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The most common treatment is to replace the diseased cornea by standard corneal transplantation. In eyes at high risk of graft failure, the Boston keratoprosthesis type 1 (KPro) can be used to restore vision and is currently the most frequently used artificial cornea in the world. However, glaucoma is a well\u2010known complication of KPro surgery and is the most important threat to vision in KPro\u2010implanted eyes (paper I). This chronic disease is influenced by elevated intraocular pressure (IOP) and damages the optic nerve, leading to progressive vision loss. In KPro patients, glaucoma is highly prevalent and extremely challenging to manage, yet its exact cause remains unknown.<\/jats:p>\n                    <jats:p>The overall purpose of this PhD Thesis (Geoffrion, 2021) was to better understand the mechanisms and how to improve management of glaucoma after KPro implantation. The approaches used in this thesis included investigating one of the largest KPro patient cohorts in North America, with a total of 157 operated patients at that time, as well as studying KPro surgery and outcomes in mice.<\/jats:p>\n                    <jats:p>The first objective was to identify risk factors for glaucoma development and progression after KPro implantation (paper II). Multivariate logistic regression revealed that high preoperative IOP signals a higher risk for both glaucoma development and progression. Stromal and endothelial corneal disorders were less associated with glaucoma progression, while autoimmune and ocular surface diseases precipitated glaucoma development.<\/jats:p>\n                    <jats:p>Second, there is no objective evidence that indicates the best order for glaucoma surgeries and KPro implantation. By comparing medical and surgical management in KPro eyes with either preexisting or de novo glaucoma (paper III), we showed that glaucoma surgery may be performed before or at the time of KPro in eyes with preexisting glaucoma to limit progression without increasing complications. In eyes with de novo glaucoma, glaucoma surgery did not increase complications compared with medications.<\/jats:p>\n                    <jats:p>Third, among glaucoma surgery interventions, the two most frequently implanted glaucoma drainage devices were compared in KPro patients (paper IV). Compared with the Ahmed glaucoma valve, the Baerveldt glaucoma implant was associated with lower failure rates, without increased postoperative complications.<\/jats:p>\n                    <jats:p>Fourth, even with aggressive management, many KPro patients suffer from progressive optic nerve damage, sometimes despite normal IOP. Inflammatory cytokines play an important role in glaucomatous optic neuropathy, but their role in KPro\u2010associated glaucoma is still unknown. By analysing tear fluid of KPro patients by multiplex bead immunoassay (paper V), we identified that cytokines TNF\u2010a, IL\u20101b, FGF\u2010basic and IFN\u2010g were elevated in KPro patients with glaucoma compared to those without. These cytokines correlated with optic nerve excavation and IOP. For the first time in humans, these results concorded with the elevations of TNF\u2010a and IL\u20101b documented in the mouse KPro model. Ocular surface inflammation may thus reflect the inflammatory processes that perpetuate glaucoma damage years after KPro surgery.<\/jats:p>\n                    <jats:p>Fifth, we determined that miniaturized mouse KPro implantation requires extensive practice to be used as a reproducible model of glaucoma post\u2010KPro (paper VI). KPro animal models with larger eyes and a full\u2010thickness, 360\u2010degree corneal excision should be prioritized to best validate human outcomes.<\/jats:p>\n                    <jats:p>In conclusion, glaucoma in KPro eyes is a long\u2010lasting and multifactorial process. Most probable mechanisms combine IOP\u2010independent inflammation mediated by TNF\u2010a and IL\u20101b that prolong glaucoma damage, together with post\u2010surgical angle closure elevating the IOP. Altogether, our results inform glaucoma risk profiling of transplant recipients, improvement of surgical management of KPro patients with glaucoma and development of targeted treatments to minimize glaucomatous damage after KPro. Ultimately, this work has the potential to preserve the vision of thousands of patients who undergo KPro surgery every year worldwide and to provide insight for the role of inflammation in other diseases involving neuronal damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>R\u00c9SUM\u00c9 (FRENCH SUMMARY)<\/jats:title>\n                    <jats:p>La c\u00e9cit\u00e9 corn\u00e9enne est l'une des causes les plus importantes de d\u00e9ficience visuelle dans le monde. Le traitement usuel est de remplacer la corn\u00e9e malade par une greffe de corn\u00e9e traditionnelle. Dans les yeux \u00e0 haut risque d'\u00e9chec de greffe, la k\u00e9ratoproth\u00e8se de Boston de type 1 (KPro) peut r\u00e9tablir la vision et est la corn\u00e9e artificielle la plus utilis\u00e9e au monde. Cependant, le glaucome est une complication importante de la KPro (papier I). Cette maladie chronique est influenc\u00e9e par une pression intraoculaire (PIO) \u00e9lev\u00e9e et endommage le nerf optique, menant \u00e0 une perte de vision. Chez les patients avec KPro, le glaucome est fr\u00e9quent et difficile \u00e0 contr\u00f4ler, mais sa cause exacte demeure inconnue.<\/jats:p>\n                    <jats:p>L'objectif principal de cette th\u00e8se est de d\u00e9couvrir les m\u00e9canismes et d'optimiser la prise en charge du glaucome apr\u00e8s l'implantation de la KPro. Pour ce faire, nous avons investigu\u00e9 l'une des plus grandes cohortes de patients KPro en Am\u00e9rique du Nord avec un total de 157 patients, ainsi qu'un groupe de souris ayant re\u00e7u une implantation de k\u00e9ratoproth\u00e8se.<\/jats:p>\n                    <jats:p>Le premier but \u00e9tait d'identifier les facteurs de risque pour le d\u00e9veloppement et la progression du glaucome apr\u00e8s la KPro (papier II). Par r\u00e9gression logistique multivari\u00e9e, nous avons d\u00e9montr\u00e9 qu'une PIO pr\u00e9op\u00e9ratoire \u00e9lev\u00e9e m\u00e8ne \u00e0 un plus grand risque de d\u00e9veloppement et de progression du glaucome. Les maladies corn\u00e9ennes stromales ou endoth\u00e9liales sont moins associ\u00e9es \u00e0 une progression, alors que les maladies autoimmunes ou de la surface oculaire pr\u00e9cipitent le d\u00e9veloppement du glaucome.<\/jats:p>\n                    <jats:p>Deuxi\u00e8mement, il n'existe aucune donn\u00e9e objective pour indiquer le meilleur ordre des chirurgies de glaucome et de KPro. En comparant les traitements m\u00e9dicaux et chirurgicaux des yeux KPro avec glaucome (papier III), nous avons d\u00e9montr\u00e9 que les chirurgies de glaucome peuvent limiter la progression en \u00e9tant effectu\u00e9es avant ou pendant l'implantation de KPro dans les yeux avec glaucome pr\u00e9existant, sans augmenter les complications. Dans le glaucome de novo, les chirurgies de glaucome n'augmentent pas les complications en comparaison aux m\u00e9dicaments.<\/jats:p>\n                    <jats:p>Troisi\u00e8mement, les deux implants de glaucome les plus communs ont \u00e9t\u00e9 \u00e9tudi\u00e9s chez les patients KPro (papier IV). Compar\u00e9 \u00e0 la valve Ahmed, l'implant Baerveldt est associ\u00e9 \u00e0 des taux d'\u00e9chec plus bas, sans augmentation des complications.<\/jats:p>\n                    <jats:p>Quatri\u00e8mement, m\u00eame avec une prise en charge agressive, plusieurs patients KPro souffrent de glaucome qui progresse, parfois sans PIO \u00e9lev\u00e9e. Les cytokines inflammatoires jouent un r\u00f4le dans la pathophysiologie du glaucome, mais leur r\u00f4le dans le glaucome associ\u00e9 \u00e0 la KPro est inconnu. En analysant les larmes de patients KPro (papier V), nous avons identifi\u00e9 que les cytokines TNF\u2010a, IL\u20101b, FGF\u2010basic et IFN\u2010g sont \u00e9lev\u00e9es chez les patients KPro avec glaucome compar\u00e9 \u00e0 ceux sans glaucome. Ces cytokines corr\u00e8lent avec l'excavation du nerf optique et la PIO. Pour la premi\u00e8re fois chez les humains, ces r\u00e9sultats concordent avec les niveaux \u00e9lev\u00e9s de TNF\u2010a et IL\u20101b document\u00e9s dans le mod\u00e8le murin de KPro. L'inflammation de la surface oculaire pourrait donc refl\u00e9ter les processus inflammatoires qui perp\u00e9tuent le dommage glaucomateux.<\/jats:p>\n                    <jats:p>Cinqui\u00e8mement, nous avons d\u00e9termin\u00e9 que l'implantation de la KPro miniature chez la souris requiert beaucoup de pratique pour \u00eatre utilis\u00e9 comme mod\u00e8le de glaucome post\u2010KPro (papier VI). Des mod\u00e8les animaux avec des yeux plus larges et une excision corn\u00e9enne de pleine \u00e9paisseur sur 360 degr\u00e9s devraient \u00eatre prioris\u00e9s pour valider les r\u00e9sultats chez l'humain.<\/jats:p>\n                    <jats:p>En conclusion, le glaucome associ\u00e9 \u00e0 la KPro est un processus multifactoriel qui persiste \u00e0 long terme. Les m\u00e9canismes probables combinent l'inflammation m\u00e9di\u00e9e par TNF\u2010a et IL\u20101b et une fermeture de l'angle qui augmente la PIO. Nos r\u00e9sultats contribuent \u00e0 \u00e9tablir les facteurs de risque de glaucome pour les receveurs de KPro, \u00e0 am\u00e9liorer leur prise en charge et \u00e0 d\u00e9velopper des th\u00e9rapies cibl\u00e9es. Ce travail a le potentiel de pr\u00e9server la vision de milliers de patients recevant une KPro chaque ann\u00e9e dans le monde et d'aider \u00e0 mieux comprendre le r\u00f4le de l'inflammation dans d'autres maladies avec atteinte neuronale.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aos.15292","type":"journal-article","created":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T21:30:40Z","timestamp":1670535040000},"page":"3-17","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Probing mechanisms and improving management of glaucoma following Boston keratoprosthesis surgery"],"prefix":"10.1111","volume":"100","author":[{"given":"Dominique","family":"Geoffrion","sequence":"first","affiliation":[{"name":"Department of Experimental Surgery, Faculty of Medicine McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert 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