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

Abstract

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 histopathologic findings after penetrating keratoplasty.DESIGN: This was an observational case series. METHODS: The study population included 6 patients during an acute attack, 18 patients in the chronic phase, and 1 patient who underwent penetrating keratoplasty. Interventions included Sanger sequencing for the NLRP3 variant c.61C>G, a clinical examination, corneal photography, IVCM, light microscopy, and immunohistochemistry. Our primary outcome measures included IVCM and histopathologic 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 the extracellular matrix. Using 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 depo-Supplemental Material available at AJO.com.

In Vivo Confocal Microscopy Observation of Cell and Nerve Density in Different Corneal Regions with Monocular Pterygium

“…e highly reflective microdots and needle-shaped structures found in the stromal layers by IVCM had been observed in several different corneal inflammations. It is deduced to correspond to disorganized extracellular material, hyperreflective extracellular matrix, around degenerated collagen fiber bundles associated with deposition of lipid [14].…”

Clinical Spectrum and Geographic Distribution of Keratitis Fugax Hereditaria Caused by the Pathogenic Variant c.61G>C in NLRP3

“…1 The second Finnish family was reported in 1987, whereupon the disease was renamed keratoendotheliitis fugax hereditaria 2 based on misinterpretation of specular endothelial microscopy findings. 3 We recently discovered in 23 affected Finnish families that this autosomal dominant disease is caused by a heterozygous pathogenic variant c.61G>C, p.(Asp21His) in the nucleotidebinding domain, leucine-rich repeat (NLR) family Pyrin Domain Containing 3 (NLRP3) gene, and showed that endothelial cells were uninvolved. 3,4 Unilateral ocular pain, conjunctival injection, photophobia, and tearing characterize the acute inflammatory attacks of KFH that last for 1 to 3 days and leave a blurry vision for several weeks.…”

“…3 We recently discovered in 23 affected Finnish families that this autosomal dominant disease is caused by a heterozygous pathogenic variant c.61G>C, p.(Asp21His) in the nucleotidebinding domain, leucine-rich repeat (NLR) family Pyrin Domain Containing 3 (NLRP3) gene, and showed that endothelial cells were uninvolved. 3,4 Unilateral ocular pain, conjunctival injection, photophobia, and tearing characterize the acute inflammatory attacks of KFH that last for 1 to 3 days and leave a blurry vision for several weeks. 1,2,4 Our confocal microscopy suggests influx of leukocytes into the corneal stroma during the attack.…”

“…1,2,4 Our confocal microscopy suggests influx of leukocytes into the corneal stroma during the attack. 3 The attacks begin at the median age of 11 years, and recur 1 to 6 times a year. Repeated attacks result in one half of the patients in bilateral horizontally oval central stromal opacities that can reduce visual acuity.…”

“…Repeated attacks result in one half of the patients in bilateral horizontally oval central stromal opacities that can reduce visual acuity. 3,4 NLRP3 encodes cryopyrin, a crucial member of the NLRP3 inflammasome. 5 Pathogenic variants in NLRP3 cause rare autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS).…”