Aqueous Macrophages Contribute to Conserved CCL2 and CXCL10 Gradients in Uveitis.

Purpose: Uveitis is a heterogenous group of inflammatory eye disease for which current cytokine-targeted immune therapies are effective for only a subset of patients. We hypothesized that despite pathophysiologic nuances that differentiate individual disease states, all forms of eye inflammation might share common mechanisms for immune cell recruitment. Identifying these mechanisms is critical for developing novel, broadly acting therapeutic strategies. Design: Experimental study. Subjects: Biospecimens from patients with active or inactive uveitis and healthy controls. Methods: Protein concentration and single cell gene expression were assessed in aqueous fluid biopsies and plasma samples from deidentified patients with uveitis or healthy controls. Main Outcome Measures: The concentration of 31 inflammatory proteins was measured in all aqueous samples, as well as plasma samples from patients with active uveitis. Chemokine and cytokine ligand and receptor expression were assessed in individual cell types from aqueous biopsies obtained from patients with active uveitis. Results: We identified 6 chemokines that were both elevated in active uveitis compared with controls and enriched in aqueous compared with plasma during active uveitis (C-C motif chemokine ligand [CCL]2, C-X-C motif chemokine ligand [CXCL]10, CXCL9, CXCL8, CCL3, and CCL14), forming potential gradients for migration of immune cells from the blood to the eye. Of these, CCL2 and CXCL10 were consistently enriched in the aqueous of all patients in our cohort, as well as in a larger cohort of patients from a previously published study. These data suggest that CCL2 and CXCL10 are key mediators in immune cell migration to the eye during uveitis. Next, single cell RNA sequencing suggested that macrophages contribute to aqueous enrichment of CCL2 and CXCL10 during human uveitis. Finally, using chemokine ligand and receptor expression mapping, we identified a broad signaling network for macrophage-derived CCL2 and CXCL10 in human uveitis. Conclusions: These data suggest that ocular macrophages may play a central role, via CCL2 and CXCL10 production, in recruiting inflammatory cells to the eye in patients with uveitis. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides.

Human leucocyte antigen B*27 (HLA-B*27) is strongly associated with inflammatory diseases of the spine and pelvis (for example, ankylosing spondylitis (AS)) and the eye (that is, acute anterior uveitis (AAU))1. How HLA-B*27 facilitates disease remains unknown, but one possible mechanism could involve presentation of pathogenic peptides to CD8+ T cells. Here we isolated orphan T cell receptors (TCRs) expressing a disease-associated public ß-chain variable region-complementary-determining region 3ß (BV9-CDR3ß) motif2-4 from blood and synovial fluid T cells from individuals with AS and from the eye in individuals with AAU. These TCRs showed consistent α-chain variable region (AV21) chain pairing and were clonally expanded in the joint and eye. We used HLA-B*27:05 yeast display peptide libraries to identify shared self-peptides and microbial peptides that activated the AS- and AAU-derived TCRs. Structural analysis revealed that TCR cross-reactivity for peptide-MHC was rooted in a shared binding motif present in both self-antigens and microbial antigens that engages the BV9-CDR3ß TCRs. These findings support the hypothesis that microbial antigens and self-antigens could play a pathogenic role in HLA-B*27-associated disease.

Corneal perforation in ocular graft-versus-host disease.

PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome. METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology. RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal "melt" in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar. CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies.

Autism Spectrum Disorder in Pediatric Idiopathic Intracranial Hypertension.

In recent years, the substantial burden of medical comorbidities in autism spectrum disorder (ASD) populations has been described. We report a retrospective observational case series of pediatric patients with suspected idiopathic intracranial hypertension (IIH) and concurrent ASD. Pediatric subjects with suspected IIH aged 2-18 years were identified by review of a pediatric neuro-ophthalmologist's database spanning from July 1993 to April 2013. ASD diagnoses were identified within this cohort by an ICD-9 diagnosis code search and database review. Three subjects had concurrent ASD diagnoses; all were non-obese males. Since the retrospective observational case series was performed in April 2013, we identified three additional IIH cases in boys with ASD. Our experience suggests that IIH may be a comorbidity of ASD, particularly in non-obese boys.

Tofacitinib for refractory ocular mucous membrane pemphigoid.

PURPOSE: To report the successful use of tofacitinib in the treatment of refractory ocular mucous membrane pemphigoid (MMP). OBSERVATIONS: Two patients with ocular MMP presented with refractory disease after failure of multiple therapies. Treatment with tofacitinib led to durable control of conjunctival inflammation within 8 weeks and no apparent progression of sub-conjunctival fibrosis. One patient maintained absence of apparent disease activity over 16 months of follow-up. Cessation of tofacitinib in the other patient led to disease relapse which was reversed by re-initiation of therapy. CONCLUSIONS AND IMPORTANCE: Small molecule inhibitors of Janus kinases, such as tofacitinib, may offer an effective treatment option for refractory ocular MMP.

Crowdsourced Assessment of Surgical Skill Proficiency in Cataract Surgery.

OBJECTIVE: To test whether crowdsourced lay raters can accurately assess cataract surgical skills. DESIGN: Two-armed study: independent cross-sectional and longitudinal cohorts. SETTING: Washington University Department of Ophthalmology. PARTICIPANTS AND METHODS: Sixteen cataract surgeons with varying experience levels submitted cataract surgery videos to be graded by 5 experts and 300+ crowdworkers masked to surgeon experience. Cross-sectional study: 50 videos from surgeons ranging from first-year resident to attending physician, pooled by years of training. Longitudinal study: 28 videos obtained at regular intervals as residents progressed through 180 cases. Surgical skill was graded using the modified Objective Structured Assessment of Technical Skill (mOSATS). Main outcome measures were overall technical performance, reliability indices, and correlation between expert and crowd mean scores. RESULTS: Experts demonstrated high interrater reliability and accurately predicted training level, establishing construct validity for the modified OSATS. Crowd scores were correlated with (r = 0.865, p < 0.0001) but consistently higher than expert scores for first, second, and third-year residents (p < 0.0001, paired t-test). Longer surgery duration negatively correlated with training level (r = -0.855, p < 0.0001) and expert score (r = -0.927, p < 0.0001). The longitudinal dataset reproduced cross-sectional study findings for crowd and expert comparisons. A regression equation transforming crowd score plus video length into expert score was derived from the cross-sectional dataset (r2 = 0.92) and demonstrated excellent predictive modeling when applied to the independent longitudinal dataset (r2 = 0.80). A group of student raters who had edited the cataract videos also graded them, producing scores that more closely approximated experts than the crowd. CONCLUSIONS: Crowdsourced rankings correlated with expert scores, but were not equivalent; crowd scores overestimated technical competency, especially for novice surgeons. A novel approach of adjusting crowd scores with surgery duration generated a more accurate predictive model for surgical skill. More studies are needed before crowdsourcing can be reliably used for assessing surgical proficiency.

Clinicomolecular Identification of Conserved and Individualized Features of Granulomatous Uveitis.

Objective: To identify molecular features that distinguish individuals with shared clinical features of granulomatous uveitis. Design: Cross-sectional, observational study. Participants: Four eyes from patients with active granulomatous uveitis. Methods: We performed single-cell RNA-sequencing with antigen-receptor sequence analysis to obtain an unbiased gene expression survey of ocular immune cells and identify clonally expanded lymphocytes. Main Outcomes Measures: For each inflamed eye, we measured the proportion of distinct immune cell types, the amount of B or T cell clonal expansion, and the transcriptional profile of T and B cells. Results: Each individual had robust clonal expansion arising from a single T or B cell lineage, suggesting distinct, antigen-driven pathogenic processes in each patient. This variability in clonal expansion was mirrored by individual variability in CD4 T cell populations, whereas ocular CD8 T cells and B cells were more transcriptionally similar between patients. Finally, ocular B cells displayed evidence of class-switching and plasmablast differentiation within the ocular microenvironment, providing additional support for antigen-driven immune responses in granulomatous uveitis. Conclusions: Collectively, our study identified both conserved and individualized features of granulomatous uveitis, illuminating parallel pathophysiologic mechanisms, and suggesting that future personalized therapeutic approaches may be warranted.

Histopathologic Analysis of Explanted KAMRA Corneal Inlays Demonstrating Adherent Fibroconnective Tissue Scar Formation.

OBJECTIVE: To investigate the histologic composition of opaque membranes associated with corneal intrastromal inlays implanted for the surgical treatment of presbyopia. METHODS: This is an observational case series of KAMRA corneal inlays explanted due to the presence of adherent opaque membranes associated with peri-inlay corneal stromal haze and sent for histopathologic analysis. Routine histology was performed in addition to immunohistochemical staining with myofibroblast and keratocyte markers. RESULTS: Eleven explanted inlay specimens were received, of which, after histologic processing, four demonstrated suf-ficient cellular material for histopathologic analysis. The opaque membranes surrounding the explanted inlays were composed of fibroconnective tissue, and myofibroblasts (positive for smooth muscle actin immunostain) were the predominant cell type. Immunostaining for the keratocyte marker CD34 was negative, confirming that the membranes were the result of a reactive scar-tissue formation process and not simply normal corneal stroma adherent to the explant. CONCLUSIONS: Corneal inlay implantation can lead to the formation of an adherent fibroconnective tissue membrane, suggesting keratocyte-to-myofibroblast transdifferentiation and reactive fibroconnective tissue scar formation that could potentially impact visual potential. Prospective patients should be counseled regarding the risk of this complication, as this may be associated with some risk of incomplete reversibility of the procedure.

Magnetic Resonance Imaging Findings in Pediatric Pseudotumor Cerebri Syndrome.

BACKGROUND: Revised diagnostic criteria for pseudotumor cerebri syndrome require three of four neuroimaging findings in the absence of papilledema. We examined the sensitivity and specificity of three or more of four of these magnetic resonance imaging (MRI) findings for pseudotumor cerebri syndrome in children. METHODS: As part of clinical care, patients in whom there was suspicion for pseudotumor cerebri syndrome underwent neurological and fundoscopic examinations, lumbar puncture, MRI, or magnetic resonance venogram. For this retrospective study, we used this information to classify 119 subjects into definite (n = 66) or probable pseudotumor cerebri syndrome (n = 12), elevated opening pressure without papilledema (n = 23), or controls who had normal opening pressure without papilledema (n = 24). A neuroradiologist, unaware of the clinical findings or original MRI report, reviewed MRIs for pituitary gland flattening, flattening of the posterior sclera, optic nerve sheath distention, and transverse venous sinus stenosis. RESULTS: The presence of three or more MRI findings has a sensitivity of 62% (95% confidence interval: 47% to 75%) and a specificity of 95% (95% confidence interval: 77% to 100%), compared with controls. Two of three (transverse venous sinus stenosis, pituitary gland flattening, flattening of the posterior sclera) had a similar sensitivity and specificity. Transverse venous sinus stenosis alone had a slightly higher sensitivity (74%, 95% confidence interval: 60% to 85%) and specificity (100%, 95% confidence interval: 80% to 100%). CONCLUSIONS: In children, three of four of the proposed neuroimaging criteria and transverse venous sinus stenosis alone have a moderate sensitivity and robust specificity for pseudotumor cerebri syndrome. MRIs should be reviewed for these criteria, and their presence should raise suspicion for pseudotumor cerebri syndrome in children, particularly if the presence of papilledema is uncertain.

Headache Characteristics in Children With Pseudotumor Cerebri Syndrome, Elevated Opening Pressure Without Papilledema, and Normal Opening Pressure: A Retrospective Cohort Study.

BACKGROUND: Certain headache characteristics and associated symptoms are commonly attributed to increased intracranial pressure, but they have not been systematically studied among children in the context of revised diagnostic criteria for pseudotumor cerebri syndrome (PTCS). METHODS: We performed a retrospective cohort study of patients treated for suspected or confirmed PTCS. Charts were reviewed for PTCS and headache diagnostic criteria and associated characteristics. Chi-squared or Fisher's exact tests were used to compare the frequency of headache characteristics between groups. RESULTS: One hundred and twenty-seven individuals were identified: 61 had definite PTCS, 10 had probable PTCS, 31 had elevated opening pressure (OP) without papilledema, and 25 had normal OP without papilledema. Eleven children had no headache (6 with definite PTCS, 5 with probable PTCS). Headache pattern was episodic in 49% (95% CI: 34-64%) of those with definite PTCS, 18% (95% CI 6-37%) of those with elevated OP without papilledema, and 16% (5-36%) of those with normal OP without papilledema. Headache location was more likely to involve the head along with neck or shoulders in those with definite PTCS compared with elevated OP without papilledema (OR = 7.2, 95% CI: 1.9-27.6) and normal OP (OR = 4.5, 95% CI: 1.3-15.6) groups. DISCUSSION: While missing data and small cohort size are limitations, this study suggests that headache in PTCS is more likely to involve the head along with neck/shoulders, and that headache in PTCS may be episodic or constant. Headache is occasionally absent in PTCS.

Clinical and Prognostic Significance of Cerebrospinal Fluid Opening and Closing Pressures in Pediatric Pseudotumor Cerebri Syndrome.

BACKGROUND: The purpose of this study was to determine the prognostic utility of closing pressure and volume of cerebrospinal fluid removed with respect to papilledema resolution and headache improvement in pediatric pseudotumor cerebri syndrome. METHODS: This is a retrospective observational study of 93 children with definite pseudotumor cerebri syndrome. The primary outcome measure was time to resolution of papilledema, and the secondary outcome measure was time to resolution of headache. RESULTS: There were no significant differences in gender, age, or body mass index z score observed between subjects with (N = 35) and without (N = 58) documented closing pressure. The median time to resolution of papilledema was not statistically different between children above or equal to and those below the median closing pressure (170 mm of cerebrospinal fluid, n = 31, P = 0.391) or the volume of median cerebrospinal fluid removed (16 mL, n = 19, P = 0.155). There was no statistically significant difference detected in days of headache between the children with opening pressure above and equal to the median (400 mm of cerebrospinal fluid) and the children with opening pressure below the median (n = 44, P = 0.634). CONCLUSIONS: No significant association between closing pressure, amount of cerebrospinal fluid removed, and time to resolution of papilledema due to pseudotumor cerebri syndrome was detected. The diagnostic and therapeutic purposes of either measuring the closing pressure or maximizing the volume of cerebrospinal fluid removed were not evident in these analyses.

Toxic Keratoconjunctivitis.

Toxic keratoconjunctivitis (TK) is an underrecognized complication of ophthalmic drug use and various environmental or occupational exposures. A detailed history and clinical examination are important to identify the offending agent(s). Common drug-related causes of TK include preservatives in ophthalmic medications, topical antimicrobials, and topical anesthetics. Alternatives to benzalkonium chloride as well as preservative-free formulations should be considered in patients requiring long-term topical medication. More advanced cases of TK may require preservative-free topical steroids and/or antibiotics, and occasionally surgical intervention. Early recognition and appropriate management of TK may help prevent permanent ocular and visual damage.

Unilateral Posterior Interstitial Keratitis as a Clinical Presentation of Herpes Simplex Virus Disease.

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.

Pediatric Pseudotumor Cerebri Syndrome: Diagnosis, Classification, and Underlying Pathophysiology.

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure in the setting of normal brain parenchyma and cerebrospinal fluid. PTCS can occur in the pediatric and adult populations and, if untreated, may lead to permanent visual loss. In this review, discussion will focus on PTCS in the pediatric population and will outline its distinct epidemiology and key elements of diagnosis, evaluation and management. Finally, although the precise mechanisms are unclear, the underlying pathophysiology will be considered.

Assessing Progression of Resident Proficiency during Ophthalmology Residency Training: Utility of Serial Clinical Skill Evaluations.

OBJECTIVE: The Accreditation Council for Graduate Medical Education (ACGME) has mandated that residency programs document progression of competency-based outcomes. The Ophthalmic Clinical Evaluation Exercise (OCEX) assesses clinical skills in ophthalmology residents during patient encounters. Although OCEX has been validated for assessing several of the ACGME-mandated competencies, it was unclear whether OCEX can measure the development of proficiency during residency. This study evaluated whether OCEX can discriminate skill levels across years in training. METHODS: In 2017, the authors performed a retrospective analysis on modified OCEX evaluations collected for 22 residents over 3 years at 2 residency programs. OCEX subcomponent scores were averaged to generate a mean score for each evaluation, followed by linear regression analysis for mean scores over time for individual residents. One-way ANOVA with repeated measures was used to compare scores aggregated over an academic year between resident classes. The authors also surveyed internal faculty evaluators and nationwide ophthalmology residency program directors on their use of OCEX. RESULTS: Mean OCEX scores for individual residents and resident class averages showed variable trajectories over the course of residency. There was no consistent effect of increasing level of training on scores. Surveys of evaluators and program directors indicated different interpretations of the grading scale anchors and irregular participation by faculty. CONCLUSION: This dataset suggests that, despite clear behavioral anchors and faculty development on the use of the tool, evaluators still apply inconsistent grading standards that limit the OCEX from accurately monitoring longitudinal development of resident clinical performance in real-world practice.

Pediatric Idiopathic Intracranial Hypertension: Age, Gender, and Anthropometric Features at Diagnosis in a Large, Retrospective, Multisite Cohort.

PURPOSE: To examine anthropometric and maturational characteristics at diagnosis in pediatric idiopathic intracranial hypertension (IIH). DESIGN: Retrospective, international, multisite study. PARTICIPANTS: Pediatric patients (2-18 years of age at diagnosis) with IIH. MAIN OUTCOME MEASURES: Body mass index (BMI), height, and weight Z-scores; sexual maturation. METHODS: Cases of IIH were identified retrospectively based on diagnostic code, pediatric neuro-ophthalmologist databases, or both and updated diagnostic criteria (2013) were applied to confirm definite IIH. Anthropometric measurements were converted into age- and gender-specific height, weight, and BMI Z-scores CDC 2000 growth charts. When available, sexual maturation was noted. RESULTS: Two hundred thirty-three cases of definite IIH were identified across 8 sites. In boys, a moderate association between age and BMI Z-scores was noted (Pearson's correlation coefficient, 0.50; 95% confidence interval [CI], 0.30-0.66; P < 0.001; n = 72), and in girls, a weak association was noted (Pearson's correlation coefficient, 0.34; 95% CI, 0.20-0.47; P < 0.001; n = 161). The average patient was more likely to be overweight at diagnosis at age 6.7 years in girls and 8.7 years in boys, and obese at diagnosis at age 12.5 years in girls and 12.4 years in boys. Compared with age- and gender-matched reference values, early adolescent patients were taller for age (P = 0.002 in girls and P = 0.02 in boys). Data on Tanner staging, menarchal status, or both were available in 25% of cases (n = 57/233). Prepubertal participants (n = 12) had lower average BMI Z-scores (0.95±1.98) compared with pubertal participants (n = 45; 1.92±0.60), but this result did not reach statistical significance (P = 0.09). CONCLUSIONS: With updated diagnostic criteria and pediatric-specific assessments, the present study identifies 3 subgroups of pediatric IIH: a young group that is not overweight, an early adolescent group that is either overweight or obese, and a late adolescent group that is mostly obese. Data also suggest that the early adolescent group with IIH may be taller than age- and gender-matched reference values. Understanding these features of pediatric IIH may help to illuminate the complex pathogenesis of this condition.