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Purpose: Small-fiber neuropathy (SFN) is known to be associated with Sjögren disease (SjD), and in vivo corneal confocal microscopy can identify features compatible with SFN. Here, we performed a descriptive study to identify features of SFN of the corneal subbasal nerve plexus using in vivo confocal microscopy., Methods: We recruited 10 participants from the Sjögren's International Collaborative Clinical Alliance (SICCA), 1 new participant (in an effort to expand the SICCA cohort), and 22 healthy controls. All participants underwent slit-lamp examination and in vivo confocal microscopy of the central corneal subbasal nerve plexus centered about the central whorl to create a 30-image montage. Each image was analyzed with automated software (ACCmetrics, Manchester, United Kingdom) to produce 7 nerve metrics. We performed t-tests and age-adjusted regressions to make comparisons of nerve metrics between participants with SjD and healthy controls., Results: Most nerve metrics were significantly lower in participants with SjD compared with healthy controls. The mean corneal nerve fiber density was found to be 3.5 mm/mm 2 in participants with SjD compared with 10.6 mm/mm 2 in healthy controls (95% confidence interval, -8.4 to -0.93; P = 0.02). Within the 11 participants with SjD, 22 eyes were analyzed on confocal microscopy, and 16 of those eyes (from 9 individuals) did not have an identifiable central whorl. Within the 22 healthy controls, 22 eyes (right eye alone) were analyzed on confocal microscopy, and 21 of those eyes had an identifiable central whorl., Conclusions: SjD exhibits lower corneal nerve metrics compared with healthy controls. These findings suggest that features compatible with SFN can distinguish SjD from healthy controls and may serve as a potential novel biomarker in identifying SjD., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: In the absence of a gold-standard diagnostic test for different subtypes of dry eye disease (DED), we aimed to identify latent subtypes of DED within a well-characterized cohort., Design: This is a cross-sectional study of participants enrolled in the Sjögren International Collaborative Clinical Alliance (SICCA)., Methods: A latent class analysis was applied to different dry eye-related signs/tests and symptoms of ocular pain (particularly those that aligned with corneal neuropathic pain) giving relative specificities and sensitivities of each diagnostic test or symptom in the SICCA population., Results: Four subtypes of DED were identified with putative designations including normal, asymptomatic dry eye, symptomatic dry eye, and corneal neuropathic pain., Conclusions: More specific classification criteria are needed for DED. Latent class analysis applied to the signs and symptoms captured in the SICCA cohort may allow for the development and refinement of classification criteria for specific subtypes of dry eye., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To report the findings of a comprehensive eye examination from an individual with congenital insensitivity to pain because of loss-of-function mutations in the SCN9A gene., Methods: Ophthalmologic examination and confocal microscopy were performed on a patient with congenital insensitivity to pain., Results: A 39-year-old man with compound heterozygous mutations in the SCN9A gene underwent examination. Cochet-Bonnet esthesiometry readings averaged 38 mm (SD 8 mm) in the right eye and 55 mm (SD 7 mm) in the left eye. Other corneal findings included mild conjunctival lissamine green staining, nonvisually significant corneal scars, mild anterior basement membrane dystrophy, and a tear breakup time of 3 seconds in each eye. In vivo confocal microscopy of the corneal subbasal nerve plexus revealed relatively normal corneal nerve morphology, but a reduction in corneal nerve fiber density., Conclusions: An individual with loss-of-function mutations in SCN9A had reduced corneal nerve fiber density but normal corneal mechanoreception., Competing Interests: A. Delwig is an employee of SiteOne Therapeutics. S. G. Waxman is a consultant to SiteOne. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purposes of this study were to assess the reproducibility of a novel standardized technique for capturing corneal subbasal nerve plexus images with in vivo corneal confocal microscopy and to compare nerve metrics captured with this method in participants with dry eye and control participants., Methods: Cases and controls were recruited based on their International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnoses. Participants completed the following 3 ocular symptom questionnaires: the Ocular Surface Disease Index, Neuropathic Pain Symptom Inventory, and Dry Eye Questionnaire 5. A novel eye fixation-grid system was used to capture 30 standardized confocal microscopy images of the central cornea. Each participant was imaged twice by different operators. Seven quantitative nerve metrics were analyzed using automated software (ACCmetrics, Manchester, United Kingdom) for all 30 images and a 6-image subset., Results: Forty-seven participants were recruited (25 classified as dry eye and 22 controls). The most reproducible nerve metrics were corneal nerve fiber length [intraclass correlation (ICC) = 0.86], corneal nerve fiber area (ICC = 0.86), and fractal dimension (ICC = 0.90). Although differences were not statistically significant, all mean nerve metrics were lower in those with dry eye compared with controls. Questionnaire scores did not significantly correlate with nerve metrics. Reproducibility of nerve metrics was similar when comparing the entire 30-image montage to a central 6-image subset., Conclusions: A standardized confocal imaging technique coupled with quantitative assessment of corneal nerves produced reproducible corneal nerve metrics even with different operators. No statistically significant differences in in vivo corneal confocal microscopy nerve metrics were observed between participants with dry eye and control participants., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To develop a screening questionnaire to identify patients with dry eye with a high likelihood of having underlying Sjögren syndrome (SS)., Methods: This was a cross-sectional study of participants with dry eye complaints who were self-referred or referred by an ophthalmologist to the Sjögren's International Collaborative Clinical Alliance study. Symptoms and ocular surface examination findings were candidate predictors. Univariable and multivariable logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of a symptom and/or ocular sign with SS. Area under the receiver operating characteristic curve (AUC) was used to summarize the predictive ability of different regression models and the derived likelihood score., Results: Four questions were statistically significant in the final multivariable model: 1) Is your mouth dry when eating a meal? [Yes = OR 1.63 (1.18-2.26)]; 2) Can you eat a cracker without drinking a fluid or liquid? [No = OR 1.46 (1.06-2.01)]; 3) How often do you have excessive tearing? [None of the time = OR 4.06 (1.81-9.10)]; and 4) Are you able to produce tears? [No = OR 2.24 (1.62-3.09)]. The SS likelihood score had an AUC of 0.70 (95% CI, 0.66-0.73), and when including tear break-up time and conjunctival staining, it yielded an AUC of 0.79 (95% CI, 0.77-0.82)., Conclusions: This questionnaire can be used to identify patients with dry eye with a high likelihood of having SS. With future refinement and validation, this screening tool could be used alone or in combination with examination findings to identify patients with SS earlier, thereby facilitating better clinical outcomes., Competing Interests: V. Y. Bunya: Bausch & Lomb (funding for research study); Celularity (consultant); Verily (consultant). E. K. Akpek: Allergan Inc. (institutional support), Novalique Gmb. (consultant), Regeneron (consultant), Sjogren's Syndrome Foundation (unpaid board member). M. Massaro-Giordano: Celularity (consultant); PRN (personal financial interest); Verily (consultant). F. B. Vivino: Novartis (consultant), Biogen-Idec (consultant), Celularity (consultant), Boston Pharmaceuticals (consultant) Bristol-Myers Squibb (consultant), Immco Diagnostics (consultant). A. N. Baer: Bristol-Myers Squibb (consultant), Abbvie (consultant), Sanofi (consultant). The remaining authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Iridocorneal endothelial (ICE) syndrome is a group of rare ocular conditions that result from abnormal corneal endothelial cells, leading to secondary glaucoma, iris distortions, and corneal edema. The etiology of ICE is unknown, although it has been associated with viral infections, such as herpes simplex virus. In this study, we sought to identify an infectious etiology for ICE using advanced molecular techniques., Methods: Metagenomic RNA sequencing (MDS) is a high-throughput sequencing approach that can identify all pathogens in any clinical sample, including RNA viruses. Descemet membrane and aqueous fluid from patients with ICE syndrome were subjected to MDS testing., Results: Samples from 3 patients with ICE were analyzed. MDS was performed on the aqueous fluid of 3 patients and Descemet membrane and endothelial cell tissue from 1 patient. Viral pathogens were not identified in any of the samples., Conclusions: We were unable to identify a viral etiology in the tissues of patients with the Chandler variant of ICE syndrome, although this study was limited by sample size.

Purpose: To evaluate the ocular signs and tests for keratoconjunctivitis sicca (KCS) in the absence of a gold standard., Methods: Cross-sectional study of participants from the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Participants had oral/ocular/rheumatologic examinations, blood/saliva samples collected, and salivary gland biopsy. Latent class analysis (LCA) identified clusters of patients based on 3 to 4 predictor variables relating to signs or tests of KCS. The resulting model-based "gold standard" classification formed the basis for estimated sensitivity and specificity associated with these predictors., Results: A total of 3514 participants were enrolled into SICCA, with 52.9% classified as SS. LCA revealed a best-fit model with 2 groups. For the gold standard-positive group, an abnormal tear breakup time, ocular staining score (OSS), and Schirmer I had a sensitivity of 99.5%, 91.0%, and 47.4%, respectively. For the gold standard-negative group, an abnormal tear breakup time, OSS, and Schirmer I had a specificity of 32.0%, 84.0%, and 88.5%, respectively. OSS components (fluorescein and lissamine staining), exhibited a sensitivity of 82.6% and 90.5%, respectively, in the gold standard-positive group, whereas these signs in the gold standard-negative group had a specificity of 88.8% and 73.0%, respectively., Conclusions: OSS and its components (fluorescein and lissamine staining) differentiated 2 groups from each other better than other KCS parameters and had relatively high sensitivity and specificity.

Purpose: Cytomegalovirus is an increasingly recognized cause of anterior uveitis. We present clinical features of cytomegalovirus anterior uveitis (CMVAU) and outcomes of oral valganciclovir treatment at a tertiary referral center in North America., Methods: This is a retrospective case series review (2002-2014) of immunocompetent patients with CMVAU treated with valganciclovir 900 mg BID and subsequent maintenance dosing of ≤450 mg BID. Most patients were prescribed topical corticosteroids concurrently. Diagnostic evaluations and clinical features at baseline and follow-up were reviewed. Resolution time, maintenance of quiescence, and adverse events were assessed., Results: Eighteen eyes of 16 patients were included. The mean age of diagnosis was 41 years. At diagnosis, mean best-corrected visual acuity was 0.30 LogMAR and mean intraocular pressure (IOP) was 18.4 mm Hg; 14 eyes (78%) had an active anterior chamber (AC) cell, 8 (44%) had circinate keratic precipitates, and 6 (33%) had iris atrophy. The mean follow-up duration was 48 months. Fourteen eyes of 12 patients were available for the 12-month follow-up; patients demonstrated improvement in best-corrected visual acuity (difference: -0.21 LogMAR, 95% CI -0.33 to -0.09; P = 0.003), AC cell (OR = 0.10, 95% CI 0.02-0.41; P = 0.002), and IOP (difference: -4.21 mm Hg, 95% CI -7.98 to -0.44; P = 0.03) compared with baseline. One patient experienced a serious adverse event likely due to valganciclovir. Thirteen eyes experienced recurrence of inflammation: 7 (54%) on prophylactic dose of valganciclovir and 6 (46%) after stopping., Conclusions: Valganciclovir appears effective and safe for treating CMVAU in this retrospective case series. Long-term antiviral prophylaxis does not abolish recurrences, although it may possibly reduce their frequency when compared with no prophylaxis.

Purpose: To evaluate the prevalence of novel candidate autoantibodies associated with Sjögren syndrome (SS) and their ability to identify those with SS among participants with dry eye enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) study at the University of Pennsylvania (Penn)., Methods: All participants previously underwent a full ocular and systemic evaluation for possible SS as part of the SICCA study. An enzyme-linked immunosorbent assay was used to detect IgG, IgA, and IgM autoantibodies to salivary protein 1 (SP-1), parotid secretory protein (PSP), and carbonic anhydrase 6 from previously banked baseline serum samples from SICCA study participants enrolled at Penn. The prevalence rate of each autoantibody, calculated by considering the presence of any isotype as antibody positive, was compared between participants with dry eye with SS (n = 81) or without SS (n = 129) using the Fisher exact test., Results: The prevalence of SP-1 IgM autoantibodies was higher in those with SS compared with those without SS (14% vs. 5%; P = 0.03). Similarly, the prevalence of PSP IgA autoantibodies was higher in those with SS compared with non-SS dry eye participants (21% vs. 11%; P = 0.048). There was no statistically significant difference in the prevalence of carbonic anhydrase 6 autoantibodies between those with or without SS (15% vs. 20%; P = 0.36)., Conclusions: In the Penn SICCA cohort, SP-1 IgM and PSP IgA autoantibodies were more prevalent in the serum of SS-related dry eye participants compared with those without SS. Further longitudinal studies are needed to determine the clinical significance of these findings.

Purpose: To describe a case series of patients with unilateral, posterior interstitial keratitis presumed to be caused by herpes simplex virus., Methods: Retrospective case series., Results: Five patients were found to have unilateral, posterior interstitial keratitis. Three of the involved eyes had decreased corneal sensation, and 2 eyes had corneal stromal neovascularization. All patients were treated with topical steroids and an oral antiviral, and among those with long-term follow-up, clinical improvement required treatment over an extended duration. A review of the literature revealed 1 reported case with a similar clinical appearance, although that case was attributed to Lyme disease., Conclusions: The clinical presentation of unilateral, posterior interstitial keratitis may be a rare manifestation of herpes simplex virus keratitis.