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Contact Lens and Anterior Eye xxx (xxxx) xxx
Please cite this article as: Jacinto Santodomingo-Rubido, Contact Lens and Anterior Eye, https://doi.org/10.1016/j.clae.2021.101559
1367-0484/© 2021 The Authors. Published by Elsevier Ltd on behalf of British Contact Lens Association. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Keratoconus: An updated review
Jacinto Santodomingo-Rubido
a
,
*
, Gonzalo Carracedo
b
, Asaki Suzaki
c
, Cesar Villa-Collar
d
,
Stephen J. Vincent
e
, James S. Wolffsohn
f
a
Global R&D, Menicon Co. Ltd, Nagoya, Japan
b
Department of Optometry and Vision, Faculty of Optics and Optometry, Universidad Complutense de Madrid, Madrid, Spain
c
Clinical Research and Development Center, Menicon Co., Ltd., Nagoya, Japan
d
Department of Pharmacy, Biotechnology, Nutrition, Optics and Optometry, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, Madrid, Spain
e
Contact Lens and Visual Optics Laboratory, School of Optometry and Vision Science, Centre for Vision and Eye Research, Queensland University of Technology,
Brisbane, Australia
f
School of optometry, Health and Life Sciences, Aston University, Birmingham B4 7ET, United Kingdom
ARTICLE INFO
Keywords:
Epidemiology
Detection
Classication
Histopathology
Aetiology
Management
ABSTRACT
Keratoconus is a bilateral and asymmetric disease which results in progressive thinning and steeping of the
cornea leading to irregular astigmatism and decreased visual acuity. Traditionally, the condition has been
described as a noninammatory disease; however, more recently it has been associated with ocular inamma-
tion. Keratoconus normally develops in the second and third decades of life and progresses until the fourth
decade. The condition affects all ethnicities and both sexes. The prevalence and incidence rates of keratoconus
have been estimated to be between 0.2 and 4,790 per 100,000 persons and 1.5 and 25 cases per 100,000 per-
sons/year, respectively, with highest rates typically occurring in 20- to 30-year-olds and Middle Eastern and
Asian ethnicities. Progressive stromal thinning, rupture of the anterior limiting membrane, and subsequent
ectasia of the central/paracentral cornea are the most commonly observed histopathological ndings. A family
history of keratoconus, eye rubbing, eczema, asthma, and allergy are risk factors for developing keratoconus.
Detecting keratoconus in its earliest stages remains a challenge. Corneal topography is the primary diagnostic
tool for keratoconus detection. In incipient cases, however, the use of a single parameter to diagnose keratoconus
is insufcient, and in addition to corneal topography, corneal pachymetry and higher order aberration data are
now commonly used. Keratoconus severity and progression may be classied based on morphological features
and disease evolution, ocular signs, and index-based systems. Keratoconus treatment varies depending on disease
severity and progression. Mild cases are typically treated with spectacles, moderate cases with contact lenses,
while severe cases that cannot be managed with scleral contact lenses may require corneal surgery. Mild to
moderate cases of progressive keratoconus may also be treated surgically, most commonly with corneal cross-
linking. This article provides an updated review on the denition, epidemiology, histopathology, aetiology
and pathogenesis, clinical features, detection, classication, and management and treatment strategies for
keratoconus.
1. Introduction
In 2010, a comprehensive review of keratoconus was published in
Contact Lens & Anterior Eye, which became the most cited article of the
journal to date [1]. This article reviewed the denition, epidemiology,
clinical features, classication, histopathology, aetiology and patho-
genesis, and management and treatment strategies for keratoconus.
Over the last decade, numerous epidemiological studies have been
conducted allowing for better estimates of the incidence and prevalence
of keratoconus. Many other studies have also contributed to a better
understanding of keratoconus, particularly due to the adoption of new
technologies for imaging the human cornea. Improvements in corneal
topography and the advent of corneal tomography has increased the
ability of eye care practitioners to diagnose corneal ectasia at a much
earlier stage than was previously possible. These imaging techniques,
along with the increased use of wavefront aberrometry, have allowed
better characterisation of the optical, anatomical, biomechanical and
histopathological changes associated with keratoconus [2]. The latter,
* Corresponding author at: Global R&D, Menicon Co. Ltd, Nagoya, Japan.
E-mail address: j.santodomingo@menicon.com (J. Santodomingo-Rubido).
Contents lists available at ScienceDirect
Contact Lens and Anterior Eye
journal homepage: www.elsevier.com/locate/clae
https://doi.org/10.1016/j.clae.2021.101559
Received 19 August 2021; Received in revised form 23 November 2021; Accepted 12 December 2021
Contact Lens and Anterior Eye xxx (xxxx) xxx
2
together with recent developments of contact lens and surgical options
for keratoconus, have ultimately lead to improved clinical management
[3,4]. The present article provides an updated review of keratoconus
and expands on areas of recently acquired knowledge. In preparing this
review, each author was given the lead to prepare one or more of the
different sections or subsections covered in the review, although some
sections/subsections had contributions from other authors. Adopting a
search strategy using the keywords “keratoconus” and “denition” or
“epidemiology” or “histopathology” or “aetiology” or “pathogenesis” or
“features” or “clinical features” or “detection” or “classication” or
“management” or “treatment”, articles were retrieved from two search
databases (i.e., PubMed and Embase). Other searches were also made
using different combinations of key terms at the authors’ discretion.
Articles available in the database from their inception to between
January and July 2021 were included, with the cut-off date for the
search for articles being freely chosen by each individual author,
although other articles were added to this review at a later date as part of
the review process. Pertinent articles for each section were identied;
abstracts reviewed; and relevant papers read in full, along with addi-
tional relevant papers identied in the reference lists. When several
research papers reporting on similar ndings appeared during the
literature search, the most updated article(s) was typically used for
review.
2. Denition
The word keratoconus derives from the Greek words ‘k´
eras’, mean-
ing cornea, and ‘c¯
onus’, meaning cone, which together means ‘cone-
shaped’ cornea. Although the presentation, clinical features, and
refractive consequences of keratoconus were described with reasonable
accuracy by a few European oculists in the early 18th and 19th cen-
turies, it was not until 1854 that John Nottingham provided a compre-
hensive understanding of what is currently understood as keratoconus,
which allowed the condition to be distinguished from other corneal
ectasias [5].
Today, keratoconus is considered a bilateral and asymmetric ocular
disease which results in progressive thinning and steepening of the
cornea leading to irregular astigmatism and decreased visual acuity
[6–8]. Corneal thinning occurs in the central or paracentral cornea, most
commonly infero-temporally [9]. Traditionally, keratoconus has been
described as a noninammatory disease [10,11]; however, several
studies have reported associations with signicant alterations in in-
ammatory mediators [12–16], indicating that keratoconic eyes often
experience some form of ocular inammation [12,17,18]. Although a
bilateral condition, one eye is typically more severely affected than the
other [19–23]. The condition affects all ethnicities and both sexes. It is
commonly an isolated ocular condition, but sometimes coexists with
other ocular and systemic diseases [10].
3. Epidemiology
Determining the prevalence and incidence of a particular disease is
critical, because it can aid in identifying potential underlying causative
factors, assessing methods to prevent, monitor, and treat the condition
[24], and formulate and evaluate healthcare policies [25]. The preva-
lence of a condition is dened as ‘the part (percentage or proportion) of a
dened population affected by a particular medical disorder at a given
point in time, or over a specied period of time’ while the incidence rate
represents ‘the frequency of new occurrences of a medical disorder in the
studied population at risk of the medical disorder arising in a given
period of time’ [25]. The prevalence of a condition is assessed in a cross-
sectional sample, and the incidence is assessed employing longitudinal
study designs [26].
Early studies in which the diagnosis of keratoconus was based upon
the scissor movement observed during retinoscopy, irregular kera-
tometry mires, and the subjective assessment of clinical signs were more
likely to identify advanced keratoconus. However, the widespread use of
corneal topography, and more recently corneal tomography, together
with built-in software to aid in keratoconus detection has facilitated the
ability to diagnose patients with keratoconus even at incipient stages of
the disease, ultimately leading to greater rates of keratoconus being
reported in studies conducted in recent years (Table 1).
Epidemiological studies indicate substantial global variation as the
prevalence and incidence rates of keratoconus have been estimated to be
between 0.2 and 4,790 per 100,000 persons and 1.5 and 25 per 100,000
persons/year, respectively (Table 1; Figs. 1 and 2), with the highest
prevalence and incidence rates typically occurring in 20 to 30 year olds
[27–29]. Differences between studies have been attributed to differ-
ences in geographic location and ethnicity, the denition of keratoconus
and diagnostic criteria, study design, and the age and cohort of subjects
assessed (Table 1; Figs. 1 and 2). Furthermore, fair comparisons between
studies of keratoconus are difcult to make due to differences in the
criteria used for dening the numerators and denominators used for
calculating the incidence and prevalence rates [25].
In hospital/clinic-based studies, a high prevalence of keratoconus
has been reported in the Middle East with rates up to 4,790 per 100,000
in Saudi Arabia adolescents [53] compared to 0.2 to 0.4 per 100,000 in
Russia [34] (Table 1 and Fig. 1). Incidence rates of keratoconus from
hospital/clinic studies have been reported to be as low as 1.5 per
100,000 persons/year in Finland [32] to over 20 per 100,000 persons/
year in Asian and Middle East populations [35,37,38] (Table 1 and
Fig. 2). However, hospital/clinic-based epidemiological data should be
interpreted with caution since the true prevalence of keratoconus within
the wider population may be underestimated. Patients with keratoconus
presenting to a hospital/clinic are likely to be those who are symp-
tomatic and with access to health care, thus early forms of the disease
might not be detected. Furthermore, these studies do not take into ac-
count the number of patients treated outside of the hospital/clinic(s)
where the study is conducted [29]. Therefore, population-based epide-
miological studies provide a more representative estimate of the true
prevalence and incidence of keratoconus in the general population. In
population based studies, the prevalence of keratoconus has been re-
ported to be as low as 4 in Denmark [54] and up to 22 per 100,000
persons in the Middle East [45] (Table 1 and Fig. 1), and the incidence of
keratoconus has been reported to be as low as 3.6 in Denmark [54], up to
22.3 per 100,000 persons/year in Iran [45] (Table 1 and Fig. 2).
The prevalence and incidence of keratoconus varies with regard to
ethnicity and geographical location (Table 1 and Figs. 1 and 2). Studies
of predominantly Caucasian populations report prevalence rates under
1,000 per 100,000 persons, whereas studies conducted in Asian and
Middle East populations report prevalence rates between 1,500 and
5,000 per 100,000 persons. Similarly, the incidence of keratoconus in
Caucasians appears to be around 2 to 4 per 100,000 persons/year
compared to around 20 per 100,000 persons/year in Asia and the Middle
East. Two studies conducted in the United Kingdom found a signicantly
higher prevalence and incidence of keratoconus in Asians (primarily
Indian and Pakistani) compared to Caucasians [35,37] which might
indicate that such differences are related to ethnicity rather than
geographic location. Similarly, a more recent study of high school stu-
dents in New Zealand found a signicantly higher prevalence of kera-
toconus in Maori islanders in comparison with a predominantly
Caucasian cohort [55].
Although some studies have reported greater rates of keratoconus in
males, many studies have found the opposite (or no signicant differ-
ence), which most likely indicates that keratoconus affects both sexes
similarly (Table 1).
4. Histopathology
All corneal layers have been reported to experience histopathological
changes in keratoconus, which are much more pronounced in the central
compared to the peripheral cornea; however, in early forms of the
J. Santodomingo-Rubido et al.
Contact Lens and Anterior Eye xxx (xxxx) xxx
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Table 1
Prevalence and incidence rates of keratoconus reported as per 100,000 persons and 100,000 person-years, respectively in studies conducted around the world. NA, not available;
a
Reported prevalence for denite
keratoconus cases only;
b
Asian are mostly Indian;
c
Asian are mostly Pakistani;
d
Prevalence recalculated based on number of subjects rather than number of eyes;
e
Corrected value provided by study author (personal
communication);
f
Population-based studies with claims health data from national or insurance registration.
Study Year Location Sample Size
(Catchment
Population/n◦
keratoconus)
Population
mean/median
Age [range]
(years)
Diagnostic criteria Study
Duration
(years)
Study Design Source Incidence
[95% CI]
Prevalence [95% CI] Male/
Female
ratio
Hofstetter [30] 1959 Indianapolis,
USA
13,395/16 eyes NA [1-78] Placido-disc keratoscopy 0.03 Prospective,
cross-sectional
Population NA 120 (0.12%) [NA]
a
0.22
Tanabe et al. [31] 1985 Japan 8,539,000/742
subjects
NA [25-29] NA 21 Retrospective,
cross-sectional
Population NA 9 (0.009%) [NA] 2.86
Ihalainen [32] 1986 Finland 260,000/75
patients
NA [15-69] Retinoscopy +
keratometry
20 Retrospective Hospital/clinic 1.5 30 (0.03%) [NA] 1.68
Kennedy et al. [8] 1986 Minnesota, USA Census data/64
subjects
25 [12-76] Retinoscopy +
keratometry
48 Retrospective Hospital/clinic 2.0 [NA] 54.5 (0.0545%) [NA] 1.2
Santiago et al. [33] 1995 France 670/18 subjects NA [18-22] Topography (power and
indices)
NA Prospective,
cross-sectional
Population
(Army recruits)
NA 750 (0.75%) [NA] NA
Gorskova and
Sevost’ianov [34]
1998 Urals, Russia NA NA NA NA NA Hospital/clinic NA 0.2–0.4
(0.0002–0.0004%)
[NA]
3
Pearson et al. [35] 2000 Midlands,
United
Kingdom
~900,000/271
patients for
incidence and 338
patients for
prevalence
NA [10-44] Diagnosis by
ophthalmologist
10 Retrospective Hospital/clinic Asian
b
=
19.6
[7.0–31.3]
White =4.5
[1.7–7.3]
Asian
b
=229
(0.229%) [NA]
White =57 (0.057%)
[NA]
Asian
b
=
1.5
Whites =
1.85
Ota et al[36] 2002 Tokyo, Japan 2,456,406 /220
patients
NA [15-34] NA 1 Retrospective,
longitudinal
Hospital/clinic 9 [NA] NA 2.31
Georgiou et al [37] 2004 United
Kingdom
176,774/74
patients
NA [13-36] History of progressive,
irregular, myopic
astigmatism, and clinical
signs
6 Retrospective,
longitudinal
Hospital/clinic Asian
c
=25
White =3.3
NA 2.52
Assiri et al. [38] 2005 Asir, Saudi
Arabia
654,163/125
patients
NA [6-28] Visual acuity, family
history, keratometry,
retinoscopy,
ophthalmoscopy, and
clinical signs
1 Prospective Hospital/clinic 20 [NA] NA 0.69
Jonas et al [39] 2009 Maharashtra,
India
4,677/128 subjects Entire sample:
49.5 ±13.4 [30
to 100]
Keratometry >48D NA Prospective,
cross-sectional
Population NA 2737 (2.737%)
[10.3–36.7]
d
0.29
Ljubic [40] 2009 Skope,
Macedonia
2 million/136
e
subjects
Entire sample:
NA
Keratoconus
cohort: 26.81 ±
1.25 [NA]
Keratometry ≥48D 8 Retrospective,
longitudinal
Hospital/clinic NA 6.8 (0.0068%) [NA] 1.13
Reeves et al. [41] 2009 USA 5% Medicare
beneciaries ≥65
years/1165
≥65 NA 5 Longitudinal,
retrospective,
cross-sectional
Population NA 17.5 (0.0175%) [NA] No
difference
Millodot et al. [42] 2011 Jerusalem,
Israel
981/23 subjects Entire sample:
24.4 ±5.7 [18-
54]
Keratoconus
cohort: NA
Topography (power,
pattern, and indices)
1.33 Prospective,
cross-sectional
Population
(college
students)
NA 2340 (2.340%)
[1400–3300]
2.28
Waked et al. [43] 2012 Beirut, Lebanon 92/3 Entire sample:
23.6 ±1[22-26]
Questionnaire +
Topography
0.33 Prospective,
cross-sectional
Hospital/clinic
(medical
students)
NA 3261 (3.261%) [NA] 1.43
Xu et al. [44] 2012 Beijing, China 3468/27 NA NA 0.17
(continued on next page)
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Table 1 (continued )
Study Year Location Sample Size
(Catchment
Population/n◦
keratoconus)
Population
mean/median
Age [range]
(years)
Diagnostic criteria Study
Duration
(years)
Study Design Source Incidence
[95% CI]
Prevalence [95% CI] Male/
Female
ratio
Entire sample:
64.6 ±9.8 [50-
92]
Keratoconus
cohort: 64.2 ±
11.3
Optical low-coherence
reectometry ≥48D
Prospective,
cross-sectional
Population
(subjects ≥50
years)
900 (0.9%)
[600–1200]
Ziaei et al [45] 2012 Yazd, Iran 990,818/536
subjects
Entire sample:
NA
Keratoconus
group: 25.7 ±9
Topography (pattern and
indices) +clinical
examination
1 Prospective Population 22.3
[19.5–25.4]
NA 1.11
Hashemi et al. [46] 2013 Shahroud, Iran 4592/35 Entire sample:
50.83 ±0.12
[40-64]
Keratoconus
cohort: 47.6 ±
4.7 [NA]
Topography (Holladay
criteria)
NA Prospective,
cross-sectional
Population NA 760 (0.76%)
[510–1010]
0.58
Hashemi et al. [47] 2013 Teheran, Iran 426/14 Entire sample:
40.8 ±17.1 [14-
80]
Keratoconus
cohort: 53.6 ±
14.9 [22-74]
Topography +thinnest
corneal point
NA Prospective,
cross-sectional
Population NA 3300 (3.3%)
[1000–5500]
0.75
Hashemi et al. [48] 2014 Mashhad, Iran 1027/26 Entire sample:
26.1 ±2.3 [20-
34]
Keratoconus
cohort: NA
Topography +thinnest
corneal point
NA Prospective,
cross-sectional
Population
(university
students)
NA 2500 (2.5%)
[1600–3500]
0.86
Shneor et al. [49] 2014 Haifa, Israel 314/10 Entire sample:
25.1 ±8.8 [18-
60]
Keratoconus
cohort: 25.1 ±
8.8 [19-28]
Topography (power and
indices) +clinical
examination
0.42 Prospective,
cross-sectional
Population
(university
students)
NA 3180 (3.18%)
[1200–5100]
0.25
Valdez-García et al.
[50]
2014 Monterrey,
Mexico
500/9 subjects Entire sample:
NA [10-20]
Keratoconus
cohort: 16.1
[NA]
NA NA Retrospective,
cross-sectional
Hospital/clinic NA 1800 (1.8%) [0–30] 0.33
Shehadeh et al. [51] 2015 Nablus,
Palestine
620/9 Entire sample:
20.1 ±1.6 [17-
27]
Keratoconus
cohort: NA
Topography indices NA Prospective,
cross-sectional
Population
(university
students)
NA 1500 (1.5%) [NA] Higher in
females
Godefrooij et al
f
[52] 2017 The
Netherlands
1,635,517/218 for
incidence
4,357,044/NA for
prevalence
Entire sample:
NA [10-40]
Keratoconus
cohort: NA
Diagnosis by
ophthalmologist
1 Retrospective,
longitudinal
Population 13.3
[11.6–15.2]
265 (0.265%) [256-
266]
1.54
Hwang et al
f
[28] 2018 South Korea 47,990,761/
17,931 for
prevalence
47,986,173/
Entire sample:
NA
Keratoconus
cohort
(prevalence):
Diagnosis by
ophthalmologist
6 for
prevalence
5 for
incidence
Retrospective,
longitudinal
Population 5.66
[5.47–5.66]
37.36 (0.03736%)
[36.82–37.91]
1.00
(continued on next page)
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Table 1 (continued )
Study Year Location Sample Size
(Catchment
Population/n◦
keratoconus)
Population
mean/median
Age [range]
(years)
Diagnostic criteria Study
Duration
(years)
Study Design Source Incidence
[95% CI]
Prevalence [95% CI] Male/
Female
ratio
13,343 for
incidence
31.2 ±14.2[0-
>85]
Keratoconus
cohort
(incidence):
31.9 ±15.1 [0-
>85]
Torres Netto et al.
[53]
2018 Riyadh, Saudi
Arabia
522/25 patients Entire sample:
16.8 ±4.2 [6-
21]
Keratoconus
cohort: NA
Topography (power and
indices) +subjective
screening criteria
NA Prospective,
cross-sectional
Hospital/clinic
(paediatric
patients)
NA 4790 (4.79%)
[2920–6620]
NA
Bak-Nielsen et al.
f
[54]
2019 Denmark 28,020,821/1008
subjects for
incidence
5,707,251/2846
subjects for
prevalence
NA NA 5 for
incidence
38 for
prevalence
Retrospective,
longitudinal
Population 3.6 [NA] 44 (0.044%) [NA] NA
Papali’i-Curtin et al.
[55]
2019 Wellington,
New Zealand
1,916/10 subjects Entire sample:
14.6 [NA]
Keratoconus
cohort: 14.9
[12.7– 16.1]
Topography (power,
pattern and indices)
NA Prospective,
cross-sectional
Population
(high school
students)
NA Entire cohort: 520
(0.52%) [NA]
Maori islanders:
2250 (2.25%) [NA]
2.33
Armstrong et al.
2020 [56]
2020 Abu Dhabi,
United Arab
Emirates
339/9 subjects Entire sample:
NA [10-19]
Keratoconus
cohort: NA
Topography indices +
clinical examination
0.25 Prospective,
cross-sectional
Population
(secondary
school
students)
NA 1500 (1.5%)
[700–2900]
NA
¨
Ozalp et al. [57] 2021 Eskis¸ehir,
Turkey
585/14 subjects Entire sample:
21.6 ±2.6 [≥18
to ≤30]
Keratoconus
cohort: NA
Topography (power and
indices) +pachymetry
NA Prospective,
cross-sectional
Population
(university
students and
faculty
members)
NA 2393 (2.393%)
[1426–4015]
Higher in
males
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disease only the anterior cornea appears to be compromised
[4,17,58,59]. There is some controversy as to whether the endothelium
is affected in keratoconus, since many patients with keratoconus wear
different types of contact lenses, including rigid corneal, corneoscleral
and scleral lenses, soft and hybrid (i.e., rigid corneal lens with a pe-
ripheral soft skirt) lenses, and piggyback systems (i.e., rigid corneal lens
tted over a soft contact lens) which can alter endothelial morphology,
and the endothelium can be difcult to image as the disease progresses
[4,10,60]. Histopathological changes are primarily found in the corneal
epithelium, anterior limiting lamina (Bowman’s layer) and stroma,
while the posterior limiting lamina (Descemet’s membrane) appears to
be much less frequently affected.
Although corneal epithelial thinning around the apical cone region is
believed to be the most common histopathological change associated
with keratoconus [61–63], some studies have reported either no sig-
nicant change [64] or an increase in epithelial thickness [59,65].
Furthermore, one study reported that epithelial thinning was negatively
correlated with disease severity [66], whereas another study found
epithelial thickening was associated with breaks in the anterior limiting
lamina [62]. In keratoconus, it has been proposed that epithelial thin-
ning might occur due to apoptosis because of chronic epithelial injury
subsequent to environmental risk factors, which in turn release
apoptotic cytokines (see Section 5). Of interest is that the thinnest
corneal location in eyes with keratoconus does not overlap with the
location of the maximum axial and tangential curvatures or the
maximum front and back elevation locations, although all these points
are typically located in the inferior-temporal cornea. This indicates that
in keratoconus the point of maximal corneal curvature is displaced
relative to the thinnest corneal location [9].
The epithelium losses its cellular uniformity and is compromised by
the loss or damage to the anterior limiting lamina [58], with epithelial
changes being more pronounced with increasing severity of the disease
Fig. 1. Reported prevalence rates (per 100,000 persons) of keratoconus around the world. In countries where several epidemiological studies have been conducted,
the results of the study with the largest sample size and those representing the most predominant ethnic group are reported.
Fig. 2. Reported incidence rates (per 100,000 persons/year) of keratoconus around the world. In countries where several epidemiological studies have been con-
ducted, the results of the study with the largest sample size and those representing the most predominant ethnic group are reported.
J. Santodomingo-Rubido et al.
Contact Lens and Anterior Eye xxx (xxxx) xxx
7
[67]. The epithelium may display basal cell degeneration, exhibiting
enlargement and irregular arrangement [66,68,69], and a decrease in
basal cell density compared to normal corneas [70], which correlates
with disease severity [71]. Using confocal microscopy, it has been re-
ported that in severe cases, the epithelium displays supercial cells,
which are elongated and spindle shaped, larger and irregularly spaced
wing cell nuclei, and attened basal cells [67]. Breaks in the corneal
epithelium, accompanied by a downgrowth of basal cells into the
anterior limiting lamina, and an accumulation of ferritin particles within
and between epithelial cells (most prominently in the basal layer), have
also been reported in keratoconus [10,67,72]. Supercial iron deposits
and scarring are other less frequently observed changes in the corneal
epithelium typically affecting one in ve eyes with keratoconus [62,63].
Increased visibility of corneal nerves at the sub-basal corneal nerve
plexus, located between the basal epithelium and anterior limiting
lamina, as a result of corneal thinning is sometimes seen in keratoconus
patients with different grades of severity [6,60]. Keratoconic eyes have
decreased corneal innervation, sensation, and basal and sub-basal
epithelial density in comparison to normal eyes [73–75], with central
sub-basal nerve density correlating with disease severity [71]. Localised
nerve thickening within the epithelium has also been reported [76]. A
study conducted in a small number of eyes using in-vivo confocal mi-
croscopy reported that keratoconic corneas exhibit abnormal sub-basal
nerve architecture compared with normal corneas [73]. Furthermore,
at the apex of the cone, a tortuous network of nerve bre bundles was
noted, many of which formed closed loops; and at the topographic base
of the cone, nerve bre bundles followed the contour of the cone base,
with many of the bundles running concentrically in this region [73].
Breaks in the anterior limiting lamina are one of the most common
histopathological signs seen in keratoconus typically affecting over
seven in ten keratoconic eyes [61,62]. The breaks normally show Z-
shaped interruptions due to collagen bundle separation, which are lled
with proliferative collagenous tissue derived from the anterior stroma
and positive nodules of Schiff’s periodic acid [60,72]. Despite being
acellular, cellular components have been observed in the anterior
limiting lamina [62,77], including epithelial cells and stromal kerato-
cytes [67], and anterior keratocyte nuclei have been reported to wrap
around corneal nerves as they pass through this layer [76]. Hyper-
reective keratocyte nuclei observed in keratoconus are thought to
indicate the presence of broblastic cells [67].
The well-organised architecture of the corneal stroma, which is
responsible for the transparency of the cornea, is compromised in ker-
atoconus [4]. The keratoconic cornea has been reported to show a
reduction in the number of lamellae, particularly in regions associated
with cone development without breaks in the anterior limiting lamina or
scarring [78]. The width and angle relative to the anterior limiting
lamina of collagen lamellae have been reported to be signicantly larger
and smaller, respectively, relative to those in the normal cornea [79].
Furthermore, it has been proposed that collagen lamellae are expanded
in association with protrusion of the cone [79]. A gross rearrangement of
vertical and horizontal collagen lamellae occurs in keratoconus [80]. A
decrease in the interbrillar distance of collagen sheets and the increase
of proteoglycans have also been reported [81]. Ectasia and thinning in
keratoconus are associated with lamellar splitting into multiple bundles
of collagen brils and loss of anterior lamellae. These structural changes,
possibly in addition to lateral shifting of lamellae due to the pressure
gradient over the cornea, provide a potential explanation to the central
loss of mass ultimately leading to reduced stromal thickness [82].
Alternating dark and light bands, most commonly found in the posterior
stroma, have been seen in keratoconus patients using confocal micro-
scopy [83]. These bands, which are believed to represent collagen
lamellae under stress, correspond with the appearance of Vogt’s striae
on slit-lamp biomicroscopy examination.
Breaks and deformities in the posterior limiting lamina have been
reported to occur in approximately one in ve keratoconus eyes
–typically affecting more severe cases [62,63]. Breakage in the posterior
limiting lamina, allowing aqueous to enter the corneal stroma and
epithelium, is a serious complication, known as corneal hydrops,
[84,85] which may require surgical treatment [86,87].
Although the corneal endothelium is generally unaffected in kera-
toconus, this issue is controversial [4]. While several studies found no
endothelial change with disease progression [70,88–90], one study re-
ported a slight increase in endothelial cell density in keratoconus [14],
while two others reported a signicant decrease in endothelial cell
density, particularly in moderate to severe keratoconus [63,65,68].
5. Aetiology and pathogenesis
Understanding of the mechanism behind the development of kera-
toconus is still limited. There are no well-established animal models for
the disease; mouse models have been developed, but mouse and human
genomes are not organised in a similar pattern. Hence, research has
mainly focused on clinical observations and donor corneal samples
(extracted during a corneal graft operation) and hence are generally
from more severe cases. Obtaining demographically matched, healthy
corneas for comparison is also difcult and samples degrade rapidly
after extraction. Keratoconus progresses as a combination of simulta-
neously occurring destructive and healing processes [76].
5.1. Genetics
Keratoconus has long been considered to have a genetic component,
given its association with other genetic syndromes (such as Down’s
syndrome [91], Leber’s congenital amaurosis [92,93], Ehlers-Danlos
syndrome [94] and Noonan syndrome [95]), its prevalence in rst-
degree relatives [96–99] and occurrence in monozygotic twins
[100,101]. It has been estimated that a relative of an individual with
keratoconus has a 15 to 67 times greater risk of developing keratoconus
than an individual with no family history of keratoconus [102]. Kera-
toconus follows an apparently autosomal dominant/recessive mode of
inheritance in some families [103,104]. However, sporadic cases show
no Mendelian patterns of inheritance [105], but computer-assisted
corneal topography in parents of patients with keratoconus detects the
disease in more family members than previously diagnosed, which af-
fects familial analysis [99,106,107].
Loci on 73% (16 out of 22) of human autosomal chromosomes have
been suggested to be involved in keratoconus and 59% of these could be
considered to show statistically signicant associations [108]. To date,
only a single keratoconus locus (5q21.2) has been replicated across
multiple linkage studies [103,109], suggesting that it could be a poly-
genic disease (two or more affected genes are required for keratoconus
to develop). Detailed studies of the key candidate genes (VSX1 and
SOD1) and others [110] have been inconclusive, leading to the hy-
pothesis that mutations, in the presence of other gene variants (referred
to as modier genes), are required to elicit keratoconic traits [109]. This
supports the notion that keratoconus is a multifactorial disease [111]
and that multiple genetic factors, together with other factors inuence
the development of keratoconus traits. Keratoconus may even be a range
of diseases that have relatively similar manifestations [96].
5.2. Cellular biochemistry
To date, 117 proteins and protein classes have been implicated in the
pathophysiology of keratoconus [3]. Differential expression of several
corneal proteins results in changes in the structural integrity and
morphology of the keratoconic cornea, through altering its collagen
content and keratocyte apoptosis and necrosis in the stroma [112,113].
Oxidative stress markers and antioxidants are dysregulated in kerato-
conus, involving an imbalance of redox homeostasis in tears, cornea,
aqueous humour and blood [114]. Keratoconus is associated with an
overall increase in oxidative stress markers, particularly in reactive
oxygen and nitrogen species and malondialdehyde. It is also associated
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with an overall decrease in antioxidants, including a signicant decrease
in total antioxidant capacity/status, aldehyde/NADPH dehydrogenase,
lactoferrin/transferrin/albumin and selenium/zinc. Oxidative stress
markers are higher in tears and in the cornea of keratoconic than in the
aqueous humour, and antioxidants were decreased in tears, aqueous
humour and blood. Oxidative stress markers increased in stromal cells
and antioxidants decreased in endothelium [114]. The disease is asso-
ciated with an up regulation of degradative enzymes and inhibition of
the activity of protease inhibitors [115], resulting in corneal thinning
[112]. The increase of proteinase activity results in the induction of a
degradative process in the cornea [115–117].
In the keratoconic cornea, there is a gradient of damage between the
centre of the cone (which shows the greatest level of damage) and the
periphery [76]. At a cellular level, penetration of ne keratocyte pro-
cesses into the anterior limiting membrane have been observed in
localised regions, generally in association with localised indentation of
the basal epithelium, often where nerves penetrate between the stroma
and epithelium. Increased levels of lysosomal enzymes (Cathepsin B and
G) have been measured in these stromal keratocytes in the disrupted
regions, which have been hypothesised as the driving force to structural
damage to the anterior limiting membrane and underlying stroma [77].
Physical stresses from the intraocular pressure and eye rubbing are
likely to exacerbate this degradation. Nerve associated Schwann cells
express higher levels of Cathepsin B and G in keratoconic corneas and
these enzymes are known to be active in other disease neural tissues
[77].
5.3. Biomechanical factors
The degeneration of the proteoglycans around the stromal collagen
brils in keratoconic corneas leads to breakage of, and degeneration of
the microbrils within, collagen brils [118]. These changes result in a
reduction of the diameter of the collagen brils, and the reduced number
and different distribution of lamellae, composed of these degenerated
brils, are biomechanically weak and prone to disorganisation and un-
dulation [80,118,119]; hence, these changes eventually result in alter-
ation of the curvature of the cornea ultimately leading to cone
formation. Polymorphisms of the antioxidant enzymes (catalase and
glutathione peroxidase) have been shown to act as independent pre-
dictors of the severity of keratoconus, perhaps due to mechanical insult
to the cornea, highlighting the role of oxidative stress in the pathogen-
esis of the disease [120]. Keratoconic corneas have decreased levels of
aldehyde dehydrogenase Class 3 [121] and superoxide dismutase en-
zymes [122]. Both enzymes play important roles in the reactive oxygen
processes of different species. The reactive oxygen accumulation causes
cytotoxic deposition of malondialdehyde and peroxynitrites, which
could potentially damage corneal tissue [114,123–125].
Matrix stiffness, which regulates the physiology of the cells in tissues
throughout the body and plays an important role in maintaining their
homeostasis, is altered in keratoconus. Additionally, it has been reported
to regulate cell division, proliferation, migration, extracellular uptake,
and various other physiological processes. There is a connection be-
tween endocytosis and matrix stiffness in keratoconus which may
explain the link between mechanical and biochemical factors [126].
Although rigid contact lens wear has also been associated with ker-
atoconus development [127], perhaps as a result of altered cell
morphology following lens wear [128], it seems unlikely that contact
lens wear could trigger the development of keratoconus.
5.4. Risk factors
Several environmental and familial factors are associated with an
increased risk of developing keratoconus (Table 2). Allergy and atopy
have long been associated with keratoconus, with the majority of studies
showing a positive association and the reported prevalence being 11 to
30% [129]. Another strongly associated risk factor in the pathogenesis
of keratoconus is eye rubbing [130]. A common mediator to these major
risk factors is Immunoglobulin E, which has been identied as elevated,
even in some patients with keratoconus without inammatory symp-
toms and signs [129]. In keratoconus patients, the incidence of elevated
levels of total serum Immunoglobulin E was between 52% and 59% for
raised serum specic Immunoglobulin E levels [131]. A recent system-
atic review and meta-analysis, in which 3996 articles were retrieved, of
which 29 were analyzed including 7,158,241 participants from 15
countries, identied the odds ratios (OR) of having keratoconus to be
3.09 times (95% CI: 2.17–4.00) for those reporting eye rubbing, 1.42
times (95% CI: 1.06–1.79) for those with allergy, 1.94 times (95% CI:
1.30–2.58) for those with asthma and 2.95 times for those with eczema
(95% CI: 1.30–4.59); however, the odds ratio for those with a family
history of keratoconus was 6.42 (95% CI: 2.59–10.24), showing the
signicant inuence of genetics [130]. One other recent study reported
eye rubbing (odds ratio: 4.93), family history of keratoconus (odds ratio:
25.52) and parental consanguinity (odds ratio: 2.89) to be signicant
risk factors for keratoconus [98], whereas another study also reported
eye rubbing (odds ratio: 3.53,) and consanguineous marriage (odds
ratio: 12.87) to be independent risk factors for keratoconus [57].
Another recent study, which involved an analysis of 2,051 keratoconus
cases and 12,306 matched controls, identied novel associations be-
tween keratoconus and Hashimoto’s thyroiditis (OR =2.89; 95% CI:
1.41 to 5.94) and inammatory skin conditions (OR =2.20; 95% CI:
1.37 to 3.53), and conrmed known associations between keratoconus
and atopic conditions, including allergic rash (OR =3.00; 95% CI: 1.03
to 8.79), asthma and bronchial hyperresponsiveness (OR =2.51; 95%
CI: 1.63 to 3.84), and allergic rhinitis (OR =2.20; 95% CI: 1.39 to 3.49)
[132]. These latter results indicate that keratoconus appears positively
associated with multiple immune-mediated diseases, which provides an
argument that systemic inammatory responses may inuence its onset.
6. Clinical features
Keratoconus usually develops in the second and third decade decades
of life and progresses until the fourth decade, when it stabilises [27–29],
although it can develop earlier [50,53,55,56] or later in life
[39,44,46,47] (Table 3). The condition typically affects both eyes,
although with different degrees of severity, and it has well-established
signs and symptoms, although there is no clear consensus regarding
the signs and symptoms associated with early keratoconus (Table 3)
[1,10,133]. The early stages of the disease are commonly referred to as
subclinical or form-fruste keratoconus, although there is a lack of unied
criteria in the use of these two terms [134]. Subclinical keratoconus
typically refers to an eye with topographic signs of keratoconus (or
suspicious topographic ndings) with normal corneal slit-lamp ndings
and keratoconus in the fellow eye [134]. Form fruste keratoconus
typically refers to an eye with normal topography, normal corneal slit-
lamp ndings, and keratoconus in the fellow eye [134]. It has been
recently reported that eyes with form fruste keratoconus have an
increased central epithelial to stromal thickness ratio and asymmetric
superior-nasal epithelial thinning, whereas keratometric and corneal
volumetric alterations are more prominent in subclinical keratoconus
[135]. Characteristics of eyes with subclinical keratoconus also include
an asymmetrically displaced anterior and posterior corneal apex,
corneal thinning, and loss of corneal volume [136].
Table 2
Environmental and familial risk factors for keratoconus [108,130].
Factor Relative Risk
Family history of keratoconus 6.4
Eye rubbing 3.1
Eczema 3.0
Asthma 1.9
Allergy 1.4
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Detecting the earliest stages of keratoconus remains a challenge,
although it is particularly important as it can lead to better management
and long-term prognosis. In its early stages, the symptoms of keratoco-
nus can mimic the symptoms of simple refractive errors, and if a cor-
rected visual acuity of 6/6 (i.e., 20/20) is achieved without obvious
clinical signs of keratoconus, detection of the disease is unlikely unless
corneal imaging is performed. Particular attention should be given to the
results of the axial curvature map from the corneal topographer to depict
any patterns typically associated with keratoconus [135]. As keratoco-
nus progresses, symptoms can include mild blurring or slightly distorted
vision along with a reduction in spectacle best corrected visual acuity.
Other common signs preceding ectasia include mild, localised corneal
steepening, an increasing difference between the inferior and superior
corneal curvature, and increasing anterior corneal aberrations, partic-
ularly coma-like aberrations [2,135]. Corneal thinning typically occurs
in the central or paracentral cornea, often in the inferior-temporal
corneal quadrant [9], although occasional superior localisations have
also been reported [48,137–139]. Nipple and oval cones located in the
central or paracentral cornea are most common, whilst globus cones and
peripherally located cones are rare [140].
Several clinical signs are associated with keratoconus. The ‘scissor
reex’ is observed during retinoscopy assessment. Charlouex’s oil
droplet reex is also commonly seen in early keratoconus using retro-
illumination with a dilated pupil, which produces a dark, round shadow
in the corneal midperiphery [141]. Fleischer’s ring and Vogt’s striae can
be observed as the disease severity increases (Table 3). Fleischer’s ring is
believed to be a subepithelial deposition of iron oxide hemosiderin
within the posterior limiting lamina membrane that manifests as yel-
low–brown to olive-green pigmentation in an arc or ring shape around
the base of the cone [142]. Vogt’s striae may be seen as ne as well as
relatively thick, vertical, stress lines within the posterior stroma and
posterior limiting lamina due to stretching and thinning of the cornea,
that disappear while exerting gentle pressure to the globe, although they
may also have a fanlike appearance around the base of the cone. Oc-
casionally, striae can be observed without the use of a slit lamp.
Fleischer’s ring and Vogt’s striae are observed in one or both eyes in
86% and 65%, respectively of patients with keratoconus [143,144] and
it has been proposed that the presence of these two signs may conrm
diagnosis in borderline cases [145]. Supercial and deep corneal opac-
ities and increased visibility of corneal nerves are also commonly
observed in keratoconus [6]. Although these signs can manifest at any
point during disease development and progression, the more advanced
the disease the greater the likelihood that Vogt’s striae, Fleischer’s ring,
and/or corneal scarring will be present [7].
Epithelial or subepithelial corneal scarring is also a characteristic
sign of keratoconus (Fig. 3), and is more commonly observed in patients
with: a younger age at diagnosis; corneal staining; greater corneal cur-
vature (i.e., >55 D or steeper than 6.13 mm); and who wear contact
Table 3
Signs and symptoms based on keratoconus severity. Of note is that the time course for the development of keratoconus signs and symptoms, and their association with disease severity are highly variable. VA, visual acuity;
BCVA, best corrected visual acuity; D, dioptres.
Stage Signs Symptoms
1 –
Subclinical
Suspicious topography; normal slit-lamp ndings; and ~ 6/6 VA achievable with spectacle correction. None or slight blurring of vision
2 – Early ‘Scissor reex’; Charlouex’s oil droplet reex; mild, localised corneal steepening and thinning; increasing keratometric differences between inferior and
superior cornea; increases in corneal aberrations (particularly coma-like aberrations); mild changes in refractive error; and reduction of spectacle BCVA.
Mild blurring or slightly distorted vision
3 – Moderate Those of stage 2 (normally of greater severity) plus: signicant corneal thinning; Vogt’s striae; Fleischer’s ring; <6/6 spectacle BCVA, but ~ 6/6 spectacle
BCVA with contact lenses; increased refractive changes; increased visibility of corneal nerves; corneal scarring and opacities normally absent.
Moderate blurring and distorted vision
4 – Severe Those of stage 3 (normally of greater severity) plus: severe corneal thinning and steepening (>55D); corneal scarring; <6/7.5 VA with contact lens
correction; Rizzuti’s sign; Munson’s sign; corneal opacities; and corneal hydrops;
Severe blurring and distorted vision, and monocular polyopia
(typically reported as ‘ghost’ images)
Fig. 3. Slit-lamp images showing corneal scarring.
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lenses [146]. This slit lamp nding also corresponds with stromal haze
and hyperreectivity as observed using confocal microscopy [67]. In
severe cases, highly pronounced cones can create a V-shaped deforma-
tion of the lower eyelid during downgaze, known as Munson’s sign
[141,147]. Rizzuti’s sign, a bright reection of the nasal area of the
limbus when light is directed to the temporal limbal area, is another sign
frequently observed in advanced stages [148]. Severe keratoconus may
result in corneal hydrops, characterised by marked corneal oedema due
to a break in the posterior limiting lamina, which allows aqueous to
enter the corneal stroma and epithelium. Although hydrops can be self-
limiting within ~3 months, acute cases may require corneal suturing or
intracameral gas injection depending upon the severity [149]. Corneal
hydrops can results in central vision-impairing scar tissue and corneal
irregularity, necessitating in many cases the need for scleral contact
lenses to achieve functional vision [150], and in some cases corneal
transplantation [84]. Signicant risk factors independently associated
with the development of hydrops in keratoconus (using multivariate
analysis to address co-dependencies) include vernal keratoconjunctivitis
(adjusted odds ratio (AOR) 15.00x), asthma (AOR 4.92x), and visual
acuity in the worse eye (i.e. disease severity, AOR 4.11x) [151].
Corneal protrusion, the scissors reex, corneal thinning, Fleischer’s
ring, and prominent corneal nerve bres are the most prevalent clinical
signs in keratoconus (Fig. 4), with all signs observed in over 50% of
patients with keratoconus [141]. However, the time course of the
development of these clinical signs and their association with disease
severity are highly variable. Although identifying clinical symptoms and
slit-lamp ndings in keratoconus are important, corneal topography is
currently the primary diagnostic tool for keratoconus detection [2]. In
incipient cases, however, the use of a single parameter as a diagnostic
factor is not sufciently accurate, and pachymetry and corneal aberra-
tion data are now also commonly used in conjunction with corneal
topography to aid early diagnosis and monitor progression and treat-
ment outcomes [2,152]. In addition to corneal topography that provides
two-dimensional imagining of the corneal surface based on curvature
data, corneal tomography is a three-dimensional imaging technique that
characterises the anterior/posterior corneal surfaces based on curvature
data of the anterior surface and elevation data of both the anterior and
posterior corneal surfaces, along with corneal thickness distribution
[153], which have found critical to enhance the sensitivity and
specicity for detecting corneal ectasia in comparison to corneal
topography [133,154]. Furthermore, various machine learning algo-
rithms have been developed using routinely collected clinical parame-
ters that can assist in the objective detection of early forms of the disease
[2,155].
7. Detection
The early detection of keratoconus can lead to improved patient
outcomes though more frequent review to monitor disease progression
and timely interventions when indicated (e.g., corneal collagen cross-
linking), ultimately reducing the need for corneal transplantation.
Consequently, most research concerning the detection of keratoconus
has focused on identifying the rst clinical signs of corneal disease. For
example, differentiating between “form fruste keratoconus” (no corneal
topography or slit lamp abnormalities, but keratoconus in the fellow
eye) or “keratoconus suspects” (preclinical or subclinical keratoconus,
typically dened as a cornea with no detectable abnormalities based on
slit lamp examination, but inferior corneal steepening/asymmetry with
unaffected visual acuity) from non-keratoconic eyes [156]. Addition-
ally, efforts have also been made to obtain consensus from a panel of
ophthalmology experts from around the world that resulted in deni-
tions, statements, and recommendations for the diagnosis and man-
agement of keratoconus and other ectatic diseases that should help eye
care providers around the world to adopt best practices for these often
visually debilitating conditions [133]. Studies assessing the diagnostic
utility of a particular corneal metric typically report the sensitivity (the
ability to correctly identify eyes with keratoconus), the specicity (the
ability to correctly identify eyes without keratoconus), and the threshold
beyond which a cornea would be considered keratoconic. Importantly,
there is currently no single metric that can unequivocally differentiate
emerging disease from normal corneal data, so a diagnosis of kerato-
conus must consider a range of corneal parameters, including their
interocular asymmetry. Scoring indices that combine several different
corneal parameters have been developed to improve diagnostic accu-
racy. This section reviews emerging methods of keratoconus detection
over the past decade.
Fig. 4. Vertical Scheimpug image (left) and anterior axial curvature map (right) of a cornea with advanced keratoconus; mean central anterior keratometry 56 D,
anterior corneal astigmatism 11.8 D, thinnest corneal pachymetry 381 µm. The white dot on the top left indicates the superior aspect of the image and the arrow
indicates the region of central-inferior corneal thinning.
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7.1. Corneal morphology
7.1.1. Thickness prole
Since the advent of high-resolution anterior segment optical coher-
ence tomography (OCT) imaging, numerous studies have investigated
the thickness prole of individual corneal layers in keratoconus. Kera-
toconic eyes typically display epithelial thinning at the corneal apex
(cone), surrounded by an annulus of epithelial thickening, thought to be
an epithelial remodelling response in order to provide a smooth optical
surface over a an increasingly irregular and steepening anterior stroma
[157–159]. A reduction in epithelial basal cell density may also lead to
the thinning and fragmentation of the anterior limiting lamina [72],
which also appears to be indicative of early keratoconus [160].
The stroma of keratoconic eyes is also typically thinner infero-
temporally (correlating with the average cone location) and thicker
superior-temporally compared to non-keratoconic eyes with astigma-
tism; however, these regional variations are more apparent in the
epithelial prole [161], even in subclinical keratoconus [162]. For
example, Li et al [162] reported that an epithelial thickness metric has
96% sensitivity and 100% specicity for distinguishing subclinical
keratoconus from normal eyes compared to stromal (92%, 80%) and
total corneal thickness (92%, 92%) metrics. This approach using an
epithelial thickness metric derived from OCT imaging appears to be
more suitable for detecting subclinical keratoconus compared to
numerous studies using central or minimum total corneal thickness data
[2].
A limitation of detecting keratoconus using corneal epithelial
thickness proling is that image segmentation can be difcult in the
presence of changes in the anterior limiting lamina and thickness mea-
surements are typically less reliable in keratoconic compared to non-
keratoconic corneas [163,164]. Epithelial thickness metrics should
still be considered in conjunction with other clinical measures in the
diagnosis of keratoconus [165].
7.1.2. Tomographic indices
Although anterior corneal curvature and anterior and posterior
astigmatism are signicantly elevated in keratoconus compared to non-
keratoconic eyes, these parameters are not particularly useful in the
differentiation of subclinical keratoconus from normal eyes [2]. Since
changes in the posterior corneal surface may be one of the rst clinically
detectable signs of keratoconus [166–168] numerous studies have
investigated the utility of posterior corneal metrics. These metrics
cannot be obtained from traditional reection-based topographers, but
are measured using Scheimpug imaging, slit scanning tomography, or
optical coherence tomography. One of the most commonly used metrics
is the posterior corneal elevation (i.e., how the elevation of the posterior
cornea deviates relative to a reference body such as a sphere or ellipse)
[169] (Fig. 5). The utility of this metric for identifying emerging kera-
toconus varies with respect to the analysis diameter and reference body
used (Table 4). A panel of ophthalmology experts from around the world
have proposed that posterior corneal elevations abnormalities must be
present to aid in the diagnosis of early or subclinical keratoconus [133].
Fig. 6.
7.1.3. Other corneal morphological characteristics
7.1.3.1. Corneal surface area. The ratio of anterior and posterior
corneal surface areas (derived from OCT or Scheimpug imaging) is
signicantly decreased in keratoconic compared to non-keratoconic
eyes [175–177], potentially due to pathological changes in both
Fig. 5. Posterior corneal elevation maps relative to the best sphere reference body (8 mm diameter) for a non-keratoconic (left, maximum elevation 10 µm) and a
keratoconic eye (right, maximum elevation 88 µm). For this metric, a maximum elevation>12 µm is typically indicative of keratoconus (Table 3).
Table 4
Table summarising all studies which provided the sensitivity, specicity, and a
threshold value of posterior corneal elevation to differentiate form fruste or
suspected keratoconus from non-keratoconic eyes. BFS, best t sphere; BFTA,
best-t toric and aspheric body/ellipsoid; E-BFS, enhanced best t sphere (3.5
mm diameter removed centred on thinnest point); MEL, maximum elevation;
TEL, elevation at thinnest corneal point.
Author, Year Reference body
(diameter, mm)
Threshold
(µm)
Specicity
(%)
Sensitivity
(%)
de Sanctis et al,
2013 [170]
BFS (9) 27 87 73
E-BFS (8) 12 84 60
Muftuoglu et al,
2013 [171]
BFS (9) 9 59 67
Smadja et al,
2013 [172]
BFS (8) MEL 14 55 51
BFTA (8) MEL 13 80 82
Sideroudi et al,
2014 [173]
BFS (8) MEL 12 86 83
BFS (8) TEL 10 97 70
BFTA (8) MEL 9 79 91
BFTA (8) TEL 5 97 82
Golan et al,
2018 [174]
BFTA (8) MEL 11.5 85 80
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anterior and posterior corneal surfaces and appears to be a useful metric
to differentiate form fruste keratoconus from non-keratoconic eyes
(specicity 96% and sensitivity 92%) [178].
7.1.3.2. Corneal light intensity distribution. Recently, the light intensity
distribution derived from Scheimpug imaging has been modelled to
evaluate microscopic corneal properties following contact lens wear
[179], and as a novel approach to differentiate keratoconic and non-
keratoconic corneas when imaged during mechanical stimulation
[180,181]. The statistical parameters derived from these analyses have
good sensitivity (76–96%) and specicity (76–88%) for detecting ker-
atoconus, which increases when combined with measures of central
corneal thickness (sensitivity 100%, specicity 95–100%) [181]. The
same image analysis approach has been used to identify the base of the
cone [182]; however, further research is required to assess if this tech-
nique has any clinical utility in the early detecting keratoconus or
monitoring disease progression.
7.1.3.3. Articial intelligence. Over the past decade, different ap-
proaches (machine and deep learning algorithms) have been utilised in
an attempt to automate the detection and classication of keratoconus
based on a wide range of corneal parameters [183,184]. In general, al-
gorithms designed to differentiate manifest keratoconus from non-
keratoconic eyes using corneal topography or tomography [185–191]
or OCT data [192–194] are highly reliable with specicity and sensi-
tivity scores typically>95%. Several techniques have also shown
excellent potential to differentiate form fruste or suspected keratoconus
from normal eyes [155,185,188,189,194–196] or manifest keratoconus
from suspected keratoconus [191,197]. In the future, longitudinal
corneal data may be used to develop algorithms to predict future disease
progression to identify eyes that may benet from more frequent review
or early intervention.
7.2. Optical
7.2.1. Anterior corneal higher order aberrations
Anterior corneal higher order aberration (HOA) metrics, derived
from the corneal elevation prole, that are particularly useful in the
detection of keratoconus (specically differentiating normal eyes from
sub-clinical, form fruste, or emerging keratoconus) include; vertical
coma (C(3,-1)), the root mean square error (RMS) of horizontal and
vertical coma, and the RMS of 3rd radial order (which includes vertical
coma) [198–203]. Table 5 summarises the specicity and sensitivity of
these metrics for specic thresholds. For a 6 mm corneal diameter,
vertical coma <~-0.17 µm, RMS coma >~0.275 µm, and 3rd order
RMS >~1.80 µm, are indicative of keratoconus. The ability to
discriminate between healthy eyes and sub-clinical keratoconus is
improved when anterior corneal HOA metrics are considered together
with other corneal parameters such as pachymetry and posterior corneal
aberrations [198].
7.2.2. Posterior corneal higher order aberrations
Posterior keratoconus is a rare corneal condition that affects only the
posterior corneal surface [204,205]. However, in keratoconus that in-
volves the anterior cornea, the internal ocular HOAs, that arise from the
posterior corneal surface and crystalline lens, are also elevated in
comparison to healthy controls [206–208]. This is due to changes in the
posterior corneal surface [208] and can result in signicant residual
HOA (predominantly vertical coma) when the aberrations of the ante-
rior corneal surface are effectively neutralised with the post-lens tear
layer of a rigid contact lens [209]. Although posterior corneal HOA’s
increase considerably with moderate to advanced keratoconus
compared to healthy controls, these data do not signicantly enhance
the ability to differentiate normal corneas from subclinical keratoconus
compared to anterior corneal HOA data alone [201,207].
7.2.3. Total ocular higher order aberrations
Although the internal optics of the eye (the contribution of the
posterior corneal surface and the crystalline lens) partially compensate
Fig. 6. Refractive power maps derived from the anterior corneal higher order aberration “coma-like” data (Zernike radial orders 3, 5, and 7) demonstrating the
increase in vertical coma with increasing severity of keratoconus (Alio-Shabayek [235] classication system). Warmer (i.e., red) and cooler (i.e., blue) colours
represent increased and decreased corneal power. The coma-like RMS values across a 6 mm pupil are: non-keratoconic =0.25 µm; Grade I =1.50 µm; Grade II =
2.52 µm; Grade III =3.84 µm; and Grade IV =4.60 µm. (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of
this article.)
Table 5
Table summarising all studies which provided the sensitivity, specicity, and a threshold value of anterior corneal higher order aberration (HOA) metrics to differ-
entiate normal and form fruste or suspected keratoconus.
Author, Year HOAMetric Threshold (µm) Diameter (mm) Specicity(%) Sensitivity(%)
Gobbe & Guillon, 2005 [199] Vertical coma <−0.116 6 72 89
Buhren et al, 2007 [200] Vertical coma ≤ − 0.202 6 94 100
Coma RMS ≥0.248 6 74 100
Buhren et al, 2010 [201] Vertical coma ≤ − 0.200 6 97 94
Saad & Gatinel, 2012 [198] Vertical coma <−0.095 5 78 71
Coma RMS >0.157 5 80 71
Xu et al, 2017 [202] 3rd order RMS >1.852 6 78 68
Naderan et al, 2018 [203] Vertical coma <−0.180 6 64 68
Coma RMS >0.305 6 73 55
J. Santodomingo-Rubido et al.
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for anterior corneal higher order aberrations (potentially more so in
keratoconus [207]), several studies have shown that total ocular higher
order aberrations can also be used to differentiate normal healthy eyes
from sub-clinical keratoconus. Eyes with sub-clinical (form fruste) ker-
atoconus typically display substantially more negative vertical coma and
consequently elevated total ocular third order and higher order RMS
values [203,209–211]. However, the ability to differentiate between
healthy eyes and sub-clinical keratoconus is improved if the total
wavefront is considered in combination with anterior corneal higher
order aberration data [198,212]. As outlined above, this suggests that
with respect to HOA, the contribution from the anterior corneal surface
is the most important to detect subclinical keratoconus.
7.3. Corneal biomechanics
Over the past decade, interest in corneal biomechanics in relation to
the detection of keratoconus has increased considerably due to the
availability of instruments (e.g., Ocular Response Analyzer and CorVis
Scheimpug Technology) that can quantify in-vivo corneal viscoelastic
properties based on its deformation response [2,213,214]. Since corneal
biomechanical properties are altered in keratoconus (based on in-vitro
analyses of donor corneas) [215–217], it has been hypothesised that
biomechanical metrics may be a sensitive marker to detect sub-clinical
keratoconus. However, while some biomechanical properties are
partially related to corneal thickness [218] and are signicantly altered
following corneal surgery [219,220], there is limited evidence sup-
porting the ability of these devices to differentiate normal eyes and those
with subclinical or established keratoconus [221–225]. A constraint of
current commercially available instrumentation is that only central
corneal measurements can be obtained and are unlikely to align with the
cone location or thinnest corneal point in keratoconus. Currently, in-vivo
corneal biomechanical parameters are not a sensitive and reliable metric
to differentiate normal eyes and sub-clinical keratoconus in isolation,
but may be of use in multivariate modelling of disease progression [89]
or in clinical practice following the development of more suitable met-
rics [226,227]. Emerging techniques such as optical coherence elas-
tography [228] or the analysis of OCT speckle [229] may help to identify
microstructural corneal changes allowing earlier detection of
keratoconus.
8. Classication
The time course for the development of keratoconus signs and
symptoms, and their association with disease severity are highly vari-
able, making the classication of keratoconus severity challenging.
Although several classication systems have been developed, which
primarily rely on corneal morphology or changes such as corneal thin-
ning, anterior and posterior corneal curvature, and cone position and
shape [10], there is no clinically adequate classication system for
keratoconus [133]. Assessment of optical and visual function, such as
higher order aberrations, visual acuity and astigmatism is also
commonly used for grading the severity of the disease [1]. Furthermore,
some classication systems take into consideration keratoconus signs
such as scars, Vogt’s striae and Fleischer’s ring [230]. In this section, the
different classication systems currently available for assessing kerato-
conus severity based on (1) corneal morphology and disease evolution;
(2) optical and visual function; and (3) descriptors of corneal shape (i.e.,
index-based systems), are discussed.
8.1. Morphological and disease evolution
The most commonly used classication systems based on morpho-
logical changes and disease evolution are:
Morphological (Buxton) classication [231] – This system classies
the disease based on the shape and position of the cone into oval, nipple
and globe keratoconus: (1) in oval keratoconus the cone affects one or
two corneal quadrants, with the inferior quadrant being the most
commonly affected location; (2) in nipple keratoconus the cone diameter
is ≤5 mm and located in the central or paracentral cornea; and (3) in
globe keratoconus the cone affects a large region of the anterior cornea
(>75%).
Keratometric classication [232] – This system categorises kerato-
conus into four grades based on the magnitude of the cornea’s central
corneal power: (1) Mild (<45 D); (2) Moderate (between 46 D and 52 D);
(3) Advanced (between 53 D and 59 D); and (4) Severe (>59 D).
Hom’s classication [10] – This system classies keratoconus into
four grades based on clinical signs: (A) Preclinical indicates that no
keratoconus signs are detected; (B) Mild cases display mild corneal
thinning and scissors reex; (C) Moderate indicates poor visual quality
and corneal thinning without corneal scarring; and (D) Severe kerato-
conus includes the presence of scars, unreliable refraction and severe
corneal thinning.
Amsler-Krumeich classication [233] – This classication system,
which seems to be the most frequently applied in clinical practice to
classify keratoconus, uses a number of morphological and clinical fea-
tures associated with keratoconus employed in the other classication
systems described above (Table 6). It has been proposed, however, that
this relatively old and outdated classication system fails to consider
currently available clinical information and technological advances
[133].
Keratoconus has been dened as progressive by some authors when
one (or several) of the following changes occur in an interval of less than
1 year [234]:
•Increase in astigmatism ≥1.0 D
•Signicant changes in the orientation of refractive axes
•Increase of 1.0 D or more in the optical power of the steepest corneal
meridian
•Decrease of 25 µm or more in corneal thickness.
8.2. Optical and visual function
Changes associated with the development of keratoconus are not
limited to anatomical and morphological alterations of the cornea; the
disease is also associated with a signicant decrease in optical quality
resulting from increases in ocular aberrations and a loss of corneal
transparency in some cases which can affect quality of life [236]. Clas-
sication systems which primarily consider optical and visual function
are as follows:
Table 6
The Amsler-Krumeich [233] and Alio-Shabayek [235] classication systems for
grading keratoconus severity. Coma-like RMS values refer to a 6 mm analysis
diameter.
Amsler – Krumeich Alio – Shabayek
Grade I
Corneal steepening No scars
Refraction >−5 D Coma-like RMS 1.50 to 2.50 µm
Mean central K readings <48 D Mean central K readings <48 D
Grade II
No scars No scars
Corneal thickness >400 µm Corneal thickness >400 µm
Refraction >−8 D Coma-like RMS >2.50 to ≤3.50 µm
Mean central K readings <53 D Mean central K readings <53 D
Grade III
No scars No scars
Corneal thickness >300 µm Corneal thickness >300 µm
Refraction >−10 D Coma-like RMS >3.50 to ≤4.50 µm
Mean central K readings <55 D Mean central K readings <55 D
Grade IV
Central scarring Central scarring
Corneal thickness >200 µm Corneal thickness >200 µm
Not reliable refraction Coma-like RMS >4.50 µm
Mean central K readings >55 D Mean central K readings >55 D
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Alio-Shabayek [235] - This system, which is based on the
Amsler–Krumeich classication, in addition to the assessment of kera-
tometric readings and corneal thinning, takes into consideration corneal
scarring and anterior corneal aberrations (i.e., RMS coma-like aberra-
tions) to grade keratoconus severity (Table 6).
Keratoconus Severity Score (KSS) [230] - This system grades the
severity of keratoconus from 0 (suspect) to 5 (severe) based on two
corneal topographic indices (i.e., anterior corneal higher order aberra-
tion RMS error and mean central keratometry), the topographical
pattern of keratoconus and slit-lamp clinical signs (i.e., Vogt’s striae,
corneal scarring and Fleischer’s rings).
RETICS classication [237] – In addition to clinical signs and optical
and visual function variables, this classication system also takes into
consideration corneal biomechanical parameters (i.e., hysteresis and
resistance factor).
Belin ABCD grading system [238] – Keratoconus severity is graded
based on four variables: (A) anterior and posterior corneal radius; (B)
curvature of the 3.0 mm central zone of the thinnest corneal location;
(C) thinnest pachymetry; and (D) distance best corrected visual acuity.
This grading system is included in the Oculus Pentacam Scheimpug-
based system (Oculus GmbH, Wetzlar, Germany).
8.3. Index-based systems
Several index-based systems for keratoconus detection have been
included in various instruments of corneal shape assessment. These
systems may include one or more variables for keratoconus detection
and typically use cut-off values to allow differentiation between normal
corneas, keratoconus suspects, and clinical keratoconus (Table 7).
9. Management and treatment
Keratoconus treatment varies depending on the disease severity and
progression (see section 8. Classication). A keratoconus treatment
owchart has been developed by consensus from a panel of ophthal-
mology experts from around the world [140]. Typically, mild cases are
treated with spectacles, moderate cases with contact lenses, while severe
cases that cannot be managed with scleral contact lenses may require
corneal surgery (Fig. 7). To prevent keratoconus progression, corneal
cross-linking is recommended to increase the biomechanical stability
and rigidity of the cornea, with early intervention normally warranted,
which highlights the importance of early diagnosis and close moni-
toring. Keratoconus patients should be advised to avoid eye rubbing as
the latter is commonly associated with keratoconus and may contribute
to disease onset and progression [248]. Education and counselling
appear to be the foundations for helping patients to control chronic
habits of abnormal eye rubbing [249].
9.1. Mild keratoconus
Spectacles can only be used in mild cases of keratoconus, and often
result in poor visual acuity [10]. Although spectacles are unable to
compensate for irregular astigmatism, a novel design that considers the
possible non-orthogonal positions of the eye’s two optical power me-
ridians has been proposed and has been shown to improve best-
corrected spectacle acuity by 1–4 lines in two participants with mild
keratoconus (refractive astigmatism ≤2.50 D) [250].
9.2. Moderate keratoconus
Currently, it is estimated that 90% of patients affected by corneal
irregularity utilise contact lenses [251]. Several options are available for
keratoconus management including gas permeable contact lenses (i.e.,
corneal, corneoscleral and scleral), piggyback systems (i.e., a rigid
corneal lens tted on top of a soft contact lens), soft contact lenses, and
hybrid lenses (i.e., rigid centre and soft peripheral hydrophilic skirt)
[252,253]. Any of these lens types may be tted to manage mild and
moderate keratoconus, whereas scleral lenses might be the best option
for successfully managing advanced cases.
9.2.1. Rigid contact lenses
Rigid lenses offer the greatest level of adaptability for managing
keratoconus patients as it is only possible to reliably correct high levels
of corneal irregular astigmatism through neutralization by the tear lens
with this type of contact lens [144,254–256].
Table 7
Index-based classication systems for keratoconus detection from normal
cornea. Values greater than the proposed cut-off indicate suspected keratoconus.
K, keratometry; Kmax, steepest anterior corneal curvature within the 3 mm
central cornea; skewed radial axes (SRAX); D, dioptres; mm, millimetre.
Univariate Index
Index
[Reference]
Description Cut-off Specicity
(%)
Sensitivity
(%)
SIMK [197] Simulated
Keratometry is the
difference in corneal
power between the
attest (K1) and
steepest (K2) corneal
meridians
45.57 D 80 76
Q [239] Anterior corneal
asphericity (central
8 mm) describes
how corneal
curvature changes
from the centre to
the periphery.
¡0.65 90 93
I-S [240] Inferior-Superior
index is the power
difference between
superior and inferior
cornea
>2.33 D 95 89
SRI [241] Surface Regularity
Index describes
corneal regularity
within the 4.5 mm
central cornea
>1.52 100 65
SAI [242] Surface Asymmetry
Index is the average
corneal power from
128 corneal
meridians
1.25 95 92
BCV [243] Baiocchi Calossi
Versaci index is the
difference through
the analysis of the
coma, trefoil, and
spherical aberration
components
>0.524 99 97
Kmax/TP
[244]
Max keratometry
combined with
thinnest pachymetry
>0.08 95 97
Multivariate Index
KPI [240] A combination of
SimK1, SimK2, DSI,
OSI, UPS, CSI, IAI
and AA indices
>18.55 95 96
KSI [197] Keratoconus
Severity Index (also
known as Smolek-
Klyce) combines ten
topographic indexes
>30% 93 93
KISA%
[245]
A combination of K,
SimK, I-S and SRAX
>60% 100 96
BADIII
[246,247]
Based on anterior
and posterior
parameters, corneal
thickness variables
and Kmax
>2.6 61 100
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9.2.1.1. Rigid corneal contact lenses and piggyback systems. Three stra-
tegies have been traditionally used for tting rigid corneal contact lenses
in keratoconus including apical clearance, apical touch, and three-point
touch [257,258]. A lens tted using the apical clearance technique
vaults the corneal apex and bears on the paracentral cornea. A lens tted
with apical touch exhibits light bearing on the central cornea, and can
provide good vision. However, an increase in corneal scarring has been
associated with this tting technique [257,259]. The three-point touch
technique, aims to provide lens support (corneal bearing) at three points
along each meridian, including light apical touch and heavier para-
central corneal touch. A higher rate of optimal lens ts can be achieved
using the three-point-touch approach (83%) compared to apical touch
ttings (71%) [257]. Although no differences in comfort have been re-
ported between these two tting approaches [260,261], a greater level
of corneal attening is associated with the apical touch technique [258].
Currently, multiple keratoconus rigid corneal contact lens designs
are commercially available, including multi-curve and aspherical de-
signs with unique or variable back surface asphericity (quadrant-specic
designs) [262], which have been shown to be successful in managing
keratoconus patients [263]. Reverse geometry back surface contact lens
designs have also been used in the optical correction of keratoconus;
however, their use is limited since the anterior corneal surface in kera-
toconus is typically prolate [264].
Piggyback systems, which consists of a rigid corneal contact lens
tted over a soft contact lens, are also used for keratoconus manage-
ment. The use of a soft contact lens can improve comfort and a rigid
corneal contact lens centration and stability [265,266]. While low
positive-powered soft contact lenses have traditionally been used in
piggyback systems, a mild negative-powered soft contact lens can
facilitate the tting of a atter and less minus powered rigid corneal
contact lens, which may result in improved centration and movement
and subsequently a reduction in spherical and coma-like aberrations.
Oxygen transmissibility at the centre of the piggyback system may also
be improved [267,268].
9.2.1.2. Corneoscleral and scleral lenses. Corneoscleral lenses are
dened as any rigid contact lens with shared bearing between the pe-
ripheral cornea and conjunctiva overlying the sclera, irrespective of the
overall lens diameter [269]. The major advantages of these lens designs
compared with rigid corneal lenses are improved comfort due to the
reduced lens edge-eyelid interaction and enhanced stability and cen-
tration with larger optical zones for more consistent vision across a
range of pupil diameters [270]. They are particularly useful for inferi-
orly located cones [271] or when other contact lens options (i.e., soft,
corneal rigid, piggyback or hybrid lenses) fail to provide an acceptable
visual outcome. As for rigid corneal lenses, corneoscleral designs can
also be customised to improve lens centration and the overall t (e.g.,
multicurve and aspheric designs, or toric/quadrant specic peripheral
curves), and the location of corneal bearing varies with lens design and
tting philosophy [272]. Corneoscleral lenses display less movement
upon blinking (up to ~ 0.5 mm) compared to rigid corneal lenses (1–2
mm), but more movement than scleral lens designs which settle back
into the underlying conjunctival tissue over the course of the day [273].
Consequently, oxygen delivery is enhanced in corneoscleral designs
compared to sealed scleral lenses, due to tear exchange and a thinner
post-lens uid reservoir which minimises corneal oedema [274,275].
Limbal compression must be avoided in corneoscleral designs since any
insult at this anatomical location can potentially trigger a neovascular
response [276]. Limited long-term data is available on corneoscleral lens
designs in the management of keratoconus; however, signicant im-
provements in higher order aberrations and visual acuity [277]
compared to spectacles or habitual contact lens corrections have been
reported for a range of corneal irregularities [272,277–279], with no
apparent alteration in corneal biomechanics [280] or limbal stem cell
health (based impression cytology and DNA analysis), after 12 months of
lens wear [281].
Scleral lenses are dened as any rigid lens that vaults the cornea
entirely, including the limbus, and rests upon the conjunctival tissue
overlying the sclera [282]. They are particularly useful in the visual
rehabilitation of advanced keratoconus when other lens modalities
typically fail to achieve a physiologically acceptable t due to central
bearing or excessive lens decentration, and can delay or eliminate the
need for a corneal graft in corneas with minimal central scarring
[283–286]. Many scleral lens designs are available in prolate and oblate
(i.e., reverse geometry) back surface lens designs, with a prolate prole
recommended for keratoconic eyes to mimic the anterior corneal
Fig. 7. Flowchart for keratoconus management. PRK, photorefractive keratectomy; pIOL, phakic and pseudophakic intraocular lens; IOL, intraocular lens; CL,
contact lens; ICRS, intracorneal ring segments; BCVA, best-corrected visual acuity; PK, penetrating keratoplasty; DALK, deep anterior lamellar keratoplasty.
J. Santodomingo-Rubido et al.
Contact Lens and Anterior Eye xxx (xxxx) xxx
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contour. In recent years, with advances in anterior segment imaging,
scleral lens prescribing has increased [287,288], including as a rst lens
of choice for healthy eyes with high regular astigmatism or ocular sur-
face disease.
Despite increased lens stability and comfort of scleral lenses
compared to rigid corneal or corneoscleral lenses, a disadvantage of
scleral lenses is the increased potential for corneal hypoxia in healthy
eyes [179,274,275,289–292], keratoconics [293], and following pene-
trating keratoplasty [294] due to reduced tear exchange [295–297] and
the thicker central post-lens uid reservoir (e.g. 200 µm compared to 20
µm in some corneoscleral designs). There is also a lens handling learning
curve for patients during the rst 6 months of lens wear [298] and ~
30% of them experience regular fogging (i.e., uid reservoir debris)
[299,300] throughout the day that often necessitates lens removal and
reapplication. Practitioners should also be aware that although scleral
lenses vault the cornea, anterior corneal attening can be observed
immediately after lens removal [301–306]. Therefore, a period out of
scleral lenses (in addition to rigid corneal lenses [307]) is required prior
to corneal imaging to assess disease progression.
There has been some debate whether rigid corneal or scleral lenses
provide superior visual outcomes [308,309], but only recently have
well-controlled studies shed further light on this question. Bergmanson
et al reported that 75% of keratoconics who had worn a range of
different contact lens corrections previously and were successfully
retted into scleral lenses (75% of habitual contact corrections were
corneal rigid, piggyback or hybrid lenses), reported a subjective
improvement in their vision [310]. Using a cross-over study design,
Kumar et al [311] compared the visual performance of a customised soft
lens (Kerasoft), two rigid corneal lenses (a conventional design and Rose
K2), and a scleral lens design (PROSE) in contact lens neophytes with
keratoconus. All rigid lenses outperformed the customised soft lens for
measures of distance visual acuity and contrast sensitivity, and the Rose
K2 and scleral lens outperformed the conventional rigid corneal lens for
more advanced keratoconus (steep K >53 D). In contrast, in a rando-
mised crossover trial [312] of successful and asymptomatic rigid corneal
lens wearers (93% of eyes with keratoconus), no signicant differences
in objective measures of distance visual acuity, contrast sensitivity, or
subjective reports of visual quality were observed between a rigid
corneal lens (Rose K2, Menicon Co., Ltd, Nagoya, Japan) and scleral lens
design (ZenLens, Bausch +Lomb, Bridgewater, NJ, USA). Residual ab-
errations that can arise from the posterior corneal surface in keratoconus
during rigid lens wear can be minimised by incorporating an aspheric
[313,314] or wavefront guided front surface design [315,316]. Scleral
lenses provide an ideal platform for such front surface designs due to
minimal movement upon blinking.
9.2.2. Soft contact lenses
In recent years, there have been signicant developments in soft
contact lens design for the correction of keratoconus [270,307]. Soft
lenses are available in high spherical and toric powers for the correction
of myopia and astigmatism in early keratoconus, decentred cones, and
for patients with rigid lens intolerance [317,318].
Although soft contact lenses offer improved initial comfort compared
to rigid lenses, they conform to the irregular corneal shape of the ker-
atoconic cornea resulting in suboptimal visual correction. As such, soft
contact lenses for keratoconus are designed with a thicker centre
thickness (i.e., 0.2 mm to 0.6 mm) in an attempt to mask the irregular
corneal shape and correct slight to moderate irregular astigmatism. The
increased centre thickness decreases lens oxygen transmissibility; how-
ever, silicone hydrogel materials (e.g., Denitive 74, Contamac, UK) are
now used for manufacturing these lenses.
Several soft toric contact lenses for keratoconus are currently avail-
able, including HydroCone® (Toris K, SeissLens, Switzerland)
[318–320], KeraSoft® IC (UltraVision CLPL, UK) [321], and Rose K2
Soft (Menicon Co., Ltd, Japan), which show comparable clinical per-
formance [311]. These lenses employ prism-ballast and peri-ballast
features as well as distinct differences in the centre and peripheral
lens design to prevent undesirable lens rotation. The combination of all
these features is reported to restore visual acuity to optimum levels by
reducing irregular astigmatism from a range of aetiologies including
keratoconus, trauma, and intrastromal ring surgery [320,322,323].
There has also been increasing interest in the development of
aberration-controlled soft contact lenses for keratoconus [316,324–326]
since wavefront sensors became commercially available about two de-
cades ago [327]. Signicant improvements in vision can theoretically be
expected using contact lenses that correct both lower- and higher-order
ocular aberrations [328]. However, lens exure, translation, rotation,
and tear layer effects associated with soft contact lens wear make the
correction of higher order aberrations challenging. Since vertical coma
is typically the most elevated higher-order aberration in keratoconus
[209,235,329,330], contact lens designs that correct comatic aberra-
tions have been a focus of numerous studies. Soft contact lenses designed
to correct coma aberrations alone can signicantly improve visual
quality in keratoconus patients without correcting other higher-order
aberrations [325,331–333]. Lens centration is a major factor that af-
fects the clinical performance of aberration-controlled contact lenses,
with visual performance decreasing when the decentration exceeds 0.5
mm [334]. More recently, a different approach has been proposed that
utilises a standardised soft lens tting set with several different verti-
cally asymmetric powers and axes, in a similar manner to soft toric
contact lens tting [333,335]. Using this approach, a prototype soft
contact lens design successfully corrected vertical coma and improved
quality of vision in keratoconus patients [333]. Further enhancements to
this approach included optimisation of the optic zone relative to the
pupil centre, which resulted in further improvements of the correction of
coma aberrations and overall visual performance [335]. Reverse ge-
ometry soft contact lens designs have also been used for keratoconus
correction [251,321,331,336].
9.2.3. Hybrid contact lenses
A hybrid contact lens consists of a rigid corneal lens and a peripheral
soft skirt to combine the optical benets of corneal rigid lenses and the
comfort provided by soft contact lenses. Early generation hybrid lenses
were often associated with decreased comfort, complications due to the
use of low oxygen permeability materials, and reduced durability of the
GP/soft material interface [337–339]. Current hybrid lens designs, such
as the ClearKone (Synergeyes, USA) or the Eyebrid (LCS laboratories,
France), have overcome some of these issues, but are still not widely
utilised in keratoconus management [340]. Their similar clinical per-
formance in terms of visual quality and comfort, but higher cost in
comparison with GP lenses may explain this limited uptake by eye care
practitioners [341–343].
9.3. Severe keratoconus
Severe cases of keratoconus may be managed with scleral lenses,
particularly when other lens modalities typically fail to achieve a
physiologically acceptable t [283–286]. If contact lens tting fails,
these cases may require corneal surgery, including corneal cross-linking,
refractive surgery, corneal transplantation, or a combination of several
refractive surgery procedures, for visual rehabilitation (Fig. 7). How-
ever, some surgical procedures are also used in mild to moderate cases of
keratoconus, such as corneal cross-linking, to prevent further progres-
sion regardless of the severity, and certain types of refractive surgery
which can be used in incipient cases as well. The different corneal sur-
gery procedures for keratoconus management are summarised in the
following section.
9.3.1. Surgical procedures
9.3.1.1. Corneal cross-linking (CXL). Cross-linking increases the
J. Santodomingo-Rubido et al.
Contact Lens and Anterior Eye xxx (xxxx) xxx
17
biomechanical stability and rigidity of the cornea in an attempt to pre-
vent keratoconus progression. The technique consists of the removal of
central 6–7 mm of corneal epithelium followed by the subsequent
application of 0.1% riboavin solution and corneal radiation of
ultraviolet-A light at 370 nm [344–346]. Ultraviolet-A radiation acti-
vates riboavin leading to the formation of covalent bonds between
collagen brils and the corneal stroma and an intense process of
apoptosis of keratocytes in the anterior stroma [347]. The irradiation at
the corneal endothelium, crystalline lens and retina is signicantly
smaller than the damage threshold [348]. This technique is contra-
indicated in corneas<400 µm in central thickness as it may cause toxic
reactions in the corneal endothelium [349,350].
Conventional CXL treatment involves removal of the corneal
epithelium prior to riboavin application and ultraviolet radiation (i.e.,
“epi-off” CXL). A number of long-term studies have demonstrated that,
on average, epi-off CXL typically attens the central cornea, improves
visual quality and reduces cone progression [351–353]. As such, this
surgical intervention is the rst treatment of choice for progressive
keratoconus patients [354], although clinical outcomes vary signi-
cantly from patient to patient [354–357]. This surgical procedure was
found to be safe and effective for keratoconus in children and adoles-
cents as evaluated post-operatively for periods ranging from 1 to 3 years
[358–361], with similar initial efcacy as in adults [362], particularly in
terms of improvement in visual and topographic outcomes following the
rst year of treatment [358]. Patients undergoing CXL typically still
require contact lens correction following surgery [363]. More recently,
several methods of “epi-on” (i.e., transepithelial) CXL have been pro-
posed as keeping the corneal epithelium intact is likely to be less painful
and may help avoid epi-off CXL-associated adverse events. Although
transepithelial methods are gaining popularity, epi-off CXL has been
shown to provide a better regularisation of the corneal surface and an
improvement of HOAs in comparison with epi-on CXL [364]. A study
investigated the 1-year outcomes of using 8 different combinations of
CXL techniques for treating keratoconus, including 2 different CXL
techniques (i.e., epi-on or epi-off), 7 riboavin formulations, and 2
ultraviolet-A protocols (i.e., conventional 3 mW/cm or accelerated 9
mW/cm), in 670 eyes of 461 patients with progressive keratoconus
[365]. Patients treated using the Dresden protocol were used as the
reference group. Epi-on CXL, the use of Meran riboavin, and applying
the accelerated irradiation protocol appeared to be associated with
reduced efcacy regarding controlling keratoconus progression, with
one-third of cases treated using epi-on CXL required re-treatment.
Corneal cross-linking has also been used successfully in combination
with corneal ring segments and other surgical techniques [366–371].
9.3.1.2. Refractive surgery. Various refractive surgery interventions
have been used for keratoconus management, with phakic lens im-
plantation and photorefractive keratectomy (PRK), being the two most
widely studied [372,373]. These techniques are contraindicated in
progressive keratoconus and are performed when the condition stabil-
ises. Refractive surgery techniques for keratoconus management may be
classied into: (1) corneal, which includes excimer laser surgery,
intracorneal ring segments, radial keratotomy and thermal therapy; (2)
intraocular, including phakic and pseudophakic intraocular lenses; and
(3) combinations of these procedures.
9.3.1.2.1. Corneal. Photorefractive keratectomy (PRK) uses an
excimer laser to permanently modify the shape of the anterior central
cornea by removing a small section of stromal tissue by vaporisation.
Results in keratoconic eyes have been moderately successful, with some
studies observing a signicant reduction in cone evolution in incipient
cases [374], as well as improved visual acuity and a reduction in higher-
order aberrations [375,376]. PRK is usually performed in combination
with CXL. A recent study which assessed the clinical outcomes of the use
of topography/wavefront-guided PRK using a new high-denition
aberrometer (iD2 system) in combination with CXL in mild to
moderate keratoconus reported a signicant improvement in corneal
shape regularity and visual and refractive outcome post- vs. pre-
operatively [369].
Intracorneal ring segments (ICRS) were initially developed to treat
low myopia [377], but have now evolved as a treatment for mild to
moderate keratoconus. This surgical intervention is indicated in trans-
parent corneas with a minimum thickness of 450 µm at the site of
incision [378,379] and involves the implantation of one or two segments
of polymethacrylate material into the corneal stroma to reshape the
irregular surface. This can lead to an improvement in uncorrected and
corrected visual acuity [379,380], a reduction in high-order corneal
aberrations [381], and a more regular corneal shape that facilitates the
tting of contact lenses [382]. This surgical intervention may prevent or
delay the need for corneal transplantation [380], and in combination
with CXL can reduce anterior corneal higher-order comatic aberrations
[370]. Although ICRS implantation can corneal curvature and improve
visual acuity irrespective of the patient’s age, this technique does not
seem to stabilise the disease progression, particularly in young patients
with more aggressive keratoconus [353].
Other refractive surgery techniques used in the past for the treatment
of keratoconus include radial keratotomy [383,384] and thermal ther-
apy [385–389]; however, they are no longer commonly used due to their
limited success rate.
9.3.1.2.2. Toric intraocular lens implantation (IOL). Phakic and
pseudophakic intraocular lens implantation for the treatment of kera-
toconus is usually performed in conjunction with other corneal refrac-
tive surgery methods, such as corneal rings or keratoplasty [234]. The
combination of these techniques, which are typically used to correct
high levels of astigmatism in intolerant contact lens wearers, has been
reported to improve visual acuity [390–392]. Of interest, however, is
that toric IOLs should only be considered in mild-moderate cases of
stable keratoconus with low levels of irregular corneal astigmatism,
when the patient has satisfactory visual acuity with spectacles (i.e. pa-
tients who are highly unlikely to require rigid corneal or scleral contact
lens correction following cataract surgery to improve vision) [393].
9.3.1.2.3. Combined procedures. The aforementioned surgical tech-
niques can be used in combination for keratoconus treatment, including
double (i.e., ICRS with IOL; ICRS with phakic IOL; ICRS with pseudo-
phakic IOL; Corneal CXL and corneal refractive surgery; and CXL with
phakic or pseudophakic IOL) and triple procedures with relative success
(i.e., ICRS with CXL, PRK or phakic IOL) [394–396].
9.3.2. Corneal transplantation and implantation
Corneal transplantation is the traditional treatment for advanced
keratoconus. Keratoconus has been reported to be the reason for 18% of
penetrating keratoplasty procedures, and 40% of deep anterior lamellar
keratoplasty interventions [397,398]. Anterior limiting lamina trans-
plantation might be benecial in certain cases of keratoconus with
extreme corneal thinning, although further research is necessary to
improve the technique [399,400]. Intrastromal implantation of stem
cells has also been proposed for regeneration or subtotal replacement of
the corneal stroma in advanced cases of keratoconus [401,402].
9.3.2.1. Keratoplasty. Penetrating keratoplasty (PK), which consists of
the removal of the entire thickness of the cornea and replacement with
donor tissue [403], is one of the most commonly used surgical tech-
niques for advanced keratoconus that cannot be successfully managed
with contact lenses [37,404–406], with 10 to 20% of keratoconics
eventually undergoing PK [8,407,408].
Deep anterior lamellar keratoplasty (DALK) is another surgical
technique used to replace diseased recipient stroma with donor corneal
stroma, while the recipient corneal endothelium and posterior limiting
lamina are retained. This technique preserves the ocular integrity,
permitting earlier suture removal and faster visual rehabilitation due to
faster wound recovery and, consequently, fewer wound healing-related
J. Santodomingo-Rubido et al.
Contact Lens and Anterior Eye xxx (xxxx) xxx
18
problems [409–411]. Patients that undergo PK are more likely to ach-
ieve better visual acuity than those that undergo DALK [405]; however,
there is an increased risk of endothelial cell loss and graft rejection with
PK compared to DALK [406].
9.3.2.2. Anterior limiting lamina transplantation. Anterior limiting lam-
ina transplantation is a novel technique that may stabilise progressive
ectatic corneal changes in eyes with advanced keratoconus, which are
too steep or too thin for CXL or ICRS [399]. In this way, patients can
maintain stable vision with contact lenses, and avoid or postpone more
invasive corneal transplants, such as PK or DALK. Recently, a new
technique has been reported in which an isolated anterior limiting
lamina’s layer is transplanted (as a corneal stromal inlay or as a corneal
onlay) into a manually dissected mid-stromal corneal pocket in patients
with advanced keratoconus. The technique has recently shown to be
effective in halting keratoconus progression and maintaining visual
acuity with contact lenses, at least up to 5–7 years postoperatively
[400].
9.3.2.3. Intrastromal implantation of stem cells. Different approaches to
regenerate or replace the corneal stroma in keratoconus have been
tested in-vitro and in-vivo in preclinical studies and include a range of
different stem cells such as: the intrastromal injection of stem cells
alone; intrastromal implantation of stem cells with a biodegradable
scaffold; intrastromal implantation of stem cells with a nonbiodegrad-
able scaffold; and intrastromal implantation of stem cells with a decel-
lularized corneal stromal scaffold [398,402].
10. Conclusions
Keratoconus is a bilateral and asymmetric ocular disease which has
been traditionally described as a noninammatory condition, but more
recently it has been associated with ocular inammation. It normally
develops in the second and third decades of life and typically progresses
until the fourth decade. The condition affects all ethnicities and both
sexes. Epidemiological studies indicate substantial global variation in
the prevalence and incidence of keratoconus, with highest rates typi-
cally occurring in 20- to 30-year-olds and Middle Eastern and Asian
ethnicities. The adoption of new technologies for imaging the human
cornea has contributed to a better understanding of the disease. These
imaging techniques, together with the increased use of wavefront
aberrometry, have allowed better characterisation of the optical,
anatomical, biomechanical, and histopathological changes associated
with keratoconus. Keratoconus progresses as a combination of simulta-
neously occurring destructive and healing processes. Corneal protru-
sion, the scissors reex, corneal thinning, Fleischer’s ring, and
prominent corneal nerve bres are the most prevalent clinical signs in
keratoconus, with all these signs observed in over 50% of patients with
keratoconus. However, the time course of the development of these
clinical signs and their association with disease severity are highly
variable. Although identifying clinical symptoms and slit-lamp ndings
in keratoconus are important, corneal topography is currently the pri-
mary diagnostic tool for keratoconus detection. In incipient cases,
however, the use of a single parameter as a diagnostic factor is not
sufciently accurate, and pachymetry and corneal aberration data are
now also commonly used in conjunction with corneal topography to aid
early diagnosis and monitor progression and treatment outcomes.
Corneal tomography that characterizes the anterior/posterior corneal
surfaces, along with corneal thickness distribution, has been found to
enhance the sensitivity and specicity for detecting corneal ectasia in
comparison to corneal topography, thus increasing the ability to detect
early or subclinical keratoconus. Furthermore, various machine learning
algorithms can be developed using routinely collected clinical parame-
ters that can assist in the objective detection of early forms of the dis-
ease. Keratoconus has long been considered to have a genetic
component. Although it is commonly an isolated ocular condition, it
sometimes coexists with other ocular and systemic diseases. A family
history of keratoconus, eye rubbing, eczema, asthma, and allergy are
risk factors for developing keratoconus. Keratoconus severity and pro-
gression may be classied based on morphological features and disease
evolution, ocular signs, and index-based systems. Treatment varies
depending on disease severity and progression. Mild cases are typically
treated with spectacles, moderate cases with contact lenses, while severe
cases that cannot be managed with scleral contact lenses may require
corneal surgery. Aberration-controlled soft contact lenses for keratoco-
nus are being developed, particularly with regards to correcting vertical
coma as this is typically the most elevated higher-order aberration in
keratoconus. Corneoscleral and scleral lenses have gained signicant
popularity in recent years, particularly because these lenses have been
able to provide successful outcomes when other contact lens options fail.
There have also been signicant developments in surgical options for
keratoconus, with mild to moderate cases of progressive keratoconus
now being commonly treated with corneal cross-linking; however,
randomized studies with larger cohorts and longer follow-up periods are
needed to determine which surgical procedure is most suitable for each
patient. The substantial amount of research activity conducted over the
last decade has contributed to advance our understanding of
keratoconus.
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