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Alio JL, Vega-Estrada A, Sanz P, et al. Corneal Morphologic Characteristics in Patients With Down Syndrome. JAMA Ophthalmol. 2018;136(9):971–978. doi:10.1001/jamaophthalmol.2018.2373
What is the frequency of corneal morphologic abnormalities similar to keratoconus and what are the main corneal characteristics in patients with Down syndrome?
In this multicenter observational study, the presence of corneal features similar to the ones found in patients with keratoconus might be present in more than 70% of patients with Down syndrome.
This study suggests a high incidence of keratoconus in patients with Down syndrome and the potential need to perform a more detailed corneal examination to provide a more accurate therapeutic approach and avoid further complications in these patients.
Literature suggests corneal morphologic characteristics compatible with keratoconus are present in a high percentage of patients with Down syndrome (DS), suggesting the need to perform a detailed examination of the anterior segment to try to avoid serious visual impairment in this group of patients.
To characterize the abnormal features of the cornea in patients with DS and compare these with a control group.
Design, Setting, and Participants
Multicenter case-control study at Vissum Alicante, Alicante, Spain, and the Ophthalmology and Pediatric Department, Cairo University, Cairo, Egypt. Data collection took place between May 2013 and May 2016. Data were analyzed between June 2016 and August 2016. The study included 321 eyes of 217 participants from 2 groups: 112 participants in the DS group and 105 healthy participants in the control group.
Patients were evaluated using Placido disc/Scheimpflug camera topographer (Sirius, CSO). Visual, refractive and anterior, and posterior corneal characteristics were assessed and compared in both groups.
Main Outcomes and Measures
Keratoconus diagnosis. Incidence of corneal morphologic irregularities similar to keratoconus in patients with DS.
In the DS group, mean (SD) age was 14.88 (15.76) years, 54 (48%) were women, 66 (59%) were white, and 46 (41%) were Arab. In the control group, mean (SD) age was 40.29 (14.66) years, 54 (51%) were women, and all were white. Clinical assessment of corneal topography showed that 71.3% (95% CI, 45.2-97.4) of patients in the DS group showed characteristics compatible with keratoconus. Differences were found in steepest keratometry of 47.35 diopters (D) in patients with DS vs 43.70 D in control individuals (difference, 3.65 D; 95% CI, 3.23-4.35 D; P <.001) and in corneal pachymetry of 503 μm in patients with DS vs 545 μm in control individuals (difference, 42 μm; 95% CI, 38.8-56.7 μm; P <.001).
Conclusions and Relevance
Patients with DS have steeper and thinner corneas and more corneal aberrations than those without genetic alterations and normal corneas. The findings suggest a detailed corneal study should be considered in such patients to detect keratoconus and implement treatment as appropriate to try to avoid serious visual impairment in this group of patients.
Down syndrome (DS) was first described by John Langdon Down in 1866.1 This condition is a developmental disorder caused by an extra copy of chromosome 21 and is typically caused by what is defined as chromosomal nondisjunction.2
Several ophthalmic comorbidities have been described in these patients such as nasolacrimal duct obstruction, epicanthus, blepharoconjunctivitis, ectropion, nystagmus, strabismus, high myopia, lens opacities, and keratoconus.3-8 Additionally, patients with DS are usually affected by collagen-related disorders, which may also explain the corneal changes that patients with DS frequently show.9-14 Furthermore, it has been reported that patients with DS frequently rub their eyes,11 which is a habit related to keratoconus development owing to the inflammation process and biomechanical alterations linked to eye rubbing habit.11
Keratoconus is a corneal ectatic condition characterized by corneal thinning, gradual corneal protrusion, and progressive irregular astigmatism.9 The incidence in the general population is relatively low and variable, between 4 of 1000 and 6 of 1000,9 with other authors reporting that the current incidence is 1 of 2000 per year.10,11 The incidence may vary according to the geographic region, although there are also studies supporting the fact that the prevalence is higher in zones with higher ultraviolet exposure or with a combination of genetic and environmental factors.12 Some authors have reported that the incidence of keratoconus in patients with DS may be between 10 and 300 times more frequent than in individuals without DS.13,14 Therefore, the purpose of this study is to report the corneal morphologic characteristics in a large series of patients with DS, with special attention to detect corneal ectatic disorders and to compare it with a control group.
This was a multicenter, case-control study including 216 eyes of 112 patients diagnosed as having DS. A control group (healthy corneas), included 105 eyes of 105 patients without any ocular, genetic, or systemic disease and without previous ocular surgery.
The inclusion criteria for the DS group were patients diagnosed as having DS with genotypic confirmation. Patients with previous eye surgical procedure were not included.
Patients were recruited by asking DS institutions located in Alicante, Spain, to bring patients for an ophthalmological examination in Vissum, Alicante, Spain. Additionally, all patients with DS diagnosis attending the ophthalmologic and pediatric department from Cairo University, Cairo, Egypt, underwent an ophthalmologic examination to be included in this study.
This investigation was conducted in accordance with the ethical standards stated in the Declaration of Helsinki and approved by the institutional ethical board committee of the different institutions involved in this investigation (Vissum ethical board committee, Alicante, Spain, and ethical committee board of the Ophthalmology Department, Cairo University, Cairo, Egypt). Parental written informed consent was obtained for the purpose of the study.
The DS group was divided into 2 groups according to the level of patient cooperation during eye examination: the cooperative group (group 1) consisted of 113 eyes of 59 patients, and the uncooperative group (group 2) consisted of 103 eyes of 53 patients. Both groups underwent a full ocular examination and refraction and ophthalmoscopic examination. In the cooperative group, corneal topography, tomography, aberrometry, and pachymetry were done additionally. In the uncooperative group, corneal topography was not performed. The patients in the control group were selected consecutively from patients who came to routine eye examinations and corneal refractive surgery candidates.
The ocular examination protocol included the following: uncorrected distance visual acuity; best-corrected distance visual acuity; manifest refraction; slitlamp biomicroscopy; retinoscopy; and Goldmann tonometry and corneal topography, aberrometry, pachymetry, and volume analysis with Sirius System (CSO). An experienced optometrist certified in Good Clinical Practice performed all measurements in each center. Sirius System is a topography device that uses a combination between rotating Scheimpflug camera and Placido disk that allows full analysis of the cornea and anterior segment. The system measures 35 632 points on the anterior corneal surface and 30 000 points on the posterior corneal surface. Anterior corneal surface data from both Placido and Scheimpflug images are consolidated using an internal mechanism. It has been demonstrated that this system provides a good repeatability on pachymetric and corneal profile measurements.15,16
The following posterior and anterior corneal surface parameters were analyzed:
Simulated mean keratometry represents the simulation of the readings that would be obtained with a keratometer, ie, the mean sagittal curvature from the fourth to the eighth Placido ring.
Keratometrics meridians: corneal dioptric power in the steepest and the flattest meridians at 3.0-mm, 5.0-mm, and 7.0-mm zones of the cornea.
Aberrometry: total root mean square, high-order aberrations, astigmatism Z (2, ±2), coma (3, ±1), spherical aberration (4, 0), comalike, and spherical-like were analyzed. All Zernike coefficients were calculated for a pupil diameter of 6.0 mm.
Sirius System has a section called Keratoconus Screening that describes and analyzes the corneal morphology, which is processed by a neural network to classify the case in 1 of the following groups: normal, subclinical keratoconus, keratoconus, abnormal or treated, and myopic postoperative. To avoid methodologic bias, only those cases labeled as normal by the Sirius system within DS group were compared with the topographic findings in the control group.
Corneal topographic analysis was performed by 3 experience investigators (J.L.A., A.V.E., and P.S.) who performed a blind observation (each investigator assessed the topographic pattern independently from each other) of the topographies belonging to the DS group. Corneal topographies were classified according to the morphology of the pattern into 3 different types: normal, abnormal, or undefined.
Normal topographic patterns were defined as those patients with regular astigmatism but no presence of asymmetric bowtie, inferior steepening, skewed radial axis, or asymmetric bowtie with skewed radial axis pattern on topography. Abnormal topographical patterns were defined based on keratoconus Rabinowitz patterns: presence of asymmetric bowtie, inferior steepening, skewed radial axis, or asymmetric bowtie with skewed radial axis pattern.17 Finally, undefined cases were those in which topographic analysis could not be performed mainly owing to poor collaboration of the patients. Severity of those cases typified as abnormal, according to the Rabinowitz pattern for keratoconus, were classified according to the degree of coma-like aberrations.18
Statistical analysis was performed with the SPSS statistical software package, version 15.0 (SPSS). Normality of the data was confirmed by the Kolmogorov-Smirnov test. A Mann-Whitney U Wilcoxon test for unpaired data was performed to describe the differences between normal and keratoconus groups in all the measurements proposed. Results were not adjusted for age. P values were 2-sided. Differences were considered statistically significant when the P value was less than .05.
This study was a multicenter, observational study where a total of 321 eyes of 217 patients were divided into 2 groups: DS group and control group. The distribution of the sample was homogeneous among the centers involved in the study. Age was the only variable that showed differences judged relevant between the DS population in both centers. Subsequent results were not adjusted for age.
The first group consisted of 112 patients diagnosed as having DS, with age ranging from 3 months to 60 years (mean [SD] age of 14.88 [15.76] years). Fifty-four (48.21%) were women; 66 (59%) were white and 46 (41%) were Arab. The second group included 105 white patients with healthy corneas and an age ranging between 15 and 63 years (mean [SD] age, 40.29 [14.66] years). Fifty-four (51.43%) were women.
Figure 1 and 2 show the topographic pattern of 8 patients selected from those representative cases of each group (4 from the DS and 4 from the control group, respectively) to show the main characteristics of the topographic pattern in the patients in the study.
A complete examination was possible to accomplish in 113 of 216 eyes (52.31%) from DS group. In these cases, corneal topography, tomography, aberrometry, pachymetry, and ophthalmoscopic examination could be performed. A total of 47.69% of patients with DS were not able to perform a complete eye examination (refraction and retinoscopy examination only) owing to poor collaboration, severe lens opacities, severe corneal irregularity, or severe incapacitating visual loss.
An individual observation of each topography from the DS group was performed by 3 experience investigators (J.L.A., A.V.E., and P.S.). This analysis was concluded with 3 types of patterns: normal, abnormal, and undefined. The following ranges of percentages were reported: between 13% (n = 15) and 20% (n = 23) of patients were defined as normal, between 67% (n = 78) and 82% (n = 93) of patients were defined as abnormal, and between 9% (n = 10) and 20% (n = 23) were labeled as undefined. Clinical assessment of corneal topography showed that 71.3% (95% CI, 45.2 to 97.4) of patients in the DS group showed characteristics compatible with keratoconus. From those patients typified as abnormal, 71.8% (n = 61) were classified as grade I keratoconus, 15.6% (n = 13) as grade II, 3.1% (n = 3) as grade III, and 9.3% (n = 8) as grade IV keratoconus, based on Alio-Shabayek aberrometric grading system.18
This group consisted of a total of 103 eyes of 53 patients, of whom 24 were women (45.28%), with ages ranging from 3 months to 60 years (mean [SD] age, 8.90 [16.89] years). A complete ocular examination could not be performed on the patients in this group.
This group comprised patients who underwent a full ocular examination including corneal topography and tomography. A total of 113 eyes of 59 patients (30 female patients [50.85%]) with ages ranging from 4 to 60 years (mean [SD] age, 20.81 [12.32] years) were included. Table 1 summarizes the main outcomes of the visual, refractive, corneal topography, tomography, corneal aberrometric, and pachymetric data of the DS group.
To avoid methodologic bias when comparing the DS group with control group, only those patients in the DS group who were defined by the Sirius System as normal were compared with the control group. The latest consisted of 105 eyes of 105 patients (54 female patients [51.43%]), with ages ranging from 15 to 63 years (mean [SD] age, 40.29 [14.66] years). The normality group in patients with DS comprised a total of 38 eyes of 26 patients (14 female patients [53.85%]), with ages ranging from 4 to 46 years (mean [SD] age, 19.87 [11.32] years). Table 2 compares all the parameters analyzed between both groups.
Differences were found in uncorrected and corrected distance visual acuity and in orthogonal components of anterior and posterior corneal surface (simulated mean keratometry values in flat and steepest meridians). Differences were found in steepest keratometry of 47.35 diopters (D) in patients with DS vs 43.70 D in control individuals (difference, 3.65 D; 95% CI, 3.23-4.35 D; P <.001), and in corneal pachymetry of 503 μm in patients with DS vs 545 μm in control individuals (difference, 42 μm; 95% CI, 38.8-56.7 μm; P <.001). Regarding corneal aberrometric parameters, differences were found in most of the Zernike components analyzed for both anterior and posterior surface (Table 2). Finally, differences were observed between both groups in those variables associated with corneal pachymetry and corneal volume.
This study was performed to analyze the incidence of corneal abnormalities similar to keratoconus in patients with DS as well as to characterize the main features of the corneal morphology in these patients and compare it with a control group of patients with healthy corneas.
It was observed that around 75% of the patients with DS diagnosis had corneal morphologic irregularities compatible with keratoconus. There are great variability and contradictory published data regarding the frequencies of keratoconus in patients with DS. Reported incidences vary between 0% and 30%,4 with some authors reporting that keratoconus may be between 10 to 300 times more frequent in patients with DS.13,14 These differences likely reflect dissimilarities in the corneal assessment of the DS population investigated owing to lack of cooperation during the corneal examination, or the studies were performed in a time in which corneal examinations were done with incomplete or obsolete technology; the latest may be also the reason why the incidence of keratoconus in these patients has been underestimated in the literature. Using the latest technology regarding corneal topographic analysis as the one uses in this study, we found a high frequency of corneal abnormalities similar to the ones observed in keratoconus when evaluating patients with DS diagnosis. To our knowledge, the 75% reported in this study is the highest frequency of keratoconus observed in patients with DS and, to our knowledge, in any sample population study up to now. These findings suggest that patients with DS may show a high incidence of keratoconus, and thus, a close corneal evaluation should be carry out in this patients.
In this investigation, we observed differences between patients with DS and a control group of patients with no chromosomic or ocular pathologies in those variables that are characteristic of corneal ectatic disorders. Specifically, we found that patients with DS were more prone to have steep and thin corneas when compared with those from the control group. Such findings have been also previously reported by other investigators who observed keratometric readings and corneal pachymetries with levels similar to the ones reported in our study.19 In addition, we also found differences when evaluating the posterior corneal surface and corneal higher order aberrations. To our knowledge, this is the first study reporting the posterior corneal surface features and corneal higher order aberrometric data of patients with DS. In this field, there are investigations in the literature that have found an increase in the posterior corneal curvature in patients with keratoconus.20 In this study, we found that patients with DS showed a steeper posterior corneal surface in comparison with the patients classified as normal. Additionally, we also found that patients with DS present more corneal higher-order aberrations than those patients without any pathology. We specifically observed that there was a 2-fold increase in the asymmetric aberrations (coma and comalike), which are characteristic of patients with keratoconus.4,21 The aforementioned findings clearly suggest that corneal morphology frequently differs from normal patients in patients with DS, showing features that are characteristic of the patients who develop keratoconus.
Some of the reasons that could explain the association between keratoconus and DS have been previously analyzed in the literature. Wang et al22 reported that alterations in the chromosome 21 from patients with DS might have a genetic variation that affects the corneal collagen fibers and in consequence the biomechanical stability of the cornea. Additionally, some pathologies, such as atopy and allergies, are often associated in both patients with DS and patients with keratoconus, which may suggest a common genetic alteration.22-24 Moreover, several studies have reported that eye rubbing habit, which is also a common finding in patients with DS and patients with keratoconus, leads to a chronic and maintained inflammation of the eye surface that induces biomechanical alterations of the corneal collagen fibers.11,25-27
The limitations of this study that could be related to the high incidence of this corneal pathology observed in our cohort may be owing to several factors. The first limitation is the nature of our study, which was designed with the purpose of identifying and characterizing the corneal morphology in patients with DS. Second, we have used new diagnosis instruments that include the latest technologies in software designs for refractive surgery screening and corneal ectatic disorder recognition that may increase the sensitivity in the keratoconus diagnosis. Another known factor is that defining a corneal topographic pattern is subjective and depends on the experience of the observer. Finally, sociodemographic variables, such as race/ethnicity, may also play a role in the rate of keratoconus diagnosis in our patients with DS. This investigation is a multicenter observational study in which a Egyptian center participated, and it has been reported that patients with Arab ethnicity may have an increased incidence in keratoconus.28 Finally, the fact that we did not adjust the results for age means the results could be biased by differences in age between the groups.
The findings from this investigation in relation to the characteristics of the cornea in patients with DS, together with the scientific-based evidence published in the literature, bring us to the conclusion that changes in the corneal morphology compatible with the diagnosis of keratoconus are a common finding in patients with DS, an issue that appears underreported in the scientific literature until now. These observations should be considered when examining patients with DS to detect possible changes associated with corneal ectatic disorders, especially now that therapeutic alternatives exist for the control of the evolution of keratoconus to advanced stages in which visual loss is a frequent end point complication that may limit further the quality of life of these patients. Finally, it seems necessary to conduct long-term prospective studies to further complete and understand better the findings from this investigation and to define new and more adequate medical diagnostic and therapeutic standards to prevent severe visual impairment owing to corneal ectatic disorders in patients with DS.
Corresponding Author: Jorge L. Alio, MD, PhD, FEBO, Miguel Hernandez University, Vissum Alicante, Calle Cabañal, 1 03016 Alicante, Spain (firstname.lastname@example.org).
Accepted for Publication: April 16, 2017.
Published Online: June 21, 2018. doi:10.1001/jamaophthalmol.2018.2373
Author Contributions: Drs Alió and Vega-Estrada had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Alio, Vega-Estrada, Osman.
Acquisition, analysis, or interpretation of data: Vega-Estrada, Sanz Diez, Osman, Kamal.
Drafting of the manuscript: Alio, Vega-Estrada, Kamal.
Critical revision of the manuscript for important intellectual content: Alio, Vega-Estrada, Sanz Diez, Osman.
Statistical analysis: Sanz Diez.
Obtained funding: Alio, Sanz Diez.
Administrative, technical, or material support: Alio, Vega-Estrada, Sanz Diez, Osman, Kamal.
Supervision: Alio, Vega-Estrada, Osman.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: This study was funded by the Red Temática de Investigación Cooperativa en Salud (reference number RD12/0034/0007), the Instituto Carlos III - General Subdirection of Networks and Cooperative Investigation Centers (2008-2011), and the European Regional Development Fund (Fondo europeo de desarrollo regional.
Role of the Funder/Sponsor: The funding sources had a role in the collection, management, and analysis of the data but had no role in the design and conduct of the study; interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Ahmed M. Sherif, MD, PhD, and Ashraf M. Zeid, MD, Ophthalmology Department, Cairo University for their great support and assistance.
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