Autoimmunity in the pathogenesis and treatment of keratoconjunctivitis sicca.

Dry eye is a chronic corneal disease that impacts the quality of life of many older adults. Keratoconjunctivitis sicca (KCS), a form of aqueous-deficient dry eye, is frequently associated with Sjögren's syndrome and mechanisms of autoimmunity. For KCS and other forms of dry eye, current treatments are limited, with many medications providing only symptomatic relief rather than targeting the pathophysiology of disease. Here, we review proposed mechanisms in the pathogenesis of autoimmune-based KCS: genetic susceptibility and disruptions in antigen recognition, immune response, and immune regulation. By understanding the mechanisms of immune dysfunction through basic science and translational research, potential drug targets can be identified. Finally, we discuss current dry eye therapies as well as promising new treatment options and drug therapy targets.

Suspicious eyes - Elvis's glaucoma battle.

Elvis Presley (1935-1977) is an iconic figure in modern pop culture. Although many of his medical conditions have been the subject of extensive speculation, less is known about his ophthalmological problems, including steroid-induced glaucoma caused by a life-long use of steroids, both prescribed and self-administered, and secondary angle closure glaucoma most likely due to anterior uveitis. Further, he had an episode of acute angle closure glaucoma in 1971 that was treated with a subconjunctival injection of a mydriatic agent or, less likely, a paracentesis combined with an iridotomy. David Meyer, MD, was Presley's main ophthalmologist from 1971 until the latter's death in 1977.

Glaucoma Tube Outcomes with and without Anti-VEGF in Patients with Age-related Macular Degeneration.

PURPOSE: To compare glaucoma tube outcomes of wet age-related macular degeneration (AMD) eyes receiving anti-VEGF injections versus dry AMD eyes and no anti-VEGF. DESIGN: Retrospective clinical cohort study. PARTICIPANTS: Patients with wet AMD and a history of anti-VEGF within a year prior or after stand-alone glaucoma tube surgery and eyes with dry AMD and no history of anti-VEGF with at least 6 months of follow-up. Eyes with neovascular glaucoma or anti-VEGF for reason other than wet AMD were excluded. METHODS: A Kaplan-Meier analysis compared survival for wet versus dry AMD eyes. Failure was defined as intraocular pressure (IOP) > 21 mmHg or < 20% IOP reduction from baseline or IOP ≤ 5 mmHg for 2 consecutive postoperative visits starting at month 3, additional glaucoma surgery, or no light perception. Complete success was defined as no failure or medications at final follow-up. Hypertensive phase was defined for valved tubes as IOP > 21 mmHg within 3 months of surgery after a reduction to < 22 mmHg during the first postoperative week. Intraocular pressure, percent reduction in IOP, number of glaucoma medications, and early (< 1 year) and late (> 1 year) complications were compared through 5 years. MAIN OUTCOME MEASURES: Survival analysis, IOP, number of medications. RESULTS: Baseline IOP, number of medications, or tube type were not significantly different between wet (n = 24) and dry AMD eyes (n = 54). No wet AMD eyes failed versus 10 (18%) dry AMD eyes (P = 0.03). Five-year survival was estimated as 100% for wet AMD and 72% for dry AMD (P = 0.04). Wet AMD eyes had lower IOP (10.6 vs. 12.7 mmHg, P = 0.05), greater IOP reduction (60% vs. 49%, P = 0.04), fewer medications (1.2 vs. 2.1, P = 0.02), and more complete success (50% vs. 15%, P = 0.001) at final follow-up (32 vs. 36 months, P = 0.42). Fewer wet than dry AMD eyes experienced hypertensive phase (0/10 [0%] vs. 4/10 [40%], P = 0.04). There were no significant differences in early or late complications. CONCLUSIONS: Exposure to anti-VEGF may influence postoperative wound healing and capsule formation which may improve glaucoma tube surgical outcomes. Prospective data is needed to consider perioperative administration of anti-VEGF for glaucoma tube surgery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Perineural optic nerve enhancement on magnetic resonance imaging in giant cell arteritis.

Giant cell arteritis (GCA) may cause visually devastating optic neuropathy. In atypical cases, diagnosis of optic neuropathy can be delayed. We present 2 such atypical cases and demonstrate that contrast-enhanced orbital magnetic resonance imaging may be a valuable tool in patient evaluation and aid in the diagnosis of GCA.

Incident glaucoma and ocular hypertension after periocular and intravitreal steroid injections: a claims-based analysis.

BACKGROUND/AIMS: This study aims to determine the incidence and risk of open-angle glaucoma or ocular hypertension (OHT) following ocular steroid injections using healthcare claims data. METHODS: We retrospectively reviewed deidentified insurance claims data from the IBM MarketScan Database to identify 19 156 adult patients with no prior history of glaucoma who received ocular steroid injections between 2011 and 2020. Patient demographics and steroid treatment characteristics were collected. Postinjection glaucoma/OHT development was defined as a new diagnosis of glaucoma/OHT, initiation of glaucoma drops, and/or surgical or laser glaucoma treatment. Cox proportional hazards models were used to determine the risk of glaucoma/OHT development within 5 years after first steroid injection. RESULTS: Overall, 3932 (20.5%) patients were diagnosed with new glaucoma/OHT, 3345 (17.5%) started glaucoma drops and 435 (2.27%) required a laser or surgical glaucoma procedure within 5 years of first steroid injection. Triamcinolone subconjunctival injections were associated with a lower risk of glaucoma/OHT development than retrobulbar or intravitreal steroid injections (p<0.001, HR 0.68, 95% CI 0.59 to 0.79), whereas the 0.59 mg fluocinolone acetonide intravitreal implant had the highest risk of glaucoma/OHT development (p=0.001, HR 2.01, 95% CI 1.34 to 3.02). The risk of glaucoma/OHT development was also higher for patients receiving multiple steroid injections (p<0.001), with the largest increase in risk occurring after three total steroid injections. CONCLUSION: Patients receiving ocular steroid injections are at risk of developing glaucoma/OHT, even with no prior glaucoma/OHT diagnosis or treatment. Patients should be closely monitored for the development of glaucoma following ocular steroid injections, particularly in the setting of intravitreal and/or repeated steroid administration.

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

Netarsudil Improves Trabecular Outflow Facility in Patients with Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 2 Study.

PURPOSE: Intraocular pressure (IOP) reduction is key to controlling primary open angle glaucoma (POAG). Pharmacotherapies for POAG or ocular hypertension (OHT) commonly lower IOP by increasing uveoscleral outflow or decreasing aqueous humor production. Netarsudil (Rhopressa), a Rho kinase inhibitor, reduces IOP by improving trabecular outflow facility, which is reduced in POAG. We investigated the effects of netarsudil on aqueous humor dynamics in patients with POAG or OHT. DESIGN: Double-masked, randomized, vehicle-controlled, Phase 2 trial. METHODS: Netarsudil 0.02% was instilled in 1 eye and vehicle into the contralateral eye of 20 patients once daily in the morning for 7 days. The primary endpoint was change in mean diurnal outflow facility on day 8 versus that on day 1 (baseline). Outflow facility was measured by using Schiøtz tonography, IOP by pneumotonometry, and episcleral venous pressure (EVP) by automated venomanometry. RESULTS: Eighteen patients (90%) completed the study. Mean diurnal outflow facility increased 0.039 versus 0.007 µL/min/mm Hg from baseline in the netarsudil- and the vehicle-treated groups, respectively (P < .001 vs. baseline for netarsudil), a treatment difference of 0.03 µL/min/mm Hg (P ≤ .001). Mean diurnal IOP change from baseline at day 8 was -4.52 mm Hg for netarsudil versus -0.98 mm Hg for vehicle, a treatment difference of -3.54 mm Hg (P < .0001). Mean diurnal EVP change from baseline was -0.79 mm Hg in the netarsudil-treated group versus 0.10 mm Hg for vehicle, a treatment difference of -0.89 mm Hg (P < .001). All patients reporting an adverse event reported conjunctival hyperemia of mild or moderate severity. CONCLUSIONS: Netarsudil acts on the conventional outflow pathway, both proximal and distal, to significantly reduce IOP in POAG and OHT by improving trabecular outflow facility and decreasing EVP.

Recurrent Tube Erosions with Anti-Vascular Endothelial Growth Factor Therapy in Patients with Age-Related Macular Degeneration.

PURPOSE: To determine the rates of primary and recurrent glaucoma tube shunt erosions in patients with age-related macular degeneration (AMD) receiving anti-vascular endothelial growth factor (VEGF) intravitreal injections. DESIGN: Retrospective case series. PARTICIPANTS: Patients with AMD who underwent tube revision for erosion at the Duke Eye Center from January 1, 1999, to January 1, 2019, were identified. Patients with and without anti-VEGF injections were compared. METHODS: Patient demographics, ocular diagnoses, glaucoma tube shunt types and locations, and dates of glaucoma surgeries and anti-VEGF injections were collected. Statistical analyses were performed with P < 0.05 as significant. MAIN OUTCOME MEASURES: Outcome measures included the number of tube erosions, time from anti-VEGF injection to tube erosion, and secondary complications after tube revisions. RESULTS: A total of 150 patients with AMD with anti-VEGF (309 tubes) and 262 patients with AMD without anti-VEGF (459 tubes) were identified. There was no statistically significant difference in the number of tube erosions in patients with anti-VEGF (15 tubes, 4.8%) versus without anti-VEGF (12 tubes, 2.6%) (P = 0.10). However, patients receiving anti-VEGF had on average a greater number of tube erosion events (2.1±0.7 events) compared with patients without anti-VEGF (1.3±0.7, P < 0.01). Ten patients (91%) received concurrent anti-VEGF injections at the time of tube erosion, and the average duration of prior anti-VEGF therapy was approximately 2 years. Tube erosion was noted 46.5±60.7 days from the preceding anti-VEGF injection. Secondary complications after tube revision in the anti-VEGF group included 5 explanted tubes for recurrent erosions. CONCLUSIONS: Our results suggest intravitreal anti-VEGF injections are linked to higher rates of recurrent glaucoma tube erosions in patients with AMD. The majority of patients received chronic and serial anti-VEGF injections. Thus, additional consideration should be given to glaucoma surgical planning in patients receiving anti-VEGF injections, especially in those with a primary tube erosion.

Reticular Bullous Epithelial Edema in Corneas Treated with Netarsudil: A Case Series.

PURPOSE: To describe the patient characteristics and the clinical course of an unusual reticular pattern of bullous epithelial corneal edema in a series of patients treated with netarsudil. DESIGN: Retrospective case series. METHODS: Case series at a single academic center where treatment with netarsudil produced a particular pattern of bullous epithelial corneal edema. RESULTS: Six episodes of reticular bullous epithelial corneal edema were identified in 5 eyes of 5 patients treated with netarsudil. A total of 4 of 5 patients had a history of corneal edema in the affected eye, and the fifth patient had risk factors for corneal edema including a history of anterior uveitis and an anterior chamber glaucoma drainage device. In 4 of 6 episodes, corneal edema was present, typically in the corneal stroma at the time of netarsudil initiation. In 5 of 6 cases, visual acuity worsened with onset of bullous epithelial edema, and in all cases, visual acuity stabilized or improved following discontinuation of netarsudil. In all cases, the reticular bullous epithelial edema improved or resolved after discontinuation of netarsudil. CONCLUSIONS: The patient characteristics and natural history of a particular pattern of reticular bullous epithelial edema in a series of patients treated with netarsudil once daily is reported. Most patients had a history of corneal edema or predisposing risk factors for corneal edema. All patients demonstrated improvement in bullous epithelial edema after netarsudil discontinuation. Visual acuity improved in most patients within weeks after discontinuation of netarsudil, although 2 patients also underwent surgical interventions that might have contributed to improved visual acuity.

Current concepts of cerebrospinal fluid dynamics and the translaminar cribrosa pressure gradient: a paradigm of optic disk disease.

Modern advances in measuring and studying cerebrospinal fluid dynamics have furthered our understanding of intracranial pressure and its pathophysiological effects on the eye. In particular, the cerebrospinal fluid pressure and composition within the optic nerve subarachnoid space are key factors in diseases of the optic disk. Intracranial pressure and intraocular pressure establish a pressure gradient across the lamina cribrosa. Alterations in this translaminar cribrosa pressure difference induce structural deformations in the lamina cribrosa manifested clinically by the appearance of optic disk edema or optic disk cupping. Much has been learned about papilledema (i.e., optic disk edema due to elevated intracranial pressure) from clinical observations and studies on patients with idiopathic intracranial hypertension. Furthermore, optic nerve subarachnoid space hydrodynamics and translaminar cribrosa pressure difference are postulated to contribute to the pathogenesis of optic disk edema observed in spaceflight-associated neuroocular syndrome. Recently, a substantial body of literature has accumulated suggesting low intracranial pressure may be a risk factor for the development of glaucomatous optic disk cupping within the context of the translaminar cribrosa pressure difference and posterior scleral biomechanics.

Presentation and Progression of Papilledema in Cerebral Venous Sinus Thrombosis.

PURPOSE: To determine the natural history and visual outcomes of papilledema in cerebral venous sinus thrombosis (CVST). DESIGN: Retrospective observational case series. METHODS: This multicenter study included 7 tertiary care neuro-ophthalmology clinics. Sixty-five patients with CVST were identified who received serial eye examinations with documented papilledema from 2008-2016. Outcome measures included time from diagnosis to papilledema documentation, papilledema progression, time to papilledema resolution, treatment interventions and final visual outcomes. RESULTS: Papilledema was present on initial presentation in 54% of patients or detected later during the course of the disease in 46% of patients. The average time from CVST diagnosis to papilledema documentation was 29 days with a mean (SD) initial Frisén grade of 2.7 (1.3). In 21.5% of cases, papilledema progressed over an average of 55.6 (56.6) days. Time to papilledema resolution was approximately 6 months. Final visual acuity ranged from 20/20 to light perception, with 40% of patients having residual visual field defects on standard automated perimetry. Frisén grade ≥3 (odds ratio [OR] 10.21, P < .0053) and cases with worsening papilledema (3.5, P < .043) were associated with permanent visual field deficits. CONCLUSIONS: Our study indicates the importance of serial ophthalmic evaluation in all cases of CVST. Follow-up fundoscopy is critical given that a subset of cases can show delayed onset and/or worsening of papilledema with time. Specifically, we recommend an ophthalmic examination at the time of initial diagnosis, with repeat examination within a few weeks and further follow-up depending on the level of papilledema or vision changes.

Ocular involvement in neurolymphomatosis.

PURPOSE: To describe the ophthalmic symptoms and histopathological findings in a case of primary neurolymphomatosis (NL). OBSERVATIONS: A man in his 60s with a prior diagnosis of chronic inflammatory demyelinating polyneuropathy developed facial numbness, diplopia, drooling, and difficulty swallowing. Over a 3-month period, he developed total ptosis and ophthalmoplegia of the right eye with a dilated, non-reactive pupil considered secondary to cranial nerve III and VI palsies. His left pupil subsequently became non-reactive to light and accommodation, and extraocular motility of the left eye was partially limited in all directions of gaze without ptosis. Autopsy findings included primary NL, diffuse large B-cell lymphoma of activated B-cell subtype, involving right and left cranial nerves V, VI, IX, and X; spinal nerve roots; both femoral nerves; and extrascleral, intrascleral, and intraocular short and long posterior ciliary nerves with extension into the adjacent choroid of both eyes. No evidence of lymphoma was identified elsewhere in the body. CONCLUSIONS AND IMPORTANCE: Our patient is only the second histological demonstration of ciliary nerve involvement by NL, and the first, to our knowledge, of primary NL spreading secondarily from the ciliary nerves into the choroid. Our patient demonstrates that NL, though rare, should be included in the differential diagnosis of ocular cranial nerve palsies and ophthalmoplegia.

Pediatric conjunctival melanoma arising from a compound nevus.

We present a rare case of conjunctival melanoma in a 9-year-old girl who presented with a conjunctival lesion of the left eye, growth of which was documented by patient photographs. Examination showed a raised pigmented lesion at the temporal limbus, with fine surrounding vessels. Enhanced depth imaging-optical coherence tomography showed no invasion into the sclera. The patient underwent excisional biopsy, and histopathology revealed conjunctival melanoma arising from a nevus with malignant cells that stained positively with markers HMB-45 and Ki-67. Systemic workup was negative for metastatic disease. Conjunctival nevi are the most common melanocytic conjunctival lesions in children and generally demonstrate physiologic growth during adolescence. Thus, there may be a greater risk of misdiagnosis of conjunctival melanoma in a child.

Venous Loop Reveals an Occult Retinoblastoma Tumor.

A 14-day-old girl presented with bilateral hereditary retinoblastoma. At 3 months, a slight bend in the superotemporal arcade was observed to have developed into a venous loop. With concern for an occult lesion along the arcade, handheld optical coherence tomography (hhOCT) confirmed a small tumor and helped to guide prompt laser treatment while sparing the venous arcade. A venous loop is a previously unrecognized clinical finding that preceded the clinical detection and hhOCT confirmation of the tumor. The authors hypothesize that the venous loop was induced by pro-angiogenic factors secreted by the tumor. Portable hhOCT is a valuable adjunct imaging modality in the diagnosis and management of small retinoblastoma tumors. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:768-770.].

VEGF as a Paracrine Regulator of Conventional Outflow Facility.

Purpose: Vascular endothelial growth factor (VEGF) regulates microvascular endothelial permeability, and the permeability of Schlemm's canal (SC) endothelium influences conventional aqueous humor outflow. We hypothesize that VEGF signaling regulates outflow facility. Methods: We measured outflow facility (C) in enucleated mouse eyes perfused with VEGF-A164a, VEGF-A165b, VEGF-D, or inhibitors to VEGF receptor 2 (VEGFR-2). We monitored VEGF-A secretion from human trabecular meshwork (TM) cells by ELISA after 24 hours of static culture or cyclic stretch. We used immunofluorescence microscopy to localize VEGF-A protein within the TM of mice. Results: VEGF-A164a increased C in enucleated mouse eyes. Cyclic stretch increased VEGF-A secretion by human TM cells, which corresponded to VEGF-A localization in the TM of mice. Blockade of VEGFR-2 decreased C, using either of the inhibitors SU5416 or Ki8751 or the inactive splice variant VEGF-A165b. VEGF-D increased C, which could be blocked by Ki8751. Conclusions: VEGF is a paracrine regulator of conventional outflow facility that is secreted by TM cells in response to mechanical stress. VEGF affects facility via VEGFR-2 likely at the level of SC endothelium. Disruption of VEGF signaling in the TM may explain why anti-VEGF therapy is associated with decreased outflow facility and sustained ocular hypertension.

Intravitreal Anti-VEGF Injections Reduce Aqueous Outflow Facility in Patients With Neovascular Age-Related Macular Degeneration.

Purpose: We assess the effect of intravitreal anti-VEGF injections on tonographic outflow facility. Methods: Patients with age-related macular degeneration who had received unilateral intravitreal anti-VEGF injections were recruited into two groups, those with ≤10 and those with ≥20 total anti-VEGF injections. Intraocular pressure and tonographic outflow facility of injected and uninjected fellow eyes were measured and compared between groups. Risk factors for development of reduced outflow facility also were assessed. Results: Outflow facility was 12% lower in the injected eyes of patients who received ≥20 anti-VEGF injections, compared to contralateral uninjected eyes (P = 0.02). In contrast, there was no facility reduction for patients with ≤10 anti-VEGF injections (P = 0.4). In patients with ocular hypertension in the uninjected eye (IOP > 21 mm Hg, n = 5), the outflow facility of injected eyes was on average 46% lower (P = 0.01) than in the uninjected fellow eyes. This was significantly greater than the difference observed in patients with IOP ≤ 21 mm Hg in the uninjected eye (P = 2 × 10-4). In patients with ocular hypertension in the injected eye (n = 6) the differences in facility and IOP between contralateral eyes were significantly greater than in patients with IOP ≤ 21 mm Hg in the injected eye (P = 2 × 10-4 and P = 7 × 10-4, respectively). Conclusions: Chronic anti-VEGF injections significantly reduce outflow facility in patients with AMD. The greatest facility reduction is observed in patients with baseline ocular hypertension. Ophthalmologists who administer anti-VEGF injections should be aware of these findings and monitor patients closely for changes in IOP or evidence of glaucoma, especially in those with pre-existing ocular hypertension.