AIMING FOR THE BULL'S EYE: The Cost-Utility of Screening for Hydroxychloroquine Retinopathy.

BACKGROUND: Throughout medicine, the cost of various treatments has been increasingly studied with the result that certain management guidelines might be reevaluated in their context. Cost-utility is a term referring to the expense of preventing the loss of quality of life, quantified in dollars per quality-adjusted life year. In 2002, the American Academy of Ophthalmology published hydroxychloroquine screening recommendations which were revised in 2011. The purpose of this report is to estimate the cost-utility of these recommendations. METHODS: A hypothetical care model of screening for hydroxychloroquine retinopathy was formulated. The costs of screening components were calculated using 2016 Medicare fee schedules from the Centers for Medicare and Medicaid Services. RESULTS: The cost-utility of screening for hydroxychloroquine retinopathy with the 2011 American Academy of Ophthalmology guidelines was found to vary from 33,155 to 344,172 dollars per quality-adjusted life year depending on the type and number of objective screening tests chosen, practice setting, and the duration of hydroxychloroquine use. Screening had a more favorable cost-utility when the more sensitive and specific diagnostics were used, and for patients with an increased risk of toxicity. CONCLUSION: American Academy of Ophthalmology guidelines have a wide-ranging cost-utility. Prudent clinical judgment of risk stratification and tests chosen is necessary to optimize cost-utility without compromising the efficacy of screening.

Ocular surface disease and dacryoadenitis in aging C57BL/6 mice.

Dry eye in humans displays increased prevalence in the aged and in women. Here, we investigated the ocular surfaces and lacrimal glands of aged mice of both sexes. We surveyed three different ages [young, middle-aged (6 to 9 months), and elderly] by investigating severity markers of dry eye disease (DED). We observed an age-dependent dry eye phenotype as early as 6 to 9 months: increased corneal surface irregularity, increased corneal barrier disruption, conjunctival CD4(+) T-cell infiltration, and loss of mucin-filled goblet cells. Expression of interferon-γ, IL-17 mRNA transcripts was increased in the conjunctiva and IL-17A, matrix metallopeptidase 9, and chemokine ligand 20 in the corneas of elderly mice. Elderly male mice develop more of a skewed response of type 1 T helper cell, whereas female mice have a bias toward type 17 T helper cell in the conjunctiva. In the lacrimal gland, an increase in CD4(+) and CD8(+) T cells and B cells and a decrease in activated dendritic cells were observed. Adoptive transfer of CD4(+) T cells isolated from elderly mice transferred DED into young immunodeficient recipients, which was more pronounced from male donors. Our findings show the development of DED in aging mice. Pathogenic CD4(+) T cells that develop with aging are capable of transferring DED from older mice to naive immunodeficient recipients. Taken together, our results indicate that age-related autoimmunity contributes to development of DED with aging.

Follow the nevus: the cost-utility of monitoring for growth of choroidal nevi.

AIM: To develop a model to evaluate the cost-utility of choroidal nevi monitoring recommendations with varying clinical risk factors. METHODS: A Markov model was created to evaluate the cost-utility in cost per quality-adjusted life-year ($/QALY) for monitoring patients with choroidal nevus. This probabilistic model was applied both to a hypothetically monitored and unmonitored group of patients beginning at different ages and with varying clinical risk factors of the nevus. Duration of screening was modeled for the remainder of the patients' life expectancy. Best available clinical data on the prevalence and incidence of choroidal nevi/melanoma, and relative risk of nevus transformation were combined with the initial and downstream costs of screening, downstream costs of melanoma-related mortality, and QALY saved by monitoring, to estimate the best monitoring regimen. Main outcome measures were average $/QALY saved by consensus recommended monitoring scenarios for the duration of a patient's remaining life expectancy in comparison with no follow-up, and the cost-utility of modified regimens. RESULTS: The $/QALY of the recommended monitoring scenarios varied substantially based on nevus clinical risk factors, patient age, frequency of follow-up, and objective testing utilized. The $/QALY for the recommended monitoring scenario of a flat nevus without risk factors in a 60-year-old patient was $77 180. The $/QALY for monitoring a nevus with 3 clinical risk factors in a 60-year-old patient was $85 393. The $/QALY values for differently-aged patients were larger, and intermediate degrees of risk factors for nevus growth varied, depending largely upon the specifics of the modeled monitoring scenarios. CONCLUSION: The average $/QALY of currently recommended monitoring scenarios fall within economically acceptable standards and could provide insight for formulating appropriate clinical strategies. Cost-utility could be enhanced by targeting higher risk groups and considering less frequent monitoring for the lower risk groups.

Empowering a database with national long-term data about mortality: the use of national death registries.

The interest of professional medical societies in research about outcomes, mixed with the recent accessibility to management of data on the internet, has moved many societies to create national databases or registries for their specialty. In societies with procedure-based specialties such as surgery, these databases will help with the care of patients by predicting prognosis, defining risk-factors, and aiding with the selection of patients who are the best candidates for these procedures. These databases eventually will also help to establish standards of care. The latter is rapidly growing in importance as governments attempt to create "pay-for-performance" programs in many of the surgical specialties. It is essential to create a database from which a specialty can provide accurate data and standards to its members, its patients, and third parties, such as regulatory bodies and agencies of re-numeration. Unfortunately, surgeons often only care for their patients in the short-term peri-operative period, typically lasting weeks to months; and therefore, the ability of surgeons to create databases with long-term follow-up has been limited. The introduction of "personal health information" into a surgical database, with the intention of linking with other societies or national databases that have long-term follow-up, can remedy this weakness. This article describes the investigation by one surgical society into the available national registries of death and examines their accuracy, accessibility, cost, and their suitability in respect to the goals of that society. The information gathered, the comparisons outlined, and the processes used to determine the best combination of indices of death for this society should be translatable and hopefully useful for other societies and registries who wish to empower their databases with long-term national data about mortality.

Reversal of cilioretinal artery occlusion with intra-arterial tissue plasminogen activator.

PURPOSE: To present the reversal of a cilioretinal artery occlusion with the use of intra-arterial tissue plasminogen activator. OBSERVATIONS: A monocular 74 year old male presented with a cilioretinal artery occlusion. Treatment with intra-arterial tissue plasminogen activator 7 hours after the onset of symptoms led to a complete restoration of vision. CONCLUSIONS AND IMPORTANCE: Early intervention with tissue plasminogen activator reversed acute onset loss of vision from cilioretinal artery occlusion.

Comparison of Regional vs. General Anesthesia for Surgical Repair of Open-Globe Injuries at a University Referral Center.

PURPOSE: This study compares the clinical features and physician selection of either Regional Anesthesia (peribulbar or retrobulbar block) with Monitored Anesthesia Care (RA-MAC) or General Anesthesia (GA) for open globe injury repair. DESIGN: A non-randomized, comparative, retrospective case series at a University Referral Center. PARTICIPANTS: All adult repairable open globe injuries receiving primary repair between January 1st, 2004 and December 31st, 2014 (11 years). Exclusion criteria were patients less than 18 years of age and those treated with primary enucleation. METHODS: Data was gathered via retrospective chart review. MAIN OUTCOME MEASURES: Data collected from each patient was age, gender, injury type, location, length of wound, presenting visual acuity, classification of anesthesia used, duration of the procedure performed, months of clinical follow-up, and final visual acuity. RESULTS: During the 11 years study period, 448 patients were identified who had open globe injuries with documented information on zone of injury. Globe injury repair was performed using RA-MAC in 351/448 (78%) patients and general anesthesia in 97/448 (22%) patients. Zone 1, 2 and 3 injuries were recorded in 241, 135, and 72 patients respectively. The rates in specific zones, of RA-MAC versus GA were as follows: Zone 1 - 213/241 (88%) vs 28/241 (12%), Zone 2 - 104/135 (77%) vs 31/135 (23%) and Zone 3 - 34/72 (47%) vs 38/72 (53%). Open globe injuries repaired under RA-MAC had significantly shorter wound length (p<0.001), more anterior wound location (p<0.001) and shorter operative times (p<0.001). RA-MAC cases also had a better presenting and final visual acuity (p<0.001). Neither class of anesthesia conferred a greater visual acuity improvement (p=0.06). The use of GA did not cause any delay in the time elapsed from injury until surgical repair (p=0.74). CONCLUSIONS: RA-MAC is a reasonable alternative to GA for the repair of open globe injuries in selected adult patients. RA-MAC was selected more often for Zone 1 and Zone 2 injuries. For eyes with Zone 3 injuries, there are equal selection ratio for RA-MAC and GA.

Retinal Detachment in a Combined Case of Stickler Syndrome and X-Linked Retinoschisis.

A 12-year-old boy presented with a total rhegmatogenous retinal detachment and a giant retinal tear in the right eye. Clinical examination, optical coherence tomography, and fundus images showed an optically empty vitreous, lattice degeneration, and retinoschisis of the macula. Genetic testing revealed mutations in the COL2A1 and RS1 genes, confirming a dual diagnosis of Stickler syndrome and X-linked retinoschisis, respectively. This represents the first published account of a patient with both Stickler syndrome and X-linked retinoschisis. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:83-86.].

Culture-Positive Endophthalmitis After Open Globe Injuries With and Without Retained Intraocular Foreign Bodies.

BACKGROUND AND OBJECTIVE: To report the visual and anatomical outcomes and microbiologic spectrum of culture-positive endophthalmitis in open globe injuries (OGIs) with or without intraocular foreign bodies (IOFBs). PATIENTS AND METHODS: A retrospective, interventional case series of OGIs (n = 718) treated between 2004 and 2015. Patients underwent a management protocol for OGI, including systemic broad-spectrum antibiotics, on presentation. RESULTS: Culture-positive cases of endophthalmitis after open globe repair occurred in 2.1% of eyes (n = 15 of 718 eyes); two eyes had evidence of endophthalmitis on presentation. The most common organism was Staphylococcus species (five of 17 eyes). An IOFB was present in 6.8% of eyes (n = 49 of 718 eyes). All of these eyes received prophylactic intravitreal antimicrobials. In eyes with IOFB, the rate of culture-positive endophthalmitis after initial globe repair was 8.1% (n = 4 of 49 eyes) versus 1.6% (n = 11 of 669 eyes) in eyes without IOFB (P < .01). CONCLUSION: Culture-positive endophthalmitis was identified after OGIs more often in eyes with a concurrent IOFB. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:632-637.].

In Vivo Porcine Model of Venous Air Embolism During Pars Plana Vitrectomy.

PURPOSE: Venous air embolism (VAE) during pars plana vitrectomy (PPV) can occur owing to improper positioning of the infusion cannula in the suprachoroidal space and may lead to sudden compromise of cardiac circulation and death. This was an in vivo demonstration of fatal VAE during PPV to show that air can travel from the suprachoroidal space into the central circulation. DESIGN: Experimental in vivo surgical study on porcine eyes. METHODS: Experimental PPV under general anesthesia was performed on porcine eyes (Yorkshire species) at a University Surgical Training & Education Center. Infusion cannulas were placed into the suprachoroidal space and fluid-air exchange (FAE) was started with sequential increases in infusion air pressure. Vital signs of porcine animals were continuously monitored and recorded in real time during the PPV, including end-tidal carbon dioxide (ETCO2), oxygen saturation (SaO2), intra-arterial blood pressure, electrocardiography (EKG), and transesophageal echocardiography (TEE). RESULTS: Intracardiac air was detected on TEE less than 30 seconds after increasing air infusion pressure to 60 mm Hg. ETCO2 declined precipitously, followed by hypotension and EKG changes. Oxygen desaturation was a late phenomenon. The animal died within 7 minutes of VAE. During autopsy, the heart was open under water and air escaped from the right ventricle. CONCLUSION: This in vivo porcine model confirms that during the FAE in PPV, pressurized air from an infusion cannula malpositioned in the suprachoroidal space can transit through the eye to the central circulation, resulting in fatal VAE.

Epidemiology of Ocular Surface Squamous Neoplasia in a Veterans Affairs Population.

PURPOSE: To evaluate the epidemiology of ocular surface squamous neoplasia (OSSN) and its associated risk factors in a South Florida Veterans Affairs Hospital population. METHODS: Retrospective case-control study. Twenty-eight confirmed cases of OSSN from 24,179 veterans who received care at the Miami Veterans Affairs Healthcare System and affiliated satellite eye clinics between March 1, 2007, and March 1, 2012. Data extracted from the veterans administration database that comprised demographic information and medical diagnosis information [based on International Classification of Disease (ICD-9) codes]. The main outcome measures were the period prevalence of OSSN and identification of factors associated with the presence of disease. RESULTS: The period prevalence of OSSN in our population was 0.1%. The risk factors studied included UV-related dermatologic diseases (melanoma, squamous and basal cell cancer, and actinic keratosis), UV-related ocular conditions (pterygium), HIV seropositivity, human papilloma virus-related diseases, and tobacco use. The presence of skin malignancy (squamous cell carcinoma and/or basal cell carcinoma) and pterygium was found to be significantly associated with the presence of OSSN [odds ratio, 4.40; 95% confidence interval, 2.03-9.55; P < 0.0005 and odds ratio, 16.2; 95% confidence interval, 7.11-36.9; P < 0.0005, respectively]. CONCLUSIONS: The presence of neoplasias and ocular conditions related to sun exposure was the most important risk factor for the occurrence of OSSN in a South Florida Veterans Affairs Healthcare System population consistent with previous epidemiological reports worldwide.

Long-term Supplementation With n-6 and n-3 PUFAs Improves Moderate-to-Severe Keratoconjunctivitis Sicca: A Randomized Double-Blind Clinical Trial.

PURPOSE: Supplementation with gamma-linolenic acid (GLA) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) has been found to decrease the production of disease-relevant inflammatory mediators that are implicated in the pathogenesis of chronic dry eye. This study evaluated the effect of a supplement containing both GLA and n-3 PUFAs on signs and symptoms of moderate-to-severe keratoconjunctivitis sicca in postmenopausal patients. METHODS: This multicenter, double-masked placebo-controlled clinical trial enrolled 38 patients (both eyes) with tear dysfunction who were randomized to supplemental GLA + n-3 PUFAs or placebo for 6 months. Disease parameters, including Ocular Surface Disease Index, Schirmer test, tear breakup time, conjunctival fluorescein and lissamine green staining, and topographic corneal smoothness indexes (surface asymmetry index and surface regularity index), were assessed at baseline and at 4, 12, and 24 weeks. The intensity of dendritic cell CD11c integrin and HLA-DR expression was measured in conjunctival impression cytologies. RESULTS: The Ocular Surface Disease Index score improved with supplementation and was significantly lower than placebo (21 ± 4 vs. 34 ± 5) after 24 weeks (P = 0.05, n = 19 per group). The surface asymmetry index was significantly lower in supplement-treated subjects (0.37 ± 0.03, n = 15) than placebo (0.51 ± 0.03, n = 16) at 24 weeks (P = 0.005). Placebo treatment also significantly increased HLA-DR intensity by 36% ± 9% and CD11c by 34% ± 7% when compared with supplement treatment (n = 19 per group, P = 0.001, 24 weeks). Neither treatment had any effect on tear production, tear breakup time, or corneal or conjunctival staining. CONCLUSIONS: Supplemental GLA and n-3 PUFAs for 6 months improved ocular irritation symptoms, maintained corneal surface smoothness, and inhibited conjunctival dendritic cell maturation in patients with postmenopausal keratoconjunctivitis sicca.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00883649.

Biodegradable PLGA-Based Drug Delivery Systems for Modulating Ocular Surface Disease under Experimental Murine Dry Eye.

OBJECTIVE: Continuous drug delivery to the ocular surface remains difficult due to the rapid tear clearance of topically applied agents. The purpose of this study was to evaluate biodegradable and biocompatible drug delivery systems on the ocular surface using poly-lactic-co-glycolic acid (PLGA) based polymers. METHODS: Fluorescein-labeled albumin and doxycycline were individually encapsulated into a PLGA-based matrix using a water-oil-water double emulsion method. The drug elution rates for various microspheres were evaluated spectrofluorometrically. Particle size was measured using image analysis software. Subconjunctival injections of PLGA microspheres were used to evaluate safety and inflammatory response to the polymer in the murine model. Efficacy of the drug delivery system was evaluated by a single subconjunctival injection of PLGA-doxycycline (a broad metalloproteinase inhibitor) prior to induction of desiccating stress (DS) model in C57BL/6 mice for 5 days. RESULTS: PLGA-based microspheres successfully elute encapsulated drugs of interest continuously over controlled periods of time. Mean PLGA-based microparticle diameter was 4.6 µm±1.54 µm. Drug elution rates and delivery times were easily modifiable by altering polymers and synthesis parameters. In vitro studies demonstrate successful continuous elution of encapsulated drugs for at least 2 weeks. In vivo testing of PLGA-doxycycline was efficacious in preventing DS-induced corneal barrier disruption with desiccating stress, similarly to topically applied doxycycline. CONCLUSIONS: PLGA-based drug delivery systems are safe and non-inflammatory. They can be successfully used to treat ocular surface and corneal diseases by continuously delivering biopharmaceuticals of interest.

Interferon-γ exacerbates dry eye-induced apoptosis in conjunctiva through dual apoptotic pathways.

PURPOSE: To investigate the role of interferon (IFN)-γ in dry eye-associated conjunctival apoptosis. METHODS: Desiccating stress (DS) was created in C57BL/6 (B6) and C57BL/6 IFN-γ-knockout (B6γKO) mice. A separate group of mice of both strains also received subconjunctival injections of exogenous IFN-γ or vehicle control (BSA) at days 0, +2, and +4 after DS. Immunoreactivity to active (Ac)-caspase-3, -8, and -9 and terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) were evaluated in cryosections. Goblet cell apoptosis was assessed by MUC5AC and TUNEL double staining. Levels of caspase-3, -8, -9, Fas, and Fas-associated protein with Death Domain (FADD) mRNA in conjunctiva were measured by real-time PCR. The activity of caspase-3, -8, or -9 was measured using fluorometric assay. RESULTS: Increased Ac-caspase-3 and -8 and TUNEL immunoreactivity were noted in conjunctival epithelia in B6 mice compared with B6γKO mice after DS, and exogenous IFN-γ administration further increased these parameters. DS-induced conjunctival apoptosis was greatest in the goblet cell area and was accompanied by a decrease in MUC5AC expression in the B6 and B6-IFN-γ-injected groups compared with the B6γKO and B6-BSA-injected groups. B6γKO mice were resistant to DS-induced apoptosis; however, B6γKO receiving IFN-γ yielded results similar to those for B6 wild-type. Caspase-9 production and activity were not increased with DS in B6 or B6γKO mice; however, the administration of IFN-γ significantly increased caspase-9 production and activity in both strains compared with vehicle-injected mice. CONCLUSIONS: IFN-γ plays a pivotal role in exacerbating conjunctival apoptosis through dual apoptotic pathways with DS.

Pharmacological cholinergic blockade stimulates inflammatory cytokine production and lymphocytic infiltration in the mouse lacrimal gland.

PURPOSE: To investigate the effects of cholinergic blockade on inflammatory cell infiltration and cytokine production in the mouse lacrimal gland (LG). METHODS: C57BL/6 mice were untreated (UT) or received subcutaneous injections of either scopolamine hydrobromide (SCOP; 0.5 mg/0.2 mL) or saline (SAL) four times daily for 2 or 5 days (2D, 5D). This was followed by a 7-day rest period in separate groups. Tear volume (cotton thread) and tear epidermal growth factor (EGF, by ELISA) concentrations were measured. Extraorbital LGs were surgically excised and sectioned or lysed for gene expression analysis. Immunohistochemistry evaluated immunophenotype of infiltrating cells. Expression of EGF and T helper (Th)-1, -2, and -17-associated cytokines in LGs was evaluated by real-time PCR. Goblet cell density was evaluated in periodic acid Schiff-stained conjunctival sections. RESULTS: Tear volume and EGF protein levels were significantly reduced in SCOP5D mice compared with controls, indicating that cholinergic blockade decreased LG secretory function. LGs of SCOP2D and SCOP5D mice showed an increased density of CD4(+), CD11c+, CD11b+, and myeloperoxidase+ cells compared with UT controls. At day 5, these cells were significantly elevated compared with SAL-treated counterparts. Elevated levels of IL-17A, IL-17R, IFN-γ, IL-12Rß1, IL-2, IL-13, IL-6, IL-1ß, and TNF-α transcripts were noted in SCOP2D mice and IFN-γ, TGF-ß1, and IL-18R transcripts in SCOP5D mice. CONCLUSIONS: Pharmacological blockade of lacrimal secretion induced a significant CD4(+) infiltration in the LG, mimicking Sjögren's syndrome. The mRNA expression profile revealed elevations of a mix of inflammatory cytokines and Th-1-associated factors.