The Effect of Glaucoma Treatment on Aniridia-Associated Keratopathy (AAK) – A Report from the Homburg Register for Congenital Aniridia

Abstract

Background Congenital aniridia is a severe malformation of almost all eye segments. Aniridia-associated keratopathy (AAK) and secondary glaucoma, which occur in more than 50% of affected individuals, are typically progressive and pose a high risk of blindness for patients with congenital aniridia. Our aim was to investigate the effect of glaucoma treatment on AAK in patients of the Homburg Aniridia Center.

Methods Our retrospective monocentric study included patients who underwent a comprehensive ophthalmological examination at the Homburg Aniridia Center between June 2003 and January 2022.

Results There were 556 eyes of 286 subjects (20.1 ± 20.1 years; 45.5% males) included. In 307 (55.2%) eyes of 163 subjects (27.5 ± 16.3 years; 43.1% males), glaucoma was present at the time of examination. The mean intraocular pressure in the glaucoma group was 19.0 mmHg (± 8.0), while in the non-glaucoma group, it was 14.1 mmHg (± 3.6) (p < 0.001). In the glaucoma group, 68 patients used antiglaucomatous topical monotherapy, 51 patients used 2 agents, 41 patients used 3 agents, 7 patients used quadruple therapy, and 140 did not use topical therapy (e.g., after pressure-lowering surgery, pain-free end-stage glaucoma, or incompliance). Patients were classified according to the following stages of AAK: Stage 0 (96 eyes [17.2%], no keratopathy), Stage 1 (178 eyes [32.0%]), Stage 2 (107 eyes [19.2%]), Stage 3 (67 eyes [12.0%]), Stage 4 (62 eyes [11.1%]), Stage 5 (45 eyes [8.0%]). The mean stage of AAK was 1.4 (1.2 – 1.5) in the group without eye drops, 1.9 (1.5 – 2.2) in the group with monotherapy, 1.8 (1.5 – 2.1) in the group with 2 drugs, 1.9 (1.5 – 2.2) in the group with 3 drugs, 3.4 (2.3 – 4.6) in the group with 4 drugs, and 3.3 (3.1 – 3.6) after antiglaucomatous surgery. The stage of AAK was significantly positively correlated with the number of pressure-lowering eye drops (p < 0.05) and prior pressure-lowering surgery (p < 0.05). Prostaglandin analogues were not correlated with a higher AAK stage compared to the other drug groups.

Conclusions At the Homburg Aniridia Center, patients using topical antiglaucomatous quadruple therapy or who had previously undergone antiglaucomatous surgery had by far the highest AAK stage. The different drug groups had no influence on the AAK stage.

Zusammenfassung

Hintergrund Die kongenitale Aniridie ist eine schwere Fehlbildung fast aller Augensegmente. Insbesondere die Aniridie-assoziierte Keratopathie (AAK) sowie das bei mehr als 50% der Betroffenen auftretende Sekundärglaukom verlaufen typischerweise progressiv und stellen ein hohes Risiko der Erblindung für Patienten mit kongenitaler Aniridie dar. Unser Ziel war es, bei Patienten des Homburger Aniridie-Zentrums die Auswirkung der Glaukombehandlung auf die AAK zu untersuchen.

Methoden Unsere retrospektive, monozentrische Studie umfasste Patienten, die sich zwischen Juni 2003 und Januar 2022 einer umfassenden augenärztlichen Untersuchung durch das Homburger Aniridie-Zentrum unterzogen.

Ergebnisse Es wurden 556 Augen von 286 Probanden (20,1 ± 20,1 Jahre; 45,5% Männer) eingeschlossen. Bei 307 (55,2%) Augen von 163 Patienten (27,5 ± 16,3 Jahre; 43,1% Männer) lag zum Zeitpunkt der Untersuchung ein Glaukom vor. Der Augeninnendruck lag in der Glaukomgruppe im Mittel bei 19,0 mmHg (± 8,0) während er bei den Patienten ohne Glaukom bei 14,1 mmHg (± 3,6) lag (p < 0,001). In der Glaukomgruppe nutzten 68 Patienten eine lokale antiglaukomatöse Monotherapie, 51 Patienten nutzten 2 Wirkstoffe, 41 Patienten nutzten 3 Wirkstoffe, 7 Patienten nutzten eine Vierfachtherapie, 140 nutzten keine Lokaltherapie (z. B. nach drucksenkender Operation, schmerzfreies Glaukom-Endstadium oder Incompliance). Die Patienten wurden nach den folgenden Stadien der Aniridie-assoziierten Keratopathie (AAK) eingeteilt: Stadium 0 (96 Augen [17,2%], keine Keratopathie), Stadium 1 (178 Augen [32,0%]), Stadium 2 (107 Augen [19,2%]), Stadium 3 (67 Augen [12,0%]), Stadium 4 (62 Augen [11,1%]), Stadium 5 (45 Augen [8,0%]). Das Stadium der Aniridie-assoziierten Keratopathie lag in der Gruppe ohne Augentropfen im Mittel bei 1,4 (1,2 – 1,5), in der Gruppe mit Monotherapie bei 1,9 (1,5 – 2,2), in der Gruppe mit 2 Wirkstoffen bei 1,8 (1,5 – 2,1), in der Gruppe mit 3 Wirkstoffen bei 1,9 (1,5 – 2,2), in der Gruppe mit 4 Wirkstoffen bei 3,4 (2,3 – 4,6) und nach antiglaukomatöser Operation bei 3,3 (3,1 – 3,6). Das Stadium der Aniridie-assoziierten Keratopathie war signifikant positiv korreliert mit der Anzahl der drucksenkenden Augentropfen (p < 0,05) und einer zuvor durchgeführten drucksenkenden Operation (p < 0,05). Prostaglandinanaloga waren im Vergleich zu den anderen Wirkstoffgruppen nicht mit einem höherem AAK-Stadium korreliert.

Schlussfolgerungen Im Homburger Aniridie-Zentrum wiesen die Patienten, die eine lokale antiglaukomatöse Vierfachtherapie nutzten oder zuvor antiglaukomatös operiert wurden mit Abstand das höchste AAK-Stadium auf. Die verschiedenen Wirkstoffgruppen hatten keinen Einfluss auf das AAK-Stadium.

Conclusion Box

Already known:

• In congenital aniridia, there is an increased risk of developing blindness during life.

• AAK and glaucoma are the most common causes of blindness in congenital aniridia.

• In order to develop better treatment options in congenital aniridia, establishment of an aniridia register is necessary.

Newly described:

• A more intensive pressure-lowering topical therapy is associated with a higher stage of AAK.

• AAK stage of patients that had previously undergone glaucoma surgery was comparable to patients who used antiglaucomatous topical quadruple therapy.

• Our aniridia register will support further validation of previously observed trends with growing numbers of cases.

Conclusions:

At the Homburg Aniridia Center, patients using topical antiglaucomatous quadruple therapy or who had previously undergone pressure-lowering surgery had the highest AAK stage. The different drug substance groups had no influence on the AAK stage. Our registry will allow further detailed analysis of ophthalmic and systemic disease in patients with congenital aniridia over the long term.

Key words

congenital aniridia - Homburg Aniridia Center - severity of glaucoma - number of antiglaucomatous eye drops - progression of aniridia-associated keratopathy

Schlüsselwörter

kongenitale Aniridie - Homburger Aniridie-Zentrum - Schweregrad des Glaukoms - Anzahl der antiglaukomatösen Augentropfen - Progression der Aniridie-assoziierten Keratopathie

Publication History

Received: 29 July 2023

Accepted: 18 August 2023

Accepted Manuscript online:
18 October 2023

Article published online:
22 December 2023

• References

• 1 Fries FN, Náray A, Munteanu C. et al. A Cross-sectional Analysis of 556 Eyes Entering the Homburg Aniridia Centre. Klin Monbl Augenheilkd 2023; 240: 1-8
• 2 Käsmann-Kellner B, Latta L, Fries FN. et al. Diagnostic impact of anterior segment angiography of limbal stem cell insufficiency in PAX6-related aniridia. Clin Anat 2018; 31: 392-397
• 3 Muñoz-Negrete FJ, Teus MA, García-Feijoó J. et al. Aniridic glaucoma: An update. Arch Soc Esp Oftalmol (Engl Ed) 2021; 96 (Suppl. 1) S52-S59
• 4 Viestenz A, Seitz B, Deland E. et al. Clinical anatomy of the anterior chamber angle in congenital aniridia and consequences for trabeculotomy/cyclophotocoagulation. Clin Anat 2018; 31: 64-67
• 5 Käsmann-Kellner B, Fries FN, Latta L. et al. Aniridie bei PAX6-Syndrom: Eine potenziell zur Erblindung führende Erkrankung. Etablierung eines Deutschen Aniridie-Registers. Concept Ophthalmologie 2019 (05).
• 6 Käsmann-Kellner B, Seitz B. [Aniridia syndrome: clinical findings, problematic courses and suggestions for optimization of care (“aniridia guide”)]. Ophthalmologe 2014; 111: 1145-1156
• 7 Käsmann-Kellner B, Seitz B. [Congenital aniridia or PAX6 syndrome]. Ophthalmologe 2014; 111: 1144
• 8 Seitz B, Käsmann-Kellner B, Viestenz A. [Stage-related therapy of congenital aniridia]. Ophthalmologe 2014; 111: 1164-1171
• 9 Farah CJ, Fries FN, Latta L. et al. An attempt to optimize the outcome of penetrating keratoplasty in congenital aniridia-associated keratopathy (AAK). Int Ophthalmol 2021; 41: 4091-4098
• 10 Soyugelen Demirok G, Ekşioğlu Ü, Yakin M. et al. Short- and Long-term Results of Glaucoma Valve Implantation for Aniridia-related Glaucoma: A Case Series and Literature Review. Turk J Ophthalmol 2019; 49: 183-187
• 11 Kohlhaas M, Boehm AG, Spoerl E. et al. Effect of central corneal thickness, corneal curvature, and axial length on applanation tonometry. Arch Ophthalmol 2006; 124: 471-476
• 12 Landsend ECS, Lagali N, Utheim TP. Congenital aniridia – A comprehensive review of clinical features and therapeutic approaches. Surv Ophthalmol 2021; 66: 1031-1050
• 13 van Velthoven AJH, Utheim TP, Notara M. et al. Future directions in managing aniridia-associated keratopathy. Surv Ophthalmol 2023; 68: 940-956
• 14 Grainger RM, Lauderdale JD, Collins JL. et al. Report on the 2021 Aniridia North America symposium on PAX6, aniridia, and beyond. Ocul Surf 2023; 29: 423-431
• 15 Gupta V, Somarajan BI, Gupta S. et al. A new association of PAX6 variation with Juvenile onset open angle glaucoma. J Hum Genet 2023; 68: 355-358
• 16 Bremond-Gignac D. [Glaucoma in aniridia]. J Fr Ophtalmol 2007; 30: 196-199
• 17 Fries FN, Moslemani K, Utheim TP. et al. Early ocular surface and tear film status in congenital aniridia indicates a supportive treatment window. Br J Ophthalmol 2022;
• 18 Katiyar P, Stachon T, Fries FN. et al. Decreased FABP5 and DSG1 protein expression following PAX6 knockdown of differentiated human limbal epithelial cells. Exp Eye Res 2022; 215: 108904
• 19 Lagali N, Wowra B, Fries FN. et al. PAX6 Mutational Status Determines Aniridia-Associated Keratopathy Phenotype. Ophthalmology 2020; 127: 273-275
• 20 Lagali N, Wowra B, Fries FN. et al. Early phenotypic features of aniridia-associated keratopathy and association with PAX6 coding mutations. Ocul Surf 2020; 18: 130-140
• 21 Latta L, Figueiredo FC, Ashery-Padan R. et al. Pathophysiology of aniridia-associated keratopathy: Developmental aspects and unanswered questions. Ocul Surf 2021; 22: 245-266
• 22 Latta L, Knebel I, Bleil C. et al. Similarities in DSG1 and KRT3 Downregulation through Retinoic Acid Treatment and PAX6 Knockdown Related Expression Profiles: Does PAX6 Affect RA Signaling in Limbal Epithelial Cells?. Biomolecules 2021; 11: 1651
• 23 Latta L, Ludwig N, Krammes L. et al. Abnormal neovascular and proliferative conjunctival phenotype in limbal stem cell deficiency is associated with altered microRNA and gene expression modulated by PAX6 mutational status in congenital aniridia. Ocul Surf 2021; 19: 115-127
• 24 Latta L, Nordström K, Stachon T. et al. Expression of retinoic acid signaling components ADH7 and ALDH1A1 is reduced in aniridia limbal epithelial cells and a siRNA primary cell based aniridia model. Exp Eye Res 2019; 179: 8-17
• 25 Schlötzer-Schrehardt U, Latta L, Giessl A. et al. Dysfunction of the limbal epithelial stem cell niche in aniridia-associated keratopathy. Ocul Surf 2021; 21: 160-173