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Abstract
Aims To characterise posterior corneal surface features in patients with Down syndrome (DS) and to compare them with healthy and mild keratoconus corneas.
Methods This restrospective, comparative, non-randomised, clinical study included 123 eyes, divided into three groups (37 eyes of patients with DS, 46 with mild keratoconus and 40 controls), and took place at Vissum Alicante. Only patients with no previous ocular surgery, no corneal scars and no active ocular disease other than keratoconus were included. The Sirius System topographer (CSO, Firenze, Italy) was used in order to analyse posterior corneal surface keratometry, shape and keratoconus screening indices, posterior corneal aberrations, corneal volume and pachymetry.
Results Patients with DS, when compared with healthy controls, have a steeper (mean keratometry 7 mm (KM): −6.30±0.44 vs −6.15±0.22; p<0.05) and more irregular (root mean square per unit of area: 4.5 mm 0.22±0.22 vs 0.09±0.03, p<0.001; posterior vertex of the ectatic area: 33.22±44.29 vs 10.63±2.88, p<0.001) posterior corneal surface, with higher aberrations (high-order aberrations (HOAs): 1.07±1.43 vs 0.15±0.06, p<0.001; coma-like: 0.88±1.09 vs 0.13±0.07, p<0.001) and thinnest pachymetry (497.68±26.88 vs 538.95±31.67, p<0.001). At the same time, no statistically significant difference was found between patients with DS and patients with mild keratoconus (p>0.05) in KM (−6.38±0.34), HOA (0.56±0.36), coma-like (0.51±0.34) and pachymetry (500.56±36.83).
Conclusions Posterior corneal surface of patients with DS is steeper, more irregular and shows more higher order aberrations, as well as reduced volume and thinner pachymetry than patients with healthy corneas. Additionally, posterior corneal surface in patients with DS shows similar characteristics to those found in mild keratoconus.
- cornea
- dystrophy
- diagnostic tests/investigation
- genetics
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Introduction
Down syndrome (DS) is a common genetic disorder caused by trisomy of chromosome 21 that was first described by John Langdon Down in 1866.1 2 Besides systemic pathologies, patients with DS can present several ophthalmic pathologies including corneal alterations.3 Furthermore, patients with DS used to rub their eyes, and it is well known that the eye rubbing habit is an important risk factor for keratoconus development.4–7
Keratoconus is a corneal ectasia characterised by progressive corneal thinning that results in gradual corneal protrusion, irregular astigmatism and decreased vision.8 The incidence of this corneal disorder in the general population is about 4–6 of 1000 but can vary between studies depending on two aspects: the ethnic group evaluated, in fact the pathogenesis of the disease is a combination of genetic and environmental factors, and the criteria used to establish the diagnosis.9 In a recent work developed by our investigation team,10 it was reported that patients with DS may present corneal morphological alterations similar to keratoconus in more than 70% of the cases, emphasising the importance of an early ophthalmic evaluation in this group of patients. Different studies report that posterior corneal surface data are useful in the diagnosis of keratoconus11–13 and show a high discrimination capability in the early stages of the disease.14 Additionally, posterior corneal surface characteristics correlate well with the degree of visual impairment in patients with keratoconus and might be used to determine the severity of the disease.10
Therefore, the purpose of this study was to assess posterior surface characteristics in patients with DS and determine the features that resemble the ones found in patients with keratoconus.
Materials and methods
This restrospective, comparative, non-randomised, clinical study evaluated 123 eyes divided into three groups: 37 eyes of patients with DS, 46 eyes affected by mild keratoconus and 40 healthy control eyes. Only patients with no previous ocular surgery, no corneal scars and no active ocular disease other than keratoconus were included. Patients in the DS group that did not cooperate to performed corneal topography were excluded from the study. The procedure was conformed to the tenets of the Declaration of Helsinki, and all patients gave informed consent after the purpose of the study was explained. For patients with DS, also the parental written informed consent was obtained. The patients in the DS group were patients diagnosed as having DS with genotypic confirmation of the disease. Mild keratoconus group was defined based on Rabinowitz topographical pattern8 15 16 and on the degree of visual limitation: patients affected by grade I keratoconus with spectacle corrected visual acuity of 0.90 or better.17 The patients in the control group were selected consecutively from patients who came to routine examinations or for corneal refractive surgery screening and did not have any genetical or corneal topographic alteration.
All patients underwent a full ocular, refraction and ophthalmoscopic examination, including uncorrected distance visual acuity, corrected distance visual acuity (CDVA), manifest refraction, slit-lamp biomicroscopy, Goldmann tonometry and fundus evaluation. Corneal topography, tomography, aberrometry, pachymetry and volume analysis was performed with Sirius system (CSO, Firenze, Italy), which is a topographer that combines a rotating Scheimpflug camera and a Placido disk and allows full analysis of the cornea and anterior segment of the eye. Three measurements were performed per eye, and only the examination with the higher acquisition quality index (higher than 90%) was selected. The Sirius system provides an acquisition quality display, and only those images that showed more than 90% of coverage and centration of the Scheimpflug and keratoscopy images were taken for the corneal examination. Repeatability of the measurements taken with the Sirius system have been previously demonstrated in normal and keratoconic eyes.18 19
The following topographic variables were analysed:
Posterior corneal surface keratometry: mean keratometry (KM) and keratometry in the flattest (K1) and steepest (K2) meridians for 3.0, 5.0, 7.0 mm zones of the cornea.
Shape indices (4.5 and 8.0 mm corneal diameter):
Flat radius (rf): apical radius of the flattest meridian of the asphero-toric surfacem which best approximates the measured surface.
Steepest radius (rs): apical radius of the steepest meridian of the asphero-toric surface, which best approximates the measured surface.
Asphericity (Q): conic section that can be described by the apical radius of curvature in the meridian studied.
Root mean square per unit of area (RMS/A): deviation of the surface being examined from the asphero-toric best-fit surface characterised by rf, rs, Q and toricity axis. A higher RMS values represents a greater corneal irregularity.
Keratoconus screening indices:
Posterior asymmetry index (Sib): difference of the mean posterior tangential curvature of two circle areas, centre in the vertex, from the superior and inferior hemisphere.
BCVb: analysis of the posterior Zernike components for the coma, trefoil and spherical aberrations in the infero-temporal area of the cornea.
KVb: posterior vertex of the ectatic area.
ThkMin: minimal thickness.
Corneal volume at a diameter of 10 mm.
Corneal pachymetry: central, nasal, temporal, superior and inferior pachymetry.
Posterior corneal higher order aberrations: root mean square (RMS) for total, high-order aberrations, primary coma, spherical aberrations, coma-like aberrations and spherical-like aberrations were calculated for a 6 mm of corneal diameter.
Statistical analysis
Statistical analysis was performed using the SPSS statistics software package V.22. Normality of all data samples was evaluated by means of the Kolmogorov-Smirnov test. When parametric analysis was possible, the one-way analysis of variance with Bonferroni post hoc comparison procedure was used for the comparison groups. When the parametric analysis was not possible, the Kruskal-Wallis test was used to compare the analysed parameters between groups. For post hoc analysis, the Mann-Whitney test with Bonferroni’s adjustment was used to avoid the experimental error rate in these cases. For all statistical tests, the same level of significance was used (p<0.05).
Results
This study comprises a total of 123 eyes of 79 patients: 37 eyes of 20 patients with DS (10 men and 10 women, mean age of 24.03±11.72), 46 eyes of 39 patients diagnosed for having mild keratoconus (25 men and 14 women, mean age of 37.91±11.81) and 40 eyes of 20 patients with healthy cornea (11 men and 9 women, mean age of 37.70±16.48). The three groups differed significantly in refractive errors and in CDVA: the mean spherical equivalent and the CDVA were 0.31±3.45 and 0.48±0.21 in patients with DS, −2.80±3.87 and 0.95±0.03 in patients with mild keratoconus and −0.93±3.78 and 0.99±0.08 in control patients.
Figure 1 shows the representative corneal topographical image as found in each one of the groups under analysis. It was found that corneal topographic appearance in DS group shows central steepening, an increased posterior elevation and higher posterior corneal irregularities as represented by the RMS/A indices. These characteristics are similar to the ones found in patients with mild keratoconus and are different to those observed in the control group.
Corneal topographic aspect of the three groups under analysis: control, Down syndrome and mild keratoconus patients. At the bottom of the image, it can be seen the keratometric (K) readings, shape indices and keratoconus screening indices.
Posterior corneal surface keratometry
Regarding posterior keratometry, KM and the flattest keratometry (K1) at 3, 5 and 7 mm zones of the cornea showed a statistically significant difference between DS patients and controls and between mild keratoconus patients and controls, but no statistically significant difference was found between DS and mild keratoconus patients (table 1 and figure 2). The steepest posterior keratometry (K2) at 3 and 5 mm showed a statistically significant difference between all the three groups, meanwhile K2 at 7 mm showed no statistically significant difference between patients with DS and mild keratoconus (table 1 and figure 2).
Comparison between the three groups (DS group, mild keratoconus group and control group) in relation to keratometry, shape indices and keratoconus indices of the posterior corneal surface
Bar graphs showing the difference in the three groups in mean keratometry, root mean square per unit of area (RMS/A), analysis of the posterior Zernike components for the coma, trefoil and spherical aberrations in the infero-temporal area of the cornea (BCVb) and posterior vertex of the ectatic area (KVb). The asterisk shows the presence of a statistically significant difference (p<0.05).
Shape and keratoconus posterior indices
In relation to shape indices at a corneal diameter of 4.5 mm, rf and Q showed statistically significant difference between patients with DS and controls and between patients with mild keratoconus and controls, and no statistically significant difference between DS and patients with mild keratoconus (table 1). At a corneal diameter of 8 mm, rf showed a statistically significant difference between patients with DS and controls and between patients with mild keratoconus and controls, and no statistically significant difference between patients with DS and patients with mild keratoconus; in the same line, posterior corneal asphericity at 4.5 mm (Q) showed a statistically significant difference between patients with DS and patients with mild keratoconus and between mild keratoconus and controls, and no statistically difference between patients with DS and controls; RMS/A showed a statistically significant difference between all the three groups (table 1 and figure 2).
Regarding posterior keratoconus indices, a statistically significant difference was found between all the three groups for Sib, BCVb and KVb. ThKMin showed a statistically significant difference between DS patients and control and between mild keratoconus and control, and no statistically significant difference between patients with DS and patients with mild keratoconus (table 1 and figure 2).
Corneal volume and pachymetry
A statistically significant difference between patients with DS and patients with mild keratoconus, between patients with DS and controls and also between mild keratoconus and control group was observed when analysing corneal volume (table 2 and figure 3).
Bar graphs showing the difference in the three groups regarding corneal volume, central pachymetry, posterior corneal higher order aberrations (high-order RMS) and posterior corneal coma-like aberrations (coma-like RMS). The asterisk shows the presence of a statistically significant difference (p<0.05). RMS, root mean square.
Comparison between the three groups (DS group, mild keratoconus group and control group) in relation to pachymetry, corneal volume and corneal aberrometry of the posterior surface
In relation to corneal pachymetry, no statistically significant difference was found between patients with DS and patients with mild keratoconus, but a statistically significant difference was found between patients with DS and control group and also between patients with mild keratoconus and control group (table 2 and figure 3).
Posterior corneal higher order aberrations
Finally, when analysing posterior corneal surface aberrometry, it was observed that RMS total, high-order aberrations, coma, spherical aberrations, coma-like and spherical-like aberrations showed no statistically significant difference between patients with DS and patients with mild keratoconus and statistically significant difference between patients with DS and control and between patients with mild keratoconus and control patients (table 2 and figure 3).
Discussion
The present study analyses the posterior surface characteristics in patients with DS and compares them with a group of patients with normal corneas and also with patients who suffer from mild keratoconus.
Posterior surface of the cornea gains every time more importance in the analysis of different corneal pathologies and in other situations of clinical relevance such as the screening in corneal refractive surgery candidates and for the proper biometry assessment for intraocular lens implantation. Specifically in keratoconus it has been reported that posterior surface variables might be useful in detecting early changes of the pathology and helping in classifying the severity of the disease.10 14 In a recent study published by our research team, it was found that more than 70% of patients with DS shows corneal morphological alterations similar to the ones observed in patients with keratoconus, hence the relevance of the posterior surface analysis in this group of patients.
In the current study, it was observed that patients with DS show posterior surface keratometries significantly steeper than the ones found in control patients. Patients with DS were found to present posterior surface keratometries statistically significant similar to those observed in patients with mild keratoconus. Different studies that have analysed the posterior aspect have reported that patients with keratoconus have posterior surfaces that are more curved than normal. Therefore, the results of the present studies show that the posterior surface of patients with DS is more curved than normal and resembles the posterior surface of patients with keratoconus.
In the present study, some indices of shape of the posterior cornea that are closely related to the regularity of the surface were also analysed, as is the case of the RMS/A index. The posterior vertex of the cornea represented by KVb index was also analysed and finally the posterior surface aberrations represented by the BCVb index. When analysing the aforementioned indices of form, it was observed that these were statistically different among the three groups analysed. Nevertheless, once again, the shape indices in patients within DS group were out of normal levels when compared with the control group. In a study recently published by our research group it was observed that the cut-off point of the RMS/A index of the posterior corneal surface between normal patients and mild keratoconus was 0.12 with a sensitivity and specificity above 93%.10 In the current study, it was found that the mean RMS/A in patients with DS was 0.22, that is almost double the cut-off point that was reported as the reference value between normal and patients with keratoconus. In the same way, in the aforementioned study, it was also found that the reference value to differentiate between normal and patients with keratoconus in relation to KVb was 13.5 microns. Once again, in the present investigation, we found that the average value of the KVb in patients with DS was 33.2, which also represents almost three times of what is considered to be the normal cut-off value. The results of the present study in relation to the shape and keratoconus indexes show that the posterior surface of patients with DS is more irregular and has a steeper posterior apex than patients with normal corneas.
Additionally, in the present investigation, we have studied the behaviour of high-order corneal aberrations of the posterior corneal surface in patients with DS, mild keratoconus and the control group. In this sense, we observed that patients with DS presented posterior surfaces of the cornea with more aberrations than the corneas of the control group, especially in those aberrations typical of the ectatic processes such as high-order aberrations and coma-like aberrations. Moreover, these differences were not as marked between patients with DS and patients with mild keratoconus, which means that the posterior surface in patients with DS presents more aberrations than patients without pathology and are corneas with posterior surface aberrations similar to that observed in patients with keratoconus. In the same line, pachymetry and corneal volume of patients with DS presented significantly lower values than patients in the control group. Once again, these variables were not statistically different when comparing the patients of the group with DS and the patients with early keratoconus. These results suggest that the corneas of patients with DS are thinner and have reduced volume than patients with corneas without apparent pathology, which is also a typical characteristic of patients suffering from corneal ectatic disorders such as keratoconus. These observations had already been reported previously in a study conducted by our research group where it was observed that patients with keratoconus also had thinner corneas and a smaller volume than the control group.17
The results of the present study suggest that the posterior surface of patients with DS differs significantly from patients with normal corneas and also shows a clear similarity with the posterior surface of patients with mild keratoconus. However, some of the variables studied are also different between patients with DS and mild keratoconus, which leads us to suggest that the morphological alterations found in the corneas of patients with DS are in an area between normality and mild keratoconus, which could even being interpreted as a specific keratopathy of this group of patients. Although this is just a hypothesis and should be corroborated with further studies.
The observations found in the present study are of great relevance and make necessary to carry out a close examination in patients with DS to rule out the presence of a specific corneal alteration and establish an early therapeutic approach to avoid possible corneal blindness in these already handicapped patients.
The retrospective nature of this research as well as the fact that the analysis was done with a single diagnostic instrument are within the limitations of the present study. Another limitation can be the different mean age of DS patients (24.03) if compared with mild keratoconus and control patients (37.91 and 37.70, respectively). Posterior corneal alterations in patients with DS patients, which maybe could be younger due to their reduced life expectancy, can change according to the age, considering the progressive nature of the alterations themselves. Patients with DS as older as mild keratoconus and control patients could present a posterior corneal surface even more similar to patients with mild keratoconus and even more different from controls. Future perspectives and lines of research that can be developed from the findings of the current investigation are the genetic analysis of a possible chromosomal alteration in common between DS and keratoconus or that helps to determine the possible presence of a specific keratopathy in this group of patients.
In conclusion, we can say that patients with DS have a steeper corneal posterior surface, more irregular and with more high-order aberrations than patients with normal corneas, as well as thinnest pachymetry and a reduced corneal volume. Moreover, such posterior corneal alterations of the cornea are out of the norm and significantly resemble the morphological alterations observed in patients with keratoconus.
References
Footnotes
Contributors AV-E and JLA conceived and designed the study. AV-E and JLA provided patients. CF collected data and performed the statistical analysis. AV-E and CF performed the literature search and the interpretation of data. AV-E and CF wrote the manuscript.
Funding This publication has been carried out in the framework of the Red Temática de Investigación Cooperativa en Salud (RETICS), reference number RD16/0008/0012, financed by the Instituto Carlos III – General Subdirection of Networks and Cooperative Investigation Centers (R&D&I National Plan 2008-2011) and the European Regional Development Fund (Fondo Europeo de Desarrollo Regional FEDER).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
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