Extraglandular ocular involvement and morbidity and mortality in primary Sjögren's Syndrome.

PURPOSE: To report the significance of extraglandular ocular involvement and long-term systemic morbidity and mortality in primary Sjögren's Syndrome (SS). METHODS: This retrospective, longitudinal cohort study included consecutive patients with primary SS evaluated at a tertiary referral center. An electronic chart review was performed and all available data were extracted from clinic visits between October 1999 and March 2019. The primary outcome measures included occurrence of extraglandular ocular manifestations of SS, serological markers, prevalence of malignancy, and incidence of death. RESULTS: One hundred and twenty-six SS patients with minimum 3 years of follow-up (median 9.6, range 3.0-15.9 years, total of 1,235 patient-years) were included. Of those, 10 patients with inflammatory keratolysis or scleritis had 2.3 times greater likelihood of death compared to the rest of the cohort (OR = 2.3, 95% confidence interval [CI] 0.5 to 4.0, p = 0.01) due to SS related complications. The lifetime prevalence of any malignancy in the entire cohort was 15.5%. The most common hematologic malignancy was non-Hodgkin's lymphoma (4.8%) and the most common solid malignancy was breast cancer (6.0%). Men SS patients were more likely to have a history of or concurrent malignancy compared to women (30.0% versus 13.7%, p = 0.16) and double the mortality (OR = 2.1, 95% CI 0.09 to 1.4, p = 0.04), independent of malignancy. CONCLUSIONS: SS patients with serious ocular manifestations, particularly men, may be at greater risk for mortality due to SS complications. The eye seems to be the barometer of systemic disease activity.

Frequent Dosing of Topical Cyclosporine A for Severe Ocular Surface Disease.

PURPOSE: To study the systemic safety and patient tolerability of frequent dosing of cyclosporine A (CsA) 0.05% eyedrops in the treatment of ocular surface disease. This is a retrospective case series. Patients with significant ocular surface diseases who were treated using topical CsA higher than the usual twice daily dosing (3-8 times daily and over a treatment period of 1-70 months). The main outcome measures are plasma levels of CsA and local tolerability. METHODS: Symptom assessment, corneal staining using fluorescein, conjunctival staining using lissamine green, tear film breakup time, and other signs according to the disease process were monitored. Discontinuation of treatment due to intolerability was recorded. CsA levels were measured in the plasma at a clinical laboratory. RESULTS: Plasma levels of CsA were below the level of detection (7 ng/mL) in all the 41 patients included. All patients tolerated the treatment well with none discontinuing due to any treatment-related local adverse effects. CONCLUSIONS: This study demonstrates that CsA 0.05% ophthalmic emulsion applied more frequently than the usual twice daily dosing was safe and well tolerated in patients with significant ocular surface diseases.

PROSE Treatment for Ocular Chronic Graft-Versus-Host Disease as a Clinical Network Expands.

BACKGROUND: Keratoconjunctivitis sicca occurs in 40% to 90% of patients with ocular chronic graft-versus-host disease (cGVHD). Ocular symptoms can have profound effects in both the visual function and quality of life of patients with GVHD. We report the impact of prosthetic replacement of the ocular surface ecosystem (PROSE) treatment in patients with cGVHD as a clinical network expands. METHODS: We queried the BostonSight PROSE manufacturing database from January 2002 to December 2011. Patients treated for ocular cGVHD were reported by age, gender, year, and network site where the treatment was undertaken. The baseline and six-month follow-up scores of visual function using a standardized validated instrument, the National Eye Institute Visual Function Questionnaire (NEI VFQ-25), were evaluated for a period in 2006 and again in 2010 after network expansion had occurred. RESULTS: A total of 407 patients with a male:female ratio of 226:181, mean age was 51 years with ocular cGVHD underwent PROSE treatment from January 2002 to December 2011. By 2011, 67% of all cases were treated at network clinics. Baseline characteristics of patients treated throughout the network in 2010 were similar to that of 2006 and 2010 cohorts from the main center. There was a significant improvement of 41 points (P<0.001) in composite NEI VFQ score among patients treated across the network in 2010, similar to the improvement of 30 points (P<0.001) seen among the patients treated at the main center in 2010. There was a trend toward lower baseline self-reported general health status (SRGHS) and VFQ scores among patients treated at network clinics, suggesting that expansion of the network allows treatment of sicker patients (lower general health status) or those more severely affected by ocular cGVHD. CONCLUSIONS: PROSE treatment of ocular cGVHD has increased in the last decade with the establishment of BostonSight network clinics across the United States. Patients treated at network clinics showed similar levels of baseline visual function and SRGHS, and achieved a similar high level of improvement in visual function as those treated at the main center. Patient-reported measures of functional status are useful in evaluating treatment options for patients with cGVHD. PROSE treatment has significant positive impact on the visual function of patients with ocular cGVHD regardless of whether the patient is treated at the main center or at a network site.

The relationship between Graves' ophthalmopathy and dry eye syndrome.

BACKGROUND: A complex relationship between Graves' ophthalmopathy (GO) and dry eye syndrome exists. New research brings more insight into the association between these two diseases. METHODS: A review of the literature was conducted using the query terms "Graves' Ophthalmopathy", "Thyroid Eye Disease", and "Dry Eye" in MedLine (PubMed) and Scopus. A total of 55 papers were reviewed. Case reports were excluded. CONCLUSION: This review paper shows the close relationship between dry eye syndrome and GO. The underlying mechanisms behind their association suggest mechanical impairment of orbital muscles and immune-mediated lacrimal gland dysfunction as the causes of dry eye in GO patients. However, there are a variety of treatment options available for patients with GO with signs of dry eye, which help combat this issue.

Patient ocular conditions and clinical outcomes using a PROSE scleral device.

PURPOSE: To determine the type and distribution of ocular conditions cared for in a clinic dedicated to scleral devices and to report the clinical outcomes afforded by this approach. METHODS: Fifty-one charts of patients fitted unilaterally or bilaterally with a scleral device (Prosthetic Replacement of the Ocular Surface Ecosystem - PROSE) in a two year period were retrospectively reviewed. Patient demographics, ocular diagnoses, associated systemic conditions, best corrected visual acuity (BCVA) before and after fitting, Visual Function Questionnaire score (VFQ-25), and ocular surface disease index (OSDI) score were collected. RESULTS: All 51 patients were successfully wearing the PROSE device for a period of anywhere from weeks to years. The most common reasons for fitting were to relieve symptoms of moderate to severe dry eye syndrome ("DES", n=25), management of refractive problems ("refractive", n=23) with keratoconus being the most common (n=14), and to manage other anomalies ("other", n=3). Best corrected visual acuity (logMAR) improved with the wearing of the PROSE device for both the DES (17 letters) and the refractive group (10 letters), but not the "other" group. No serious complications were recorded for any of the patients. CONCLUSIONS: The PROSE device is a useful option not only for the management of ocular surface disease and optical imperfections, but also for other ophthalmic conditions. Moderate to severe dry eye was the most common anomaly managed, followed by eyes with irregular corneal astigmatism. DES and refractive patients experienced improvement in visual acuity with wearing of the PROSE device.

PROSE treatment for lagophthalmos and exposure keratopathy.

Prosthetic replacement of the ocular surface ecosystem is a treatment developed by the Boston Foundation for Sight that uses a Food and Drug Administration-approved prosthetic device for the treatment of severe ocular surface disease to improve vision and discomfort in addition to supporting the ocular surface. Facial nerve paralysis has multiple causes including trauma, surgery, tumor, stroke, and congenital lagophthalmos. Subsequent lagophthalmos leading to exposure keratitis has been treated with copious lubrication, tarsorrhapy, eyelid weights, chemodenervation to yield protective ptosis, and palpebral spring insertion. Each of these treatments, however, has limitations and potential complications. The prosthetic replacement of the ocular surface ecosystem device provides a liquid bandage to protect the cornea from eyelid interaction and dessication in addition to improving vision. This report describes 4 patients with exposure keratitis who were successfully treated with prosthetic replacement of the ocular surface ecosystem devices at 2 clinical sites.

PROSE therapy used to minimize corneal trauma in patients with corneal epithelial defects.

PURPOSE: To review the effectiveness of continuous or extended daily wear of Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) for treating recurrent or persistent corneal epithelial defects from a variety of causes that were refractory to conventional therapy in 9 patients. DESIGN: Retrospective case series. METHODS: The medical records of 9 patients with a history of recurrent or persistent corneal epithelial defects resistant to conventional medical treatment who received treatment at the Cullen Eye Institute between January 2011 and July 2012 were reviewed. Demographic information, etiology, prior treatment, and outcome of PROSE treatment were analyzed. Recurrence after cessation of PROSE and complications were also identified. RESULTS: The etiologies of recurrent or persistent corneal epithelial defects in this series included neurotrophic keratopathy, lattice and Avellino dystrophy, Stevens-Johnson syndrome, and chemical/thermal injury. All patients were initially treated with bandage contact lens; however, continuous silicone hydrogel lens wear was not effective in preventing recurrence or healing corneal epithelial defects in all patients. Epithelial defects healed without recurrence in all 9 patients treated with PROSE. Eight patients developed recurrent epithelial defects when PROSE was discontinued, but rehealed after resuming PROSE. Visual acuity improved in 8 patients (88.9%) treated with PROSE. CONCLUSIONS: Complex persistent or recurrent corneal epithelial defects that failed to heal with extended silicone hydrogel contact lenses healed with PROSE. PROSE therapy was well tolerated, but corneal epithelial defects recurred in all but 1 case following cessation of therapy.

In vitro effects of medium tonicity, nutrient concentration, and free chlorine content on Acanthamoeba.

BACKGROUND: The environment preferred by Acanthamoeba trophozoites and the mechanism by which the amebae enters the cornea are not yet fully understood. A better understanding of the pathogenesis of this disease may help with prevention and treatment. PURPOSE: To define the preferred environments for Acanthamoeba survival and proliferation in vitro by examining the effect of tonicity, nutrient concentration, and free chlorine content on Acanthamoeba. MATERIALS AND METHODS: Human corneal isolates of Acanthamoeba castellanii and Acanthamoeba polyphaga trophozoites were cultured at 22°C (room temperature) in PYG (peptone-yeast extract-glucose) medium. The effect of tonicity on amebae was determined by incubating trophozoites in sodium chloride solutions in concentrations ranging from 0% to 10% for 19 days. Two different sets of media were prepared-one with and the other without added nutrients. The tonicity varied from 50 to 3438 mOsm/L while the pH was maintained at 6.7-6.8. Aliquots were recovered to determine the number and morphologic type of the amebae. To test the effect of chlorine, Acanthamoeba trophozoites were incubated for 7 days in buffered solutions with free chlorine concentrations varying from 0 to 5 mg/L free chlorine at 22°C. The pH was maintained at 7.2 and the tonicity varied from 88 to 92 mOsm/L. Trophozoites were enumerated by hemocytometer. RESULTS: Low tonicity solutions (<300 mOsm/L) favored the trophozoite stage, but elevating tonicity encouraged encystment. Only 3.3-3.9% of the trophozoites remained in 10% NaCl, while 46-58% of the trophozoites were present in distilled water. Increasing osmolality yielded a smaller number of Acanthamoeba with a greater proportion of cysts. Nutrients improved the replication rate at lower concentrations, increased the number of trophozoites and reduced the percentage of cysts. Chlorine completely inhibited both species of Acanthamoeba at free chlorine levels of 5mg/L, while lesser concentrations were less inhibitory. CONCLUSIONS: Acanthamoeba prefer hypotonic environments. Nutrients merely slowed the conversion of trophozoites to cysts at higher tonicity levels. Chlorine concentrations less than 5 mg/L, ocular irritation level, did not effectively convert trophozoites into cysts. We conclude that contact lens patients should avoid hypotonic ocular exposures, especially tap water and stagnant media such as lake water, and water from poorly maintained swimming pools and hot-tubs.

The impact of the Boston ocular surface prosthesis on wavefront higher-order aberrations.

PURPOSE: To evaluate the effect of the Boston Ocular Surface Prosthesis (Boston Foundation for Sight) on higher-order wavefront aberrations in eyes with keratoconus, eyes that have undergone penetrating keratoplasty, eyes that have undergone refractive surgery, and eyes with ocular surface diseases. DESIGN: Prospective, clinical study. METHODS: The study evaluated 56 eyes of 39 patients with irregular astigmatism who were treated with the Boston Ocular Surface Prosthesis when conventional treatments failed. Patients were sorted into 4 clinical groups based on the underlying cause of irregular astigmatism, including keratoconus (group 1), post-penetrating keratoplasty (group 2), post-refractive surgery (group 3), and ocular surface diseases (group 4). Another 6 eyes of 5 patients who were treated with rigid gas permeable lenses also were evaluated. Best-corrected visual acuity; topographic refractive indices, including spherical, cylindrical, spherical equivalent values; and higher-order and total wavefront aberration errors were noted at baseline and after fitting the lens. RESULTS: In all groups, higher-order wavefront aberration error was noted to decrease significantly in eyes wearing the Boston Ocular Surface Prosthesis (P<.001, P=.001, P=.002, and P=.001, respectively). By post hoc analysis, significant differences in the level of higher-order aberrations were observed only between groups 1 and 4 (P=.012) and groups 1 and 2 (P=.033). In the overall group, mean correction rate of higher-order aberration error with the Boston Ocular Surface Prosthesis was 72.3%. However, in eyes with rigid gas permeable lenses, 2 eyes demonstrated increased higher-order aberration error, whereas the mean correction rate in other 4 eyes was only 42.5%. CONCLUSIONS: With its unique structure, the Boston Ocular Surface Prosthesis was found to be very effective in reducing higher-order wavefront aberrations in patients with irregular astigmatism resulting from a number of corneal and ocular surface conditions who had not responded satisfactorily to conventional methods of optical correction.

The successful use of Boston ocular surface prosthesis in the treatment of persistent corneal epithelial defect after herpes zoster ophthalmicus.

PURPOSE: To describe the use of the Boston ocular surface prosthesis (BOSP) to successfully treat a persistent corneal epithelial defect (PCED) after herpes zoster ophthalmicus that was minimally responsive to conventional therapies. METHODS: A case report. RESULTS: A 44-year-old man who developed a PCED in the right eye after herpes zoster ophthalmicus was treated with conventional therapies, including topical difluprednate opthalmic emulsion, 0.05% cyclosporine ophthalmic emulsion, topical autologous plasma, and oral doxycycline. Silicone plugs were inserted in the right upper and lower puncta. An 18-mm therapeutic hydrogel contact lens was placed in the right eye. After 4 weeks of this treatment, double layer amniotic membrane transplantation and temporary lateral tarsoraphy were performed. Ten days after the procedure, the amniotic membrane had dissolved and the tarsorrhaphy was opened. Because only partial healing of the corneal epithelial defect was observed, the patient was fit with the BOSP that he wore all waking hours. A soft contact lens was worn overnight after the BOSP was removed. Rapid reepithelization was observed within the week after starting the BOSP. The epithelial defect completely healed after 3 weeks, and the uncorrected visual acuity in the right eye improved to 20/50. CONCLUSIONS: The BOSP should be considered as an important treatment option for management of PCEDs in eyes with altered corneal sensitivity.

Corneal and conjunctival epithelial staining in hydrogel contact lens wearers.

OBJECTIVES: The purpose of this study was to investigate the prevalence of conjunctival and corneal epithelial staining in soft contact lens wearers and to see if staining could be associated with factors such as type of lens worn, wearing time, care system, age, and sex. METHODS: The records of 338 adapted hydrogel contact lens wearers were examined retrospectively. RESULTS: Conjunctival staining was found to be present in 32.5% of the subjects and corneal staining was found to be present in 19.5% of subjects. None of the subjects had staining above grade 2 using the Cornea and Contact Lens Research Unit scale. Because of the low prevalence of staining, the low grading of staining found and the large variation in refractive power, lens type worn, wearing modality, and solution used statistical analysis for association between staining and different factors could only be performed for the association between sex and staining and between corneal and conjunctival staining. However, no statistical significant association could be demonstrated. DISCUSSION: Despite the low prevalence of staining the conjunctiva and cornea should be examined carefully in contact lens wearers and prospective wearers because the conjunctival and corneal epithelium serve as protective barriers for the underlying layers of the cornea and conjunctiva. To allow comparison of data obtained in different studies assessing corneal staining, it is recommended that clinicians develop and adopt a universal standard protocol for this measure.

Mutations in the TOPORS gene cause 1% of autosomal dominant retinitis pigmentosa.

PURPOSE: The purpose of this project was to determine if mutations, including large insertions or deletions, in the recently identified RP31 gene topoisomerase I-binding arginine-serine rich (RS) protein (TOPORS), cause an appreciable fraction of autosomal dominant retinitis pigmentosa (adRP). METHODS: An adRP cohort of 215 families was used to determine the frequency of TOPORS mutations. We looked for mutations in TOPORS by testing 89 probands from the cohort without mutations in other known adRP genes. Mutation detection was performed by fluorescent capillary sequencing and by multiplex ligation probe amplification. RESULTS: Two different TOPORS mutations, p.Glu808X and p.Arg857GlyfsX9, were each identified in one proband. Patients with these mutations exhibited clinical signs typical of advanced adRP. No large deletions or insertions of TOPORS were identified in our study. CONCLUSIONS: Point mutations and small insertions or deletions in TOPORS cause approximately 1% of adRP. Large deletions or insertions of TOPORS are not an appreciable cause of adRP. Contrary to previous reports, no distinct clinical phenotype was seen in these patients.

The Gly56Arg mutation in NR2E3 accounts for 1-2% of autosomal dominant retinitis pigmentosa.

PURPOSE: Mutations in the orphan nuclear receptor gene NR2E3 have been found to cause both recessive and dominant retinopathies. The purpose of this study was to determine the prevalence of the recently described Gly56Arg mutation in a well characterized cohort of families with autosomal dominant retinitis pigmentosa (adRP). METHODS: A cohort of 215 families with adRP which have already been screened for mutations in 13 of the other known adRP genes was used to determine the frequency of the Gly56Arg mutation. The 92 families without a disease-causing mutation in a known gene were tested for the presence of the Gly56Arg mutation using direct DNA sequencing. An additional set of 100 normal controls (200 chromosomes) was also screened by DNA sequencing. RESULTS: The Gly56Arg mutation was found in three of the 92 adRP families studied and was not found in unaffected control samples. CONCLUSIONS: The Gly56Arg mutation in NR2E3 accounts for approximately 1%-2% of adRP, making it one of the more common single mutations in adRP.

Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families.

PURPOSE: To survey families with clinical evidence of autosomal dominant retinitis pigmentosa (adRP) for mutations in genes known to cause adRP. METHODS: Two hundred adRP families, drawn from a cohort of more than 400 potential families, were selected by analysis of pedigrees. Minimum criteria for inclusion in the adRP cohort included either evidence of at least three generations of affected individuals or two generations with evidence of male-to-male transmission. Probands from each family were screened for mutations in 13 genes known to cause adRP: CA4, CRX, FSCN2, IMPDH1, NRL, PRPF3 (RP18), PRPF8 (RP13), PRPF31 (RP11), RDS, RHO, ROM1, RP1, and RP9. Families without mutations in autosomal genes and in which an X-linked mode of inheritance could not be excluded were tested for mutations in ORF 15 of X-linked RPGR. Potentially pathogenic variants were evaluated based on a variety of genetic and computational criteria, to confirm or exclude pathogenicity. RESULTS: A total of 82 distinct, rare (nonpolymorphic) variants were detected among the genes tested. Of these, 57 are clearly pathogenic based on multiple criteria, 10 are probably pathogenic, and 15 are probably benign. In the cohort of 200 families, 94 (47%) have one of the clearly pathogenic variants and 10 (5%) have one of the probably pathogenic variants. One family (0.5%) has digenic RDS-ROM1 mutations. Two families (1%) have a pathogenic RPGR mutation, indicating that families with apparent autosomal transmission of RP may actually have X-linked genetic disease. Thus, 107 families (53.5%) have mutations in known genes, leaving 93 whose underlying cause is still unknown. CONCLUSIONS: Together, the known adRP genes account for retinal disease in approximately half of the families in this survey, mostly Americans of European origin. Among the adRP genes, IMPDH1, PRPF8, PRPF31, RDS, RHO, and RP1 each accounts for more than 2% of the total; CRX, PRPF3, and RPGR each accounts for roughly 1%. Disease-causing mutations were not found in CA4, FSCN2, NRL, or RP9. Because some mutations are frequent and some regions are more likely to harbor mutations than others, more than two thirds of the detected mutations can be found by screening less than 10% of the total gene sequences. Among the remaining families, mutations may lie in regions of known genes that were not tested, mutations may not be detectable by PCR-based sequencing, or other loci may be involved.

Spectrum and frequency of mutations in IMPDH1 associated with autosomal dominant retinitis pigmentosa and leber congenital amaurosis.

PURPOSE: The purpose of this study was to determine the frequency and spectrum of inosine monophosphate dehydrogenase type I (IMPDH1) mutations associated with autosomal dominant retinitis pigmentosa (RP), to determine whether mutations in IMPDH1 cause other forms of inherited retinal degeneration, and to analyze IMPDH1 mutations for alterations in enzyme activity and nucleic acid binding. METHODS: The coding sequence and flanking intron/exon junctions of IMPDH1 were analyzed in 203 patients with autosomal dominant RP (adRP), 55 patients with autosomal recessive RP (arRP), 7 patients with isolated RP, 17 patients with macular degeneration (MD), and 24 patients with Leber congenital amaurosis (LCA). DNA samples were tested for mutations by sequencing only or by a combination of single-stranded conformational analysis and by sequencing. Production of fluorescent reduced nicotinamide adenine dinucleotide (NADH) was used to measure enzymatic activity of mutant IMPDH1 proteins. The affinity and the specificity of mutant IMPDH1 proteins for single-stranded nucleic acids were determined by filter-binding assays. RESULTS: Five different IMPDH1 variants, Thr116Met, Asp226Asn, Val268Ile, Gly324Asp, and His 372Pro, were identified in eight autosomal dominant RP families. Two additional IMPDH1 variants, Arg105Trp and Asn198Lys, were found in two patients with isolated LCA. None of the novel IMPDH1 mutants identified in this study altered the enzymatic activity of the corresponding proteins. In contrast, the affinity and/or the specificity of single-stranded nucleic acid binding were altered for each IMPDH1 mutant except the Gly324Asp variant. CONCLUSIONS: Mutations in IMPDH1 account for approximately 2% of families with adRP, and de novo IMPDH1 mutations are also rare causes of isolated LCA. This analysis of the novel IMPDH1 mutants substantiates previous reports that IMPDH1 mutations do not alter enzyme activity and demonstrates that these mutants alter the recently identified single-stranded nucleic acid binding property of IMPDH. Studies are needed to further characterize the functional significance of IMPDH1 nucleic acid binding and its potential relationship to retinal degeneration.

Phenotypic characterization of a large family with RP10 autosomal-dominant retinitis pigmentosa: an Asp226Asn mutation in the IMPDH1 gene.

PURPOSE: To evaluate the clinical features associated with the RP10 form of autosomal-dominant retinitis pigmentosa in 11 affected members of various ages from one family with a defined IMPDH1 mutation (Asp226Asn). DESIGN: Prospective, observational case series. METHODS: Visual function assessment included visual acuity, color vision, visual field, dark adaptometry, full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Ophthalmologic examinations, fundus photography, and optical coherence tomographic scans were also performed. Blood samples were obtained to screen for basic immune function. RESULTS: Visual acuity was slightly reduced in the teenage years and substantially reduced in association with cystoid macular edema (CME) at all ages. Color defects were observed in three patients (one teen, two adults). Dark-adapted thresholds were elevated. Visual fields were markedly constricted by age 40 (