In Vivo Corneal Confocal Microscopy and Histopathology of Keratitis Fugax Hereditaria from a Pathogenic Variant in NLRP3

Purpose To apply in vivo corneal confocal microscopy (IVCM) to study the pathogenesis of keratitis (keratoendotheliitis) fugax hereditaria, an autosomal dominant cryopyrin-associated periodic keratitis, associated with the c.61G>C pathogenic variant in the NLRP3 gene, in its acute and chronic phase, and to report histopathological findings after penetrating keratoplasty. Design Observational case series Methods Study population: Six patients during an acute attack, 18 patients in the chronic phase, and one patient who underwent penetrating keratoplasty.Intervention: Sanger sequencing for the NLRP3 variant c.61C>G. Clinical examination, corneal photography, IVCM, light microscopy and immunohistochemistry. Main Outcome Measures: IVCM and histopathological findings. Results During the acute attack, hyperreflective cellular structures consistent with inflammatory cells transiently occupied the anterior to middle layers of the corneal stroma. Other corneal layers were unremarkable. With recurring attacks, central oval stromal opacities accumulated. IVCM revealed that they contained long hyperreflective needle-shaped structures in extracellular matrix. By light microscopy, the anterior half of the stroma displayed thin and finely vacuolated lamellae, and keratocytes throughout the stroma were immunopositive for syndecan. Conclusions The acute attacks and chronic stromal deposits mainly involve the anterior to middle layers of the corneal stroma, and the disease is primarily a keratitis rather than a keratoendotheliitis. IVCM shows that inflammatory cells invade only the stroma during an acute attack. IVCM and light microscopic findings suggest that the central corneal opacities represent gradual deposition of extracellular lipids. The disease could make a good in vivo model to study activation of the NLRP3 inflammasome in cryopyrin-associated periodic syndromes.Peer reviewe