Purpose
To report the outcomes of medical and surgical management for congenital aniridia-associated keratopathy (AAK) over a long-term follow-up period.
Design
Retrospective, comparative case series.
Methods
Medical records of patients diagnosed with congenital aniridia were retrospectively reviewed. Age, sex, ethnicity, follow-up time, AAK stage, noncorneal abnormalities, ocular surgeries, and complications were recorded. The visual acuity equivalent (VAE), approximate Early Treatment Diabetic Retinopathy Study (appETDRS) letter score, was calculated using recorded Snellen visual acuities.
Results
A total of 92 eyes of 47 patients (31 females) with mean age of 48.0 ± 18.0 years and mean follow-up of 78.6 ± 42.2 months were included. At the initial visit, 12 eyes (13%) were classified as Stage I AAK, 33 eyes (35.9%) were Stage II, 25 eyes (27.2%) were Stage III, 17 eyes (18.5%) were Stage IV, and 5 eyes (5.4%) were Stage V. Limbal stem cell transplantation (LSCT) and Boston keratoprosthesis (KPro) were frequently performed in eyes with Stages III-V. These advanced corneal surgeries significantly improved the median (95% confidence interval [CI]) of calculated appETDRS scores from 2 (0-20) to 26 (15-41) (Snellen values, 20/20,000 to 20/300; P = 0.0004). Patients with earlier Stages (I-II) of AAK were managed medically and had stable visual acuity through their final visits (appETDRS score of 26 [20-35] to 35 [26-35]; Snellen, 20/300 to 20/200; P > 0.05). The appETDRS VAE was significantly improved from 20 (0-35) to 30 (20-55), Snellen, 20/400 to 20/250, following LSCT ( P = 0.021) and from 2 (0-20) to 2 (0-41) after KPro; Snellen, 20/20,000 VAE but with improved 95% CI after follow-up ( P = 0.019).
Conclusions
With proper characterization and staging of AAK, individualized medical and advanced surgical interventions preserves and improves visual acuity.
Introduction
Congenital aniridia is a condition which manifests as a constellation of ophthalmic findings of varying severities including keratopathy, foveal hypoplasia, nystagmus, cataract, glaucoma, and iris hypoplasia. This condition has been associated with dominantly inherited mutations or deletions involving the PAX6 gene. Aniridia-associated keratopathy (AAK), characterized by progressive corneal pannus and opacification, can be seen in up to 80% of patients in varying degrees of severity. , Signs of keratopathy can appear as early as the first decade of life, although the median age of diagnosis is 33 years old. In addition to glaucoma, AAK is the most common cause of progressive vision loss in cases of aniridia. AAK begins with “conjunctivization” and vascularization of the peripheral cornea, with slow, progressive encroachment onto the central cornea. These findings are a direct result of the loss of function of the limbal epithelial stem cells. In vivo confocal microscopy studies in aniridic patients have shown a strong correlation between the morphology of the palisades of Vogt and the stage of AAK. The progressive morphologic degradation of palisades of Vogt correlates with the loss of normal limbal and corneal epithelial phenotypes. In addition to the abnormalities of the limbal stem cell/niche in AAK, many studies have demonstrated corneal epithelial cell dysfunction as a result of abnormal differentiation, defective cell adhesion, increased sensitivity to oxidative stress, and impaired wound healing. ,
Clinically, patients with AAK experience recurrent erosions, corneal ulceration, chronic pain, and eventually, loss of vision. Patients with AAK often have concomitant meibomian gland dysfunction, tear film insufficiency, and decreased corneal sensitivity, all of which are correlated with the severity of the corneal disease.
Conventionally, management of early AAK has been supportive, reserving penetrating keratoplasty for severe stromal scarring. The outcomes of keratoplasty alone for AAK are poor, although they may still be helpful adjunctive procedures for restoring corneal clarity. Current methods such as limbal stem cell transplantation (LSCT), including keratolimbal allograft transplantation, and living-related conjunctiva-limbal allograft (lr-CLAL) transplantation, as well as Boston keratoprosthesis (KPro) implantation, have been effective treatments for AAK. , , In contrast to penetrating keratoplasty, LSCT addresses the underlying pathophysiology of AAK, whereas KPro circumvents it.
Studies detailing the outcomes of these different strategies at the different stages of AAK are limited. In the present study, the charts of patients diagnosed with AAK and managed at a tertiary care academic center were reviewed and analyzed, focusing on management, complications, and visual outcomes. The results of this study led to the development of an evidence-based algorithm based on the stage of keratopathy to guide management of patients with AAK.
Patients and Methods
In this retrospective cohort study (comparative case series), the clinical charts of 47 patients (92 eyes) diagnosed with congenital aniridia by the cornea service at the Illinois Eye and Ear Infirmary (Chicago, Illinois) from 2005 to 2018 were reviewed. The diagnosis of congenital aniridia was established based on the clinical presentation including but not limited to foveal hypoplasia, absence or hypoplasia of the iris, and nystagmus. The study was approved by the Institutional Review Board (IRB) of the College of Medicine, University of Illinois at Chicago.
Data included demographic information, clinical examination data (including visual acuity, and corneal pathology); surgical interventions, medications, and side effects. The severity of AAK was staged ( Supplementary Table 1 ) as defined in the study by Holland and associates. , Stage I consists of abnormal peripheral corneal epithelium, manifested by increased uptake of fluorescein (late staining); Stage II is characterized by centripetal extension of epithelial changes; Stage III is characterized by central corneal epithelial changes and peripheral superficial neovascularization; Stage IV consists of abnormal epithelium over the entire cornea with subepithelial fibrosis; Stage V, the most advanced, describes abnormal epithelium over the entire cornea with deep and permanent stromal scarring.
For the purpose of the present study, patients were managed using medical treatments (mainly those in lower AAK stages). These patients were grouped under a “no advanced corneal surgeries” group (“no-surgery”). The medical management of no-surgery group patients included administration of nonpreservative artificial tears, autologous serum tears, and scleral contact lenses. LSCT and Boston KPro patients were grouped under the advanced corneal surgery group for management of higher stages of aniridic keratopathy. Visual acuities at the initial visit and subsequent follow-up visits were recorded. Improvement in visual acuity was defined as a final recorded best corrected visual acuity (BCVA) greater than the visual acuity at the initial visit.
Visual Acuity Equivalents and Statistical Analysis
Data are mean ± standard deviation (SD), number (percentage), and median (95% confidence interval [CI]). For statistical analysis and comparison, BCVA was converted into approximate Early Treatment Diabetic Retinopathy Study (appETDRS) letter scores to represent visual acuity equivalent (VAE). The appETDRS score was used for ease of statistical analysis. appETDRS letter scores were converted by applying 85 + 50 × log (Snellen fraction), which was rounded to the nearest ETDRS letter score as described earlier. Subsequently, results were converted back to Snellen equivalents for ease of comprehension (the conversion of visual acuities between Snellen and appETDRS VAEs is shown in Supplementary Table 1 ).
Statistical analyses were performed using Prism version 8.0.0 software (GraphPad, San Diego, California) for Windows (Microsoft, Redmond, Washington). Mean differences were statistically analyzed using paired and independent t -tests and one-way ANOVA with Tukey post hoc test. The chi-squared test was used for qualitative data. Ordinal data (e.g., the appETDRS score) was analyzed using nonparametric tests including the Mann-Whitney U test and the Kruskal-Wallis test with Dunn-Bonferroni post hoc test for independent measurements and Wilcoxon test for repeated/paired measurements. P values less than 0.05 were statistically significant.
Results
Demographics, Staging, and Interventions
Ninety-two eyes of 47 patients (2 eyes were excluded due to enucleation) with a diagnosis of congenital aniridia and aniridia-associated keratopathy were enrolled in this study. The mean follow-up was 78.6 ± 42.2 months (range, 10-156) months. Demographic data are summarized in Table 1 . Thirty-one patients (65.9%) were female, and 16 patients (34.1%) were male. The mean age of patients was 48.0 ± 18.0 years old (range, 11-90 years old). The majority of cases had Stage II (35.9%) and Stage III (27.2%) aniridic keratopathy. Moreover, the percentage of Stage I among enrolled eyes was 13%, Stage IV was 18.5%, and Stage V was 5.4%. The most prevalent noncorneal pathologies were glaucoma and cataract (63% and 54.3%, respectively).
| Patients | 47 |
| Eyes | 92 |
| Mean ± SD age (y) | 48.0 ± 18.0 |
| Mean ± SD follow-up (months) | 78.6 ± 42.2 |
| Sex (%) | |
| Male | 16 (34.1) |
| Female | 31 (65.9) |
| Race (%) | |
| African-American | 10 (21.3) |
| White | 29 (61.7) |
| Hispanic | 2 (4.2) |
| Other | 6 (12.8) |
| Number of aniridia-associated keratopathy eyes at first visit (%) | |
| Stage I | 12 (13) |
| Stage II | 33 (35.9) |
| Stage III | 25 (27.2) |
| Stage IV | 17 (18.5) |
| Stage V | 5 (5.4) |
| Number of noncorneal pathologies recorded during follow-up (%) | |
| Aniridia fibrosis syndrome | 5 (5.4) |
| Glaucoma | 58 (63) |
| Angle closure glaucoma | 2 (2.2) |
| Ocular hypertension | 3 (3.3) |
| Uncontrolled glaucoma (vision loss owing to glaucoma) | 1 (1.7) |
| Cataract | 58 (54.3) |
| Subluxation of the lens | 2 (2.2) |
| Central retinal vein occlusion | 1 (1.1) |
| Proliferative vitreoretinopathy | 1 (1.1) |
| Diabetic retinopathy | 1 (1.1) |
| Vitreous hemorrhage | 1 (1.1) |
Table 2 summarizes surgical procedures and postoperative complications during management of aniridic keratopathy, glaucoma, lens, and retinal pathologies. Most surgical interventions for AAK included LSCT and/or KPro. LSCT had a failure rate of 42.3%, and the patients in whom LSCT had failed subsequently underwent repeated LSCT and/or KPro. Retroprosthetic membranes formed in 40.9% of eyes managed with KPro. Penetrating keratoplasty (PKP) was performed in a subset of patients to improve corneal transparency after LSCT (n = 5 eyes) and for other indications (n = 3 eyes). Four eyes had a history of PKP prior to presentation. A total of 50% of the corneal transplants failed, requiring subsequent repeated PKP, LSCT, and/or KPro procedures. Of the 92 eyes, 58 eyes developed glaucoma that required intraocular pressure-lowering topical agents in 54 eyes and implantation of glaucoma shunts in 24 eyes; 58 eyes had lens pathology including cataract formation and crystalline lens subluxation, which was managed most commonly by cataract removal and intraocular lens placement (48 eyes). Pars-plana vitrectomy was performed in 13 eyes.
| Pathology (Intervention Required) | Intervention | Frequency within Pathology (%) | Observed Complications/Side Effects in Follow-up | Frequency of Procedures Performed (%) | |
|---|---|---|---|---|---|
| Aniridia-associated keratopathy (n = 92 eyes) | Limbal Stem Cell Transplantation | 26 (28.3) | Failure/rejection (repeat LSCT or KPro required) | 11 (42.3) | |
| Boston keratoprosthesis | 22 (23.9) | Retroprosthetic membrane | 9 (40.9) | ||
| Extrusion of KPro | 4 (18.2) | ||||
| PKP | Performed before first visit to the referral center | 4 (4.3) | Failure (necessity for LSCT, repeat-LSCT, or KPro), total of 6 (50%) of PKPs | 2 (66.6), required KPro | |
| Concurrent/after LSCT | 5 (5.4) | 3 (60), required repeat-LSCT | |||
| Performed independently | 3 (3.3) | 1 (33.3), required LSCT and KPro | |||
| Keratectomy | 4 (4.4) | – | |||
| AMT | 3 (3.3) | – | |||
| Tarsorrhaphy | 1 (1.1) | – | |||
| Glaucoma (n = 58 eyes) | Glaucoma shunt placement | 24 (41.3) | Hypotony | 1 (4.1) | |
| Glaucoma drop administration | 54 (93.1) | – | |||
| Diode and/or SLT treatment | 7 (12.1) | Aniridia fibrosis syndrome | 2 (28.5) | ||
| Lens pathology (n = 58 eyes) | Cataract surgery with IOL placement | 48 (81.1) | Complication(s) required IOL exchange/removal | 5 (10.6) | |
| Lensectomy | 3 (5.2) | – | |||
| YAG laser capsulotomy | 3 (5.1) | – | |||
| Retinal Pathology (n = 16 Eyes) | Pars plana vitrectomy/retinal detachment repair | 13 (81.2) | Suprachoroidal hemorrhage | 2 (15.4) | |
| Scleral reinforcement | 3 (18.8) | – | |||
Advanced Corneal Surgeries Improved Visual Acuity in Congenital AAK
Table 3 shows the outcomes following major corneal surgeries (LSCT and KPro), including the preservation and/or improvement of visual acuity in eyes with AAK. Overall, the median visual acuity was improved by the last follow-up visit compared to the first visit in all enrolled eyes (appETDRS score, 20 [5-30] vs. 26 [20-35]; i.e., Snellen 20/400 to 20/300, respectively; P < 0.0001). Forty-two of 92 eyes (45.7%) had improvement in their visual acuity at final follow-up. Fifty-one eyes were managed medically during the follow-up time with no advanced corneal surgery, whereas 41 eyes underwent advanced corneal surgeries (LSCT and KPro) to improve their visual acuity. Patients who underwent advanced corneal surgeries on at least 1 eye were typically older. The mean age in patients who had advanced corneal surgeries was 53.0 ± 17.2 years old (range, 20-90) and 44.0 ± 17.8 (range, 11-90) years, respectively, at last follow-up ( P = 0.016). The mean age of patients at first advanced corneal surgery was 44.5 ± 17.5 (range, 10-82) years. The prevalence of glaucoma in patients who required advanced corneal surgeries was significantly higher than that of patients with no advanced surgery ( P < 0.0001); however, the distribution of patients requiring cataract surgery was similar across both groups ( P = 0.692).
| No Advanced Corneal Surgery (n = 51 eyes) | Patients with Advanced Corneal Surgeries (LSCT and/or KPro, n = 41 eyes) | Total | P Value Cases with no surgery vs. Total cases Undergoing Advanced Surgeries | P Value Cases with no surgery vs. Subgroups of cases undergoing Advanced Surgeries | ||||
|---|---|---|---|---|---|---|---|---|
| Total | Subgroups | |||||||
| LSCT (n = 19 eyes) | LSCT-KPro (n = 7 eyes) | KPro (n = 15 eyes) | ||||||
| Mean ± SD age at last follow-up (y) | 44.0 ± 18.0 | 53.0 ± 17.2 | 56.4 ± 14.4 | 44.6 ± 19.5 | 52.5 ± 18.9 | 48.0 ± 18.0 | 0.016 (independent t -test) | 0.045 (one-way ANOVA Test) |
| Mean ± SD age at first advanced corneal surgery (y) | – | 44.5 ± 17.5 | 48.3 ± 13.4 | 33.1 ± 20.5 | 45.1 ± 19.5 | – | – | – |
| Mean ± SD follow-up (months) | 65.3 ± 43.7 | 95.2 ± 34.1 | 99.9 ± 33.2 | 96.8 ± 45.5 | 88.4 ± 30.6 | 78.6 ± 42.2 | 0.001 (independent t -test) | 0.006 (one-way ANOVA test) |
| Glaucoma | ||||||||
| Yes | 24 (47.1) | 34 (82.9) | 16 (84.2) | 6 (85.7) | 12 (80) | 58 (63) | <0.0001 (chi-square test) | 0.005 (chi-squared test) |
| No | 27 (52.9) | 7 (17.1) | 3 (15.8) | 1 (14.3) | 3 (20) | 34 (37) | ||
| Cataract surgery | ||||||||
| Yes | 27 (52.9) | 20 (48.8) | 8 (42.1) | 5 (71.4) | 5 (33.3) | 47 (51.1) | 0.692 (chi-squared test) | 0.351 (chi-squared test) |
| No | 24 (47.1) | 21 (51.2) | 11 (57.9) | 2 (28.6) | 10 (66.7) | 45 (48.9) | ||
| Aniridia-associated keratopathy stage | ||||||||
| I | 12 (23.5) | 0 | 0 | 0 | 0 | 12 (13) | <0.0001 (Mann-Whitney U test) | <0.0001 (Kruskal-Wallis test) |
| II | 30 (58.8) | 3 (7.3) | 2 (10.5) | 1 (14.3) | 0 | 33 (35.9) | ||
| III | 6 (11.8) | 19 (46.3) | 13 (68.4) | 4 (57.1) | 2 (13.3) | 25 (27.2) | ||
| IV | 2 (3.9) | 15 (36.6) | 4 (21.1) | 1 (14.3) | 10 (66.7) | 17 (18.5) | ||
| V | 1 (2) | 4 (9.8) | 0 | 1 (14.3) | 3 (20) | 5 (5.4) | ||
| BCVA at first visit | ||||||||
| Snellen equivalent | 0.005 (Mann-Whitney U test) | 0.005 b (Kruskal-Wallis test) | ||||||
| ≥20/100 | 9 (17.6) | 3 (7.3) | 3 (15.8) | 0 | 0 | 12 (13) | ||
| ≥20/400 | 28 (54.9) | 13 (31.7) | 7 (36.8) | 2 (28.6) | 4 (26.7) | 41 (44.6) | ||
| ≥20/1500 | 1 (2) | 2 (4.9) | 1 (5.3) | 0 | 1 (6.7) | 3 (3.3) | ||
| ≥20/20000 | 12 (23.9) | 23 (56.1) | 8 (42.1) | 5 (71.4) | 10 (66.7) | 35 (38) | ||
| LP | 1 (2) | 0 | 0 | 0 | 0 | 1 (1.1) | ||
| Median appETDRS VAE (95% CI) | 26 (20-35) | 2 (0-20) | 20 (0-35) | 2 (0-35) | 2 (0-20) | 20 (5-30) | 0.002 (Mann-Whitney U test) | 0.003 b (Kruskal-Wallis test) |
| BCVA at last visit | ||||||||
| Snellen equivalent | 0.069 (Mann-Whitney U test) | 0.031 c (Kruskal-Wallis test) | ||||||
| ≥20/100 | 11 (21.6) | 8 (19.5) | 5 (26.3) | 1 (14.3) | 2 (13.3) | 19 (20.7) | ||
| ≥20/400 | 26 (51) | 18 (43.9) | 11 (57.9) | 3 (42.9) | 4 (26.7) | 44 (47.8) | ||
| ≥20/1500 | 4 (7.8) | 2 (4.9) | 1 (5.3) | 0 | 1 (6.7) | 6 (6.5) | ||
| ≥20/20000 | 9 (17.6) | 4 (9.8) | 1 (5.3) | 1 (14.3) | 2 (13.3) | 13 (14.1) | ||
| LP | 0 | 4 (9.8) | 0 | 2 (28.6) | 2 (13.3) | 4 (4.3) | ||
| NLP | 1 (2) | 5 (12.2) | 1 (5.3) | 0 | 4 (26.7) | 6 (6.5) | ||
| Median appETDRS VAE (95% CI) | 35 (26-35) | 26 (15-41) | 30 (20-55) | 41 (0-55) | 2 (0-41) | 26 (20-35) | 0.396 (Mann-Whitney U test) | 0.178 (Kruskal-Wallis test) |
| Change in visual acuity | ||||||||
| Impairment | 12 (23.5) | 14 (34.1) | 5 (26.3) | 3 (42.9) | 6 (40) | 26 (28.3) | 0.494 (Mann-Whitney U test) | 0.663 (Kruskal-Wallis test) |
| Stable | 20 (39.2) | 4 (9.8) | 2 (10.5) | 0 | 2 (13.3) | 24 (26.1) | ||
| Better | 19 (37.3) | 23 (56.1) | 12 (63.2) | 4 (57.1) | 7 (46.7) | 42 (45.7) | ||
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
