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

Publisher Copyright: © 2021 The Author(s)PURPOSE: To chart clinical findings in individuals with keratitis fugax hereditaria (KFH) and the geographic distribution of their ancestors. DESIGN: A prospective cross-sectional study. METHODS: This study took place in a tertiary referral center with a cohort of 84 Finnish patients (55% female) from 25 families with the pathogenic nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3) variant c.61G>C. Observation procedures and main outcome measures were Sanger sequencing, clinical examination, corneal imaging, and a questionnaire regarding symptoms, quality of life, treatment, and comorbidities. RESULTS: The oldest members in each family were born in Ostrobothnia in Western Finland or in Southwestern Finland with historical ties to Sweden. One carrier was asymptomatic. Most (77%, 46/60) experienced their first attack between age 6 and 20 years. Three-quarters had unilateral attacks 3 to 5 times annually, primarily triggered by cold wind or air, or stress. Eighty percent (48/60) reported ocular pain (median, 7 on scale 1-10), conjunctival injection, photophobia, foreign body sensation, and tearing during attacks. Visual blur occurred in 75% (45/60) and 91% (55/60) during and after the attack, respectively, for a median of 10 days (range, 1 day-2 months). Forty-seven percent (39/60) had corneal oval opacities with irregular tomography patterns and mild to moderate decrease (20/60 or better) in best-corrected visual acuity that improved with scleral contact lenses. Except for headache in 40%, systemic symptoms were absent during the attacks. CONCLUSIONS: Symptoms and signs of KFH are restricted to the anterior segment of the eye and vary widely between individuals. We recommend scleral contact lenses as the first-line treatment for reduced vision. Allele frequencies suggest that KFH goes unrecognized in Sweden and populations with Scandinavian heritage.Peer reviewe

Bakteerien ja sienten aiheuttamat sarveiskalvotulehdukset

Keratiittien eli sarveiskalvotulehduksien etiologinen kirjo on laaja. Kyseessä on vakava infektio, joka voi vaatia kirurgistakin hoitoa akuutissa vaiheessa silmän säästämiseksi tai myöhemmin näöntarkkuuden palauttamiseksi. Yleislääkärin tärkeä tehtävä on osata epäillä keratiittia ja ohjata potilas silmälääkärille, mutta sidekalvotulehdukset tulisi hoitaa ensisijaisesti perusterveydenhuollossa. Silmälääkärin kannalta keratiitin hoidossa tärkeää on mahdollisimman tarkka diagnoosi. Bakteerit ovat yleisimpiä keratiitin aiheuttajia, ja siksi hoito aloitetaan ensisijaisesti mikrobilääketipoilla. Muu etiologia on hyvä pitää mielessä, jos keratiitti on epätyypillinen tai tulehdus ei vaikuta reagoivan hoitoon

Effects of oleoresin capsicum pepper spray on human corneal morphology and sensitivity. Invest Ophthalmol Visual Sci 2000; 42

PURPOSE. To examine the potential harmful effects on corneal structure, innervation, and sensitivity of a spray containing the neurotoxin capsaicin (oleoresin capsicum, OC). METHODS. Ten police officers who volunteered for the study were exposed to OC. Clinical signs were assessed. Corneal sensitivity was measured using a Cochet-Bonnet or a noncontact esthesiometer that provides separate measurements of mechanical, chemical, and thermal sensitivity. Tear fluid nerve growth factor (NGF) was measured. Corneal cell layers and subbasal nerves were examined by in vivo confocal microscopy. The subjects were examined before application and 30 minutes, 1 day, 1 week, and 1 month after OC exposure. RESULTS. OC spray produced occasional areas of focal epithelial cell damage that healed within 1 day. Each eye showed conjunctival hyperemia and in two subjects, mild chemosis. All except one eye had unchanged best corrected visual acuity (BCVA). A transient decrease (day 1) of mechanical sensitivity was observed with the Cochet-Bonnet esthesiometer. With the gas esthesiometer, mechanical sensitivity remained below normal values for 7 days. Chemical sensitivity to CO 2 was high for as much as 1 day and decreased below normal 1 week later, whereas sensitivity to cold was unaffected. Two subjects had measurable tear NGF that increased after exposure. Basal epithelial cell morphology suggested temporary corneal epithelial swelling, whereas keratocytes, endothelial cells, and subbasal nerves remained unchanged. CONCLUSIONS. Although OC causes immediate changes in mechanical and chemical sensitivity that may persist for a week, a single exposure to OC appears harmless to corneal tissues. The changes are possibly associated with damage of corneal nerve terminals of mainly unmyelinated polymodal nociceptor fibers. (Invest Ophthalmol Vis Sci. 2000;41:2138 -2147 T he cornea receives sensory innervation from primary sensory neurons located in the trigeminal ganglion 6 -9 Corneal nerve fibers exhibit immunoreactivity for a great variety of neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), 10 -19 as well as classic neurotransmitters, presumably associated with autonomic nerve fibers. 9,20 -22 Functionally, corneal nerve fibers have been classified as mechanosensory units, activated only by mechanical stimulation, polymodal units, responding also to chemical substance and to heat, and cold-sensitive units, that are excited by low temperatures (see Reference 23 for review). Capsaicin (8-methyl-vanilyl-6-nonenamide), the pungent component of chili peppers, has been shown to induce intense pain in humans and pseudoaffective pain reactions in animals when applied to the skin and the front of the eye, as well as neurogenic inflammation due to the release of neuropeptides contained in nerve terminals. 24 -26 Capsaicin's effects are associated with acute stimulation of primary sensory nerve endings, 39 Capsaicin treatment in adult animals causes less prominent but still detectable alterations of sensory innervation. In vitro and in vivo studies show that nerve growth factor (NGF) reverses the decrease of transmitter content and restores the peripheral function of primary afferent neurons impaired by capsaicin treatment

The effects of experimental tear film removal on corneal surface regularity and barrier function

To evaluate corneal surface regularity and asymmetry, corneal thickness, barrier function, and contrast sensitivity after experimental removal of the precorneal tear layer. Prospective, clinic-based, nonrandomized (self-controlled) comparative trial. Six eyes of six healthy volunteers (three males, three females; age range, 29–40 years). A precorneal tear lesion was created by pressing a sterile Biopore (Millipore, Bedford, MA) Teflon membrane against the central cornea. Corneal topography with both the Topographic Modeling System (TMS-1; Computed Anatomy, Tomey Technology, Cambridge, MA) and the Orbscan (Orbscan Inc., Salt Lake City, UT) were performed before the lesion was created and 30 seconds, 1 hour, and 4 hours after the lesion was created. Surface regularity and surface asymmetry indices were evaluated by the TMS-1 topography system. Maximum and minimum keratometric readings, corneal fluorescein staining, contrast sensitivity, and corneal thickness were evaluated before and after the tear lesion. Cytologic membranes were stained for MUC4 mucin using an indirect immunofluorescent staining technique. Confocal microscopy was performed to evaluate the integrity of the corneal epithelium in two eyes. Analysis of variance with polynomial contrasts was used to examine time trends of the outcome variables. The change in corneal surface regularity and asymmetry indices, corneal thickness, permeability to fluorescein dye, and contrast sensitivity before and after the lesion was made were compared. The corneal epithelium in the area of the lesion showed intense fluorescein staining 30 seconds postlesion but appeared normal by 4 hours. Confluent, homogeneous staining for MUC4 mucin was observed on the membranes used to create the lesion in all cases. The surface regularity index measured with the TMS-1 increased after the lesion was created and decreased toward normal by 4 hours ( P = 0.017). Corneal thickness measured by the Orbscan instrument significantly increased in the central ( P = 0.001), superior ( P = 0.006), inferotemporal ( P < 0.001) and superotemporal ( P = 0.001) cornea immediately following the lesion and returned to normal by 4 hours. The lesion caused a decrease in visual acuity at 6.30%, 4% and 2.5% contrast sensitivities 1 hour postlesion and these measurements returned to prelesion values by 4 hours ( P = 0.085, P = 0.005, P = 0.043). The precorneal tear layer serves as a permeability barrier and is essential for maintaining a smooth quality optical surface

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

Diagnostic accuracy of microbial keratitis with in vivo scanning laser confocal microscopy

Aims To determine the accuracy of diagnosing microbial keratitis by masked medical and non-medical observers using the Heidelberg Retina Tomograph II/Rostock Cornea Module in vivo confocal microscope. Methods Confocal images were selected for 62 eyes with culture- or biopsy-proven infections. The cases comprised 26 Acanthamoeba, 12 fungus, three Microsporidia, two Nocardia and 19 bacterial infections (controls). The reference standard for comparison was a positive tissue diagnosis. These images were assessed on two separate occasions by four observers who were masked to the tissue diagnosis. Diagnostic accuracy indices, kappa statistic and percentage agreement values were calculated. The Spearman correlation coefficient (r(s)) was calculated for the number of correct diagnoses versus duration of disease. Results The highest sensitivity and specificity values were 55.8% and 84.2%, respectively, and the lowest sensitivity and specificity values were 27.9% and 42.1%, respectively. The highest positive and lowest negative likelihood ratios were 2.94 and 0.59, respectively. Agreement values were: fair to moderate (kappa 0.22-0.44) for reference standard versus observer diagnosis, moderate to good in intraobserver variability (repeatability, kappa 0.56-0.88) and poor to moderate in interobserver variability (reproducibility, kappa 0.15-0.47). The correct diagnosis was associated with duration of disease for Acanthamoeba keratitis (r(s) = 0.60, p = 0.001). Conclusions The diagnostic accuracy of microbial keratitis by confocal microscopy is dependent on observer experience. Intraobserver repeatability was better than interobserver reproducibility. Difficulty in distinguishing host cells from pathogenic organisms limits the value of confocal microscopy as a stand-alone tool in diagnosing microbial keratitis

Autosomal recessive cornea plana: In vivo corneal morphology and corneal sensitivity

[Purpose]: Autosomal recessive corneal plana (RCP) is a rare corneal anomaly with unknown pathogenesis and a high incidence in Finland. The aim was to examine corneal sensitivity and the morphology of different corneal layers and subbasal nerves in RCP patients.[Methods]: Three patients with a diagnosed autosomal recessive cornea plana were examined. Corneal sensitivity to different modalities of stimulation was tested in four corneas using noncontact esthesiometry. Tissue morphology of three corneas was evaluated, and in two corneas thickness of corneal layers was measured using in vivo confocal microscopy.[Results]: Corneas of RCP patients appear to have mechanosensory, polymodal, and cold-sensitive nerve terminals. RCP patients had normal sensation thresholds for chemical, heat, and cold stimulation but a high threshold for mechanical stimulation. Their capacity to discriminate increasing intensities of stimulus was reduced, except for cold stimuli. Thickness of the epithelial layer was reduced, whereas total corneal and stromal thicknesses were slightly reduced or close to normal values. In all cases Bowman's layer was absent. Subbasal nerves had abnormal branching patterns. The arrangement of anterior keratocytes was altered, showing clustered and irregularly shaped nuclei. Increased backscattering of light in confocal microscopy through focusing (CMTF) profiles was observed throughout the stroma. Epithelial and endothelial cells appeared to be regular in shape.[Conclusions]: The present study revealed qualitative and quantitative alterations in corneal sensitivity, cellular morphology, and the thickness of corneal layers in RCP patients.Supported by The Finnish Medical Council; Scientific Foundation of Instrumentarium Ltd.; The Eye Foundation of Finland; The Eye and Tissue Bank Foundation, Finland; The Friends of the Blind, Finland; and the Mary and Georg C. Ehrnrooth Foundation.Peer reviewe

Corneal morphology and sensitivity in lattice dystrophy type II (familial amyloidosis, Finnish type)

[Purpose] To describe the corneal abnormalities and to measure different modalities of corneal sensitivity in corneal lattice dystrophy type II (familial amyloidosis, Finnish type, also known as gelsolin-related amyloidosis and originally as Meretoja syndrome).[Methods] Twenty eyes of 20 patients were examined by in vivo confocal microscopy and noncontact gas esthesiometry.[Results] Pleomorphism of, and dense deposits between or posterior to, the basal epithelial cells were frequently observed, as well as a reduction of long nerve fiber bundles in the subbasal nerve plexus. The anterior stroma was altered in most cases, with fibrosis and abnormal extracellular matrix. In 15 corneas, thick anterior and midstromal filaments, corresponding to lattice lines, and in 11 corneas, thin undulated structures were observed. The average mechanical sensitivity threshold of 12 subjects was increased, and in the remaining 8 subjects there was no response, even to the highest intensity of stimuli used. Three patients did not respond to CO(2), 11 to heat, and 2 to cold, but those patients who responded had normal thresholds. Patients with more long nerve fiber bundles per confocal microscopic image had better mechanical and cold sensitivity than patients with fewer nerve fiber bundles.[Conclusions] Lattice lines seem to be related to amyloid material and not to corneal nerves. However, the subbasal nerve density appears reduced, which results mainly in a decrease in mechanical and, to a lesser extent, thermal sensitivity. The location of stromal filaments and undulated structures changes with increasing age.Supported by Finska Läkaresällskapet (Medical Society of Finland); the Finnish Eye Foundation; the Dorothea Olivia, Karl Walter, and Jarl Walter ;2>Perklens Minne Foundation; the Finnish Eye and Tissue Bank Foundation; the Ella and Georg Ehrnrooth Foundation; the Mary and Georg C. Ehrnrooth Foundation; the University of Helsinki; The State EVO Grant; The Friends of the Blind, Finland; and the Instrumentarium Scientific Foundation.Peer reviewe