Diagnosis of primary vitreoretinal lymphoma masquerading infectious retinitis by retinal biopsy.

PURPOSE: To report a case of primary vitreoretinal lymphoma masquerading as infectious retinitis that was diagnosed via a retinal biopsy. OBSERVATIONS: A 72-year-old female patient was referred to our ophthalmology clinic for evaluation of retinitis and vasculitis in the right eye (OD). On examination, best-corrected visual acuities (BCVAs) were hand motions OD and 20/20 in the left eye (OS). Fundus examination revealed optic disc edema and diffuse retinal whitening superior to the superotemporal arcade OD. Given the high suspicion of infectious retinitis, the patient was treated with intravitreal foscarnet, systemic acyclovir, and oral prednisone and underwent a comprehensive uveitis workup, which was unremarkable for viral and autoimmune entities. Given the patient's history of diffuse large B cell lymphoma with cutaneous involvement, vitreoretinal lymphoma was suspected, prompting pars plana vitrectomy with a retinal biopsy. Biopsy and immunohistochemistry results were consistent with B-cell lymphoma, and the patient was treated with high-dose methotrexate and rituximab. At 5-month follow-up, BCVAs were hand motions OD and 20/30 OS, and fundus examination demonstrated disc edema with resolution of retinal whitening OD. She responded well to the treatment with regression of vitreoretinal lymphoma on examination and is being monitored closely for lymphoma recurrence. CONCLUSIONS AND IMPORTANCE: Although uncommon, patients with vitreoretinal lymphoma may masquerade as infectious retinitis, and vitreoretinal lymphoma should be suspected when refractory to antiviral therapy and in the setting of a negative workup for viral etiologies. Vitrectomy with retinal biopsy may be considered to aid the diagnosis of vitreoretinal lymphoma although careful consideration of the risks and benefits is warranted.

Indocyanine Green Angiography of Optic Disc Granuloma in Ocular Sarcoidosis.

PURPOSE: To report novel indocyanine green angiography (ICG) findings of optic disc granulomas secondary to sarcoidosis. METHODS: Observational case report. RESULTS: A 36-year-old white male, who had previously been evaluated for birdshot chorioretinopathy and tested HLA-A29 negative, was referred for evaluation of choroidal lesions in both eyes. Fundus examination revealed ovoid choroidal lesions bilaterally in the posterior pole. Optical coherence tomography demonstrated bilateral focal choroidal elevations in the posterior pole and optic discs consistent with granulomas. ICG revealed diffuse choroidal hypocyanescent spots with late-phase focal hypercyanescence of the optic discs in both eyes corresponding to the granulomas. After three months of prednisone and immunomodulatory treatment, the granulomas improved and the optic disc hypercyanescence resolved. CONCLUSION: We describe a case of ocular sarcoidosis mimicking birdshot-like lesions, and ICG findings revealed late hypercyanescence, which resolved with treatment.

Bilateral Exudative Retinal Detachments and Panuveitis in a Patient with Multiple Myeloma.

PURPOSE: To report a case of bilateral exudative retinal detachments and panuveitis in a patient with multiple myeloma (MM). CASE REPORT: A 54-year-old patient with non-proliferative diabetic retinopathy was referred with blurred vision and scotomas in both eyes (OU). Three months prior to the onset of ocular symptoms, he was diagnosed with systemic MM and was receiving chemotherapy. Clinical examination revealed best-corrected visual acuities of 20/80 OU, rare anterior chamber cell, 2+ vitreous cell, diffuse intraretinal hemorrhages, and exudative retinal detachments (RD). Optical coherence tomography of the macula showed central subretinal fluid with cystic intraretinal fluid OU. The findings were consistent with panuveitis and exudative RD in the setting of MM. He reported symptomatic improvement after plasmapheresis and oral prednisone initiation. CONCLUSION: Extensive, bilateral exudative RD and panuveitis are rare but potentially sight-threatening findings in patients with MM.

Posterior Uveitis Associated with Large Vessel Giant Cell Arteritis.

PURPOSE: To report a case of acute unilateral posterior uveitis as a rare manifestation of giant cell arteritis (GCA). OBSERVATION: A 62-year-old male presented to the clinic for evaluation of decreased vision in the right eye (OD). BCVA in OD was 20/60, and fundus examination revealed 3+ vitreous cells along with several inflammatory precipitates located in posterior vitreous and on surface of retina. Although TAB was inconclusive for GCA, the clinical diagnosis of GCA was made according to the GCA diagnostic criteria. This diagnosis was further supported by 18FDG-PET scan. The patient was started on corticosteroids, and the symptoms improved significantly after first week of treatment. At follow-up visit one month and half later, BCVA improved to 20/40 in the right eye. CONCLUSION: Although GCA is rarely present with uveitis, in case of unilateral posterior uveitis in elderly patient, it should be considered in the differential diagnosis.

Evaluating optical coherence tomography (OCT) findings as potential biomarkers in central nervous system (CNS) lymphoma with or without ocular involvement.

BACKGROUND: To evaluate spectral domain optical coherence tomography (SD-OCT) findings as biomarkers in primary central nervous system lymphoma (PCNSL) with or without ocular involvement. METHODS: This study was a cross-sectional study and patients with a confirmed diagnosis of PCNSL with or without ocular involvement were included. Patient cohort finder tool was used to identify patients with lymphoma using ICD-10 codes (C82-C88), from January 2004 to October 2017. A total of 14,820 patients were identified. Procedure code (92134) for optical coherence tomography (OCT) was then applied to identify patients who had underdone OCT imaging at ophthalmology clinic. Clinic charts of 460 patients with lymphoma and available OCT were reviewed to identify patients with confirmed diagnosis of PCNSL and divided into two groups (Group 1: with and Group 2: without ocular involvement). OCT scans of patients in both study groups were analyzed for the presence of (1) Hyperreflective deposits in choroid, retinal pigment epithelium (RPE), outer and inner retina; (2) RPE thickening; (3) Vitreous debris; (4) Intraretinal fluid; (5) Ellipsoid zone disruption by masked graders. Chi-square was used to analyze the difference between the groups. RESULTS: Twenty-two eyes (11 patients) with PCNSL were included this study (Group 1: 6 eyes and Group 2: 16 eyes). Mean age of subjects was 65 years. Five patients (45.45%) were female. There was no statistically significant difference between the groups for the presence of hyperreflective deposits in choroid, RPE, outer and inner retina, and presence of RPE thickening, intraretinal fluid, and ellipsoid zone disruption. Vitreous debris was found more commonly in group 1 subjects (83%) than group 2 (31.25%) (p = 0.029). All subjects in both groups showed hyperreflective deposits in the RPE demonstrating RPE infiltration. However, RPE thickening was noted only in 3 patients (Group1: 1 and Group2: 2). CONCLUSIONS: OCT finding of hyperreflective deposits present in eyes with lymphoma secondary to PCNSL are also observed in eyes with PCNSL without ocular disease. However, the vitreous deposits are more commonly found in eyes with ocular disease. These hyperreflective deposits can serve as biomarkers for early detection of ocular involvement by PCNSL.

Interleukin-6 inhibition in the management of non-infectious uveitis and beyond.

BACKGROUND: Uveitis consists of a spectrum of inflammatory disorders characterized by ocular inflammation. The underlying pathophysiology consists of a complex interplay of various inflammatory pathways. Interleukin 6 is an important mediator of inflammation in uveitis and constitutes focus of research toward development of newer biological therapies in the management of non-infectious uveitis. MAIN BODY: Pan-blockade of the inflammatory pathways with steroids is generally the first step in the management of acute non-infectious uveitis. However, long-term therapy with steroids is associated with systemic and ocular side effects, thereby necessitating the need for development of steroid sparing agents. IL-6 is a cytokine produced by various immune cells, in response to molecular patterns and affects multiple inflammatory cells. In particular, IL-6 is involved in differentiation of CD-4 cells into Th-17 cells that have been shown to play a significant role in various immune-mediated diseases such as uveitis. This broad-spectrum immunomodulatory activity makes IL-6 an excellent target for immunomodulatory therapy. Tocilizumab was the first IL-6 inhibitor to demonstrate efficacy in humans. It inhibits IL-6 from binding to both membrane-bound and soluble receptor and can be administered via intravenous (IV) and subcutaneous (SC) routes. It has been FDA approved for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). Following the approval in systemic diseases, its efficacy was demonstrated in various uveitis studies including a phase 2 clinical trial (STOP-Uveitis). Overall, tocilizumab has shown a good safety profile with the risk of malignancy consistent with that expected in patients with rheumatoid arthritis. However, tocilizumab therapy has been shown to increase the risk for gastrointestinal perforation and dose-dependent neutropenia. Following the success of tocilizumab, several other agents targeting the IL-6 pathway are in the pipeline. These include sirukumab, siltuximab, olokizumab, clazakizumab, and EBI-031 which target IL-6; Sarilumab and ALX-0061 act on the IL-6 receptor. CONCLUSION: Studies have shown that IL-6 inhibitors can be effective in the management of NIU. In addition, the levels of IL-6 are elevated in other ocular vascular diseases such as retinal vein occlusion and diabetic macular edema. The roles of IL-6 inhibition may be broadened in the future to include the management of retinal vascular diseases and non-uveitic macular edema.

New therapies in development for the management of non-infectious uveitis: A review.

Uveitis is a spectrum of inflammatory disorders characterized by ocular inflammation and is one of the leading causes of preventable visual loss. The main aim of the treatment of uveitis is to control the inflammation, prevent recurrences of the disease and preserve vision while minimizing the adverse effects associated with the therapeutic agents. Initial management of uveitis relies heavily on the use of corticosteroids. However, monotherapy with high-dose corticosteroids is associated with side effects and cannot be maintained long term. Therefore, steroid-sparing agents are needed to decrease the burden of steroid therapy. Currently, the therapeutic approach for non-infectious uveitis (NIU) consists of a step-ladder strategy with the first-line option being corticosteroids in various formulations followed by the use of first-, second- and third-line agents in cases with suboptimal steroid response. Unfortunately, the agents currently at our disposal have limitations such as having a narrow therapeutic window along with their own individual potential side-effect profiles. Therefore, research has been targeted to identify newer drugs as well as new uses for older drugs that target specific pathways in the inflammatory response. Such efforts are made in order to provide targeted and safer therapy with reduced side effects and greater efficacy. Several specially designed molecular antibodies are currently in various phases of investigations that can potentially halt the inflammation in patients with NIU. In the review, we have provided a comprehensive overview of the current and upcoming therapeutic options for patients with NIU.

HIV blocks Type I IFN signaling through disruption of STAT1 phosphorylation.

This study investigates the modulation of Type I IFN induction of an antiviral state by HIV. IFNs, including IFN-α, are key innate immune cytokines that activate the JAK/STAT pathway leading to the expression of IFN-stimulated genes. IFN-stimulated gene expression establishes the antiviral state, limiting viral infection in IFN-α-stimulated microenvironments. Our previous studies have shown that HIV proteins disrupt the induction of IFN-α by degradation of IFN-ß promoter stimulator-1, an adaptor protein for the up-regulation and release of IFN-α into the local microenvironment via the retinoic acid-inducible gene 1-like receptor signaling pathway. However, IFN-α is still released from other sources such as plasmacytoid dendritic cells via TLR-dependent recognition of HIV. Here we report that the activation of the JAK/STAT pathway by IFN-α stimulation is disrupted by HIV proteins Vpu and Nef, which both reduce IFN-α induction of STAT1 phosphorylation. Thus, HIV would still be able to avoid antiviral protection induced by IFN-α in the local microenvironment. These findings show that HIV blocks multiple signaling points that would lead to the up-regulation of IFN-stimulated genes, allowing more effective replication in IFN-α-rich environments.

Inhibition of human papilloma virus E2 DNA binding protein by covalently linked polyamides.

Polyamides are a class of heterocyclic small molecules with the potential of controlling gene expression by binding to the minor groove of DNA in a sequence-specific manner. To evaluate the feasibility of this class of compounds as antiviral therapeutics, molecules were designed to essential sequence elements occurring numerous times in the HPV genome. This sequence element is bound by a virus-encoded transcription and replication factor E2, which binds to a 12 bp recognition site as a homodimeric protein. Here, we take advantage of polyamide:DNA and E2:DNA co-crystal structural information and advances in polyamide synthetic chemistry to design tandem hairpin polyamides that are capable of displacing the major groove-binding E2 homodimer from its DNA binding site. The binding of tandem hairpin polyamides and the E2 DNA binding protein to the DNA site is mutually exclusive even though the two ligands occupy opposite faces of the DNA double helix. We show with circular permutation studies that the tandem hairpin polyamide prevents the intrinsic bending of the E2 DNA site important for binding of the protein. Taken together, these results illustrate the feasibility of inhibiting the binding of homodimeric, major groove-binding transcription factors by altering the local DNA geometry using minor groove-binding tandem hairpin polyamides.