] reported increased thickening
measured by time-domain optical coherence tomography of both the
central and paracentral epithelium after a single night of hyperopic
ortho-k lens wear, with greater central thickening with higher targeted
refractive change (+3.50D vs +1.50D). Instead, another study [518]
used optical pachymetry after 1 and 4 nights of ortho-k lens wear to
reveal central and paracentral stromal thickening consistent with the
expected overnight wear oedema response. However, when measure-
ments were repeated 8 h later to allow overnight oedema to subside,
only paracentral epithelial thinning was observed, leading the authors to
conclude that the anterior corneal steepening prole induced by hy-
peropic ortho-k was limited to change to the paracentral corneal
epithelium thickness alone. While it is not known whether changes to
corneal thickness induced by longer term wear of hyperopic ortho-k will
return to baseline after cessation of lens wear, it is reasonable to expect
that this would occur as in myopic ortho-k [522], given that it is only
alterations in posterior ortho-k lens curvature that differentiate the two
approaches and that corneal topography changes induced by 7 nights of
overnight hyperopic ortho-k lens wear in presbyopes return to baseline
within 1 week of cessation [525].
5. Ocular growth modication with contact lenses
5.1. Changes to axial length
Contact lens wear can have a marked impact on the axial growth of
the eye and there is increasing interest in slowing ocular growth in
children with contact lenses [526]. This is because there is mounting
evidence for the increasing frequency of myopia in many populations
around the world and across ethnicities. By 2050, it is predicted that
almost half of the world’s population - ve billion people - will be
myopic, with nearly one billion high myopes at serious risk of
myopia-related ocular pathology [527]. While high myopia is strongly
linked to higher risk of cataract, retinal detachment and myopic mac-
ulopathy, even lower levels of myopia are associated with increased
life-long risk of pathology compared to emmetropia [528]. Already,
increasing rates of vision impairment and blindness in the working age
population, due to myopic maculopathy, are evident in Asian countries
[529,530].
With recent understanding that even reducing nal myopia by 1D
over a lifetime reduces risk of myopic maculopathy by 40 % [531], there
is much scientic interest in slowing the progression of myopia in
children. Recently analyses have indicated that axial length bears a
strong relationship to risk of life-long vision impairment, with an axial
length of greater than 26 mm associated with a likely risk of vision
impairment across a lifetime of at least 25 % and over 90 % for eyes
longer than 30 mm [532]. Axial length is consistently correlated with
myopic refraction, although the refraction-to-axial-length ratio isn’t
consistent across age groups or with increasing axial length [533].
Despite this, due to the repeatability and incremental measurement
possible with axial length compared to myopic refraction, the former has
become the gold standard in assessing treatment efcacy for myopia
control in scientic studies [534]. Contact lens inuence on axial length
is therefore the focus in this review.
‘Myopia control’ is the terminology for any intervention which re-
duces the axial and refractive progression of childhood myopia, by
whatever mechanism and level of efcacy compared to a control [534].
Optical interventions for myopia control include both rigid corneal and
soft contact lens modalities. The appeal of an optical intervention is its
ability to both correct myopic ametropia as well as potentially slow its
progression as a monotherapy and thus far contact lens interventions
have performed with more consistent and statistically signicant ef-
cacy than spectacle lens interventions [535].
5.2. Single-vision contact lenses and myopia control
Studies investigating the effects of single-vision, full correction rigid
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209
corneal lenses and soft contact lenses on the progression of myopia have
demonstrated no statistically signicant efcacy [536–539]. In deter-
mining this lack of effect, rigid corneal lenses and soft contact lenses
have been compared to each other and to single-vision spectacle
corrections.
Standard-design rigid corneal lenses were rst purported to slow
myopia progression in the mid-1970’s [540] with subsequent studies in
the last 20 years both supporting [541] and refuting [537] this pre-
sumption. These studies suffered methodological limitations, most
notably very high drop-out rates of almost 50 %. Managing this with a
run-in adaptation period to rigid corneal lenses, the axial and refractive
myopia progression in 116 single-vision distance-corrected children,
aged 8–11 years, randomised to wear either rigid corneal lenses or soft
contact lenses was compared. Over the three year study, the rigid
corneal lens wearers’ myopia progressed by around 0.50D less, but the
soft contact lens wearers showed steepening of the steep corneal me-
ridian by 0.88 ±0.57D compared to 0.62 ±0.60D in the rigid corneal
lens wearers. With this different corneal steepening accounting for about
half of the refractive effect and no statistically signicant difference in
axial elongation, both single-vision contact lens correction types were
indicated as similar from a myopia control perspective [538].
A comparison of single vision distance soft contact lenses with
spectacles for their differential myopia control effect, in 484 children
aged 8–11 years, debunked the concern of ‘myopic creep’ (increasing
myopia) in soft contact lens wearers. Three years of full-time childhood
wear revealed no difference in either axial or refractive myopia pro-
gression between the groups. There was no measured change in steep
corneal meridian over time or difference between groups [539].
Subsequent contact lens myopia control studies have typically
employed single-vision distance soft contact lenses or spectacles as the
control group. Only one ortho-k study has utilised a daily wear rigid
corneal lens control, in a crossover design [542]. It is now readily
accepted by both scientic and clinical consensus that single-vision
distance corrections, of any form, do not reduce axial or refractive
myopia progression in children [543,544].
5.3. Impact of rigid corneal lenses on axial length and ocular growth in
myopia control
The evidence for overnight ortho-k rigid corneal lens wear to reduce
the excessive axial elongation seen in childhood myopia is relatively
new. Reports from 2005 [545] and 2009 [546] reported 47 % and 55 %
less axial elongation over 2 years of wear when compared to historical
controls. Several other two-year controlled trials have taken place since,
the results of which are summarised in Table 3. A novel cross-over study
design involving a daily wear, alignment t rigid corneal lenses worn in
one eye and overnight ortho-k worn on the contralateral eye demon-
strated a complete halt in myopic progression in the ortho-k treated eye
for both six-month phases [542]. Two meta-analyses of ortho-k studies
concurred in examining seven controlled trials over two years duration,
concluding that ortho-k reduced axial elongation by 0.27 mm over two
years (95 % CI 0.22 to 0.32 mm) [547,548].
The longest ortho-k intervention data reported is a retrospective
study of 203 eyes from 66 ortho-k wearers and 36 spectacle wearing
controls aged 7–17 years at baseline and with a mean follow up time of
6.32 ±0.15 years. Across the rst two years, the ortho-k group pro-
gressed 0.17 ±0.02D while the control group progressed 0.52 ±0.03D.
This statistically signicant difference was maintained from year-2-to-4
and year-4-to-6 of follow up, albeit reducing from a 0.35D difference in
the rst two years to a 0.19D difference in year-4-to-6. From year-6-to-8
of follow up, there was no statistically signicant difference between
groups [549].
5.3.1. Orthokeratology inuence on ocular component growth other than
axial length
Vitreous chamber depth changes in step with axial length changes in
ortho-k intervention studies, with a similar signicant reduction in
growth compared to historical controls [545,546]. Very similar vitreous
chamber depth and axial length changes were also found in another
study, however no comment was made on the contribution of vitreous
chamber depth to axial length changes [545]. Vitreous chamber depth
changes accounted for around 60 % of axial length changes and by
eliminating the effects of change in anterior chamber depth through
vitreous chamber depth quantication, this conrmed the slowing of
eye growth with ortho-k wear [546]. The latter authors measured
additional ocular component changes in their study, nding that change
in anterior chamber depth over time was not statistically signicant in
ortho-k wearers, but a small increase of 0.06 mm per year in soft contact
lens wearers was noted. Crystalline lens thickness changes were not
different between the groups [546]. Ortho-k can also impact corneal
nerves as detailed above in Section 4.1.6.
The sum of the available literature indicates that ortho-k consistently
reduces myopia progression by around 45 % compared to single vision
spectacle and contact lens corrections over several two-year studies,
with a statistically signicant myopia control effect likely maintained
over several years of wear.
5.4. Impact of soft contact lenses on axial length and ocular growth in
myopia control
While ortho-k rigid corneal lenses currently enjoy the largest scien-
tic volume of evidence for myopia control efcacy [547,548], the
Table 3
Summary of results for key myopia control intervention studies evaluating ortho-k. Adjusted means are presented with (standard deviations) as detailed in each paper.
N =total participants at nal analysis visit; Ortho-k =orthokeratology; SV =single vision; SCL =soft contact lens. Studies 1 and 2 measured axial length using A-scan
ultrasound; studies 3-7 employed interferometry measurement (IOL Master in all cases).
Axial length change (mm) Efcacy for reducing axial
elongation
Intervention study Control intervention N (total) Duration (years) Ortho-k wearing group Control group Per year (mm) By%
Cho et al. 2005 [545] SV spectacles (historical) 70 2 0.29 (0.27) 0.54 (0.27) 0.13 46
Walline et al. 2009 [546] SV SCLs (historical) 56 2 0.25 (0.19) 0.57 (0.23) 0.16 56
Kakita et al. 2011 [550] SV spectacles 92 2 0.39 (0.27) 0.61 (0.24) 0.11 36
Cho & Cheung 2012 [551] SV spectacles 78 2 0.36 (0.24) 0.63 (0.26) 0.14 43
Santodomingo 2012 [552] SV spectacles 53 2 0.47 (0.23) 0.69 (0.27) 0.11 32
Charm 2013 [553] SV spectacles 28 2 0.19 (0.21) 0.51 (0.32) 63
Chen 2013 [554] SV spectacles 58 2 0.31 (0.27) 0.64 (0.31) 52
META-ANALYSES Absolute difference in progression between treatment
and control groups (mm)
Sun et al. 2015 [547] 7 studies 2 0.27 (95 % CI 0.22, 0.32) 0.14 45
Si et al. 2015 [548] 7 studies 2 0.26 (95 % CI 0.21, 0.31) 0.13 45
P.B. Morgan et al.
Contact Lens and Anterior Eye 44 (2021) 192–219
210
largest volume of recent innovations in contact lens myopia control are
in various designs of soft multifocal designs. The terminology ‘multi-
focal’ is here used to denote any ‘simultaneous image’ optical design
where dioptric power varies either smoothly or discontinuously with
zonal radius [555].
Studies investigating bifocal and multifocal spectacles for myopia
control in children showed limited success in the late 20th and early 21
st century [535]. The rst publications investigating multifocal soft
contact lenses for myopia control employed designs originally designed
for presbyopia. An abstract [556] and a twin study case report [557]
investigated a commercially available multi-zone simultaneous vision
design, being distance centred with alternating near and distance zones.
The results indicated a halting of myopia progression in the twin case
report and a reduction of progression by around 2/3rds in the abstract of
a one-year randomised clinical trial. Another commercially-available,
distance-centred, continuous aspheric design was demonstrated to
reduce refractive progression by 50 % and axial elongation by 29 %
compared to single vision soft contact lenses in a two year study [558]. A
prospective, randomized controlled trial on this same lens design
revealed a 36 % reduction of axial elongation in wear of a +2.50 Add,
with no signicant effect of the +1.50 Add, both in comparison to a
single vision soft contact lens control [559].
Clinical trial results for the two rst myopia-control specic designed
soft contact lenses were reported in 2011. The rst, a dual-focus alter-
nating design, showed promise in a cross-over trial of two 10-month
phases in 2011 [560]. The second [561] is reported in Table 4, along
with several more controlled trials of at least one-year duration which
quantied axial length. Most of these studies employed novel multifocal
soft contact lenses designs rather than commercially-available presby-
opic designs.
5.4.1. Multifocal contact lens inuence on ocular component growth other
than axial length
In studies where other ocular biometry measures were taken, there
are variable outcomes. A reduction in vitreous chamber depth growth
was observed in multifocal soft contact lenses wearers, compared to a
control group, that was similar in magnitude to the axial length change.
Lens thickness did not change; anterior chamber depth increased in the
multifocal soft contact lenses group, but they were statistically different
at baseline and similar at the end of the study [558]. A novel design
multifocal soft contact lenses did not produce a statistically signicant
alteration in anterior chamber depth, crystalline lens thickness or vit-
reous chamber depth [564]. Another study echoed this result with no
statistically signicant changes in corneal curvature or anterior chamber
depth in their study [565]. Taken in sum, these appear similar to ortho-k
results in that generally vitreous chamber depth and axial length are the
key components altered in myopia control.
5.5. Potential mechanisms of contact lens myopia control
The mechanism of how ortho-k reduces the rate of axial elongation in
childhood progressive myopia is not known. The main theory involves
peripheral retinal input, involving differential optical stimulus between
localised peripheral and central retinal signals creating a ‘slow down’
signal for retinal growth, as has been shown in numerous animal models.
However there is conjecture that shifts in relative peripheral refraction
correlate with myopia progression in humans [570,571]. Ortho-k and
multifocal soft contact lenses both shift relative peripheral refraction
towards more myopia – although not equivalently [572] – and both
show statistically signicant myopia control efcacy. It has also been
demonstrated that when viewing a near target in multifocal soft contact
lenses wear and foveal hyperopic defocus is experienced, peripheral
defocus instead tended towards emmetropia [573].
Similarly, on-axis simultaneous defocus occurs through the depth of
focus created by ortho-k or multifocal soft contact lenses, due to pro-
nounced shifts in spherical aberration [574,575]. Changing spherical
aberration in turn changes accommodative demand at near [576,577]
and a single study for each of ortho-k [578] and multifocal soft contact
lenses [579] have indicated a relationship between improved accom-
modative response and a better myopia control effect in myopia control
contact lens wear.
Future research in myopia controlling contact lenses will likely
further explore these mechanisms and their specic inuence in indi-
vidual myopes, ideally leading to improved efcacy across all wearers.
Table 4
Summary of results for myopia control intervention studies evaluating multifocal soft contact lens designs. Adjusted means are presented with (standard deviations) as
detailed in each paper. N =total participants at nal analysis visit; MFCL =multifocal soft contact lens; SV =single vision; SCL =soft contact lens. Studies 2 and 4
measured axial length using A-scan ultrasound; the rest employed interferometry measurement (IOL Master in all cases except study 9 which employed the LenStar
900). Studies 2, 6 and 10 employed a commercially-available presbyopic MFCL design, while the rest employed myopia control specic designs.
Axial length change (mm) Efcacy for reducing
axial elongation
Intervention study Control intervention N
(total)
Duration
(years)
MFCL wearing group Control
group
Per year
(mm)
By%
1 Sankaridurg et al. 2011 [561] SV spectacles (non-
concurrent)
82 1 0.24 (0.17) 0.39 (0.19) 0.15 38
2 Walline et al. 2013 [558] SV SCLs (historical) 54 2 0.29 (0.03) 0.41 (0.03) 0.06 29
3 Lam et al. 2014 [562] SV SCLs 128 2 0.25 (0.23) 0.37 (0.24) 0.06 32
4 Fujikado et al. 2014 [563] SV SCLs 24 1 0.09 (0.08) 0.17 (0.08) 0.08 47
5 Paune et al. 2015 [564] SV spectacles 40 2 0.38 (0.21) 0.52 (0.22) 0.07 27
6 Aller et al. 2016 [565] SV SCLs 78 1 0.05 (0.14) 0.24 (0.17) 0.19 79
7 Cheng et al. 2016 [566] SV SCLs 106 1 0.23 (0.15) 0.37 (0.16) 0.14 38
8 Chamberlain et al. 2019 [567] SV SCLs 109 3 0.30 (0.27) 0.62 (0.30) 0.11 52
9 Sankaridurg et al. 2019 [568] (4 designs tested) SV SCLs 234 2 0.41 to 0.46 (across 4
designs)
0.58 (0.27) 0.06 to
0.09
22−32
10 Walline et al. 2020 [559] (results given for high add
power MFCL +2.50)
SV SCLs 292 3 0.42 (95 % CI 0.38,
0.47)
0.66 0.08 36
META-ANALYSIS (does not include 2019 & 2020 papers) Absolute difference in progression
between treatment and control
groups (mm)
Li et al. 2017 [569] 7
studies
1 0.27 (95 % CI 0.22, 0.32) 0.135 30−50
P.B. Morgan et al.
Contact Lens and Anterior Eye 44 (2021) 192–219
211
6. Summary and future directions
This report has provided a contemporary overview on the various
changes to ocular physiology and anatomy which are encountered
during contact lens wear. Some consequences of contact lens wear can
now be considered as largely of historic interest in many countries only
as modern lens designs and materials mean such changes are rarely seen.
These include the signs of corneal hypoxia (including epithelial micro-
cysts, stromal neovascularisation and endothelial polymegethism) – the
presence of which largely guided advances in contact lens materials over
the past 50 years – and changes to the palpebral conjunctiva which can
be readily improved with more frequent contact lens replacement as is
now commonplace. Although, overall only 23 % of ts are soft hydrogel
lenses, countries such as Denmark, Japan and China are tting
approximately equal numbers of soft hydrogel and SiHy lenses and
Taiwan ts more soft hydrogel lenses than SiHy [580].
Some changes of the eye to contact lens wear have remained stub-
bornly intransigent to improvements in both lens materials and designs.
Bulbar conjunctival hyperaemia and cellular changes at the ocular sur-
face visualised by the use of sodium uorescein and lissamine green are
sensitive and somewhat non-specic indicators of the physiological
impact of lens wear. Monitoring such changes during contact lens wear
is likely to be a requirement for ECPs into the foreseeable future.
A number of identied changes have received relatively little
attention in recent times and their signicance and/or clinical man-
agement is not well understood. These include blinking (which has
received very limited attention in the literature) and LIPCOF which is
certainly a potentially important observation and may help further un-
derstanding of the mechanical interaction between contact lens and
ocular surface. Emerging from this small group are LWE, interactions
between lenses and the Meibomian glands, and contact lens-induced
changes to ocular surface sensitivity which have received increasing
levels of attention and, given their possible relationship with contact
lens discomfort, seem likely to be areas of strong research interest in the
coming years.
This report has highlighted three particular areas of interest which
may transform the contact lens eld in future years, in rather different
ways. The rst two relate to the programmed alteration of ocular di-
mensions as seen in ortho-k and myopia control. These forms of
refractive manipulation provide distinct reasons for the use of contact
lenses beyond the more traditional refractive correction and more niche
medical usage. The third area is the growing level of interest and
expertise in the assessment of the sub-clinical inammatory response to
contact lens wear. Insights provided by techniques such as in vivo
confocal microscopy have been able to demonstrate features of the
immunological response to contact lens wear and these is reason to
believe that such research may be key to revealing the mechanisms
behind various physiological responses, adverse events and that cause of
many drop-outs: contact lens discomfort.
Acknowledgement
The CLEAR initiative was facilitated by the BCLA, with nancial
support by way of Educational Grants for collaboration, publication and
dissemination provided by Alcon and CooperVision.
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