Yaron S. Rabinowitz

KISA% index: a quantitative videokeratography algorithm embodying minimal topographic criteria for diagnosing keratoconus

PURPOSE To formulate and test an algorithm using minimal topographic criteria for accurately diagnosing clinical keratoconus. SETTING Subspecialty cornea practice and Keratoconus Genetic Research Project. METHODS Both eyes of 86 keratoconic patients who had never worn contact lenses and 195 normal participants were studied with the TMS-1 videokeratoscope to evaluate the KISA% index, an algorithm that topographically quantifies the phenotypic features of keratoconus. The diagnostic efficacy of the KISA% index was compared with that of the modified Rabinowitz/McDonnell (K- and I-S values) and the Maeda/Klyce (KCI% and KPI) indices. The same indices were calculated for an additional 8 eyes with keratoconus-suspect topography and 12 eyes with early keratoconus. RESULTS The mean KISA% was significantly greater in the keratoconus group (10,382%) than in the normal control group (20.44%) with minimal overlap. At a cutoff point for KISA% of 100, 280 of 281 participants (99.6%) were correctly classified. In contrast, the correct classification rate for the other indices were KCI%, 274 of 281 (97.5%); KPI, 249 of 281 (88.6%); K, 272 of 281 (96.8%); I-S, 269 of 281 (95.7%). Six of the 8 eyes with keratoconus-suspect topography had a KISA% between 60% and 100%, and 11 of the 12 eyes with early keratoconus had a KISA% greater than 100%. CONCLUSIONS The KISA% index set at 100 was highly sensitive and specific for diagnosing keratoconus; a range of 60% to 100% may be useful for designating suspects. This index is more useful than any of the other currently available tools for classifying patients with keratoconus for computerized segregation analysis and for distinguishing eyes with keratoconus from normal eyes in topographic screening of refractive surgical candidates.

Keratoconus and Corneal Ectasia After LASIK

From Gordon Binder Weiss Vision Institute, San Diego, Calif (Binder); Minnesota Eye Consultants, Minneapolis, Minn (Lindstrom); Emory University, Atlanta, Ga (Stulting); Ophthalmic Consultants of Long Island, Rockville Centre, NY (Donnenfeld); Tufts New England Medical Center, Boston, Mass (Wu); Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, Md (McDonnell); and Cornea Genetic Eye Institute, Cedars Sinai Medical Center, Los Angeles, Calif (Rabinowitz).

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Genetic Epidemiological Study of Keratoconus: Evidence for Major Gene Determination

Keratoconus (KC) is a noninflammatory corneal thinning disorder and the major cause of cornea transplantation in the Western world. Genetic factors have been suggested in the cause of KC. We conducted a family study to investigate genetic contributions to the development of KC by evaluating familial aggregation and testing genetic models with segregation analysis. KC was diagnosed based on clinical criteria. Familial aggregation of KC was evaluated using both clinical status and three videokeratography indices generated by the Topographic Modeling System (TMS-1). The estimated KC prevalence in first-degree relatives was 3.34% (41/1,226, 95% CI: 3. 22-3.46%), which is 15 to 67 times higher than that in the general population (0.23-0.05%). For all three videokeratography indices, CK, IS, and KISA, KC propositi had significantly higher mean values than controls (all P < 0.0001). Clinically unaffected parents also had significantly higher values for these indices than controls (all P < 0.016). The correlation of KISA in sib and parent-offspring pairs (r = 0.30 and 0.22, respectively, both P < 0.0005) was significantly greater than that in marital pairs (r = 0.14), and the latter was not significantly different from zero. We performed segregation analysis on KISA in 95 families ascertained through KC propositi. Hypotheses of both sporadic and environmental models were rejected (P < 0.001); a major gene model was not rejected (P > 0.1). Additionally, the most parsimonious model was autosomal recessive. In conclusion, we observed strong evidence of familial aggregation in KC and its subclinical indices and this aggregation is likely due to a major gene effect.

The genetics of keratoconus

Isolated keratoconus with no associations is by far the most common keratoconus presentation seen by a practicing clinician. This article explores the genetics of this most common form of keratoconus.

Accuracy of ultrasonic pachymetry and videokeratography in detecting keratoconus.

Purpose: To compare the accuracy of ultrasonic pachymetry measurements‐ and videokeratography‐derived indices in distinguishing keratoconus patients from those with normal eyes. Setting: A subspecialty cornea practice (Los Angeles, California, USA) and the Keratoconus Genetics Research Project. Methods: Corneal thickness was measured by ultrasonic pachymetry at the center and inferior margins of the pupil of 142 normal and 99 keratoconus patients. The corneal surface topography of patients was studied with the Topographic Modeling System (TMS‐1). The videokeratographs obtained were analyzed with a computer program that automatically calculates two indices derived from data points in the central and paracentral cornea: central K and I‐S values. Linear discriminant analysis was used to determine the correct classification percentages using pachymetry measurements and indices derived from videokeratography as the independent variables. Results: The range of corneal thickness in normal and keratoconic eyes overlapped considerably. In the discriminant analysis, videokeratography indices provided a 97.5% correct classification rate and pachymetry data, an 86.0% rate (P < .01, McNemar’s test). Conclusion: Keratoconus is more accurately distinguished from the normal population by videokeratography‐derived indices than by ultrasonic pachymetry measurements. This may be due to the large variation in corneal thickness in the normal population or the inability of ultrasonic pachymetry to accurately detect the location of corneal thinning in keratoconus by measuring standard points on the cornea. Pachymetry should not be relied on to exclude or diagnose keratoconus because the false‐negative and false‐positive rates are unacceptably higher than those obtained by videokeratography.

Higher Order Wavefront Aberrations and Topography in Early and Suspected Keratoconus

PURPOSE To determine whether higher order wavefront aberrations or a combination of topography and wavefront variables distinguishes between early and suspected keratoconus. METHODS This prospective comparative study evaluated 70 eyes using videokeratography (Tomey TMS-1) and aberrometry (Alcon LADARWave). Videokeratography and clinical evaluation were used to divide the eyes into three groups: 50 normal eyes, 10 eyes with early keratoconus, and 10 eyes with suspected keratoconus. Data were analyzed to determine whether higher order aberrations could separate eyes with early and suspected keratoconus from normal eyes. The product of the Inferior-Superior (I-S) topographic value in combination with the wavefront vertical coma also was evaluated to determine whether this could distinguish normal eyes from eyes with early and suspected keratoconus. RESULTS Differences in vertical coma, root-mean-square coma, and secondary astigmatism for the three groups were statistically significant. Vertical coma was -0.03 +/- 0.28 for normal eyes, -0.525 +/- 0.253 for eyes with suspected keratoconus, and -1.949 +/- 1.416 for eyes with early keratoconus. Root-mean-square coma was 0.229 +/- 0.149 for normal eyes, 0.639 +/- 0.250 for eyes with suspected keratoconus, and 2.034 +/- 1.532 for eyes with early keratoconus. The product of vertical coma and the topographic I-S value separated the three groups better than aberrometry alone (P < .0001). CONCLUSIONS Although both vertical coma and the I-S topographic value were useful for distinguishing among the three study groups, a combination of wavefront aberrometry and videokeratography appears to be the most sensitive way for distinguishing among normal eyes, eyes with suspected keratoconus, and eyes with early keratoconus.

Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1

Purpose: Keratoconus is a corneal dystrophy with an incidence of 1 in 2000 and a leading cause for cornea transplantation in Western developed countries. Both clinical observations and segregation analyses suggest a major role for genes in its pathogenesis. It is genetically heterogenous, most commonly sporadic, but inherited patterns with recessive or dominant modes have also been reported. We studied a four-generation autosomal-dominant pedigree to identify disease loci for keratoconus.Methods: A two-stage genome-wide scan was applied to 27 family members. First linkage analysis was performed with 343 microsatellite markers along the 22 autosomal chromosomes at ≈10 cM density. This was followed by fine mapping at ≈2 cM density, in regions suggestive of linkage. Multipoint linkage analysis was performed using GeneHunter2.Results: Evidence of suggestive linkage from the initial scan was observed at the 82 to 112 cM region of chromosome 5q14.1-q21.3 with a maximum lod score (LOD) of 3.48 (penetrance = 0.5). Fine mapping by testing an additional 11 microsatellite markers at 1 to 3 cM intervals revealed a narrower and higher peak (99–119 cM) with LOD 3.53. By analysis of the recombination of haplotypes, the putative locus of keratoconus was further narrowed to a 6 cM region (8.2 Mbp physical distance) between markers D5S2499 and D5S495.Conclusion: These results indicate a promising new locus for keratoconus in this pedigree. Because of the heterogeneous nature of keratoconus, this locus may be specific to familial autosomal-dominant keratoconus. Nevertheless, the identification of this locus may provide new insights into the pathogenesis of keratoconus.

INTACS inserts using the femtosecond laser compared to the mechanical spreader in the treatment of keratoconus.

PURPOSE To determine the efficacy of INTACS insertion using a femtosecond laser in the treatment of keratoconus and to compare it to the technique using a mechanical spreader. METHODS INTACS were inserted in 10 eyes using the mechanical spreader to create the channels and subsequently on another 20 eyes using the femtosecond laser. Uncorrected (UCVA) and best spectacle-corrected visual acuity (BSCVA), manifest refraction, and corneal topography were measured prior to surgery, at 6 months (femtosecond group), and 1 year (mechanical group). Pre- and postoperative data were analyzed to determine changes in the above parameters. RESULTS Both groups showed significant reduction in average keratometry (K), spherical equivalent refraction, BSCVA, UCVA, surface regularity index (SRI), and surface asymmetry index (SAI). The laser group performed better in all parameters except change in SRI. Results of the laser versus the mechanical spreader were as follows: reduction in spherical equivalent refraction (3.98 vs 2.96), change in average K (2.91 vs 2.52), improvement in UCVA (4.13 vs 3.63), improvement in BSCVA (3.92 vs 1.63), change in SRI (0.37 vs 0.64), and change in SAI (1.00 vs 0.70). Statistical analysis, however, did not reveal any statistically significant differences between the two groups for any single parameter studied. The biggest improvement in the laser group versus the mechanical group was BSCVA (P=.09). Overall success, defined as contact lens or spectacles tolerance, was 85% in the laser group and 70% in the mechanical group. CONCLUSIONS Inserting INTACS using the femtosecond laser to create the channels is as effective as using the mechanical spreader.

Videokeratography database of normal human corneas.

AIM: To form a database of videokeratography patterns and quantitative indices describing normal human corneas using the absolute scale. METHODS: Both eyes of 195 normal subjects were examined with a TMS-1 videokeratoscope. Videokeratographs were divided into 10 categories based on a classification scheme devised from the absolute scale and analysed with 10 quantitative indices devised to describe phenotypic features of keratoconus videokeratographs. Correlations were sought between videokeratograph patterns and quantitative indices. Additionally, data were analysed for differences in age, sex, and ethnicity. RESULTS: For symmetric videokeratography patterns, analysis in the absolute scale was similar to a previous study done in the normalised scale. In the asymmetric categories, analyses differed markedly. Using the absolute scale and our classification scheme more variation in normal videokeratography patterns could be appreciated. There was good correlation between quantitative indices and videokeratography patterns. Neither videokeratography patterns nor indices differed significantly between sex, ethnic groups, or age using two way analysis of variance. CONCLUSIONS: Pattern analysis of videokeratographs in the absolute scale using, a standard classification scheme, may be more useful in trying to determine whether a cornea is normal or represents subtle early disease than analysis in the normalised scale. Quantitative indices could remove the subjectivity from the decision making process thus facilitating universal reproducibility of videokeratography data interpretation.