Graefe's Archive for Clinical and Experimental Ophthalmology

https://doi.org/10.1007/s00417-021-05081-8

REVIEW ARTICLE

Eye rubbing in the aetiology of keratoconus: a systematic review

and meta-analysis
Srujana Sahebjada 1,2,3 & Haitham H. Al-Mahrouqi 4 & Sophia Moshegov 1,3 & Sathiya M. Panchatcharam 5 &
Elsie Chan 1,3,6 & Mark Daniell 1,3,6 & Paul N. Baird 1

Received: 15 September 2020 / Revised: 3 January 2021 / Accepted: 9 January 2021

# The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021

Abstract
Purpose Keratoconus is a potentially blinding condition that slowly deforms the cornea in young people. Despite the increasing
prevalence of keratoconus, the exact aetiology of the condition is unknown. This first systematic review examines the evidence of
eye rubbing and its association with keratoconus and presents the findings of the meta-analysis.
Methods Two independent reviewers searched the electronic databases for all potential articles published from 1st of January
1900 to 31st of July 2020 on eye rubbing and keratoconus. The researchers assessed the methodological quality of the studies
using the Newcastle-Ottawa scale for observational studies. The assessment for statistical heterogeneity was estimated using chi-
square and I-square (I2) tests. A p value of < 0.05 was considered as statistically significant and I2 < 30% as homogenous. Begg
funnel plot was used to interpret the asymmetry or small study effects.
Results Eight case-control studies were included in this systematic review. Two studies assessed eye rubbing without odds ratios
and thus were excluded. The pooled odds ratios for the six remaining studies included in the meta-analysis was 6.46 (95% CI
4.12–10.1). The study results were heterogenous (I2 = 71.69 [95% CI 35.14–87.88]). All the studies scored moderate quality
methodology on the Newcastle-Ottawa scale. Begg funnel plot showed asymmetry supporting heterogeneity.
Conclusion Eye rubbing showed consistent association with keratoconus. However, the current evidence is limited to only a
small number of case-control studies which present as heterogeneous and of sub-optimal methodological quality. Additionally,
the cause-effect temporal relationship cannot be determined. Further studies are needed to address this intricate relationship of eye
rubbing and its induction, ongoing progression, and severity of keratoconus.

Key messages

The relationship between eye rubbing and the pathogenesis of keratoconus is still inconclusive.

This first systematic review examines the evidence of eye rubbing and its association with keratoconus.

Although there is strong evidence of association between eye rubbing and keratoconus, there remains a need
for further elucidation of the nature of this relationship.

Srujana Sahebjada contributed equally to this work.

* Srujana Sahebjada 2
Faculty of Medicine, Dentistry and Health Sciences, The University
Srujana.sahebjada@unimelb.edu.au of Melbourne, Level 7, 32 Gisborne St, East Melbourne, VIC 3002,
Australia
3
1
Department of Surgery, Ophthalmology, The University of Centre for Eye Research Australia, Melbourne, Australia
Melbourne, Level 7, 32 Gisborne St, East Melbourne, VIC 3002, 4
Al-Nahdha Hospital, Ministry of Health, Muscat, Oman
Australia 5
Oman Medical Specialty Board, Muscat, Oman
6
Royal Victorian Eye and Ear Hospital, Melbourne, Australia

Keywords Keratoconus . Eye rubbing . Aetiology . Risk factor . Meta-analysis . Review
Introduction
Keratoconus has been classically defined as a non-inflamma-
tory, bilateral disease of the cornea characterised by progres-
sive thinning and apical protrusion [1]. This definition dates
back more than 30 years with more recent studies suggesting
that keratoconus should now be thought of as an inflammatory
disease [2–4] whereby its progression may be slowed or
halted if the inflammation is controlled [5].
As with all complex diseases, keratoconus appears to be
associated with both genetic and environmental risk factors.
First-degree relatives and twins of keratoconus patients have a
higher incidence of the disease than the general population [6,
7]. Many genetic variants have been reported to be associated
with keratoconus although few of these have been consistently
replicated [8, 9]. In addition, multiple ocular and systemic
syndromes have been linked with keratoconus including
Leber’s congenital amaurosis [10], Down syndrome [11],
and Ehlers-Danlos syndrome [12]. Nevertheless, the heredi-
tary pattern is neither common nor predictable.
Environmental factors which have been implicated in the
pathogenesis of keratoconus include eye rubbing, atopy, aller-
gic eye disease, eczema, and UV-light exposure [13, 14]. Of
these diverse factors, eye rubbing has been commonly studied
and reported.
There have been several publications exploring the rela-
tionship between eye rubbing and the pathogenesis of
keratoconus. Still, the evidence is inconclusive. Many oph-
thalmologists currently believe in the adverse effect of eye
rubbing [15].Yet, there is no systematic review and meta-
analysis to our knowledge which has exclusively explored
the association of eye rubbing with keratoconus and
scrutinised the evidence. The purpose of this article is to sys-
tematically review the evidence of eye rubbing as a risk factor
for keratoconus and assess its quality.
Materials and methods
This review was registered in the PROSPERO International
Prospective Register of systematic reviews (registration num-
ber CRD42018081275) in 2018. The review process followed
those outlined as per PRISMA checklist 2009 (PlosMed
e000097, 2009).
Definitions
– Keratoconus: A non-inflammatory disease of the cornea
characterised by thinning and apical protrusion.
Graefes Arch Clin Exp Ophthalmol
– Diagnosis of keratoconus: A constellation of signs and
symptoms including progressively worsening refractive er-
ror, scissoring reflex on retinoscopy, irregular astigmatism,
slit lamp signs (Fleischer ring, Vogt’s striae, corneal thin-
ning and scarring), and topographical or tomographical ev-
idence of corneal ectasia.
Literature search strategy
Electronic databases including, MEDLINE, EMBASE, and
PUBMED CENTRAL were searched for all potential articles
published from 1st of January 1900 to 31st of July 2020.
MeSH terms and keywords used to balance the sensitivity
and specificity in the search included keratoconus, ectasia,
corneal ectasia, eye rubbing, itch, ocular allergy, and allergic
conjunctivitis. Grey studies were identified from the refer-
ences of the included literature. This review was carried out
according to the guidelines of the Declaration of Helsinki.
Inclusion criteria
Primary studies were considered eligible for inclusion in this
review if they met the following criteria:
– Full original articles
– Published from 1st of January 1900 to 31st of July 2020
– English language only
– Studies involving human beings only
– Randomised controlled trials and non-randomised obser-
vational studies (cohort and case-control studies) which
assessed eye rubbing as a risk factor for the development
of keratoconus.
There was no limit on the population group in terms of age,
sex, ethnicity, or co-morbidities.
Exclusion criteria
– Studies assessing ocular allergy or atopy without
assessing eye rubbing independently as a risk factor.
– Cross-sectional studies which used multivariate
analysis to explore potential risk factors. Such stud-
ies are more hypothesis generating rather than hy-
pothesis testing.
– Review articles and case reports were excluded.
Graefes Arch Clin Exp Ophthalmol
Study selection
Two reviewers (H.M and S.S) independently screened the
titles of the publications for the inclusion criteria and all po-
tential studies were noted. The abstracts were then read to
further filter the included studies. The complete texts of the
studies were then obtained and read in full to fulfil the final
inclusion.
Data extraction
The two researchers (H.M and S.S) independently extracted
information from the included studies. Data extracted includ-
ed the title, authors, date, country of origin, study design,
demographics, sample size, disease definition, assessment of
eye rubbing, covariates adjusted, results including risk mea-
surements, and p values. Any disagreement was resolved by
reaching a consensus through discussion.
Outcome
Diagnosis of keratoconus.
Quality assessment of the methodology of included
studies
The researchers assessed the methodological quality of the
studies using the Newcastle-Ottawa scale [16] for observa-
tional studies. The Newcastle-Ottawa scale assigns a maxi-
mum of nine points to each study: four points for selection,
two points for comparability, and three points for exposure or
outcome. The scale does not specify a certain cut-off score for
low- or high-quality methodology. Nevertheless, we consid-
ered a score from 0 to 3 to be low quality, 4 to 6 to be moderate
quality, and 7 and above as high quality.
Statistical analysis
Pooled data were analysed using MedCalc Statistical
Software version 17.8.6 (MedCalc Software bvba,
Ostend, Belgium). The assessment for statistics hetero-
geneity was estimated depending on chi-square and I-
square (I2) tests. The random effect model was applied.
A p value of < 0.05 was used for statistical significance
and I 2 < 30% as homogenous. Begg funnel plot was
used to statistically measure the funnel plot asymmetry
(A.K.A small study effects) associated with publication
bias, methodological disparity, and true heterogeneity
[17, 18].
Results
The literature search
The initial database and grey literature search revealed 153
articles excluding duplicates (Fig. 1). A total of 129 articles
were eliminated through screening the titles and abstracts for
keywords based on the exclusion criteria mentioned above.
Additional application of the inclusion and exclusion criteria
was applied to the full text and this limited the articles down to
eight articles.
Study characteristics
Eight case-control studies were included in this systematic
review. Detailed study characteristics are presented in
Table 1. The studies were from a range of countries with 3
from Israel [19–21], one from Iran [22], and one each from
Australia [23], Canada [24], Scotland [25], and France [26].
Keratoconus case definition varied between the studies. The
size of the studies varied with three studies comprising cases
of 200 or more [22, 26].
The mean age of participants in the study ranged
between 25 and 42 years and all but one at 48% [19]
had greater than 50% male participation. Eye rubbing
was assessed using a questionnaire [19–21, 23–25] or
a person to person interview [22, 26].
Forest plot and meta-analysis
A total of eight studies were available; however, 2 of the
studies assessed eye rubbing using a visual analogue scale
[23, 25] revealing only percentages without odds ratio (OR)
which prevented their inclusion in the forest plot. All the stud-
ies did report a positive association between eye rubbing and
keratoconus. Of the six remaining studies available for inclu-
sion in the forest plot, the OR reported were between 4.33
(95% confidence interval (95% CI) of 3.20–5.85) [22] and
OR 11.95 (95% CI 7.69–18.62) [26] (Fig. 2). The pooled
OR (fixed effects) was 5.93 (95% CI 4.82–7.29), whereas
the pooled (random effects) was slightly higher (OR 6.46;
95% CI 4.12–10.13) with a p value < 0.001 (Fig. 2). The latter
value was likely most reflective as the true effect size may
have varied from study to study depending on the interven-
tion. The study results were heterogenous (I2 = 71.69 [95% CI
35.14–87.9).
Quality assessment
The quality of the studies included was assessed using the
Newcastle-Ottawa scale for case-control studies with a quality
score point applied for each of nine different measures under
broader category headings of participant selection,

Fig. 1 Flowchart of the study
selection process until 31st
Idenficaon
July 2020
Screening
Eligibility
Inclusion
comparability between cases and controls, and their exposure
(ascertainment and non-response rate) (Table 2). All studies
reported adequate case and control definition and ascertain-
ment in terms of the collection of participants; however, many
studies lost a quality score point due to lack or non-report of an
assessed factor. In some participants, the sampling method
was not specified for cases [20, 24] or controls [23, 24], and
thus, a quality score point was lost. In 2 studies, population-
based controls were used [20, 22] whereas the remaining stud-
ies lost a score point for their use of hospital-based controls. A
total of 5 studies were matched for age and sex whereas 3
studies lost a score point as they did not undertake case-
control matching [23, 25, 26]. Five of the studies controlled
for a range of confounders including wearing of contact
lenses, allergy, smoking and family history whereas one study
did not match for any risk factors [25] or had minimal con-
founders included [19] and subsequently lost a score point.
The majority of the studies (6 out of 8) undertook a written
questionnaire with two studies [22, 26] undertaking a more
extensive face-to-face interview and attaining a score point.
None of the studies reported their non-response rate and sub-
sequently lost a score point (Table 2). At the conclusion of this
scoring, all the studies scored between 5 and 6 out 9 points
which is moderate in quality (Table 2).
Funnel plot
The Begg funnel plot showed asymmetry with the Moran
et al. [26] study falling far away from the funnel (Fig. 3).
The asymmetry supports the heterogeneity found and the pos-
sibility of publication bias. It is worth noting that no
Graefes Arch Clin Exp Ophthalmol
Records idenfied through
database and grey literature
searching excluding
duplicates (n=153)
Excluded by title and abstract
(n=129)
Records screened by full text
against the eligibility criteria
(n=25)
Excluded due to failure to
meet the inclusion criteria
(n=7).
Potential articles ( n=18)
Excluded due to cross-
sectional studies or failure to
assess eye rubbing (n=11).
Studies included (n=8)
publications were found which showed a negative or neutral
association of eye rubbing and keratoconus.
Discussion
We identified a strong association between eye rubbing and
keratoconus (OR = 6.46) through this meta-analysis.
Although the eligible studies included were heterogenous,
all the studies analysed supported a positive association be-
tween eye rubbing and keratoconus. The studies included
scored moderate quality in terms of their methodology.
Begg funnel plot showed asymmetry.
The association of eye rubbing and keratoconus was con-
sistent with previous literature [27–29]. Despite eye rubbing
being generally accepted within the field, the exact mecha-
nisms of how eye rubbing is associated with keratoconus is
still not yet clear.
A limitation of the current meta-analysis rests on the qual-
ity of the included studies. The quality of these studies could
be improved through more thorough collection of sampling
methods, case-control matching, and subsequent analysis of
the data. This includes controlling for confounders, for exam-
ple, using multivariate analysis. Additionally, the examination
of risk factors in these studies indicated, a lack of
standardisation in the method of data collection, and definition
and/or criteria for eye rubbing. Establishing an effective, eas-
ily administered questionnaire for assessing eye rubbing
would strengthen the methodological quality of such studies.
The importance of question format is highlighted by Weed
et al. who utilised both a closed question method and visual
Table 1 The characteristics of the studies included involving eye rubbing and keratoconus (M- Male)

Author Study Country Type of Definition No. No. of Mean M% How is eye Covariates Results Is eye Newcastle- Exclusion
period study of controls age rubbing adjusted rubbing Ottawa
cases assessed? a risk scale
factor?

Mostovoy NA Israel Case-control Clinical signs of 50 72 32 48% Simple question Matched for Keratoconus patients were more Yes 6/9 Included
et al. keratoconus, central on the age and likely to rub their eyes more than
(2017) corneal power superior to frequency of sex only once daily. OR 4.5 (CI
48.7 D, and an inferior eye rubbing 1.76–11.45, p value <0.001).
Graefes Arch Clin Exp Ophthalmol

superior asymmetry more than

above 1.4 once a day
Bawazeer 1985–1999 Canada Case-control Four out of the five signs 49 71 32 53% Questionnaire? Matched for Keratoconus patients were more Yes 5/9 Included
et al. below: (1) Munson’s Simple age, sex, likely to rub their eyes. OR 6.41
(2000) sign, (2) Fleisher ring, (3) question and race. (CI 2.54–16.2, p value <0.001).
stress lines, (4) inferior
steepening on corneal
topography, (5) a posi-
tive I-S value (greater
than 1.26 dioptres)
McMonnies NA Australia Case-control Based on history, slit lamp 53 53 42 60.0% Questionnaire Not matched Keratoconus patients were more Yes 5/9 Included
et al. 2003 examination, using a series for age or likely: (1) to rub their eyes as a
retinoscopy, of questions sex. teenager (mean analogue score 35
keratometry, and Controlled for keratoconus, 14 for controls);
videokeratography for contact (2) to currently suffer from itchy
lens wear eyes (mean analogue score 36 for
keratoconus, 20 for controls); (3)
frequently rub their eyes as a teen-
ager (mean analogue score 44 for
keratoconus, 18 for controls); (4)
frequently rub their eyes as an
adult (mean analogue score 40 for
keratoconus, 21 for controls).
Weed et al. 1997–2000 Scotland Case-control Clinical diagnosis based on 200 100 31 63% Questionnaire Not matched Keratoconus patients were more Equivocal 5/9 Included
2008 slit lamp signs and using a visual for age, likely to rub their eyes when using
topography. analogue scale sex, or the visual analogue scale (p<
question and a contact 0.018) but not when asked a
closed-ended lens wear close-ended question.
question.
Gordon-Shaag 2010–2012 Israel Case-control Abnormal topography and 70 140 26 51% Questionnaire Matched for Multivariate analysis shows that Yes 5/9 Included
et al. 2013 at least one of the using a simple age and keratoconus patients were more
following signs: stromal question “do sex. likely to rub their eyes (OR 10.15;
thinning, Munson sign, you regularly CI 4.37–23.54, p value <0.001).
Fleischer ring, or Vogt rub your
striae eyes?” And
answer of a
scale 1 to 5.
Naderan et al. 2012–2014 Iran Case-control Slit lamp signs and 461 461 25 61% Person to person Matched for Multivariate analysis shows that Yes 6/9 Included
2015 tomography interview age and keratoconus patients were more
using a simple sex. likely to rub their eyes (OR 3.35;
question “do CI 2.35–4.77, p value <0.001).
you regularly
rub your
eyes?” And
answer of a
scale 1 to 5.
 Graefes Arch Clin Exp Ophthalmol

Newcastle- Exclusion
analogue scale within a questionnaire collecting information

Included

Included
on eye rubbing. While the data from the visual analogue scale
found a significant association between eye rubbing and
keratoconus, the closed question method did not [25]. This
rubbing Ottawa

illustrates the need for further research into the methods of

scale

6/9

5/9
data collection, and for development of a standardised ques-
tionnaire for common risk factors.
factor?
Is eye

a risk

In a similar vein, the literature on eye rubbing and

Yes

Yes
keratoconus widely differs in terms of the definitions and

knuckle (OR=8.29, CI 3.92–18.26,

likely to rub their eyes (OR=3.37,

p value=<0.001). NOTE: No OR
criteria for eye rubbing. Studies have assessed different as-
keratoconus patients were more

keratoconus patients were more

CI 1.68–6.77, p value=0.001)

likely to rub their eyes with a

pects including force, technique, and frequency which are all
Multivariate analysis shows that

Multivariate analysis shows that

incorporated under the broad term of eye rubbing [19–23, 30].

for overall eye rubbing

It is important to differentiate between these various types and
techniques as it has been suggested that only repetitive and
prolonged eye rubbing may alter corneal biomechanics to a
significant extent to thereby influence keratoconus, and great-
Covariates Results

er force of eye rubbing may be associated with a higher risk of

its progression or severity [23, 26, 31–33]. Furthermore, it will
Adjusted for
ethnicity.
Matched for
age, sex,

age only

be important to differentiate between these factors when

adjusted

and

collecting data on self-reported eye rubbing as technique and

rubbing above a certain force may be of significance. Hafezi
using a simple

et al. identified three main techniques of eye rubbing in

and the mode
they rub their
you regularly

53% Simple question

question “do

scale 1 to 5.
answer of a

on whether

of rubbing.
eyes or not
eyes?” and
Questionnaire
How is eye

keratoconus patients. These included eyes rubbing utilising

rub your
assessed?
rubbing

the fingernail, the fingertip, and the knuckle. While fingertips

have been reported as the most frequent method of rubbing, it
has been shown that knuckle eye rubbing exerts significantly
64%
No. No. of Mean M%

more force [30]. This contrasts to the study by Moran et al.

who reported that the use of the knuckle was the most signif-
controls age

icant method of eye rubbing (OR 8.29; 95% CI 3.92–18.26)

27

31

followed by fingertips (OR = 5.34; 95% CI 2.44–12.21) [26].

Despite the methodological differences in the collected
146

355

studies, the literature has been consistent in reporting that

cases

keratoconic patients rub their eyes with greater force than

202
73
of

non-keratoconus patients [27, 34]. This suggests that force

tomographic and clinical
Case-control Diagnosed based on at least

rather than technique may be more important in facilitating

and corneal topography.
Vogt’s striae, Munson,
clinical signs: stromal
thinning, Fleischer’s,
one of the following

the development of keratoconus which should be explored as

Case-control Diagnosed based on

an area of future research. Additionally, the frequency at

which keratoconus patients rub their eyes compared to non-
Definition

keratoconus individuals has not been investigated in detail.

data.

This may be important as more frequent rubbing may reduce

the propensity of the ocular surface to recover between epi-
sodes of eye rubbing which has been shown to elevate the
Country Type of
study

levels of proteases and inflammatory molecules after only

60 s [35]. Therefore, while studies have reported greater fre-
quency of eye rubbing in keratoconus patients, more specific
2014–2017 France
2012–2014 Israel

measures of frequency should be collected to gain better in-

sight into the extent of the importance of frequency in the
Table 1 (continued)

aetiology and severity of keratoconus. Thus, there is a need

period
Study

to standardise questionnaires and better quantify eye rubbing

frequency as an objective rather than as a highly variable self-
Gordon-Shaag
et al. 2015

Moran et al.

reported measure.
Author

2020

While further research on the force, frequency, and tech-

niques involved in eye rubbing may have potential for higher
Graefes Arch Clin Exp Ophthalmol

Fig. 2 Forest plot of the eye 2.541 to 16.203

rubbing studies included in the Bawazeer et al. (2000)
meta-analysis 5.232 to 22.933
Gordon-Shaag et al. (2013)
3.206 to 5.849
Naderan et al. (2015)
2.402 to 7.924
Gordon-Shaag et al. (2015)
1.767 to 11.459

C.I.
Mostovoy et al. (2017)
7.672 to 18.620
Moranetal.(2020)

4.820 to 7.285
Total (fixed effects)
4.121 to 10.130
Total (random effects)

1 10 100

quality methodology, a significant area of research that still
remains is elucidating the mechanisms which underlies the
role of eye rubbing in either the initial development or in the
progression and severity of keratoconus.
Studies have demonstrated that keratoconic corneas are
characterised by overexpression of inflammatory cytokines
including IL-1, IL-4, IL-6, IL-10, IL-17, TNF-α, and IFN-γ
[36–38]. However, only one study has investigated the effect
of eye rubbing on ocular cytokine levels in detail.
Balasubramanian et al. investigated the levels of proteases
and inflammatory molecules in normal (non-keratoconic) eyes
after 60 s of eye rubbing. MMP-13, IL-6, and TNF-α levels
were significantly increased suggesting that eye rubbing in-
duces mechanical trauma causing an increase in signalling
factors [35]. These results were consistent with several studies
finding increased levels of these enzymes and inflammatory
cytokines in the tears of keratoconus patients [36, 38].
Continued research into this area is vital for the development
of future treatment strategies for keratoconus. This is essential,
given that contact lenses, the first-line treatment for
keratoconus, have been found to trigger release inflammatory
cytokines and proteases associated with corneal scarring [3,
39, 40]. Another practical application of future research in this
area is development of a biomarker. IL-6 has been correlated
with keratoconus severity, raising the question of its use as a
marker of disease progression [36]. This was supported by
findings from Kolozsvari et al. who showed that IL-6 levels
decrease 1 year after corneal cross-linking [41]. Therefore,
further research in establishing a potential biomarker of the
impact of eye rubbing on keratoconus progression, as well as
inflammatory mediators of keratoconus in general, presents as
future novel targets for preventing onset and progression of
this disease.
Interestingly, a recent review has investigated the preva-
lence and risk factors for keratoconus through 29 articles
representing over 7 million individuals from 15 countries
[42]. In their study, they identified eye rubbing as the largest
non-genetic risk factor with OR 3.09 (95% CI 2.17–4.00).
Although the OR reported was slightly lower than the overall
OR reported in the current paper, it demonstrates a common
basis for eye rubbing in keratoconus patients. Several of the
studies included in their analysis overlapped with the studies
presented here, namely Bawazeer et al. [24], Gordon-Shaag
et al. [21], and Naderan et al. [22]. However, the studies by
Weed et al. [25], Mostovoy et al. [19], and McMonnies and
Boneham [23] were not included by Hashemi et al. [42].
Conversely, several studies [43–45] that were included in
the Hashemi et al. study (40) were not included in the current
study. This is due to the difference in aims, inclusion and
exclusion criteria, and search strategies between this system-
atic review and their review. Hashemi et al. [42] sought to
determine the prevalence and risk factors for keratoconus.
Therefore, their search terms were “keratoconus, KC, obser-
vational studies, cross-sectional studies, case–control studies,
cohort studies, and survey” rather than the search terms
“keratoconus, ectasia, corneal ectasia, eye rubbing, itch, ocu-
lar allergy, and allergic conjunctivitis” that were applied in the
current study and specifically targeted to eye rubbing terms for
a systematic review. In addition, Hashemi et al. included
cross-sectional studies. Our review article did not include
cross-sectional studies as these serve to generate a hypothesis
rather than test association. Hashemi et al. also limited their
inclusion criteria to one study from each population, stating
that “If several studies were conducted in a certain population,
the study with a higher quality was included in the analysis”.
However, they included three studies from Iran and three
Table 2 Study specific Newcastle-Ottawa scale scorning of eye rubbing studies and keratoconus (★ denotes allocation of a point)

Selection Comparability Exposure Total

Is the case Representativeness Selection of Definition Comparability of cases and controls on the basis Ascertainment Same method of Non-response rate
definition of the cases controls of controls of the design or analysis of exposure ascertainment for
adequate? cases and
Matching for age and Controlling for additional controls
sex confounders

Mostovoy et ★ ★ ★ ★ ★ Did not control for other Written ★ Not clearly 6/9
al. (2017) factors such as ocular questionnaire described
allergy, blepharitis, and
wear of contact lenses.
Bawazeer et al ★ Sampling not stated Not clear ★ ★ ★ (controlled for atopy) Written ★ Not clearly 5/9
(2000) questionnaire described
McMonnies et ★ ★ Not clear ★ Did not match for age ★ (controlled for contact lens Written ★ Not clearly 5/9
al 2003 and sex wear, but not ocular allergy) questionnaire described
Weed et al. ★ ★ ★ ★ Did not match for age Did not match for any Written ★ Not clearly 5/9
2008 and sex additional risk factor questionnaire described
Gordon-Shaag ★ Sampling not stated Hospital ★ ★ ★ (multivariate regression Written ★ Not clearly 5/9
et al. 2013 controls analysis controlling for questionnaire described
consanguinity, allergy,
education, and wear of
sunglasses. However, not
to contact lens wear)
Naderan et al. ★ ★ Hospital ★ ★ ★ (multivariate regression Interview, ★ Not clearly 6/9
2015 controls analysis controlling for interviewer described
KC in relatives, sun not blinded
exposure, itchy eyes,
smoking, and education level)
Gordon-Shaag ★ ★ Hospital ★ ★ ★ (multivariate regression Written ★ Not clearly 6/9
et al. 2015 controls analysis controlling for questionnaire described
family history of KC,
wearing a hat, time in the
shade) However, not to
contact lens wear.
Moran et al. ★ ★ Hospital ★ The study was not set ★ (multivariate regression Interview, ★ Not clearly 5/9
2020 controls to match age and analysis controlling for age, sex, interviewer described
sex allergies, dry eyes, and sleep not blinded.
position)
Graefes Arch Clin Exp Ophthalmol
Graefes Arch Clin Exp Ophthalmol

0.0 values (3.92–18.26) for knuckle rubbing. Based on the funnel

plot, it can be seen that the study by Moran at al. fell outside
0.1 the statistical boundaries expected and exclusion of the Moran
study from the current meta-analysis resulted in an overall
lowering of OR from 6.46 to 5.23 and the overall study results
0.2
became homogeneous (I2 of 29%) (Fig. 4). This further illus-
trates the need to obtain better quality data on this important
0.3 risk factor in keratoconus aetiology.
Despite this, both review articles came to the same conclu-
0.4
sion that eye rubbing presents as a significant risk factor for
keratoconus.

0.5
1 10 100
Odds rao
Conclusion
Fig. 3 Begg funnel plot (arrow points towards the location of Moran
et al. study)
Although there is strong evidence of association between eye
rubbing and keratoconus, there remains a need for further
studies from Israel. We did not apply such a limit in our study
elucidation of the nature of this relationship. Such studies
(see Table 1). Furthermore, our review was more focused on
would be greatly aided by a standardisation of methodology
eye rubbing, interpreted the quality of the methodology of the
and data collection through improved measurement of eye
studies, and included more recent articles.
rubbing including frequency, force, and technique.
In contrast to the current systematic review, the meta-
Furthermore, there remains a requirement for greater clarifi-
analysis undertaken by Hashemi et al. found that the included
cation into the temporal relationship between eye rubbing and
studies were homogenous. We therefore examined the studies
development and subsequent progression of keratoconus, es-
included in the current systematic review to investigate if any
pecially as keratoconic teenagers compared to adults have
one study was driving heterogeneity. It was identified that the
been shown to present with different levels of eye rubbing
recently published study by Moran et al. [26] that reported the
[23]. Finally, the molecular mechanisms underlying
highest OR of any of the collected studies appeared to be
keratoconus also represent an important area of future research
skewing the heterogeneity. We noted that this study reported
through investigation of the interplay between eye rubbing
the highest OR of 8.29 of any of the studies included in the
and progression of keratoconus.
current meta-analysis but also reported very wide 95% CI

Fig. 4 Forest plot of the studies

2.541 to 16.203
excluding Moran et al. study Bawazeer et al. (2000)
5.232 to 22.933
Gordon-Shaag et al. (2013)
3.206 to 5.849
Naderan et al. (2015)
2.402 to 7.924
Gordon-Shaag et al. (2015)
C.I.

1.767 to 11.459
Mostovoy et al. (2017)

3.862 to 6.178
Total (fixed effects)
3.765 to 7.273
Total (random effects)

1 10 100

Funding This study was supported by the Australian National Health and
Medical Research Council (NHMRC) project Ideas grant APP1187763
and Senior Research Fellowship (1138585 to PB), the Angior Family
Foundation (SS), Keratoconus Australia (SS), Perpetual Impact
Philanthropy grant (SS), Lions Eye Foundation Fellowship (SS), and
CERA Hector MacLean Scholarship (SM). The Centre for Eye
Research Australia (CERA) receives Operational Infrastructure Support
from the Victorian Government.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethics approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Consent to participate Not applicable.
Consent for publication All the authors consent for publication.
Declarations Not applicable.
Code availability Not applicable.
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