Keratoconus Development Risk Factors a Contralateral Eye Study

Journal of EuCornea 7 (2020) 1–3

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Journal of EuCornea

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Keratoconus development risk factors: A contralateral eye study T ⁎ Otavio A. Magalhaes ,1, Fernanda M.F. Fujihara, Eduardo B.N. de Brittes, Rafael N. Tavares

Porto Alegre Eyes Bank Hospital, 285 Engeneer Walter Boehl Street, Porto Alegre, Rio Grande do Sul, Brazil

ARTICLE INFO ABSTRACT

Keywords: Objective: The goal of this study is to evaluate risk factors for advanced keratoconus (KC) development using Keratoconus marked asymmetrical cases. Eye rubbing Methods: This is a prospective case-control contralateral eye study that evaluated 58 consecutive participants Corneal ectasia with very asymmetric KC from the department of cornea and external disease at the Porto Alegre Eye Bank Corneal transplant Hospital, Brazil between March and November 2019. Risk factors for KC development were analyzed by patient Blepharitis interview (eye-rubbing behavior, atopic related diseases and identification of dominant hand), slit-lamp ocular surface examination and dry-eye tests. KC characterization was performed using the Pentacam® HR Scheimpflug tomography (Oculus GmbH, Wetzlar, Germany). Results: The mean age of the participants was 27.17 ± 10.69 years (range: 16 to 56 years). Two thirds of patients presented history of allergic rhinitis. As expected, we found significant differences in BCSVA, K1, K2, Kmax and thinnest pachymetry (all P < 0.001) between cases and the contralateral eye. Reported eye-rubbing frequency was significantly higher in eyes with advanced KC (p < 0.001). Signs of blepharitis and dry-eye were very similar between both groups (p > 0.05). We observed no correlation between hand dominance and advanced KC laterality (p > 0.05). Conclusion: This approach enabled us to examine a pure association between risk factors and KC development. Although we reported an increased patient-reported frequency of rubbing in eyes with advanced KC, we could not find any significant difference in ocular surface parameters (blepharitis signs and dry eyes tests) between cases and control that justified increased corneal manipulation.

1. Introduction 2. Materials and methods

Keratoconus (KC) is a progressive disease characterized by thinning This case-control study followed the tenets of the Declaration of and protrusion of the central cornea. Over the last several decades, KC Helsinki and the approval of the Institutional Review Board of the has been described as a multifactorial disease involving complex in- Clinical Hospital of Porto Alegre (#19-0559), Brazil. Informed consent teractions between genetic and environmental factors, both of which was obtained from the subjects after explanation of the nature of the contribute to disease manifestation [1,2]. Expression of inflammatory study. mediators, such as proinflammatory cytokines, cell adhesion molecules, and matrix metalloproteinases, are also associated with tissue de- 2.1. Study participants gradation in KC [3,4]. The influence of atopic syndrome and eye rubbing on KC has been suggested for more than half a century, but it A total of 58 participants with KC were included in this prospective remains an unsettled issue because multiple studies have shown con- contralateral eye study between March and November 2019 via con- tradictory results [5–7]. Also, KC patients have an increased prevalence secutive enrollment at the Cornea and External Disease Clinic at Porto of signs and symptoms of blepharitis in addition to signs and symptoms Alegre Eye Bank Hospital, Brazil. For both eyes to be considered of dry-eye syndrome when compared to general population [8]. asymmetrical, the difference between the mean curvature power (Km), Thus, our goal was to compare behavioral and suspected ocular flat curvature power (K1), or steep curvature power (K2) was ≥ 5 surface characteristics between both eyes of patients with marked diopters, and the difference between the thinnest corneal points (thin- asymmetrical KC. nest pachymetry) was ≥ 50.0 μm between both eyes. The clinically

⁎ Corresponding author at: 333 Mostardeiro Street, Office 503. Porto Alegre, Rio Grande do Sul, Brazil. E-mail address: [email protected] (O.A. Magalhaes). 1 ORCID identifier 0000-0002-9429-2109. https://doi.org/10.1016/j.xjec.2020.02.003 Received 28 January 2020; Received in revised form 22 February 2020; Accepted 26 February 2020 Available online 29 February 2020 2452-4034/ © 2020 The Author(s). Published by Elsevier Inc. on behalf of European Society of Cornea & Ocular Surface Disease Specialists. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). O.A. Magalhaes, et al. Journal of EuCornea 7 (2020) 1–3 moderate to severe KC (Stage II, III, or IV according to The ABCD Table 2 Grading System) was designated as the case group [9]. The con- Contralateral Comparison of Visual Acuity and Pentacam Parameters. fi tralateral eye, clinically classi ed as forme fruste to mild KC (Stage 0 or Parameters Case Control I according to The ABCD Grading System) served as the control group. Exclusion criteria were previous corneal surgery, progressive KC, con- Mean ± SD Mean ± SD Mean difference P-value a tact lens wearer, single eye, history of other anterior segment disease, BCSVA 0.92 ± 0.35 0.18 ± 0.22 0.74 < 0.001* K1b 57.26 ± 9.96 45.76 ± 3.77 11.5 < 0.001 and active use of topical steroids. K2b 63.34 ± 10.84 48.55 ± 5.09 14.79 < 0.001 Kmaxc 71.33 ± 11.74 52.60 ± 7.42 18.73 < 0.001 d – 2.2. Definitions and examination Pachymetry 386.4 ± 71.05 475.9 ± 46.48 89.48 < 0.001 a Best-corrected spectacle visual acuity in logMAR; bKeratometry in diopters; In order to evaluate the risk factors for KC development, we per- cMaximum keratometry in diopters; dThinnest pachymetry in μm. formed patient interviews (eye-rubbing behavior, atopic related dis- fi eases, and identi cation of dominant hand), routine ophthalmic ex- Table 3 aminations consisting of best-corrected spectacle visual acuity (BCSVA) Comparison of Eye Rubbing Reported Frequency. measurements (logMAR), slit-lamp examination, tear break-up time Parameters Case Control P-value (sec), standard Schirmer II test, and dilated fundus examination. Eye-rubbing behavior was assessed by the following questions (in Never (%) 0 (0) 4 (6.8) the exact sequence): “Do or did you rub your eyes?”“Do or did you rub Once a week (%) 2 (3.4) 11 (18.9) one eye more than another?”“If yes, what eye do or did rub more?” More than once a week and less than once a 10 (17.2) 15 (25.8) day (%) How often do or did you rub each eye?” The answers were then at- Once a day (%) 13 (22.4) 16 (27.5) tributed to the eye and analysed. The Schirmer test was performed with More than once a day (%) 33 (56.9) 12 (20.6) < 0.001 paper strips (Ophthalmos Pharma; Sao Paulo, Brazil) inserted into the lower fornix for five minutes with eyes closed after 5 min of topical anesthesia. Corneal imaging was performed using the Pentacam® HR Table 4 Scheimpflug tomography system (Oculus GmbH, Wetzlar, Germany). Contralateral Comparison of Basic Ocular Surface Parameters.

Several parameters were recorded as dichotomous events (yes/no), and Parameters Case Control P-value their severity was not assessed: (1) meibomian gland dysfunction (MGD); (2) chalazion/hordeolum presence; (3) eyelid margin foam; (4) MGDa (%) 32 (55.2) 31 (53.4) 0.89 conjunctival papillae; and (5) follicles. All ophthalmic examinations Eyelid margin foam (%) 13 (22.4) 12 (20.6) 0.74 Conjunctival folicules (%) 22 (37.9) 22 (37.9) 0.99 were performed by the same researcher. (O.A.M.). Conjunctival papillae (%) 28 (48.2) 30 (51.7) 0.65 Chalazia (%) 6 (10.3) 4 (6.8) 0.32 2.3. Statistical analyses a meibomian gland dysfunction. The SPSS software version 19.0 (IBM Corporation, New York, NY) both eyes equally. was used for statistical analysis. The paired-sample t-test used to com- Results of the ocular surface examination are presented in Table 4. pare the parameters with a normal distribution, and the Wilcoxon Signs of blepharitis were very similar between both groups (no statis- signed-rank test was used to compare non-parametric parameters be- tical significance was observed; p > 0.05). tween eyes asymmetrical KC. Binary responses were assessed by the Table 5 reports the rates of dry-eye signs. Also, both tests were not McNemar’s test. Cohen’s kappa (κ) measured the degree of agreement significantly different (p > 0.05). of ordinal assessments. A P-value < 0.05 was considered statistically Concerning the dominant hand used for general activities and KC significant. laterality, Table 6 displays the information on the participants. There was no correlation between the hand dominance and advanced KC la- 3. Results terality (p > 0.05).

Our study was conducted on 58 patients with asymmetrical KC (36 males [62%] and 22 [38%] females) in order to compare risk factor 4. Discussion parameters in development. The mean age of the participants was 27.17 ± 10.69 years (range: 16–56 years). Table 1 presents partici- In the present study, we performed for the first time in a reasonable pants’ clinical background information. number of participants with marked asymmetric KC a detailed com- As shown in Table 2, there were significant differences in BCSVA, parison of both eyes. In order to prevent potential confounding vari- K1, K2, Kmax and thinnest pachymetry (all P < 0.001) between eyes ables, such as ethnic differences, environmental, hormonal and genetics with asymmetrical KC. factors, using very similar groups of case and control eyes are very Table 3 provides information about eye rubbing. The frequency of relevant. This approach enabled us to examine a pure association be- eye-rubbing was statistically significantly higher in eyes with advanced tween risk factors and KC development. KC (p < 0.001). Seventeen patients (29,3%) reported that they rubbed Micro-trauma from chronic mechanical rubbing have been shown to contribute to the pathophysiology of KC [7,10]. Associated allergic Table 1 Clinical background information. Table 5 Contralateral Comparison of Dry Eye Tests. Parameter Positive history Parameters Case Control Allergic rhinitis (%) 44 (68.9) Ashtma (%) 20 (34.4) Mean ± SD Mean ± SD Mean difference P-value Atopic dermatitis (%) 1 (1.7) TBUTa 8.56 ± 3.84 9.34 ± 4.04 -–0.78 0.12 Known family members with KC* (%) 6 (10.3) Schirmerb 14.72 ± 10.64 14.34 ± 10.75 0.38 0.65

* KC = keratoconus a Tear Brake-up time in sec; bSchirmer II test in mm.

2 O.A. Magalhaes, et al. Journal of EuCornea 7 (2020) 1–3

Table 6 (Fig. 1). We believe that eye rubbing and micro-trauma may be the Keratoconus Laterality and Hand Dominance. common underlying factor in the majority cases that leads to devel- fl Parameters Right Left Kappa* opment of KC, such as in Down syndrome (secondary to oppy eyelids, atopy and blepharitis). In a previous study, we have reported that pa- Advanced keratoconic eye (%) 30 (51.7) 28 (48.3) tients with osteogenesis imperfecta (collagen I chain mutation) have – Hand dominance (%) 52 (89.6) 6 (10.3) 0.046 homogeneously thinner corneas, however no ectatic corneal profile was observed [4]. We have decided to exclude progressive cases because the * Concordance correlation coefficient. eye with subclinical or mild KC could still progress into an advanced profile, not being truly asymmetrical anymore. In conclusion, the present study revealed a positive association between increased eye rubbing frequency and advanced KC. We do not believe that only one ocular surface change causes KC. There must be several pathophysiological reasons that cause a person to rub their eyes. Thus, it recommended to avoid eye rubbing by treating the causes of itching especially those associated with allergy and dryness of the eye. Project Number and institution responsible for the approval of the IRB: 19-0559. This study was approved by the Federal University of Rio Grande do Sul - Clinical Hospital ethical review board (CAAE 49171315.0.0000.5327)

5. Financial support

This research received no specific grant from any funding agency in Fig. 1. Eye rubbing cycle. the public, commercial or not-for-profit sectors. disorders, such as asthma and allergic rhinitis, are all associated with a Declaration of Competing Interest higher incidence of KC [6,7]. We observed that more than two thirds of participants had a positive history of allergic rhinitis and half of those The authors declare that they have no known competing financial had asthma. Likewise, one of the most reported causes of eye rubbing in interests or personal relationships that could have appeared to influ- the general population is chronic blepharitis [11]. In our study, more ence the work reported in this paper. than half of participants had signs of blepharitis. Because people with allergic disorders and dry eyes often rub their eyes, we understand that References is really difficult to separate eye rubbing due to allergic inflammation and blepharitis. [1] J. Sugar, M.S. Macsai, What causes keratoconus? Cornea 31 (6) (2012) 716–719. Although we observed an increased patient-reported frequency of [2] M.C. Kenney, A.B. Nesburn, R.E. Burgeson, et al., Abnormalities of the extracellular rubbing in eyes with advanced KC, we could not find any significant matrix in keratoconus corneas, Cornea 16 (3) (1997) 345–351. ff [3] S.A. Collier, M.C. Madigan, P.L. Penfold, Expression of membrane-type 1 matrix di erence in ocular surface parameters (blepharitis signs and dry eyes metalloproteinase (MT1-MMP) and MMP-2 in normal and keratoconus corneas, tests) between cases and controls. Our ocular surface results are similar Curr. Eye Res. 21 (2) (2000) 662–668. to a previous study that demonstrated that the signs and symptoms of [4] V. Galvis, T. Sherwin, A. Tello, et al., Keratoconus: an inflammatory disorder? Eye (Lond) 29 (7) (2015) 843–859. blepharitis are more prevalent among KC participants than in those [5] M. Shajari, E. Eberhardt, M. Müller, et al., Effects of atopic syndrome on kerato- without KC [8]. The only test result that had a notable difference (al- conus, Cornea 35 (11) (2016) 1416–1420. though not statistically significant) was TBUT. This test is not entirely [6] R.J. Harrison, P.T. Klouda, D.L. Easty, et al., Association between keratoconus and atopy, Br. J. Ophthalmol. 73 (10) (1989) 816–822. accurate in some advanced KC cases due to surface irregularity and [7] A.M. Bawazeer, W.G. Hodge, B. Lorimer, Atopy and keratoconus: a multivariate corneal scarring. analysis, Br. J. Ophthalmol. 84 (8) (2000) 834–836. We agree with previous researchers that the most significant risk [8] D. Mostovoy, S. Vinker, M. Mimouni, et al., The association of keratoconus with – factor for KC is eye rubbing [12–14]. We observed that only four eyes blepharitis, Clin. Exp. Optom. 101 (3) (2018) 339 344. [9] M.W. Belin, J.K. Duncan, Keratoconus: The ABCD Grading System, Klin. Monbl. with mild KC had no history of rubbing, and more than half of eyes with Augenheilkd. 233 (6) (2016) 701–707. advanced KC had history of been rubbed more than one time a day. Less [10] H. Najmi, Y. Mobarki, K. Mania, et al., The correlation between keratoconus and – than a third of participants could not differentiate each eye they rubbed eye rubbing: a review, Int. J. Ophthalmol. 12 (11) (2019) 1775 1781. [11] C. Auw-Haedrich, T. Reinhard, Chronic blepharitis. Pathogenesis, clinical features, more. In addition, we found no association between hand-dominance and therapy, Ophthalmologe 104 (9) (2007) 817–826. and KC laterality. It is unclear why the itching would be uneven, given [12] Z. AlShammari, R. AlShammari, S. AlOrf, et al., Prevalence, clinical features and that ocular allergy is usually a bilateral condition and we did not have associated factors of keratoconus patients attending Ophthalmology Department, King Khalid Hospital, Hail City, Saudi Arabia, EC Ophthalmology. 3 (5) (2016) evidence of asymmetric allergy by examination. We understand that 388–400. interviewing techniques may be subject to bias due to inaccurate recall. [13] H.S. Jeon, M. Choi, S.J. Byun, et al., Atopic dermatitis is not a risk factor for ker- However it is the only way to acknowledge the patients’ rubbing habits. atoconus: a population-based cohort study, J. Am. Acad. Dermatol. 79 (1) (2018) 160–162. Epithelial micro-trauma from eye rubbing could initially leads to [14] B. Jafri, H. Lichter, R.D. Stulting, Asymmetric keratoconus attributed to eye rub- oxidative damage and interleukin-1 (IL-1) release [15]. Corneal da- bing, Cornea 23 (6) (2004) 560–564. mage, via a common biochemical cascade, may lead to cellular apop- [15] O.A. Magalhaes, H.C. Rohenkohl, L.T. de Souza, et al., Collagen I Defect Corneal Profiles in Osteogenesis Imperfecta, Cornea 37 (2018) 1561–1565. tosis or repair with increased activities of degradative substances leading to tissue remodeling with thinning of epithelium and stroma