Elucidating the molecular basis of PPCD: Effects of decreased ZEB1 expression on corneal endothelial cell function.

PURPOSE: To investigate the functional role that the zinc e-box binding homeobox 1 (ZEB1) gene, which underlies the genetic basis of posterior polymorphous corneal dystrophy 3 (PPCD3), plays in corneal endothelial cell proliferation, apoptosis, migration, and barrier function. METHODS: A human corneal endothelial cell line (HCEnC-21T) was transfected with siRNA targeting ZEB1 mRNA. Cell proliferation, apoptosis, migration, and barrier assays were performed: Cell proliferation was assessed with cell counting using a hemocytometer; cell apoptosis, induced by either ultraviolet C (UVC) radiation or doxorubicin treatment, was quantified by measuring cleaved caspase 3 (cCASP3) protein levels; and cell migration and barrier function were monitored with electric cell-substrate impedance sensing (ECIS). RESULTS: ZEB1 knockdown in HCEnC-21T cells transfected with siRNA targeting ZEB1 did not result in a significant difference in cell proliferation when compared with control. Although knockdown of ZEB1 in HCEnC-21T cells sensitized the cells to UV-induced apoptosis, ZEB1 knockdown did not alter the cells' susceptibility to doxorubicin-induced apoptosis, as measured with cCASP3 protein levels, compared with controls. Similarly, no difference was observed in cell migration following ZEB1 knockdown. However, cell barrier function increased significantly following ZEB1 knockdown. CONCLUSIONS: The corneal endothelium in PPCD3 is characterized by morphologic, anatomic, and molecular features that are more consistent with an epithelial-like rather than an endothelial-like phenotype. Although these characteristics have been well documented, we demonstrate for the first time that susceptibility to UV-induced apoptosis and cell barrier function are significantly altered in the setting of reduced ZEB1. The significance of an altered cellular response to apoptotic stimuli and increased cell barrier function in the pathobiology of PPCD remains to be fully elucidated.

Identification of presumed pathogenic KRT3 and KRT12 gene mutations associated with Meesmann corneal dystrophy.

PURPOSE: To report potentially pathogenic mutations in the keratin 3 (KRT3) and keratin 12 (KRT12) genes in two individuals with clinically diagnosed Meesmann corneal dystrophy (MECD). METHODS: Slit-lamp examination was performed on the probands and available family members to identify characteristic features of MECD. After informed consent was obtained, saliva samples were obtained as a source of genomic DNA, and screening of KRT3 and KRT12 was performed. Potentially pathogenic variants were screened for in 200 control chromosomes. PolyPhen-2, SIFT, and PANTHER were used to predict the functional impact of identified variants. Short tandem repeat genotyping was performed to confirm paternity. RESULTS: Slit-lamp examination of the first proband demonstrated bilateral, diffusely distributed, clear epithelial microcysts, consistent with MECD. Screening of KRT3 revealed a heterozygous missense variant in exon 1, c.250C>T (p.(Arg84Trp)), which has a minor allele frequency of 0.0076 and was not identified in 200 control chromosomes. In silico analysis with PolyPhen-2 and PANTHER predicted the variant to be damaging to protein function; however, SIFT analysis predicted tolerance of the variant. The second proband demonstrated bilateral, diffusely distributed epithelial opacities that appeared gray-white on direct illumination and translucent on retroillumination. Neither parent demonstrated corneal opacities. Screening of KRT12 revealed a novel heterozygous insertion/deletion variant in exon 6, c.1288_1293delinsAGCCCT (p.(Arg430_Arg431delinsSerPro)). This variant was not present in either of the proband's parents or in 200 control chromosomes and was predicted to be damaging by PolyPhen-2, PANTHER, and SIFT. Haplotype analysis confirmed paternity of the second proband, indicating that the variant arose de novo. CONCLUSIONS: We present a novel KRT12 mutation, representing the first de novo mutation and the first indel in KRT12 associated with MECD. In addition, we report a variant of uncertain significance in KRT3 in an individual with MECD. Although the potential pathogenicity of this variant is unknown, it is the first variant affecting the head domain of K3 to be reported in an individual with MECD and suggests that disease-causing variants associated with MECD may not be restricted to primary sequence alterations of either the helix-initiation or helix-termination motifs of K3 and K12.

A vascular syphilitic iris lesion.

Purpose: To describe examination and imaging characteristics of presumed iris papulosa in a case of ocular syphilis. Observations: A 60-year-old man who presented with granulomatous anterior uveitis in his left eye was also noted to have an unusual vascularized iris papule associated with posterior synechiae at the nasal pupillary margin. Anterior segment OCT (AS-OCT) of the iris lesion demonstrated a hyperreflective anterior surface with multiple vascular lumen, internal hyperreflectivity, and shadowing. Ultrasound biomicroscopy (UBM) imaging revealed an echodense mass with relative hyperechogenicity in the anterior portion of the lesion. Systemic work-up confirmed a diagnosis of syphilis, and he was treated with topical steroids and parenteral penicillin. Conclusion and Importance: We characterize the rare finding of iris papulosa that may be encountered in syphilitic uveitis and its distinctive features on both UBM and AS-OCT. This report highlights that syphilis should be considered as a possible diagnosis for an undifferentiated vascular iris mass.

IgG4-related hypertensive granulomatous anterior uveitis.

Purpose: To report a case of hypertensive granulomatous anterior uveitis in the setting of IgG4-related disease (IgG4-RD). Observations: A 69-year-old man presented with no light perception vision in both eyes and bilateral granulomatous anterior uveitis with iris neovascularization and hyphema in the right eye. He also demonstrated concurrent polyuria, polydipsia, and altered mental status, and was diagnosed with new-onset diabetes mellitus. MRI revealed no orbital abnormalities, but showed bilateral occipital strokes attributed to hyperglycemic hyperosmolar syndrome. Chest CT revealed pleural-based nodules and mediastinal and abdominal lymphadenopathy, and a liver biopsy confirmed fibroinflammatory nodules with increased IgG4 positive plasma cell infiltrates, diagnostic of IgG4-RD. Serum IgG4 levels were 1381 mg/dL. The patient was treated with a combination of systemic and topical steroids, and later initiated on rituximab. Conclusion and importance: IgG4-related ophthalmic disease may present as an isolated hypertensive granulomatous anterior uveitis without associated scleral or orbital involvement.

Quantification of Anterior Chamber Cells in Children With Uveitis Using Anterior Segment Optical Coherence Tomography.

PURPOSE: To evaluate the feasibility of anterior segment optical coherence tomography (AS-OCT) for measuring anterior chamber (AC) cells in children with uveitis and to compare different AS-OCT acquisition modes. DESIGN: Validity and reliability analysis. METHODS: We enrolled children younger than 18 years who had uveitis involving the anterior segment and children without eye disease as controls. All underwent clinical grading of AC cells. AC images of each eye were obtained using the Optovue Avanti RTVue XR AS-OCT. Two acquisition modes were used: a single cross-sectional line scan and an 8-line radial scan in an asterisk pattern. Two independent, masked graders counted cells manually on AS-OCT images. Rater agreement was assessed using intraclass correlation (ICC). RESULTS: Included were 30 children (59 eyes) with uveitis (median age 13.0 years, range 3-17 years) and 20 control children (40 eyes, median age 10.5 years, range 4-17 years). The number of eyes assigned each clinical grade of cells were as follows: none, 32 (54%); 0.5+, 12 (20.3%); 1+, 5 (8.5%); 2+, 8 (13.6%); 3+, 2 (3.4%). ICC of graders for line and radial scan protocols were 0.87 and 0.90. There was no significant difference between acquisition modes for pooled grader results (95% CI for difference: -0.04 to 0.14). ICC of cell counts between line and radial scan protocols was 0.85 (95% CI: 0.69-0.90). No control eyes had cells on AS-OCT images. CONCLUSIONS: Quantification of AC cell in children with uveitis is feasible with AS-OCT and has excellent reliability between different graders and acquisition modes.

Recent advances in the treatment of juvenile idiopathic arthritis-associated uveitis.

Juvenile idiopathic arthritis-associated uveitis has an estimated prevalence of 10-20% in patients with juvenile idiopathic arthritis, making it the most common cause of chronic anterior uveitis in children. Prompt treatment is important to prevent development of ocular complications and permanent vision loss. In this review, we will discuss the use of immunosuppression in treatment of juvenile idiopathic arthritis-associated uveitis. This will include the use of conventional immunosuppressants, such as methotrexate, biologic anti-tumor necrosis factor agents, such as adalimumab, as well as other anti-tumor necrosis factor agents, including infliximab and golimumab. In addition, we will discuss medications currently in clinical trials or under consideration for juvenile idiopathic arthritis-associated uveitis, including interleukin-6 inhibitors (tocilizumab) and Janus kinase inhibitors (tofacitinib, baricitinib).

Effect of dietary modification and antioxidant supplementation on intraocular pressure and open-angle glaucoma.

Primary open-angle glaucoma (POAG) is an age-dependent, intraocular pressure (IOP)-related degeneration of the retinal ganglion cells (RGC). At present, IOP is the only modifiable factor that has been identified to prevent glaucomatous vision loss. Though the pathogenesis of glaucomatous optic neuropathy is still not well understood, increasing evidence suggests oxidative stress may contribute to the induction and progression of glaucoma. Furthermore, antioxidant use may be protective against glaucoma through various mechanisms, including reducing IOP, preserving vascular health, and preventing ganglion cell loss. This article provides a comprehensive review of the effect of oxidative stress, diet, and antioxidant therapy on IOP and open-angle glaucoma.

Multimodal imaging in pediatric uveitis.

Pediatric uveitis accounts for up to 10% of all uveitis cases, so special attention must be paid to ensure early diagnosis as well as treatment and follow-up of these young patients in order to decrease the risk of possible ocular complications and consequently vision loss. Multimodal imaging has been an effective and important adjunct in the diagnoses and management of uveitis, especially in children. Reviewed here are the currently utilized modalities, advances, as well as their applications in juvenile idiopathic arthritis-associated uveitis, pars planitis, retinal vasculitis, tubulointerstitial nephritis and uveitis syndrome, Behçet disease, Blau syndrome, and Vogt-Koyanagi-Harada syndrome.

Pediatric tonsillectomy: A short-term and long-term comparison of intracapsular versus extracapsular techniques.

OBJECTIVE: To review a cohort of over 2500 patients and investigate the short and long-term outcomes of intracapsular as compared to extracapsular tonsillectomy, and show if the complication rates are comparable between methods. STUDY DESIGN: A multicenter, retrospective chart review was conducted, evaluating pediatric tonsillectomies performed from 2004 to 2014. The electronic medical record was reviewed through December 2018, providing up to 14 years of follow-up data. SETTING: Two tertiary care, academic medical centers. SUBJECTS AND METHODS: A retrospective chart review was conducted to identify children undergoing tonsillectomy and adenotonsillectomy. A chart review was first performed of patients by a single surgeon (MEG) and then the analysis was repeated using enterprise data warehouse (EDW) to search for complications and interventions using International Classification of Diseases, ninth revision, (ICD-9) and Current Procedural Terminology (CPT) codes. The second surgeon's patients (JLC) patients were added to increase the cohort. Patients were excluded from the review of long-term outcomes if there was less than two-year follow-up. Short-term outcomes examined included rate of post-tonsillectomy hemorrhage and re-presentation for dehydration, while long-term outcomes included rates of peritonsillar abscess and tonsillar regrowth requiring revision tonsillectomy. RESULTS: A total of 2508 pediatric patients were identified who had undergone tonsillectomy or adenotonsillectomy. In 1456 (58.1%) of these patients, the intracapsular technique was used and in 1052 (41.9%) patients, the extracapsular technique was used. The mean documented follow-up time was 8.2 years. Thirty-five patients (1.4%) were identified with post-tonsillectomy hemorrhage, 2 of these patients (5.7%) with primary hemorrhage and 33 patients (94.3%) with secondary hemorrhage. 11 underwent intracapsular tonsillectomy and 24 underwent extracapsular tonsillectomy (p = 0.0042). The rate of post-tonsillectomy hemorrhage with intracapsular tonsillectomy was 0.76%, compared to 2.3% in the extracapsular group. Three patients (0.12%) undergoing intracapsular tonsillectomy required revision tonsillectomy; no patients in the extracapsular group required revision surgery. Three patients (0.12%) developed peritonsillar abscess post-operatively, two following intracapsular tonsillectomy and one following extracapsular tonsillectomy. CONCLUSION: This retrospective review comparing the intracapsular and extracapsular techniques for tonsillectomy provides further evidence of the benefits of this technique. It is worthwhile to continue offering intracapsular tonsillectomy to patients and their families during pre-operative discussions.

Perioperative Management of Uveitic Cataracts.

Uveitis patients represent a unique subset of the population undergoing cataract surgery and pose several challenges that require special consideration and strategy. Maintenance of disease quiescence for at least three months prior to surgery maximizes postoperative outcomes, though these patients remain at increased risk for pseudophakic cystoid macular edema, which can be refractory to the traditional steroid treatments. In this review, we detail the pillars of preoperative optimization, intraoperative considerations, and postoperative management of uveitic cataracts, with special attention on the evidence surrounding prevention and treatment of refractory postoperative cystoid macular edema.

Brimonidine tartrate for the treatment of glaucoma.

INTRODUCTION: Brimonidine tartrate is a commonly used eyedrop for short- and long-term lowering of intraocular pressure. Its use has been popularized due to its effects on aqueous suppression and uveoscleral outflow, as well as the suggestion of neuroprotection. Although available with alternative preservative vehicles, brimonidine is associated with high rates of local allergy and is contraindicated in breastfeeding women, neonates, young children, and the elderly due to risk of central nervous system depression. Other topical agents with differing advantages have challenged brimonidine's role in the treatment algorithm of ocular hypertension and glaucoma. Areas covered: The authors review the development of topical alpha-adrenergic agonists, with particular attention to the currently available formulations of brimonidine tartrate. Its mechanism of action, pharmacodynamics and safety, and clinical efficacy are analyzed. Expert opinion: Despite clinical familiarity with brimonidine after two decades of use, agents that offer daily dosing, nocturnal effect, and more favorable ocular and systemic side effect profiles have ultimately led to brimonidine's adjunctive use in patients with elevated intraocular pressure or high- or low-tension glaucomas. Still, brimonidine may be advantageous in patients undergoing laser trabeculoplasty or iridotomy, in certain forms of glaucoma, or in pregnant individuals prior to the last trimester, underscoring its clinical importance.

Inpatient and Emergency Room Ophthalmology Consultations at a Tertiary Care Center.

BACKGROUND: An ophthalmology consultation service is of significant benefit to patients in the hospital and is an instructive component of a residency education program. Ophthalmology consultations in a hospital present unique challenges to those seen in an outpatient clinic, for which the consulting ophthalmologist should be prepared. The purpose of this study was to profile the emergency room and inpatient ophthalmology consultations seen at an academic institution. METHODS: A prospective study of 581 patients was conducted on inpatient and emergency room ophthalmology consultations at the University of Illinois at Chicago over twelve months. Characteristics such as the consulting service, type of and reason for consultation, subspecialty staffing service, diagnosis, and suitability for in-hospital evaluation were recorded. RESULTS: Consultations were received from either inpatient wards (59.4%) or the Emergency Department (40.6%). The most common inpatient consulting services were internal medicine (22%), followed by neurosurgery (16%) and neurology (7%). All the consultations were categorized as acute (72.3%), chronic (6.0%), or screening (21.7%). Consultations categorized as screening included papilledema (31.0%), fungemia (20.6%), syndromic evaluation (19.8%), visual field evaluation (17.5%), and miscellaneous evaluation (11.1%). We classified the ophthalmic diagnoses into 63 unique diagnoses. Amongst the ophthalmic subspecialties, neuro-ophthalmologic diagnoses were the most common (32.0%), followed by retina (20.1%) and cornea (19.4%). Neuro-ophthalmology had the highest proportion of screening consultations (36.6%), while glaucoma had the least overall number of consultations (10.1%), and the least proportion of screening consultations (3.6%). A significant proportion of nonacute consultations (19.0%) was deemed to be more suitable for outpatient evaluation. DISCUSSION: Consultation databases can be useful in preparing trainees for in-hospital clinical care. A wide range of ocular pathologies may present to the ophthalmology consultant, from acute trauma to screening for systemic syndromes. Some consultations may be more suitable for outpatient evaluation which may help optimize patient care.

A complex choristoma presenting as a salmon patch lesion in the bulbar conjunctiva.

PURPOSE: We describe a rare case of a complex choristoma appearing as a salmon-patch lesion in the nasal conjunctiva. While benign, complex choristomas are grossly indistinguishable from malignant lesions, and an excisional biopsy is warranted to confirm the diagnosis. OBSERVATIONS: A 31-year-old man presented with an elevated glistening pink mass on the conjunctiva. An excisional biopsy with a "no-touch" technique was performed, followed by placement of an amniotic membrane graft without postoperative complications. No subsequent medical treatment was pursued after the biopsy and histopathologic evaluation. Histopathology confirmed a diagnosis of a complex choristoma with sections consisting of fibroadipose tissue with cartilage, smooth muscle, and nerves. Histopathology was negative for malignant cells without morphologic evidence of a lymphoma. CONCLUSIONS AND IMPORTANCE: Conjunctival tumors are difficult to distinguish clinically, and a differential diagnosis often includes the possibility of a malignancy. Histopathologic diagnosis may be required to distinguish between various entities. In our case, a salmon-patch conjunctival tumor was biopsied and confirmed to be a benign complex choristoma.

Utility of temporal bone computed tomographic measurements in the evaluation of inner ear malformations.

OBJECTIVE: To investigate whether normative inner ear measurements can assist in the evaluation of sensorineural hearing loss (SNHL). DESIGN: Retrospective cohort review. SETTING: A tertiary care hospital. PATIENTS: Computed tomography or magnetic resonance imaging was performed on 188 ears with SNHL and 220 ears without SNHL (204 children) between 2001 and 2004. INTERVENTION: Two readers measured the basal turn of cochlea (BTC) lumen, lateral semicircular canal (LSCC) bony island width, superior semicircular canal (SSCC) bony island width, and cochlear height (CH). MAIN OUTCOME MEASURES: A t test was performed comparing measurements in patients with and without SNHL. Interobserver variability was characterized by intraclass correlation coefficients and Bland-Altman plots. RESULTS: The t test results demonstrated no statistically significant differences between inner ear measurements in those with and without SNHL. The intraclass correlation coefficients for BTC lumen, CH, LSCC bony island width, and SSCC bony island width measurements was 0.612, 0.632, 0.869, and 0.912, respectively. Bland-Altman plots revealed systematic biases of 1%, 8%, 10%, and 21% for the BTC lumen, SSCC bony island width, LSCC bony island width, and CH measurements, respectively. CONCLUSIONS: Inner ear measurements in children with and without SNHL are not statistically different. Moreover, the measurements are difficult to interpret because while they demonstrate good reproducibility, they are susceptible to systematic biases. However, use of inner ear measurements is more sensitive in identifying vestibulocochlear dysplasias and should be considered to complement visual analysis.

Familial laryngomalacia in two siblings with syndromic features.

We present two siblings with severe laryngomalacia requiring surgical intervention during the newborn period, microcephaly, developmental delay, cleft palate, preaxial polydactyly, dysplastic nails and conductive hearing loss (persistent after tympanostomy tube placement). In addition the girl has microopthalmia and the boy was born with a patent ductus arteriosus, mild pelviectasis, and hypospadias. This combination of multiple congenital anomalies has not been described previously and may represent a previously undescribed syndrome with autosomal inheritance.

Acute Mastoiditis Caused by Streptococcus pneumoniae.

Acute mastoiditis (AM) is a relatively rare complication of acute otitis media (AOM). The most common pathogens include Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Pneumococcal vaccination and changes in antibiotic prescribing recommendations for AOM may change the incidence of AM in the future. Diagnosis of AM can be made based on clinical presentation, but computed tomography of the temporal bone with contrast should be considered if there is concern for complicated AM. Both extracranial and intracranial complications of AM may occur. Previously, routine cortical mastoidectomy was recommended for AM treatment, but new data suggest that a more conservative treatment approach can be considered, including intravenous (IV) antibiotics alone or IV antibiotics with myringotomy. [Pediatr Ann. 2016;45(5):e176-e179.].

Identification of the First De Novo UBIAD1 Gene Mutation Associated with Schnyder Corneal Dystrophy.

Purpose. To report the identification of the first de novo UBIAD1 missense mutation in an individual with Schnyder corneal dystrophy (SCD). Methods. A slit lamp examination was performed on a 47-year-old woman without a family history of corneal disorders. The proband's parents, two sisters, and son were also examined and genomic DNA from all six individuals was collected. The exons and exon-intron boundaries of UBIAD1 were screened using Sanger sequencing. Identified mutations were screened for in 200 control chromosomes. In silico analysis predicted the impact of identified mutations on protein function and structure. Results. Slit lamp examination of the proband revealed findings consistent with SCD. Corneas of the family members appeared unaffected. Screening of UBIAD1 in the proband identified a novel heterozygous c.308C>T mutation, predicted to encode the missense amino acid substitution p.(Thr103Ile). This mutation was not identified in any of the family members or in 200 control chromosomes and was predicted to be damaging to normal protein function and structure. Conclusions. We present a novel heterozygous de novo missense mutation in UBIAD1, p.(Thr103Ile), identified in a patient with classic clinical features of SCD. This highlights the value of genetic testing in clinical diagnostic settings, even in the absence of a positive family history.

Newborn hearing screening may predict Eustachian tube dysfunction.

INTRODUCTION: There is evidence for temporary hearing loss in neonates immediately after birth because of residual liquid derived from amniotic fluid in the ME cavity. This study examines whether a referred newborn hearing screen (NBHS) with subsequent testing confirming normal hearing can be attributed to persistence of middle ear effusion and predict poor Eustachian tube function manifested as recurrent otitis media or otitis media with effusion in the first year of life. The aims of the present study are to investigate the following: (1) whether infants who fail a neonatal hearing screen and subsequently pass are more likely to experience recurrent otitis media or otitis media with effusion, (2) whether these infants are more likely to obtain tympanostomy tubes. METHODS: This retrospective cohort study examined newborns who referred their NBHS and were subsequently noted to have normal hearing and a control group comprised of newborns who passed their NBHS. Univariate and multivariate analysis was performed on the data collected as well as generation mean cumulative function plots. RESULTS: The baseline characteristics of the case and control groups are not statistically significant with regards to gender, number of otitis media (OM), delivery mode, or the need for tubes in the follow up period. Within the refer group, those with bilateral refers were twice as likely to have otitis media than those with a unilateral refer (p=0.012). The logistic regression model for odds of subsequent otitis media was not statistically significant for bilateral or unilateral refer though the logistic regression model for odds of tubes demonstrated a statistically significant increased risk in bilateral refer patients. With time to event analysis, it was seen that bilateral refer patients are more likely to have OM than control and unilateral refer patients. CONCLUSION: There is no difference in the incidence of subsequent OM between those infants who passed the NBHS versus those who initially referred and then passed subsequent audiology examination. However there was a difference in the number of otitis media between those infants who referred bilaterally versus those who referred unilaterally.