Early,Forme Fruste keratoconus and normal thin cornea,evaluation of sensitive parameters by combined Placido Scheimpflug topography

Abstract

Purpose

To determine the sensitive indices distinguishing forme-fruste keratoconus (FFKC) and early keratoconus (early KC) from thin normal corneas, and their cutoff values using Sirius topography.

Methods

156 eyes with normal thin corneas < 500 um (group 1), 99 eyes with early KC (group 2) and 41 eyes with FFKC (group 3), were assessed retrospectively for: corneal keratometric indices, pachymetry indices, corneal aberrations, elevation indices; thinnest corneal point elevation, Q value, root mean square (RMS) withRMS/ area (RMS/A); and KC summary indices of front and back surfaces; surface asymmetry index (SIf, SIb), elevation at KC vertex (KVf, KVb), Baiocchi-Calossi-Versaci index (BCVf, BCVb) and summation of its vector (BCV). Cutoff values were calculated.

Results

Keratometry indices were significantly different between early KC and thin normal cases (apex front curvature had the highest area-under-the-ROC-curve (AUROC) (0.926) in early KC, while only apex curvature and coordinates were significant in FFKC cases. Pachymetry indices did not show any significance in differentiating either early KC or FFKC from normal thin corneas. KC summary indices were highly significant among the 3 groups. The highest AUROC was observed with KVb in early KC (0.987) and with KVf in FFKC (0.831). Vertical coma and vertical trefoil showed the highest significance of all aberration parameters differentiating the 3 groups. Thinnest point elevation, RMS and RMS/A showed the highest AUROC in differentiating early KC and FFKC cases from thin normal corneas.

Conclusion

Comparing early KC and FFKC to thin normal corneas, Sirius provided high precision in prediction.

Keywords

corneal topography forme fruste keratoconus early keratoconus thin cornea sirius topography

Introduction

Keratoconus (KC) is an ectatic dystrophy of cornea characterized by a progressive thinning and consequently steepening of the cornea, resulting in uncorrected irregular astigmatism.¹ Diagnosing KC in its earliest stage is one of the most important aspects of avoiding iatrogenic corneal ectasia during refractive surgery.²

Forme fruste keratoconus (FFKC) was firstly proposed by Amsler³ in 1961 and then adapted by Klyce⁴ as “The fellow eye of a clinical manifest KC eye that has no clinical findings of any sort except for certain topographical changes.² Differentiating FFKC from early KC is mandatory as Xiaohui et al proved that approximately 50% of clinically normal fellow eyes will progress to KC within 16 years.⁵

According to Gatinel, terms such as “subclinical KC,” “KC suspect,” and “forme fruste KC,” have been interchangeably used to describe early forms of KC, and he proposed generalizing the term “subclinical KC” to all corneas in which the phenotypic expression of KC is sufficiently minor to remain asymptomatic.⁶

Published studies indicated that the central corneal thickness was a useful parameter to identify clinical KC.^7,8 Although KC populations have significantly thinner corneas than healthy individuals, the thickness values of thin non- KC corneas partially overlap with the subclinical KC corneas,^9,10 besides corneal thickness varies among eyes from different regions and ethnicities.¹¹ Accordingly, the non-keratoconic thin corneas (<500 μm) have special considerations in refractive surgery because as corneal thickness decreases, decision making for or against refractive surgery gets more crucial.⁹

The aim of this study is to detect the most diagnostic indices to differentiate normal thin corneas from subclinical or FFKC and from early KC and to detect the cutoff values of the measured indices comparing the 3 groups.

Patients and methods

This is a retrospective cohort observational study that was carried out at the Eye World Hospital, in Dokki, Giza, Egypt. Medical records and topography scans using Sirius device (CSO, Costruzione Strumenti Oftalmici, Florence, Italy, version 3.2.1.60) of refractive surgery candidates were reviewed from Jan 2017 to June 2021. A total of 296 eyes of 296 cases were included, cases were categorized into 3 groups: Group_1 included 156 eyes of 156 candidates with thin corneas (Thinnest location < 500 µm) with normal slit lamp biomicroscopy and normal topography. While group_2 included 99 eyes of 99 cases with early KC diagnosed by slit lamp biomicroscopy when any of the following criteria was present; central/paracentral thinning of cornea, Vogt striae, Fleischer ring, distorted retinoscopic red reflex, and diagnosis was confirmed by the presence topographic criteria of KC as: Sif ≥1.25D, Sib ≥ 0.25, BCV ≥ 0.52, KVf ≥ 11, KVb ≥ 20¹² and by the artificial intelligence of Phoenix software on Sirius topography as KC compatible and were classified as early KC according to Amsler Krumeich classification of KC where the induced myopia and/or cylinder was ˂ 5Ds and corneal radius was ≤48D.

Group_3 included 41 eyes of 41 cases with FFKC which was defined by Saad and Gatinel as: Normal topography with contralateral keratoconic eye.¹³

Before examination, all candidates removed their rigid contact lenses for 3 weeks and soft lenses for 2 weeks. We did not include any opacity visible in the Scheimpflug pictures, evident corneal scarring, obvious anterior segment disease on examination, or prior ocular trauma or procedures. All participants were required to sign informed consent forms before being included in the study as part of their preoperative refractive examination, which was conducted in accordance with the tenets of the Declaration of Helsinki and authorized by Cairo University's ethical committee.

Spherical equivalent and Best Corrected Visual Acuity (BCVA) were reported for each patient. As a routine, 4 reliable scans with highest quality were obtained by Sirius topographer and the one with best acquisition quality was taken in the study.

The investigated indices included

Keratometric (curvature) indices:

- At 3- and 5-mm circles, the anterior and posterior keratometric indices (K1, K2) were obtained.

- Sim K1 and K2 values

- Curvature and XY coordinates of the front and back corneal apices (representing the points with highest keratometric value).

Pachymetry indices:

- Central Corneal Thickness (CCT)

- Thickness of the thinnest corneal point (TL) with its XY coordinates

- Thickness at the point representing the apex of cornea.

Elevation indices: Different anterior and posterior corneal reference surfaces were evaluated, including 9-mm spherical reference surfaces (which is the standard map in the 4-map display), together with 6- and 8-mm aspherotoric surfaces (present in the shape indices display)

- Best-fit sphere flat and steep radii (BFS) of aspherotoric reference surface

- Q-value, representing the asphericity of the cornea. Elevation at the thinnest point.

- Root Mean Square (RMS):

- Root Mean Square per area. (RMS/A)

Keratoconus Summary indices:

- Curvature Asymmetry: Surface asymmetry indices of the front corneal surface (SIf) and back corneal surface (SIb) are recorded.

- Vertices (elevation based): The maximum point of ectasia is represented by the KC Vertex of the front (KVf) and back (KVb) corneal surfaces, along with the XY coordinates of both points.

- Aberration based indices: Baiocchi Calossi Versaci index (BCV) is used to assess the existence of ectasia and its degree, through the analysis of some constituents of Zernike's polynomials; coma, trefoil and spherical aberration (C₃^± 1, C₃^± 3, C₄⁰) using the formula:

BCV = (α C_{3} {^{\pm 1}}_{RMS} + β C_{3} {^{\pm 3}}_{RMS}) f (C_{3}^{\pm 1} α x) + γ C_{4}^{0}

Analysis was performed on the front surface index (BCVf), back surface index (BCVb), and summation of both surfaces index (BCV). Convergence radius: Representing the radius of the above-mentioned points.

Statistical analysis

All data were collected from Sirius machine as a .csv file and converted into .xlsx files by MS 356 Excel program (Redmond, Washington, USA). Then statistical analysis was done by MedCalc Statistical Software version 18.9.1 (MedCalc Software bvba, Ostend, Belgium).

All data were shown as mean ± SD and 95% confidence interval (95% CI) except for age and gender which were shown as frequency. Comparing age between groups was done using Kruskal-Wallis ANOVA test.

We have compared the two groups by unpaired t-test in which a statistically significant value was set if (p value < 0.05).

While comparing sensitivity and specificity of different values and the defining the value with best sensitivity and specificity cut off was done using DeLong method of area under the receiver operating characteristic curve (AUROC)

Results

Table 1 showed the demographic data of included subjects in 3 groups, with no statistically significant age difference between the three groups (P = 0.572). Table 2 showed the mean and standard deviation of keratometry, pachymetry, and KC summary indices together with corneal aberrations in the 3 groups and calculated the difference between the 3 groups and their AUROC values.

Table 1.

Demographic data of 3 groups

		Thin normal (n = 156)	Early kc (n = 99)	FFKC (n = 41)
Age		29.6 ± 9.2	31.6 ± 6.5	30.9 ± 8.4
Gender	Male	52 (33.3%)	45 (45.5%)	20 (48.8%)
	Female	104 (66.7%)	54 (55.5%)	21 (51.2%)
Laterality	Right eye	98 (62.8%)	51 (51.5%)	20 (48.8%)
	Left eye	58 (37.2%)	48 (48.5%)	21 (51.2%)

Table 2.

Showing the mean and standard deviation of keratometry, pachymetry and keratoconus summary indices together with corneal aberrations in the 3 groups and calculates the difference between the 3 groups and their AUROC values

	Thin normal	Early kc	FFKC	Early KC vs Thin Normal P value	FFKC vs Thin Normal P value	Early KC vs Thin Normal AUROC	FFKC vs Thin Normal AUROC
Keratometry Values
Sim K1	7.718 ± 0.26 (7.677 to 7.759)	7.661 ± 0.32 (7.597 to 7.726)	7.783 ± 0.28 (7.696 to 7.870)	0.0874	0.1105	0.564	0.581
Sim K2	7.5 ± 0.26 (7.459 to 7.541)	7.252 ± 0.36 (7.180 to 7.323)	7.523 ± 0.27 (7.437 to 7.610)	<0.0001	0.3964	0.713	0.543
Sim K avg	7.609 ± 0.25 (7.570 to 7.648)	7.456 ± 0.33 (7.391 to 7.522)	7.653 ± 0.25 (7.574 to 7.733)	0.0001	0.2009	0.65	0.565
K1front 3mm	7.699 ± 0.26 (7.659 to 7.740)	7.606 ± 0.40 (7.527 to 7.686)	7.765 ± 0.27 (7.679 to 7.852)	0.0241	0.0878	0.584	0.587
K2front 3mm	7.471 ± 0.26 (7.430 to 7.513)	7.129 ± 0.46 (7.038 to 7.221)	7.493 ± 0.29 (7.402 to 7.584)	<0.0001	0.3778	0.743	0.545
K avg front 3mm	7.585 ± 0.25 (7.546 to 7.624)	7.368 ± 0.41 (7.286 to 7.450)	7.629 ± 0.26 (7.548 to 7.710)	<0.0001	0.1801	0.679	0.568
K1 front 5mm	7.718 ± 0.26 (7.677 to 7.759)	7.656 ± 0.33 (7.589 to 7.723)	7.784 ± 0.28 (7.697 to 7.871)	0.0689	0.1005	0.568	0.583
k2 front 5mm	7.499 ± 0.26 (7.458 to 7.540)	7.239 ± 0.37 (7.165 to 7.314)	7.525 ± 0.28 (7.438 to 7.612)	<0.0001	0.3614	0.717	0.546
K avg front 5mm	7.608 ± 0.25 (7.569 to 7.648)	7.448 ± 0.34 (7.379 to 7.516)	7.654 ± 0.25 (7.574 to 7.734)	<0.0001	0.1861	0.656	0.567
K1 back 3mm	6.627 ± 0.25 (6.587 to 6.666)	6.284 ± 0.57 (6.171 to 6.397)	6.609 ± 0.30 (6.514 to 6.704)	<0.0001	0.957	0.721	0.503
K2 back 3mm	6.219 ± 0.27 (6.176 to 6.261)	5.616 ± 0.52 (5.512 to 5.721)	6.159 ± 0.34 (6.051 to 6.267)	<0.0001	0.6256	0.857	0.525
K avg back 3mm	6.423 ± 0.25 (6.384 to 6.461)	5.95 ± 0.52 (5.846 to 6.054)	6.384 ± 0.30 (6.290 to 6.477)	<0.0001	0.713	0.568	0.519
k1 back 5mm	6.602 ± 0.25 (6.561 to 6.642)	6.366 ± 0.44 (6.279 to 6.453)	6.596 ± 0.29 (6.505 to 6.687)	<0.0001	0.8571	0.689	0.509
K2 back 5mm	6.219 ± 0.27 (6.177 to 6.261)	5.813 ± 0.39 (5.735 to 5.891)	6.185 ± 0.30 (6.089 to 6.280)	<0.0001	0.6609	0.811	0.522
K avg Back 5mm	6.41 ± 0.25 (6.371 to 6.449)	6.09 ± 0.39 (6.012 to 6.168)	6.39 ± 0.27 (6.304 to 6.476)	<0.0001	0.9154	0.759	0.505
Apex Front Curvature	7.362 ± 0.28 (7.317 to 7.406)	6.52 ± 0.52 (6.417 to 6.623)	7.253 ± 0.28 (7.165 to 7.342)	<0.0001	0.0585	0.926	0.596
Apex front X- Coordinate	0.000219 ± 0.46 (−0.0724 to 0.0728)	0.0557 ± 0.48 (−0.0406 to 0.152)	−0.108 ± 0.66 (−0.317 to 0.101)	0.6487	0.0283	0.517	0.611
Apex Front Y- Coordinate	−0.177 ± 0.69 (−0.286 to −0.0685)	−1.105 ± 0.88 (−1.280 to −0.930)	−0.957 ± 1.29 (−1.364 to −0.550)	<0.0001	<0.0001	0.827	0.743
Apex Back Curvature	5.821 ± 0.36 (5.763 to 5.878)	4.719 ± 0.65 (4.588 to 4.849)	5.59 ± 0.37 (5.473 to 5.706)	<0.0001	0.0003	0.941	0.685
Apex Back X- Coordinate	0.989 ± 1.14 (0.808 to 1.170)	0.251 ± 0.70 (0.110 to 0.391)	0.589 ± 1.008 (0.271 to 0.907)	<0.0001	0.0374	0.684	0.606
Apex Back Y- Coordinate	−0.561 ± 1.52 (−0.802 to −0.321)	−0.889 ± 0.86 (−1.061 to −0.718)	−1.007 ± 1.13 (−1.364 to −0.651)	0.2762	0.1563	0.827	0.743
Pachymetry indices
TL	478.73 ± 12 (476.883 to 480.578)	470.636 ± 44 (461.804 to 479.467)	506.924 ± 36 (495.474 to 518.374)	0.0703	<0.0001	0.567	0.721
TL X- Coordinate	−0.111 ± 0.50 (−0.190 to −0.0327)	0.0449 ± 0.54 (−0.0636 to 0.153)	−0.0199 ± 0.50 (−0.177 to 0.137)	0.031	0.3973	0.58	0.543
TL Y- Coordinate	−0.263 ± 0.23 (−0.299 to −0.226)	−0.489 ± 0.39 (−0.567 to −0.410)	−0.453 ± 0.28 (−0.543 to −0.363)	<0.0001	0.0001	0.751	0.704
Apex Thickness	486.093 ± 11 (484.333 to 487.852)	497.346 ± 52 (486.964 to 507.728)	534.993 ± 53 (518.274 to 551.712)	0.0576	<0.0001	0.571	0.78
CCT	481.732 ± 12 (479.909 to 483.556)	484.083 ± 41 (475.986 to 492.179)	512.897 ± 36 (501.528 to 524.267)	0.5916	<0.0001	0.52	0.764
Keratoconus Summary Indices:
SIf	0.208 ± 0.46 (0.134 to 0.281)	4.51 ± 3.29 (3.855 to 5.165)	1.14 ± 1.20 (0.763 to 1.517)	<0.0001	<0.0001	0.948	0.791
SIb	0.00768 ± 0.13 (−0.0121 to 0.0275)	1.213 ± 0.85 (1.044 to 1.382)	0.313 ± 0.37 (0.196 to 0.430)	<0.0001	<0.0001	0.952	0.802
BCVf	0.276 ± 0.21 (0.243 to 0.309)	2.234 ± 1.46 (1.942 to 2.525)	0.665 ± 0.49 (0.511 to 0.818)	<0.0001	<0.0001	0.978	0.813
BCVb	0.122 ± 0.18 (0.0939 to 0.149)	2.398 ± 1.55 (2.088 to 2.708)	0.577 ± 0.61 (0.385 to 0.769)	<0.0001	<0.0001	0.976	0.772
BCV	0.176 ± 0.15 (0.152 to 0.199)	2.274 ± 1.48 (1.978 to 2.570)	0.594 ± 0.53 (0.426 to 0.762)	<0.0001	<0.0001	0.983	0.82
RMSf	3.019 ± 1.29 (2.815 to 3.224)	10.517 ± 5.70 (9.379 to 11.654)	4.174 ± 1.96 (3.556 to 4.793)	<0.0001	<0.0001	0.962	0.74
RMSb	6.773 ± 2.52 (6.375 to 7.170)	23.33 ± 11.51 (21.035 to 25.625)	9.244 ± 3.71 (8.071 to 10.416)	<0.0001	<0.0001	0.973	0.719
KVF X- Coordinate	−0.24 ± 1.39 (−0.459 to −0.0208)	−0.0117 ± 0.84 (−0.179 to 0.156)	0.186 ± 1.05 (−0.144 to 0.516)	0.0561	0.0464	0.571	0.601
KVF Y- Coordinate	−0.374 ± 1.50 (−0.611 to −0.137)	−1.167 ± 0.72 (−1.310 to −1.023)	−1.142 ± 1.35 (−1.569 to −0.715)	<0.0001	0.0005	0.656	0.675
KVf	4.405 ± 1.71 (4.136 to 4.675)	22.087 ± 12.89 (19.517 to 24.658)	7.594 ± 3.93 (6.353 to 8.834)	<0.0001	<0.0001	0.984	0.831
KVB X- Coordinate	1.256 ± 1.91 (0.953 to 1.558)	0.252 ± 0.92 (0.0689 to 0.434)	0.5 ± 1.21 (0.118 to 0.883)	<0.0001	<0.0001	0.753	0.711
KVB Y- Coordinate	−0.65 ± 1.28 (−0.853 to −0.448)	−1.2 ± 0.62 (−1.324 to −1.077)	−1.608 ± 0.94 (−1.904 to −1.313)	0.0067	<0.0001	0.6	0.721
KVB	11.26 ± 3.50 (10.707 to 11.814)	52.821 ± 30.23 (46.791 to 58.851)	17.714 ± 9.91 (14.587 to 20.842)	<0.0001	<0.0001	0.987	0.732
Convergence Radius	1.349 ± 0.32 (1.298 to 1.400)	0.587 ± 0.38 (0.511 to 0.662)	0.997 ± 0.56 (0.820 to 1.174)	<0.0001	<0.0001	0.923	0.726
Corneal Aberrations
Vertical Trefoil	0.104 ± 0.16 (0.0788 to 0.129)	−0.312 ± 0.57 (−0.425 to −0.198)	−0.0117 ± 0.19 (−0.0729 to 0.0495)	<0.0001	0.0001	0.850	0.693
Vertical Coma	0.0553 ± 0.17 (0.0283 to 0.0824)	1.172 ± 0.88 (0.996 to 1.347)	0.303 ± 0.31 (0.206 to 0.400)	<0.0001	<0.0001	0.949	0.772
Hor_Coma	0.052 ± 0.27 (0.00982 to 0.0941)	−0.00894 ± 0.55 (−0.119 to 0.102)	0.0434 ± 0.20 (−0.0196 to 0.106)	0.6024	0.6924	0.519	0.52
Oblique_Trefoil	0.00255 ± 0.16 (−0.0225 to 0.0276)	0.0214 ± 0.41 (−0.0609 to 0.104)	−0.0579 ± 0.19 (−0.117 to 0.00104)	0.7406	0.0153	0.512	0.623
Sph_Ab	−0.181 ± 0.07 (−0.192 to −0.171)	−0.0688 ± 0.36 (−0.141 to 0.00372)	−0.171 ± 0.10 (−0.201 to −0.140)	0.0004	0.8692	0.633	0.508

Many of the keratometry indices showed high significance in differentiating early KC from normal thin corneas, although only a few of them; including apex curvature and its coordinates, were significant comparing FFKC and normal thin corneas. Some of the keratometry indices, such as K2 back (at 3 and 5 mm) and apex curvature (front and back), showed high AUROC in differentiating normal thin corneas from early KC, although they did not show the same predictability in differentiating thin normal corneas from FFKC.

Pachymetry indices; as the thinnest corneal thickness and CCT, were significantly thicker in FFKC than normal thin corneas, while normal thin corneas and early KC did not show a statistically significant difference.

KC summary indices showed high significance in differentiating the 3 groups, although most of the measured indices showed a higher AUROC comparing early KC and normal thin corneas.

Vertical coma and vertical trefoil showed the highest significance and highest AUROC in differentiating the 3 groups in all corneal aberrations measured.

Best-fit reference surface, Q-value, elevation at the thinnest location, RMS and RMS/A at spheric (9 mm), and aspherotoric reference surfaces at 6- and 8-mm rings were studied for both front (Table 3) and back (Table 4) corneal surfaces. All the measured elevation indices showed a high statistically significant difference between early KC and normal thin corneas while the highest AUROC (> 0.9) was recorded in elevation indices at aspherotoric reference surface at 6- and 8-mm rings. Elevation at the thinnest point, RMS and RMS/A of the front and back surfaces were the most statistically significant elevation indices differentiating FFKC from normal thin corneas, especially at aspherotoric reference surface at 6- and 8-mm rings, although only RMS and RMS/A (front) at the 6 mm ring had a moderate AUROC (> 0.8).

Table 3.

Best fit reference surface, Q-value, elevation at thinnest location, RMS and RMS/A at spheric (9 mm) and aspherotoric reference surfaces at 6 and 8 mm rings were studied for front corneal surfaces

		Best Fit Sphere at 9 mm					Aspherotoric 6mm					Aspherotoric 8 mm
		Mean ± SD	Early KC vs Thin Normal P value	FFKC vs Thin Normal P value	Early KC vs Thin Normal AUROC	FFKC vs Thin Normal AUROC	Mean ± SD	Early KC vs Thin Normal P value	FFKC vs Thin Normal P value	Early KC vs Thin Normal AUROC	FFKC vs Thin Normal AUROC	Mean ± SD	Early KC vs Thin Normal P value	FFKC vs Thin Normal P value	Early KC vs Thin Normal AUROC	FFKC vs Thin Normal AUROC
Best fit reference/flat	Thin Normal	7.706 ± 0.25 (7.667 to 7.745)	<0.0001	<0.0001	0.615	0.571	7.672 ± 0.26 (7.632 to 7.713)	<0.0001	0.0224	0.629	0.572	7.659 ± 0.26 (7.618 to 7.700)	0.0002	0.1375	0.637	0.575
	Early KC	7.602 ± 0.26 (7.550 to 7.655)					7.493 ± 0.47 (7.399 to 7.587)					7.479 ± 0.43 (7.393 to 7.565)
	FFKC	7.74 ± 0.31 (7.643 to 7.837)					7.73 ± 0.28 (7.643 to 7.817)					7.719 ± 0.28 (7.631 to 7.806)
Best fit reference/Steep	Thin Normal						7.456 ± 0.26 (7.416 to 7.497)	<0.0001	0.4915	0.747	0.535	7.44 ± 0.26 (7.399 to 7.480)	<0.0001	0.5091	0.74	0.534
	Early KC						7.085 ± 0.51 (6.983 to 7.186)					7.108 ± 0.45 (7.017 to 7.198)
	FFKC						7.47 ± 0.28 (7.381 to 7.559)					7.457 ± 0.28 (7.370 to 7.544)
Q Value	Thin Normal						−0.236 ± 0.10 (−0.251 to −0.221)	<0.0001	0.0585	0.674	0.596	−0.299 ± 0.09 (−0.313 to −0.285)	<0.0001	0.0677	0.701	0.593
	Early KC						−0.521 ± 0.84 (−0.689 to −0.353)					−0.516 ± 0.62 (−0.639 to −0.393)
	FFKC						−0.0946 ± 0.31 (−0.194 to 0.00468)					−0.139 ± 0.33 (−0.242 to −0.0359)
Elevation	Thin Normal	−0.404 ± 1.03 (−0.566 to −0.241)	0.0016	0.4634	0.872	0.75	0.359 ± 0.57 (0.269 to 0.449)	<0.0001	0.0003	0.932	0.664	1.006 ± 0.82 (0.876 to 1.137)	<0.0001	0.0061	0.93	0.631
	Early KC	6.798 ± 8.73 (5.057 to 8.539)					5.919 ± 5.42 (4.839 to 7.000)					9.263 ± 8.34 (7.600 to 10.925)
	FFKC	1.61 ± 2.57 (0.799 to 2.420)					1.195 ± 1.60 (0.690 to 1.700)					2.098 ± 2.31 (1.368 to 2.827)
RMS	Thin Normal	12.486 ± 5.67 (11.588 to 13.383)	<0.0001	<0.0001	0.87	0.565	0.963 ± 0.35 (0.908 to 1.018)	<0.0001	<0.0001	0.987	0.828	2.507 ± 1.10 (2.334 to 2.680)	<0.0001	<0.0001	0.965	0.746
	Early KC	23.348 ± 8.79 (21.595 to 25.100)					5.065 ± 2.95 (4.477 to 5.653)					8.68 ± 4.60 (7.763 to 9.597)
	FFKC	14.474 ± 7.40 (12.137 to 16.810)					1.579 ± 0.92 (1.288 to 1.870)					3.522 ± 1.73 (2.976 to 4.067)
RMS/A	Thin Normal	0.196 ± 0.09 (0.182 to 0.210)	<0.0001	0.0635	0.872	0.571	0.0341 ± 0.01 (0.0321 to 0.0360)	<0.0001	<0.0001	0.987	0.828	0.0499 ± 0.02 (0.0464 to 0.0533)	<0.0001	<0.0001	0.965	0.746
	Early KC	0.369 ± 0.14 (0.342 to 0.396)					0.179 ± 0.10 (0.158 to 0.200)					0.173 ± 0.09 (0.154 to 0.191)
	FFKC	0.229 ± 0.11 (0.193 to 0.265)					0.0558 ± 0.03 (0.0455 to 0.0661)					0.0701 ± 0.03 (0.0592 to 0.0809)

Table 4.

Best fit reference surface, Q-value, elevation at thinnest location, RMS and RMS/A at spheric (9 mm) and aspherotoric reference surfaces at 6 and 8 mm rings were studied for back corneal surfaces

		Best Fit Sphere at 9 mm					Aspherotoric 6mm					Aspherotoric 8 mm
		Mean ± SD	Early KC vs Thin Normal P value	FFKC vs Thin Normal P value	Early KC vs Thin Normal AUROC	FFKC vs Thin Normal AUROC	Mean ± SD	Early KC vs Thin Normal P value	FFKC vs Thin Normal P value	Early KC vs Thin Normal AUROC	FFKC vs Thin Normal AUROC	Mean ± SD	Early KC vs Thin Normal P value	FFKC vs Thin Normal P value	Early KC vs Thin Normal AUROC	FFKC vs Thin Normal AUROC
Best fit reference/flat	Thin Normal	6.52 ± 0.24 (6.440 to 6.550)	<0.0001	0.8732	0.697	0.527	6.59 ± 0.25 (6.551 to 6.630)	<0.0001	0.9644	0.763	0.504	6.52 ± 0.26 (6.478 to 6.561)	<0.0001	0.8474	0.759	0.516
	Early KC	6.331 ± 0.25 (6.280 to 6.382)					6.069 ± 0.68 (5.934 to 6.204)					6.061 ± 0.57 (5.946 to 6.175)
	FFKC	6.594 ± 0.54 (6.425 to 6.764)					6.561 ± 0.32 (6.459 to 6.662)					6.505 ± 0.30 (6.409 to 6.601)
Best fit reference/Steep	Thin Normal						6.258 ± 0.26 (6.217 to 6.300)	<0.0001	0.6344	0.849	0.529	6.245 ± 0.26 (6.203 to 6.286)	<0.0001	0.6213	0.843	0.53
	Early KC						5.559 ± 0.69 (5.421 to 5.696)					5.649 ± 0.59 (5.532 to 5.766)
	FFKC						6.196 ± 0.36 (6.083 to 6.309)					6.194 ± 0.33 (6.091 to 6.297)
Q Value	Thin Normal						−1.054 ± 0.18 (−1.083 to −1.025)	0.0005	0.0598	0.629	0.608	−0.188 ± 0.15 (−0.211 to −0.165)	<0.0001	0.4647	0.763	0.548
	Early KC						−1.449 ± 1.34 (−1.716 to −1.182)					−0.635 ± 0.76 (−0.787 to −0.483)
	FFKC						−0.69 ± 0.73 (−0.919 to −0.461)					−0.0975 ± 0.32 (−0.200 to 0.00481)
Elevation	Thin Normal	0.0128 ± 2.29 (−0.350 to 0.376)	<0.0001	<0.0001	0.884	0.826	0.571 ± 1.54 (0.327 to 0.814)	<0.0001	<0.0001	0.951	0.791	1.429 ± 1.97 (1.118 to 1.741)	<0.0001	<0.0001	0.957	0.784
	Early KC	20.242 ± 22.44 (15.766 to 24.719)					19.152 ± 15.46 (16.068 to 22.235)					25.606 ± 21.53 (21.312 to 29.900)
	FFKC	6.902 ± 8.31 (4.281 to 9.524)					4.3 ± 4.72 (2.791 to 5.809)					6.5 ± 6.53 (4.412 to 8.588)
RMS	Thin Normal	25.564 ± 8.68 (24.191 to 26.937)	<0.0001	<0.0001	0.895	0.577	2.446 ± 0.78 (2.322 to 2.569)	<0.0001	<0.0001	0.986	0.793	6.859 ± 2.34 (6.489 to 7.229)	<0.0001	<0.0001	0.974	0.706
	Early KC	55.093 ± 68.61 (41.409 to 68.778)					13.14 ± 7.25 (11.694 to 14.586)					20.235 ± 8.99 (18.443 to 22.027)
	FFKC	27.869 ± 10.53 (24.544 to 31.193)					4.412 ± 2.61 (3.587 to 5.237)					9.088 ± 3.38 (8.022 to 10.154)
RMS/A	Thin Normal	0.402 ± 0.13 (0.381 to 0.423)	<0.0001	0.1502	0.909	0.605	0.0865 ± 0.03 (0.0821 to 0.0909)	<0.0001	<0.0001	0.986	0.793	0.136 ± 0.05 (0.129 to 0.144)	<0.0001	<0.0001	0.974	0.706
	Early KC	0.77 ± 0.30 (0.710 to 0.829)					0.465 ± 0.26 (0.414 to 0.516)					0.403 ± 0.18 (0.367 to 0.438)
	FFKC	0.459 ± 0.16 (0.408 to 0.510)					0.156 ± 0.09 (0.127 to 0.185)					0.181 ± 0.07 (0.160 to 0.202)

The sensitivity and specificity of the examined indices were used to derive the cutoff values between early KC and normal thin corneas (Table 5) and between FFKC and normal thin corneas (Table 6). None of the measured indices comparing the 3 groups showed 100% sensitivity, KVb showed the highest sensitivity (96.97%) comparing early KC and normal thin corneas with a cutoff value of 15.96, while BCV had the highest sensitivity (90.24%) comparing FFKC and normal thin corneas with cutoff value of 0.3. A 100% specificity was met with vertical coma and SIf comparing early KC and normal thin corneas. As corneal thickness was significantly higher in FFKC, CCT and apex thickness showed 100% specificity when comparing FFKC and normal thin corneas, despite low sensitivity (63.41% both).

Table 5.

The cutoff values of all the studied indices were calculated between early KC and normal thin corneas

	AUROC	Cutoff value	Sensitivity	Specificity
KVB	0.987	>15.96	96.97	93.59
BFTEFr6mm-RMS	0.987	>1.5	94.95	93.59
BFTEFr6mm-RMS/A	0.987	>0.053	94.95	93.59
BFTEBk-6mm-RMS	0.986	>3.77	95.96	96.79
BFTEBk-6mm-RMS/A	0.986	>0.133	95.96	96.79
KVf	0.984	>7.68	91.92	96.79
BCV	0.983	>0.51	93.94	96.79
BCVf	0.978	>0.72	89.90	98.08
BCVb	0.976	>0.63	89.90	98.08
BFTEBk-8mm-RMS	0.974	>11.11	87.88	97.44
BFTEBk-8mm-RMS/A	0.974	>0.22	87.88	97.44
RMSb	0.973	>11.56	88.89	98.08
BFTEFr8mm-RMS	0.965	>3.95	86.87	94.87
BFTEFr8mm-RMS/A	0.965	>0.13	95.96	96.79
RMSf	0.962	>4.5	87.88	93.59
BFTEBk-8mm-Elevation	0.957	>5	84.85	97.44
SIb	0.952	>0.21	88.89	96.15
BFTEBk-6mm-Elevation	0.951	>3	84.85	97.44
Vertical Coma	0.949	>0.43	87.88	100
SIf	0.948	>1.26	89.9	100

Table 6.

The cutoff values of all the studied indices were calculated between FFKC and normal thin corneas

	AUROC	Cutoff value	Sensitivity	Specificity
KVf	0.831	>5.87	73.17	83.33
BFTEFr6mm-RMS	0.828	>1.25	75.61	85.26
BFTEFr6mm-RMS/A	0.828	>0.047	75.61	85.26
BFSBk-9mm-Elevation	0.826	>1	73.17	79.49
BCV	0.82	>0.3	90.24	58.33
BCVf	0.813	>0.13	65.85	85.9
SIb	0.802	>0.13	65.85	85.9
BFTEBk-6mm-RMS	0.793	>2.93	68.29	82.69
BFTEBk-6mm-RMS/A	0.793	>0.11	68.29	82.69
BFTEBk-6mm-Elevation	0.791	>0	85	58.97
SIf	0.791	>1.15	56.1	98.72
BFTEBk-8mm-Elevation	0.784	>3	55	85.9
Apex Thickness	0.78	>500	63.41	100
BCVb	0.772	>0.29	70.73	84.62
Vertical Coma	0.772	>0.39	56.1	92.95
CCT	0.764	>499	63.41	100
BFSFr6mm-Elevation	0.75	>0	60.98	64.1
BFTEFr8mm-RMS	0.746	>2.64	80.49	66.03
BFTEFr8mm-RMS/A	0.746	>0.06	80.49	66.03
Apex Front Y- Coordinate	0.743	≤ -1	58.54	91.67
Apex Back Y- Coordinate	0.743	≤ -0.55	78.05	48.08
RMSf	0.74	> 3.21	75.61	67.95
KVB	0.732	>15.96	46.34	93.59

Discussion

Differentiating KC in its early stages is difficult. Corneal thickness used to be an important diagnostic tool for early detection of KC, although a group of normal population with thin corneas, < 500 um, would be a serious challenge for refractive surgery as proper patient selection is challenging in such cases, because preoperative thin corneas and thinner residual stromal bed after excimer laser ablation are widely described as risk factors for the development of postoperative ectasia.¹⁴ Numerous studies have emphasized the value of many indices in early detection of KC as KC indices^15–18 pachymetry progression^9,19 elevations^15,16 and aberrations,²⁰ but none of them investigated the full set of diagnostic indices form the combined Scheimpflug placido tomography (Sirius) in FFKC and early KC.

It was found that combination of different keratometric (power), thickness and elevation parameters would provide more accurate diagnosis of early KC cases.²¹

KC cases included in this study were only in the early stage, this could be the reason only a few of the studied curvature indices had high predictability. The highest AUROC (> 0.9) was observed with anterior and posterior apex curvature (0.926, 0.941 respectively), and with front and back symmetry indices (0.948 and 0.952 respectively). SIf and SIb were the keratometry indices with highest predictability of FFKC (0.791, 0.802 respectively) with lower cutoff values (1.13, 0.13 respectively) than those for early KC. Our cutoff values were close to those estimated by Shetty et al comparing subclinical and KC cases to normal corneas.¹⁵

Ambrosio et al stated that single point pachymetric measurements as thinnest location, thickness at corneal center and at corneal apex are not as significant as pachymetry change and distribution indices (pachymetry progression and percentage thickness increase) in early diagnosis of KC.¹⁹ This is obviously true especially when dealing with thin cornea, which could be the reason we did not have significantly different TL or apex thickness between the early KC and thin normal groups. Thin normal corneas would be even thinner than subclinical KC cases as seen in this study, confirming that single point corneal thickness is not sufficient to distinguish thin normal corneas from FFKC deducing that significant corneal thinning may not be the earliest finding in subclinical cases. On the other hand, Huseynli found that single point pachymetry indices had perfect sensitivity in distinguishing mild KC from normal thin cornea, although they had low specificity which may result in false positive cases.⁹ The difference in our results could be attributed to the higher number of cases included in our study. The only pachymetry index we had that showed high predictive accuracy in differentiating early KC from normal thin corneas was the location of the thinnest point (Y coordinate, AUROC = 0.751). This may draw attention to the location of thinnest point rather than its thickness in picking early KC cases from thin normal corneas.

Elevation indices have shown excellent predictability for early stages of KC.^13,22,23 We agree with Huseynli et al that elevation indices have high predictability in differentiating subclinical and early KC from normal thin corneas.⁹ Huseynli found an AUROC of 1.00 of posterior elevation at 8-mm best-fit sphere (BFS) with 100% sensitivity and specificity in distinguishing mild KC from normal thin corneas, however in our study, predictability of elevation indices was higher at 6 and 8-mm anterior (0.932, 0.93) and posterior (0.951, 0.957) aspherotoric surfaces compared to that at 9-mm anterior (0.87) and posterior (0.884) conventional BFS.⁹ The previous results confirm the utmost importance of elevation indices in the diagnosis of early KC and subclinical KC, and that depending on the elevation parameters with reference to the aspherotoric surface rather than the best-fit sphere would provide higher predictive accuracy. We agree with Shetty et al that Sirius provides complex elevation indices (KV, RMS, RMS/A) of higher predictive accuracy than pure elevation at the anterior (AUROC = 0.984, 0.987, 0.965 respectively) and posterior (AUROC = 0.987, 0.986, 0.974) aspherotoric surfaces enhancing its diagnostic ability.^12,15

Knowing the cutoff values for different elevation indices using Sirius is mandatory, as it proved to have lower cutoff values than Pentacam and Orbscan topographers.¹² Elevation at the thinnest point of anterior and posterior surfaces differentiating either early or subclinical KC from normal thin corneas, showed much lower values than those recorded by Huseynli using Pentacam. It is worth mentioning that posterior elevation >0.227 um is suspicious for FFKC with good sensitivity and specificity (75.61 and 75.64%) compared to 8 um using Pentacam.⁹

The highest sensitivity of all elevation indices (96.97%) comparing mild KC to thin normal cases was noticed with maximum posterior elevation (KVb) having excellent specificity (93.59%) at a cutoff value of 15.96 um, which was close to the cutoff value estimated by Miháltz et al (15.5 um), though lower than the value estimated by Salman et al (25 um),¹⁶ that could be due to the greater severity of KC cases included in their study. Comparing FFKC to thin normal cases, maximum anterior elevation (KVf) had the highest AUROC (0.831) with sensitivity 73.17% at cutoff value 5.87 um, while RMS and RMS/A at the 8 mm anterior aspherotoric surface had the highest sensitivity (80.49% both) at cutoff value 2.64 and 0.06 respectively, which was close to the cutoff value of RMS/A estimated by Shetty (0.088).¹⁵

Comparing FFKC with thin normal corneas showed lower cutoff values than comparing them with early KC cases in all studied elevation indices, which would provide higher accuracy in early detection of suspicious cases in such a confusing population (Table 5, 6)

Anterior corneal surface changes that occur in KC would increase the higher order aberrations, especially coma like aberrations due to cone decentration.^20,24 Our study approved this hypothesis, as vertical coma in our study showed the highest predictability, either in early KC or FFKC, of all aberrations included. Alio and Shabayek ²⁰ found a positive correlation between coma-like aberrations and central corneal steepening, which could be the reason of higher predictability of vertical coma in early KC than in less steep FFKC cases.

BCV, which is an important KC screening index provided by Sirius, is obtained by combining data from different aberration coefficients including coma, trefoil and spherical aberrations at both anterior and posterior surfaces. In our study, BCVf, BCVb and their vectorial sum (BCV) showed statistically significant differences between early KC and FFKC cases compared to normal thin corneas, with high AUROC. It showed higher predictability differentiating normal thin corneas from early KC than from FFKC. This was confirmed by the higher values of coma, trefoil and spherical aberrations in early KC than in FFKC, which could be explained by the steeper cornea and higher surface irregularity seen in early KC. Our results agree with Fathy et al who found positive correlation between steep keratometry and BCV front and back, which was reflected as a progressive increase of BCVf and BCVb in suspect KC and KC cases compared to normal corneas.¹⁷ BCV showed perfect sensitivity differentiating subclinical and early KC from normal thin corneas (90.24, 93.94%) which agrees with Shetty et al (97.7, 78.8%).¹⁵

The cutoff values of BCVf, BCVb and BCV were lower in FFKC (0.13, 0.29, 0.3) than in early KC (0.72, 0.63, 0.51) which would provide more precise and higher diagnostic ability of these indices, with excellent predictability (>0.9). Our cutoff values were closer to Heidari et al ¹⁸ (BCVf = 0.245 in FFKC and 0.535 in KC), while they were lower than cutoff values elicited by Shetty et al (BCVf = 0.8 in FFKC and 1.2 in KC), which could be attributed to fewer number of cases included in their study.

In conclusion, differentiating normal thin corneas from subclinical KC and early KC is a real difficulty. This study proved that corneal thickness would be a misleading parameter in such conditions. The location of the thinnest point, elevation indices, particularly in reference to the aspherotoric surfaces, high-order aberrations specifically vertical coma, and KC summary indices provide excellent sensitivity and specificity for predicting either subclinical or early KC. As long as none of the studied indices had an AUROC of 1, and hence complete prediction, we believe that we should rely on a combination of all these indices to reach an accurate diagnosis of subclinical and early KC.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Hesham Mohamed Gharieb

Hani Mohamed Gharieb

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