Ocular Pathophysiology of Sjögren's Syndrome.

The purpose of this review is to delve into the clinical and research understanding of the pathophysiology and presentation of Sjögren's-related keratoconjunctivitis sicca in order address the diagnostic and management challenge that it represents, as well as to provide a basis for appreciating the pharmacotherapies designed to treat the ophthalmic symptoms of Sjögren's disease.

The use of self-retained, cryopreserved amniotic membrane for the treatment of Sjögren syndrome: a case series.

PURPOSE: To determine whether signs and symptoms of ocular surface disease improve after placement of a self-retained, cryopreserved amniotic membrane (CAM) in patients with Sjögren syndrome (SS). METHODS: The medical records of SS patients who received a self-retained CAM implant (Prokera or Prokera Slim; TissueTech Inc, Doral, FL) for the treatment of ocular surface disease between August 2012 and August 2016 at a single, large academic institution were reviewed retrospectively. Visual acuity, results of slit-lamp examination of the cornea and conjunctiva, and dry eye symptoms, were evaluated before and after CAM insertion. RESULTS: A total of 6 eyes of 6 patients (all female; mean age, 62.5 ± 13.0 years [range, 49-86 years]) were included. All patients were on topical medications at the time of the study and had signs of ocular surface dryness. There were reductions in corneal and/or conjunctival staining in 5 eyes (83%) after the CAM dissolved. All patients who completed therapy (5/5) experienced a relapse in their signs and symptoms within 1 month of removal of the CAM, with an average time to relapse of 24.6 days. Mean follow-up time was 54.5 days. Foreign body sensation and blurred vision were the most common complaints associated with the CAM implant. CONCLUSIONS: In this small case series, self-retained CAM implantation was found to be beneficial in SS patients with ocular surface disease that is refractory to standard therapies; however, we found that the effects were temporary. Future larger studies are needed to confirm these benefits.

A new scale for the assessment of conjunctival bulbar redness.

PURPOSE: Current scales for assessment of bulbar conjunctival redness have limitations for evaluating digital images. We developed a scale suited for evaluating digital images and compared it to the Validated Bulbar Redness (VBR) scale. METHODS: From a digital image database of 4889 color corrected bulbar conjunctival images, we identified 20 images with varied degrees of redness. These images, ten each of nasal and temporal views, constitute the Digital Bulbar Redness (DBR) scale. The chromaticity of these images was assessed with an established image processing algorithm. Using 100 unique, randomly selected images from the database, three trained, non-physician graders applied the DBR scale and printed VBR scale. Agreement was assessed with weighted Kappa statistics (Kw). RESULTS: The DBR scale scores provide linear increments of 10 from 10-100 when redness is measured objectively with an established image processing algorithm. Exact agreement of all graders was 38% and agreement with no more than a difference of ten units between graders was 91%. Kw for agreement between any two graders ranged from 0.57 to 0.73 for the DBR scale and from 0.38 to 0.66 for the VBR scale. The DBR scale allowed direct comparison of digital to digital images, could be used in dim lighting, had both temporal and nasal conjunctival reference images, and permitted viewing reference and test images at the same magnification. CONCLUSION: The novel DBR scale, with its objective linear chromatic steps, demonstrated improved reproducibility, fewer visualization artifacts and improved ease of use over the VBR scale for assessing conjunctival redness.

Effect of sex steroid hormone fluctuations in the pathophysiology of male-retinal pigment epithelial cells.

Gender-based differences may influence the occurrence of several ocular conditions suggesting the possibility that fluctuations in sex steroid homeostasis may have direct effects on the eye physiology. Here, we evaluated the effect of sex steroid hormone fluctuations in male retinal pigment epithelial cells, RPEs (ARPE-19). To mimic hormonal fluctuations occurring during aging, we exposed ARPE-19 to acute, prolonged or chronic estradiol, and progesterone challenges. We found that chronic estradiol treatment promotes a remarkable necrosis of RPE cells, and does not affect pRb2/p130 or PAI-2 sub-cellular localization. In contrast, chronic progesterone exposure induces nuclear subcellular rearrangement of pRb2/p130, co-immunolocalization of pRb2/p130 with PAI-2, and accumulation of cells in G2/M phase, which is accompanied by a remarkable reduction of necrosis in favour of apoptosis activation. This study has a high clinical significance since it considers sex steroid fluctuations as inducers of milieu change in the retina able to influence pathological situations occurring with aging in non-reproductive systems such as the eye. Exogenous administration of physiologically significant amounts of sex hormones for long periods of time is a common clinical practice for transgender patients seeking sex reassignment. In particular, our study offers the unique opportunity to unravel the effects of sex hormones, not only in determining gender differences but also in affecting the physiology of non-reproductive systems, such as the eye, in the underserved transgender community.

Survey of Ophthalmologists Regarding Practice Patterns for Dry Eye and Sjogren Syndrome.

OBJECTIVE: To survey ophthalmologists about current practice patterns regarding the evaluation of dry eye patients and referrals for a Sjogren syndrome (SS) workup. METHODS: An online survey was sent to ophthalmologists affiliated with the Scheie Eye Institute or Wills Eye Hospital using REDCap in August 2015. Descriptive statistics were used to summarize the data. RESULTS: Four hundred seventy-four survey invitations were sent out and 101 (21%) ophthalmologists completed the survey. The common traditional dry eye test performed was corneal fluorescein staining (62%) and the most common newer dry eye test performed was tear osmolarity (18%). Half of respondents (51%) refer fewer than 5% of their dry eye patients for SS workups, with 18% reporting that they never refer any patients. The most common reasons for referrals included positive review of systems (60%), severe dry eye symptoms (51%) or ocular signs (47%), or dry eye that is refractory to treatment (42%). The majority (83%) felt that there is a need for an evidence-based standardized screening tool for dry eye patients to decide who should be referred for evaluation for SS. CONCLUSIONS: Ophthalmologists continue to prefer the use of traditional dry eye tests in practice, with the most common test being corneal fluorescein staining. There is an underreferral of dry eye patients for SS workups, which is contributing to the continued underdiagnosis of the disease. Most respondents felt that there was a need for an evidence-based standardized screening tool to decide which dry eye patients should be referred for SS evaluations.

Tolerability of Topical Tocilizumab Eyedrops in Dogs: A Pilot Study.

PURPOSE: The aim of this study was to examine the tolerability of topical tocilizumab eyedrops in normal dogs and to assess whether this preparation alters tear film cytokine levels or conjunctival cytokine mRNA expression. METHODS: Two percent tocilizumab eyedrops were administered to the right eyes and artificial tears to the left eyes of 10 dogs with no anterior segment pathology 3 times daily for 4 weeks. Portable slit-lamp examinations and Schirmer tear testing were performed at baseline and day 1 week 4, as well as 2 weeks after treatment (week 6). Schirmer strips were also used to collect tears for analyses of cytokine levels using multiplex bead array. Median levels of 8 cytokines in the tear film [interferon gamma (IFN-γ), tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1ß, IL-2, IL-6, IL-8, and IL-10] were compared among tocilizumab-treated and control eyes. Conjunctival biopsies from both eyes were collected at week 4, and mRNA levels of cytokines were also evaluated. Blood samples were collected at baseline and at the end of treatment to monitor for changes in complete blood count, basic metabolic panel, or liver function tests. RESULTS: At week 4, conjunctival biopsies and tear samples showed no significant differences in either tear cytokine or mRNA levels for IFN-γ, TNF-α, IL-2, IL-6, IL-8, and IL-10. There was no evidence of local irritation or changes in bloodwork results from the topical tocilizumab formulation. CONCLUSIONS: Topical application of tocilizumab eyedrops was well tolerated when used on healthy dog eyes in this pilot study.

Clinical presentation and management of congenital ptosis.

Congenital ptosis is a rare condition characterized by lower positioning of the upper eyelid that is present at birth and is a clinical condition that is persistent if not treated. It may be unilateral or bilateral and may be associated with other ocular disorders or systemic conditions, including Marcus Gunn, Horner, and Duane syndromes. It is a benign condition but causes functional, cosmetic, and psychological problems in children. However, not all patients need to undergo surgery, and usually only patients at risk of amblyopia need a prompt surgical correction, while in other cases, surgery can be postponed. The grade of ptosis, the eyelid function, and the amblyopic risk are the parameters that affect the ophthalmologist's decision on timing of surgery and the surgical technique to be used. In fact, there are several types of surgical techniques to correct a congenital ptosis, although very often more than one is needed to obtain an acceptable result. This paper reviews the causes of congenital ptosis and associated diseases. Particular emphasis is given to surgical management and different procedures available to correct the upper eyelid anomaly and avoid permanent damage to visual function.

Effects of Sex Hormones on Ocular Surface Epithelia: Lessons Learned From Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality in women of reproductive age. Although its clinical consequences have been known for a long time to extend beyond the reproductive system, with type-2 diabetes and obesity being the most common, the involvement of the ocular surface in PCOS has been described only more recently. The ocular surface is a morphofunctional unit comprising eyelid margin, tear film, cornea, and conjunctiva. Increasing evidence indicates that these structures are under a sex hormone control and relevant diseases such as ocular allergy and dry eye are often caused by alterations in circulating or local steroid hormones levels. Novel treatments targeting sex hormone receptors on ocular surface epithelial cells are also being developed. In this review we aim to describe the current knowledge on the effects of sex hormones at the ocular surface, with a special focus on the effects of androgen imbalance in PCOS.

Pathophysiology of Corneal Dystrophies: From Cellular Genetic Alteration to Clinical Findings.

Corneal dystrophies are a heterogeneous group of bilateral, inherited, rare diseases characterized by slowly progressive corneal opacities, that lead to visual impairment. Most of them have an autosomal dominant pattern of inheritance with variable expressivity, but new mutations have been described. Many corneal dystrophies have been genetically characterized and the specific gene mutations identified, such as for the epithelial-stromal TGFBI dystrophies. Current classification systems identified four main groups of corneal dystrophies based on clinical, histologic, and genetic information. Diagnosis is performed during a routine ophthalmic examination that shows typical cellular abnormalities of the corneal epithelium, stroma, or endothelium. Disease progression should be carefully monitored to decide the proper clinical management. The treatment of corneal dystrophies is variable, depending on symptoms, clinical course, severity, and type of dystrophy. Management aimed to reduce symptoms and to improve vision, includes different surgical approaches. Novel cellular and genetic therapeutic approaches are under evaluation. J. Cell. Physiol. 231: 261-269, 2016. © 2015 Wiley Periodicals, Inc.

Diagnosis and Management of Iridocorneal Endothelial Syndrome.

The iridocorneal endothelial (ICE) syndrome is a rare ocular disorder that includes a group of conditions characterized by structural and proliferative abnormalities of the corneal endothelium, the anterior chamber angle, and the iris. Common clinical features include corneal edema, secondary glaucoma, iris atrophy, and pupillary anomalies, ranging from distortion to polycoria. The main subtypes of this syndrome are the progressive iris atrophy, the Cogan-Reese syndrome, and the Chandler syndrome. ICE syndrome is usually diagnosed in women in the adult age. Clinical history and complete eye examination including tonometry and gonioscopy are necessary to reach a diagnosis. Imaging techniques, such as in vivo confocal microscopy and ultrasound biomicroscopy, are used to confirm the diagnosis by revealing the presence of "ICE-cells" on the corneal endothelium and the structural changes of the anterior chamber angle. An early diagnosis is helpful to better manage the most challenging complications such as secondary glaucoma and corneal edema. Treatment of ICE-related glaucoma often requires glaucoma filtering surgery with antifibrotic agents and the use of glaucoma drainage implants should be considered early in the management of these patients. Visual impairment and pain associated with corneal edema can be successfully managed with endothelial keratoplasty.

Variability of Tear Osmolarity in Patients With Dry Eye.

IMPORTANCE: Knowledge about the variability of measurements using the TearLab Osmolarity System is necessary when evaluating the clinical utility of readings. OBJECTIVE: To examine the variability of tear osmolarity measured by the TearLab Osmolarity System in patients with Sjögren syndrome (SS), patients with blepharitis, and control participants. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at a tertiary care academic center from June 13, 2012, to March 21, 2013. Participants included 74 eyes of 37 patients from a volunteer sample (18 patients with SS, 11 patients with blepharitis, and 8 control participants) who were evaluated using the TearLab Osmolarity System, with 3 consecutive osmolarity measurements taken at 1-minute intervals in a session; 15 of these patients had the same measurements taken by the same examiner in 2 additional sessions on the same day (9 AM-10 AM, 12 PM-1 PM, or 3 PM-4 PM). Most patients with SS and patients with blepharitis were taking systemic or topical dry eye medications at the time of enrollment. MAIN OUTCOMES AND MEASURES: Mean osmolarity and its variability calculated from a linear mixed model for each disease group that accounts for the variations attributable to different patients, eyes, and sessions and measurement error specific to each disease group. RESULTS: Mean tear osmolarity was 307 mOsm/L, 304 mOsm/L, and 301 mOsm/L in the SS, blepharitis, and control groups, respectively (P = .46). The error associated with repeated measurements within a session in the patients without dry eye (10.5 mOsm/L [95% CI, 9.0-12.4]) was significantly lower than in the patients with blepharitis (14.6 mOsm/L [95% CI, 12.5-17.5]; P = .006) and patients with SS (15.8 mOsm/L [95% CI, 14.2-17.8]; P < .001) but a difference in the error of repeated measurements between patients with blepharitis and patients with SS was not identified (P = .46). CONCLUSIONS AND RELEVANCE: There was increased variability attributable to error in repeated measurements in patients with SS and patients with blepharitis compared with control participants. The high variability of TearLab osmolarity readings in all groups makes the clinical interpretation of measurements unclear.

Nerve growth factor modulation of retinal ganglion cell physiology.

Nerve growth factor (NGF) is an endogenous neurotrophin involved in the development, maintenance and regeneration of mammalian sympathetic and sensory neurons. Additionally, NGF is known to have trophic and differentiating activity on several populations of cholinergic neurons of the central nervous system (CNS), and to act as a differentiation factor in the development of the visual cortex. The paramount functions of NGF in the visual system are also highlighted by the presence of this neurotrophin and both its receptors TrkA and p75 in most intra-ocular tissues, including lens, vitreous, choroid, iris, and trabecular meshwork. In the retina, NGF is produced and utilized specifically by retinal ganglion cells (RGC), bipolar neurons and glial cells, and is thought to have crucial protective effects in several disease states. Studies on the role of NGF on RGCs survival following optic nerve transection, ischemic injury, ocular hypertension and glaucoma are discussed in this review.

NGF and VEGF effects on retinal ganglion cell fate: new evidence from an animal model of diabetes.

PURPOSE: To investigate if the survival effects of nerve growth factor (NGF) eyedrops on retinal ganglion cell (RGCs) are related to vascular endothelial growth factor (VEGF) in a rat model of diabetic retinopathy. METHODS: Diabetes was induced in adult rats by streptozotocin injection and changes in the NGF/TrkA and VEGF retina levels were related to the progression of RGC loss. Diabetic rats were subjected to administration of NGF eyedrops or intraocular injection of anti-NGF antibody. All morphologic, immunohistochemical, and biochemical analyses were performed on whole retinas dissected after 7 or 11 weeks after diabetes induction. RESULTS: Diabetes was successfully induced in rats as shown by glycemic levels >250 mg/dL. The NGF levels increased in diabetic retinas at 7 weeks and decreased at 11 weeks, while VEGF levels increased at all time points. The RGC loss in diabetic retinopathy worsened with anti-NGF administration, which did not alter retina VEGF levels significantly. Administration of NGF eyedrops restored TrkA levels in the retina, and protected RGCs from degeneration without influencing VEGF levels. CONCLUSIONS: The early increase of NGF in diabetic retina might be an endogenous response for protecting RGCs from degeneration. This protective mechanism is impaired at 11 weeks following diabetes induction, and results in a marked RGC degeneration that is improved by exogenous NGF administration and worsened by anti-NGF. The observed NGF-induced neuroprotection on damaged RGCs was not associated with changes in VEGF retina levels, which were constantly high in diabetic rats and were not altered by anti-NGF administration.

The cellular mechanisms of dry eye: from pathogenesis to treatment.

Dry eye is a complex disease characterized by changes in the ocular surface epithelia related to reduced quality and/or quantity of tears, inflammatory reaction, and impairment of ocular surface sensitivity. It has recently been proposed that increased tear osmolarity represents a main trigger to the altered cellular mechanisms leading to epithelial damage in dry eye. However, dry eye pathogenesis is multifactorial, with cytotoxic inflammatory mediators, altered lacrimal gland secretion and nerve function, squamous metaplasia of the conjunctival epithelium and decrease of goblet cells density, all playing a role in a detrimental loop that perpetuates and worsens damage to the corneal and conjunctival epithelia. Current topical treatments for dry eye patients include the use of lubricants and anti-inflammatory drugs. However, lubricants only improve symptoms temporarily, and chronic use of topical steroids is associated to severe ocular side effects such as cataract and glaucoma. The deeper understanding of the cellular mechanisms that are altered in dry eye is opening novel perspectives for patients and physicians, who are seeking treatments capable not only of improving symptoms but also of restoring the homeostasis of the ocular surface. In this review, we will focus on novel anti-inflammatory agents and on nerve growth factor, a neurotrophin that is altered in dry eye and has been suggested as a main player in the neuroimmune cross-talk of the ocular surface as well as in the stimulation of corneal sensitivity, epithelial proliferation and differentiation, and stimulation of mucin production by goblet cells. J. Cell. Physiol. 228: 2253-2256, 2013. © 2013 Wiley Periodicals, Inc.