ULTRA-WIDE-FIELD FUNDUS AUTOFLUORESCENCE FINDINGS IN PATIENTS WITH ACUTE ZONAL OCCULT OUTER RETINOPATHY.

PURPOSE: To determine whether ultra-wide-field fundus autofluorescence (UWFFAF) findings in acute zonal occult outer retinopathy correlated well with perimetry, optical coherence tomography, and electroretinography findings. METHODS: Retrospective observational study on 16 eyes of 10 subjects with AZOOR seen at a single referral center from October 2012 to March 2015 who had UWFFAF performed. Chi-square analysis was performed to compare categorical variables, and Mann-Whitney U test used for comparisons of nonparametric continuous variables. RESULTS: All eyes examined within 3 months of symptom onset (five of the five eyes) had diffusely hyperautofluorescent areas on UWFFAF. The remaining eyes contained hypoautofluorescent lesions with hyperautofluorescent borders. In 11/16 (68.8%) eyes, UWFFAF showed the full extent of lesions that would not have been possible with standard fundus autofluorescence centered on the fovea. There were 3 patterns of spread: centrifugal spread (7/16, 43.8%), centripetal spread (5/16, 31.3%), and centrifugal + centripetal spread (4/16, 25.0%). The UWFFAF lesions corresponded well with perimetric, optical coherence tomography, and electroretinography abnormalities. CONCLUSION: The UWFFAF along with optical coherence tomography can be useful in the evaluation and monitoring of acute zonal occult outer retinopathy patients.

Probable Association of an Attack of Bilateral Acute Angle-Closure Glaucoma With Duloxetine.

OBJECTIVE: To report a patient who had an attack of bilateral acute angle-closure glaucoma (ACG) probably associated with the use of duloxetine. CASE SUMMARY: The case reported here involves an 81-year-old Caucasian woman whose past ocular history was unremarkable except for high hyperopia and cataract. The patient developed ocular symptoms 2 days after starting duloxetine, a serotonin norepinephrine reuptake inhibitor (SNRI) and was diagnosed with acute ACG. The elevated intraocular pressure (IOP) was successfully lowered with medical treatment, and the patient was advised to discontinue duloxetine. She subsequently underwent laser iridotomy in both eyes, and her IOP remained adequately controlled. A score of 6 was obtained using the Naranjo adverse drug reaction probability scale, suggesting duloxetine as the probable cause of the attack of ACG in this patient. DISCUSSION: There are a few previous reports of acute ACG associated with venlafaxine, another member of the class of SNRIs. In addition, there are several reports of ACG associated with members of the related class of selective serotonin reuptake inhibitors (SSRIs)-namely, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, and escitalopram. The mechanism responsible for the precipitation of ACG by members of these 2 classes of drugs is likely a result of mydriasis caused by their adrenergic effects, weak anticholinergic activities, or the increased levels of serotonin. CONCLUSION: Because the SNRIs, including duloxetine, and SSRIs are commonly used in the management of depression or chronic pain, caution is warranted with the use of these drugs in patients with risk factors for ACG.

A Severe and Prolonged Case of Ocular Monkeypox Without Systemic Manifestations.

PURPOSE: The objective of this study was to present a rare case of prolonged and severe ocular monkeypox virus infection in the absence of systemic manifestations. METHODS: This was a single case report. RESULTS: A 60-year-old man, having been symptomatic for 9 days, presented with several umbilicated, ulcerated papules on the left cheek, left side of the nose, and left upper eyelid, along with marked follicular conjunctivitis and multiple conjunctival ulcerations. Two weeks after presentation, he developed an irregular, 360° circumferential opacity in the peripheral cornea that progressed to a large epithelial defect with corneal thinning. Although the initial eyelid lesions and conjunctivitis quickly resolved, the patient experienced nonresolving corneal inflammation manifest with peripheral corneal thinning, epithelial defects, and stromal keratitis. Four months after presentation, with the presumptive diagnosis of peripheral ulcerative keratitis, the patient was treated with intravenous steroids and immunosuppressive treatment, after which the ocular surface inflammation improved. However, the inflammation recurred 12 weeks later, and the patient developed severe perilimbal necrotizing conjunctivitis, followed by recurrence of ulcerated nodular eyelid lesions. Eight months after presentation, nucleic acid amplification tests from eyelid lesion swabs returned positive for nonvariola Orthopoxviruses, which led to the diagnosis of mpox. Within 2 weeks of beginning antiviral treatment with systemic tecovirimat and cidofovir and topical trifluridine, the eyelid lesions, conjunctivitis, and corneal inflammation resolved. CONCLUSIONS: We present an unusual and challenging case of ocular mpox with severe ocular surface inflammation including peripheral corneal thinning and epithelial defects, without systemic disease. Initiation of antiviral treatment resulted in a quick resolution of the ocular disease.

Corneal Sarcoidosis: Diffuse Stromal Granulomatous Inflammation in a Patient With Sarcoidosis.

PURPOSE: The purpose of this study was to present a case of diffuse noncaseating granulomas involving the corneal stroma in a patient with ocular and pulmonary sarcoidosis. METHODS: This was a single case report. RESULTS: A 31-year-old female patient presented with a 6-year history of panuveitis of the right eye along with a history of pulmonary sarcoidosis and a conjunctival biopsy of the right eye that was reported as positive for sarcoidosis. At presentation to our clinic, the patient had band keratopathy, vascularization of the inferonasal cornea, and active anterior uveitis of the right eye. When the patient returned for a follow-up of 15 months after the initial presentation, the cornea of the right eye exhibited widespread stromal scarring and vascularization. Because of the corneal scarring, the patient underwent an implantation of a Boston type 1 keratoprosthesis in the right eye. Histopathological examination of the host corneal tissue removed at the time of the keratoprosthesis procedure revealed extensive noncaseating granulomas in the deep corneal stroma. The patient underwent penetrating keratoplasty 8 months later, and histopathological examination again demonstrated noncaseating granulomas, this time at the edges of the donor corneal graft used during the keratoprosthesis implantation. CONCLUSIONS: We present the histopathological evidence of sarcoidosis involving the corneal stroma. Interestingly, the stromal keratitis also subsequently involved the donor cornea tissue after the patient underwent a keratoprosthesis implantation. It seems that sarcoidosis is a rare cause of stromal keratitis.

Effectiveness of the Dexamethasone Implant in Lieu of Oral Corticosteroids in Intermediate and Posterior Uveitis Requiring Immunosuppression.

PURPOSE: To evaluate dexamethasone intravitreal implant effectiveness in lieu of high-dose oral prednisone for short-term treatment of noninfectious intermediate and posterior uveitis in patients requiring immunosuppression. METHODS: This is a proof-of-concept, open-label, non-comparative clinical trial with 12-month follow-up. The primary outcome was uveitis control without additional prednisone at 6 and 12 months. Secondary outcomes were need for multiple implants or additional prednisone, and safety data. RESULTS: 20 patients (28 eyes) were enrolled- 16 eyes had control by 6 months; 20 by 12 months. No patients required high-dose prednisone. 6 patients enrolled on prednisone: 2 stopped; 4 tapered to 7.5 mg daily or less by 12 months. 16 eyes required multiple implants; five required cataract surgery; 12 required drops to control IOP; 2 underwent glaucoma surgery. CONCLUSIONS: The dexamethasone implant was effective in lieu of high-dose prednisone although the majority required multiple implants. All patients decreased or discontinued prednisone during follow-up.

MULTIMODAL IMAGING IN DIDANOSINE RETINOPATHY.

PURPOSE: To present the multimodal retinal imaging findings in didanosine retinopathy in a patient who presented 6.5 years after stopping the use of didanosine and to highlight the absence of progression during a 1.5-year follow-up. METHODS: Case report involving clinical examination, fundus photography, fundus autofluorescence, fluorescein angiography, optical coherence tomography, Goldmann kinetic perimetry, and full-field electroretinography. RESULTS: A 52-year-old patient presented with bilateral retinopathy 6.5 years after stopping didanosine having used the medication for 8.5 years. Fundus examination showed a ring-shaped zone of atrophy of the retinal pigment epithelium involving the midperiphery. On autofluorescence imaging, there was diffuse hypoautofluorescence involving the midperipheral retina in both eyes. On fluorescein angiography, there was a granular mottled pattern of diffuse hyperfluorescence in the midperiphery in both eyes, with baring of the large choroidal vessels in some areas. On Goldmann kinetic perimetry, both eyes showed marked constriction of the isopter to the I4e stimulus, and there was a temporal scotoma to the III4e target in both eyes. Full-field electroretinography showed generalized rod and cone photoreceptor dysfunction in both eyes. During a follow-up for 1.5 years, there was no evidence of progression. CONCLUSION: Patients who have used didanosine should be evaluated for the presence of retinopathy, which involves the midperipheral retina.

Disease Relapse After Drug-Free Remission in Ocular Mucous Membrane Pemphigoid.

PURPOSE: To quantitate the risk of relapse of ocular and extraocular disease among patients with mucous membrane pemphigoid (MMP) who had undergone drug-free remission. DESIGN: Retrospective, comparative, interventional case series. METHODS: There were 167 patients with biopsy-proven MMP who were seen at the Wilmer Eye Institute between November 1984 and December 2019. Among the 167 patients, 119 patients had ocular involvement and 103 of those patients received systemic treatment for MMP. The main outcome measures were the incidence of ocular remission, incidence rate of disease relapse after remission, and risk factors for disease relapse. RESULTS: Over a median follow-up time of 7 years, 74 of 103 treated patients (71.8%) experienced drug-free remission (incidence rate = 0.28/person-year [PY], 95% confidence interval [CI] 0.22-0.35/PY). Most patients (80/103, 77.7%) received cyclophosphamide therapy. Thirteen of the 74 patients (17.6%) had disease relapse after remission: 4 with ocular disease only, 4 with extraocular disease only, and 5 with both. The rate relapse of ocular MMP was 0.020/PY (95% CI 0.009-0.038/PY), and the rate of relapse of MMP at any site (ocular or extraocular site) was 0.029/PY (95% CI 0.015-0.050/PY). The use of cyclophosphamide was associated with a greater chance of remission (hazard ratio [HR] = 3.84, P < .0001) and a lower risk of relapse (HR = 0.32, P = .05) compared with other immunosuppressive drugs except for rituximab. Five patients experienced drug-free remission after rituximab therapy and none of them had relapse (median follow-up after remission = 3.6 years). When use of cyclophosphamide or rituximab was compared with all other treatments, the risk of MMP relapse at any site (HR = 0.17, P = .02) and of ocular MMP (HR = 0.11, P = .007) were significantly lower. CONCLUSIONS: Rates of relapse of MMP after drug-free remission are low but not zero; therefore, monitoring of patients remains necessary. Relapses were not observed among those patients treated with rituximab who had remission; however, follow-up duration in those patients was shorter than the whole MMP cohort and the sample size was small.

Identification of microbial agents in tissue specimens of ocular and periocular sarcoidosis using a metagenomics approach.

Background: Metagenomic sequencing has the potential to identify a wide range of pathogens in human tissue samples. Sarcoidosis is a complex disorder whose etiology remains unknown and for which a variety of infectious causes have been hypothesized. We sought to conduct metagenomic sequencing on cases of ocular and periocular sarcoidosis, none of them with previously identified infectious causes. Methods: Archival tissue specimens of 16 subjects with biopsies of ocular and periocular tissues that were positive for non-caseating granulomas were used as cases. Four archival tissue specimens that did not demonstrate non-caseating granulomas were also included as controls. Genomic DNA was extracted from tissue sections. DNA libraries were generated from the extracted genomic DNA and the libraries underwent next-generation sequencing. Results: We generated between 4.8 and 20.7 million reads for each of the 16 cases plus four control samples. For eight of the cases, we identified microbial pathogens that were present well above the background, with one potential pathogen identified for seven of the cases and two possible pathogens for one of the cases. Five of the eight cases were associated with bacteria ( Campylobacter concisus, Neisseria elongata, Streptococcus salivarius, Pseudopropionibacterium propionicum, and Paracoccus yeei), two cases with fungi ( Exophiala oligosperma, Lomentospora prolificans and Aspergillus versicolor) and one case with a virus (Mupapillomavirus 1). Interestingly, four of the five bacterial species are also part of the human oral microbiome. Conclusions: Using a metagenomic sequencing we identified possible infectious causes in half of the ocular and periocular sarcoidosis cases analyzed. Our findings support the proposition that sarcoidosis could be an etiologically heterogenous disease. Because these are previously banked samples, direct follow-up in the respective patients is impossible, but these results suggest that sequencing may be a valuable tool in better understanding the etiopathogenesis of sarcoidosis and in diagnosing and treating this disease.

The zinc finger domain of IKKγ (NEMO) protein in health and disease.

Inhibitor of κB kinase (IKK) gamma (IKKγ), also known as nuclear factor κB (NF-κB) essential modulator (NEMO), is a component of the IKK complex that is essential for the activation of the NF-κB pathway. The NF-κB pathway plays a major role in the regulation of the expression of genes that are involved in immune response, inflammation, cell adhesion, cell survival and development. As part of the IKK complex, IKKγ plays a regulatory role by linking the complex to upstream signalling molecules. IKKγ contains two coiled-coil regions, a leucine zipper domain and a highly conserved zinc finger domain. Mutations affecting IKKγ have been associated with X-linked hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID), with the majority of these mutations affecting the C-terminal region of the protein where the zinc finger is located. The zinc finger of IKKγ is needed for NF-κB activation in a cell- and stimulus-specific manner. The major mechanism by which the zinc finger plays this role appears to be the recognition of polyubiquitinated upstream signalling intermediates. This assertion reinforces the current notion that ubiquitination plays a major role in mediating protein-protein interactions in the NF-κB signalling pathway. Because the zinc finger domain of IKKγ is very likely involved in mediating interactions with ubiquitinated proteins, investigations that look for upstream activators or inhibitors of the IKK complex that bind to and interact with the zinc finger of IKKγ are required to gain a better insight into the exact roles of this domain and into the pathogenesis of HED-ID.

Protein-protein interactions involving IKKgamma (NEMO) that promote the activation of NF-kappaB.

Inhibitor of kappaB kinase (IKK) gamma (IKKgamma), also referred to as nuclear factor kappaB (NF-kappaB) essential modulator (NEMO), is an important regulatory component of the IKK complex. The IKK complex is a signalosome that catalyzes the inducible phosphorylation of IkappaB proteins, which is a key step that leads to the activation of NF-kappaB. The exact functions of IKKgamma (NEMO) as part of the IKK complex have not yet been fully elucidated. This mini-review covers 16 proteins that have been reported to bind to IKKgamma and lead to the enhancement of the activities of the IKK complex, thus resulting in NF-kappaB activation. The major mechanisms by which these interactions are mediated involve the recognition of ubiquitinated upstream signaling components by IKKgamma or the modification of IKKgamma itself by ubiquitination. Additional mechanisms include the sumoylation or phosphorylation of IKKgamma and the modification of the tertiary or quaternary structure of IKKgamma.

Proteins that bind to IKKgamma (NEMO) and down-regulate the activation of NF-kappaB.

Inhibitor of kappaB kinase (IKK) gamma (IKKgamma), also referred to as nuclear factor kappaB (NF-kappaB) essential modulator (NEMO), is an important component of the IKK complex. Following the exposure of cells to NF-kappaB-inducing stimuli, the IKK complex catalyzes the phosphorylation of inhibitor of kappaB (IkappaB) proteins, which is a critical step that leads to the activation of NF-kappaB via the canonical pathway. The exact functions of IKKgamma as part of the IKK complex have not been fully elucidated. A number of proteins have been identified as directly interacting with IKKgamma and modulating the activity of the IKK complex. This mini review covers eight proteins that have been reported to bind to IKKgamma and lead to the suppression of the activities of the IKK complex and hence result in the down-regulation of the activation of NF-kappaB. The reported mechanisms by which these interactions suppress the activation of the IKK complex include the deubiquitination of IKKgamma and competition with upstream activators for binding to IKKgamma.

Constitutive secretion of chemokines by cultured human trabecular meshwork cells.

Trabecular meshwork endothelial (TME) cells secrete a number of factors, such as enzymes and cytokines, which modulate the functions of the cells and the extracellular matrix of the conventional aqueous outflow pathway. TME cells usually secrete these factors in response to stimuli such as mechanical stretching, laser irradiation and pro-inflammatory cytokines. Here, we report that cultured human TME cells isolated from two non-glaucomatous individuals secrete significant quantities of the chemotactic cytokines IL8, CXCL6 and MCP1 in the absence of any stimulation. The secretion of these chemokines was augmented by treatment with the pro-inflammatory cytokines TNFalpha and IL1beta. By way of comparison, there was little or very low production of the three chemokines by human non-pigmented ciliary epithelial cells in the absence of stimulation. Our findings provide support to our recent observations that monocytes, presumably under the influence of chemotactic signals, circulate through the trabecular meshwork in the normal state and also that cytokines regulate the permeability of Schlemm's canal endothelial cells. In addition, the fact that normal TME cells constitutively secrete chemotactic cytokines strengthens the notion that cytokines play a key role in the homeostasis of the outflow of the aqueous humor and, possibly, in the pathogenesis of glaucoma.

Dupilumab-Associated Conjunctivitis in Patients With Atopic Dermatitis.

PURPOSE: To report the occurrence of conjunctivitis associated with the use of dupilumab in patients with atopic dermatitis. METHODS: A retrospective small case series. RESULTS: The first case was a 56-year-old man who developed conjunctivitis 2 weeks after starting dupilumab. The second case was a 19-year-old man who developed blepharoconjunctivitis 3 months after staring dupilumab. The ocular inflammation in both cases resolved rapidly and remained controlled with topical steroid drops without necessitating the discontinuation of dupilumab. However, the second patient had already developed conjunctival cicatrization in 1 eye at the time of presentation. CONCLUSIONS: The pathophysiology and the risk factors for the development of conjunctivitis in patients who take dupilumab for atopic dermatitis are not completely understood. However, topical steroid treatment halts the inflammation effectively without discontinuation of dupilumab therapy.

PMA induces expression from the herpes simplex virus thymidine kinase promoter via the activation of JNK and ERK in the presence of adenoviral E1A proteins.

The herpes simplex virus type 1 (HSV-1) thymidine kinase (TK) promoter contains elements involved in both constitutive and induced expression. We determined that phorbol 12-myristate 13-acetate (PMA) induces the HSV-1 TK promoter in HEK293 cells. However, PMA did not induce expression from the promoter in HeLa cells and did not result in a globally increased gene expression in HEK293 cells. Induction of HSV-1 TK promoter required activation of both of JNK and ERK pathways. However, activation of the two pathways alone was not sufficient for induction of HSV-1 TK promoter. By transiently transfecting into HeLa cells the adenoviral E1A gene, which exists as an integrant in HEK293 genome, we demonstrated that E1A proteins are necessary for induction of HSV-1 TK promoter by PMA. We propose mechanisms by which signaling pathways activated by the tumor-promoter PMA cooperate with the oncogene E1A to stimulate a eukaryotic promoter, namely the HSV-1 TK promoter.

Mutations in the zinc finger domain of IKK gamma block the activation of NF-kappa B and the induction of IL-2 in stimulated T lymphocytes.

Mutations in the zinc finger of I kappa B kinase gamma (IKK gamma) are associated with hypohidrotic ectodermal dysplasia-immune deficiency (HED-ID) in which the major immune deficit is the inability to switch Ab heavy chain class. However, the pathophysiologic role of the mutations has not been fully delineated. Since help from activated Th cells is essential in Ab class switching, we sought to examine how these mutations affect T cell activation. Using a human T cell line that was null for IKK gamma, we generated cells stably expressing two of the reported mutations, namely, D406V and C417R. Cells expressing either mutation failed to induce IL-2 following stimulation with PMA/ionomycin while the induction of IL-2 was restored in cells reconstituted with the wild type IKK gamma. The lack of IL-2 upregulation correlated with the lack of NF-kappaB activation as evidenced by the inability to induce I kappa B alpha degradation, NF-kappaB binding to DNA and the expression of a reporter gene. However, both mutations did not prevent the incorporation of IKK gamma into the IKK complex and, interestingly, the induced phosphorylation of I kappa B alpha at S32 and S36 and its subsequent ubiquitination were not affected. The suppression of IL-2 induction was solely due to the inhibition of NF-kappaB activation as the mutations did not impair the activation of AP-1 and NFAT. Our data indicated that the failure of T cells to undergo activation in response to TCR stimuli may play a role in the pathophysiology of HED-ID and also showed that IKK gamma has a role in the post-ubiquitination processing of I kappa B alpha.

Incidence and Clinical Characteristics of Ocular Involvement in Mucous Membrane Pemphigoid.

Purpose: To describe the risk of developing ocular mucous membrane pemphigoid (MMP) or a new extraocular site of MMP, and to identify risk factors for new involvement. Methods: Retrospective chart review of 162 biopsy-proven MMP patients. Results: At presentation, 109 of 162 MMP patients (67.3%) had ocular involvement and 53 patients did not. Of the 53 patients without ocular involvement at presentation followed up to 22 years, the risk of developing ocular MMP was 0.014 per person-year (PY, 95% confidence interval [CI]: 0.005/PY, 0.034/PY). The risk of developing any new location of extraocular MMP was 0.020/PY (95% CI: 0.007/PY, 0.043/PY). Smoking was a risk factor for developing an additional extraocular MMP location (hazard ratio [HR] = 4.09, p = 0.04). Conclusions: Patients presenting with extraocular MMP are at risk for developing ocular MMP, and all MMP patients are at risk for developing secondary extraocular MMP locations, although the rates were low.

Clinical Features and Incidence Rates of Ocular Complications in Patients With Retinal Vasculitis.

PURPOSE: To describe the incidence rates of visual loss and ocular complications in patients with retinal vasculitis (RV). DESIGN: Retrospective cohort study. METHODS: Clinical data were collected for 96 patients (175 eyes) diagnosed with RV from 2003 to 2013. Main outcome measures included rates of visual loss and ocular complications. Comparison of outcomes in patients with a relapsing vs nonrelapsing disease also were analyzed. RESULTS: Over a median follow-up of 44 months (range: 1-153 months), the rate of visual loss to 20/50 or worse was 0.13 per eye-year (/EY, 95% confidence interval [CI], 0.09/EY to 0.18/EY) and to 20/200 or worse was 0.06/EY (95% CI, 0.04/EY to 0.08/EY). The most common complications were cataract (0.31/EY), epiretinal membrane (0.16/EY), and recurrent macular edema (0.09/EY). Patients with a relapsing course (median number of relapses = 1, range: 1-6) appeared to have greater risk for visual loss to 20/50 (odds ratio [OR] = 2.07; 95% CI, 0.88-4.90, P = .09) and 20/200 or worse (OR = 2.49; 95% CI, 0.98-6.30, P = .05). Immunosuppressive drug therapy lowered the risk of visual loss, independent of relapsing disease course (OR = 0.79; 95% CI, 0.66-0.94, P = .01 and OR = 0.73; 95% CI, 0.57-0.93, P = .01 for the 20/50 or worse and 20/200 or worse thresholds, respectively). CONCLUSIONS: Rates of visual loss and complications among patients with RV were similar to reported rates in noninfectious uveitides. Treatment with immunosuppressive drugs lowered the risk of visual loss. A relapsing course suggested an increased risk for visual loss but was not statistically significant, perhaps owing to low numbers of recurrences.