Expert consensus on the identification, diagnosis, and treatment of neurotrophic keratopathy.

BACKGROUND: Neurotrophic keratopathy (NK) is a relatively uncommon, underdiagnosed degenerative corneal disease that is caused by damage to the ophthalmic branch of the trigeminal nerve by conditions such as herpes simplex or zoster keratitis, intracranial space-occupying lesions, diabetes, or neurosurgical procedures. Over time, epithelial breakdown, corneal ulceration, corneal melting (thinning), perforation, and loss of vision may occur. The best opportunity to reverse ocular surface damage is in the earliest stage of NK. However, patients typically experience few symptoms and diagnosis is often delayed. Increased awareness of the causes of NK, consensus on when and how to screen for NK, and recommendations for how to treat NK are needed. METHODS: An 11-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on when to screen for and how best to diagnose and treat NK. Clinicians reviewed literature on the diagnosis and management of NK then rated a detailed set of 735 scenarios. In 646 scenarios, panelists rated whether a test of corneal sensitivity was warranted; in 20 scenarios, they considered the adequacy of specific tests and examinations to diagnose and stage NK; and in 69 scenarios, they rated the appropriateness of treatments for NK. Panelist ratings were used to develop clinical recommendations. RESULTS: There was agreement on 94% of scenarios. Based on this consensus, we present distinct circumstances when we strongly recommend or may consider a test for corneal sensitivity. We also present recommendations on the diagnostic tests to be performed in patients in whom NK is suspected and treatment options for NK. CONCLUSIONS: These expert recommendations should be validated with clinical data. The recommendations represent the consensus of experts, are informed by published literature and experience, and may improve outcomes by helping improve diagnosis and treatment of patients with NK.

Phentolamine Eye Drops Reverse Pharmacologically Induced Mydriasis in a Randomized Phase 2b Trial.

SIGNIFICANCE: After a dilated eye examination, many patients experience symptoms of prolonged light sensitivity, blurred vision, and cycloplegia associated with pharmacological mydriasis. Phentolamine mesylate ophthalmic solution (PMOS) may expedite the reversal of mydriasis in patients, potentially facilitating return to functional vision and reducing barriers to obtaining dilated eye examinations. PURPOSE: The protracted reversal time after pharmacologically induced pupil dilation impairs vision. We tested the hypothesis that PMOS rapidly reduces pupil diameter in this acute indication. METHODS: In this double-masked placebo-controlled, randomized, two-arm crossover phase 2b trial, we evaluated the effects of one drop of 1% PMOS applied bilaterally in subjects who had their pupils dilated by one of two common mydriatic agents: 2.5% phenylephrine or 1% tropicamide. End points included change in pupil diameter, percent of subjects returning to baseline pupil diameter, and accommodative function at multiple time points. RESULTS: Thirty-one subjects completed the study (15 dilated with phenylephrine and 16 with tropicamide). Change in pupil diameter from baseline at 2 hours after maximal dilation with 1% PMOS was -1.69 mm and was significantly greater in magnitude compared with placebo for every time point beyond 30 minutes (P < .05). At 2 hours, a greater percentage of study eyes given 1% PMOS returned to baseline pupil diameter compared with placebo (29 vs. 13%, P = .03), which was this also seen at 4 hours (P < .001). More subjects treated with PMOS in the tropicamide subgroup had at least one eye returning to baseline accommodative amplitude at 2 hours (63 vs. 38%, P = .01). There were no severe adverse events, with only mild to moderate conjunctival hyperemia that resolved in most patients by 6 hours. CONCLUSIONS: Phentolamine mesylate ophthalmic solution at 1% reversed medically induced pupil dilation more rapidly than placebo treatment regardless of which mydriatic was used (adrenergic agonists and cholinergic blockers) with a tolerable safety profile.

Phentolamine Mesylate Ophthalmic Solution Provides Lasting Pupil Modulation and Improves Near Visual Acuity in Presbyopic Glaucoma Patients in a Randomized Phase 2b Clinical Trial.

PURPOSE: Phentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population. PATIENTS AND METHODS: In this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change in diurnal IOP, and the key secondary outcome measures included changes in PD, distance-corrected near visual acuity (DCNVA), and conjunctival hyperemia. RESULTS: Use of 1% PMOS did not lead to a statistically significant decrease in diurnal IOP compared to placebo (P = 0.89) but trended toward a greater decrease in patients with lower IOP baselines. PMOS produced a statistically significant mean 20% PD reduction under both photopic and mesopic conditions that was sustained for 36 hours post-dosing. A statistically significant number of patients with PMOS compared to placebo demonstrated ≥1 line of improvement in photopic DCNVA at day 8 (P = 0.0018), day 15 (P = 0.0072), and day 16 (P = 0.0163), with a trend for 2- and 3-line improvements at all time points. There was no statistical difference in conjunctival hyperemia compared to placebo. CONCLUSION: Although mean IOP was not lowered significantly, daily evening dosing of 1% PMOS was found to be well tolerated with no daytime conjunctival redness and demonstrated improvement in DCNVA with sustained PD reduction in a glaucomatous and presbyopic population. Smaller pupil size can have beneficial effects in improving symptoms of presbyopia and DLD, which will be the focus of further studies.

Objective Quantification of Image Quality and Optical Scatter Before and After Nd:YAG Capsulotomy Using a Double-Pass Technique.

PURPOSE: The purpose of this study is to evaluate and compare the correlation between changes in vision and HD Analyzer dual-pass metrics versus changes in vision and conventional subjective slit lamp gradings in pseudophakic patients with posterior capsular opacity undergoing neodymium:yttrium-aluminum-garnet (Nd:YAG) capsulotomy. PATIENTS AND METHODS: High contrast (HC) and low contrast (LC) best spectacle-corrected distance visual acuity (BCVA) and HD Analyzer evaluation were prospectively performed on patients with mild-to-moderate posterior capsular opacification (PCO) and monofocal and accommodating intraocular lens implants. Differences between pre- and post-operative measurements were calculated, along with the correlation of HD Analyzer metrics and slit lamp grading to changes in visual acuity. RESULTS: Following Nd:YAG capsulotomy (n=29), there was statistically significant improvement in HC-BCVA and LC-BCVA, decrease in optical scatter, and corresponding improvement in Strehl ratio and HD Analyzer values at all contrast levels tested (p≤0.05). Pearson test showed a high correlation between the improvement in HC-BCVA (r coefficient = 0.78) and LC-BCVA (r coefficient = 0.71) to the improvement in Objective Scatter Index (OSI). There was a higher correlation of change in HC-BCVA to pre-op OSI  (r2=0.61) than to the subjective PCO grading score (r2 = 0.19). There was also a higher correlation of change in LC-BCVA to pre-op OSI (r2 = 0.49) than to subjective grading (r2 = 0.16). CONCLUSION: The HD Analyzer provides objective measurements of forward light scatter (ie, light directed towards the retina) that can assist with both PCO grading and prediction of improvement of visual quality after YAG laser capsulotomy with higher accuracy than conventional slit lamp assessment based upon backscatter (ie, light traveling to the observer) in patients tested with monofocal and accommodating intraocular lens implants.

Direct and Indirect Costs of Infectious Conjunctivitis in a Commercially Insured Population in the United States.

PURPOSE: To assess the direct and indirect costs of infectious conjunctivitis and quantify medical costs due to conjunctivitis transmission in families. METHODS: In this retrospective claims analysis from the OptumHealth Care Solutions, Inc. database (1998-2016), beneficiaries with or without at least one diagnosis of infectious conjunctivitis were identified. Direct and indirect costs (in 2016 US$) during the 60 days post conjunctivitis diagnosis (or imputed date for controls) were compared using cost differences in linear regressions. For transmission cost analysis, the total cost of each conjunctivitis episode was the sum of the primary episode (seed patient) and the secondary episode (infected family members) costs. A generalized estimating equation model adjusted for seed patient characteristics was used to assess the impact of number and rate of transmissions on episode cost. RESULTS: Health care resource utilization and direct costs were significantly higher for patients with conjunctivitis (n=1,002,188) versus controls (n=4,877,210): 1.67 all-cause visits per person per month (PPPM) versus 0.79 visits PPPM, respectively; total mean direct cost of $396.04 PPPM versus $289.63 PPPM, respectively. The cost of medically related absenteeism was $105.42 (95% confidence interval [CI], $104.18-$106.75) higher for patients with conjunctivitis than for controls. Episode cost, without transmission due to seed patient, was $669.43 (95% CI, $654.67-$684.85); it increased with each additional infected family member and with increased infection transmission time between family members. CONCLUSION: Conjunctivitis was associated with a notable economic burden in terms of direct medical costs and medically related absenteeism. Family health care costs increased with transmission time and with each family member infected with conjunctivitis.

Perspective on Systematic Medical Literature Reviews and Meta-Analyses.

PURPOSE: This study sought to identify factors contributing to the inadequacies of systematic reviews and meta-analyses (SRMAs) published in the ophthalmology literature. DESIGN: Perspective. METHODS: Review and synthesis of selective literature, with interpretation and perspective. RESULTS: Although recommendations for the design, conduct, assessment of quality, and risk of bias of systematic reviews have been widely available, some recent publications illustrate a serious potential failing in this domain: inclusion of refuted science, lack of citation of post-publication correspondence and failure to use ≥1 alternative search strategy. CONCLUSIONS: Examples of inadequacies of peer review in medical literature and perpetuation of erroneous science by unfiltered inclusion in subsequent systematic reviews have been identified, and the problem can be traced to authors, peer reviewers, and editors of journals. This perspective identifies and analyzes several possible causes of the problem and recommends some specific corrective actions to improve the quality and accuracy of such reviews.

ISOPT Clinical Hot Topic Panel Discussion on Cornea Anterior Segment Disease.

The cornea and its adnexa pose a unique situation of a tightly defined set of requirements for its function. This includes: transparency, perfect built to obtain appropriate refractive power, protective barrier from microbial invaders. Moreso, the cornea also endures extreme external physical conditions (temperature, high and low humidity, winds and alike). All these functions are maintained while preserving a constant state of homogenous wetting. Toward that end the cornea is equipped with an elaborated network of sensory neural network. While enabling the blinking reflex and maintaining the physiological steady state of wetting, this neural network also makes the cornea prone to the discomfort that with or without associated changes seen on medical examination. ISOPT Clinical 2018 discussion touched upon this hypercomplex situation, addressing the role of inflammation and its resulting discomfort in dry eye conditions. The discussion also engulfed the emerging neuropathic pain syndrome that is recently gaining more attention. Another related topic was the utilization of autologous serum tears and its ability to provide amelioration to desperate patients. Finally, the panel discussed the issue of treating corneal infection, including when and how to utilize steroids in the course of therapy. We assume the reader will find interest in this discussion that directly addresses issues seen day in and day out in our busy clinics.

A randomized controlled trial of povidone-iodine/dexamethasone ophthalmic suspension for acute viral conjunctivitis.

PURPOSE: To evaluate the clinical safety and efficacy of povidone-iodine (PVP-I) 0.6%/dexamethasone (DEX) 0.1% ophthalmic suspension vs vehicle in patients with clinically suspected acute viral conjunctivitis. PATIENTS AND METHODS: This was a randomized, double-masked, parallel-group, vehicle-controlled study. Adults with a clinical diagnosis of suspected acute viral conjunctivitis were randomized 1:1 to PVP-I/DEX ophthalmic suspension or vehicle bilaterally four times daily for 5 days (Days 1-5). Evaluation was on Days 1, 3 (+1-day window), and 6 (+1). Patients with signs of acute viral conjunctivitis at the Day 6 visit received open-label PVP-I/DEX for five additional days and were evaluated on Day 11-14. The primary efficacy endpoint was clinical resolution of acute viral conjunctivitis in the study eye at the Day 6 visit. RESULTS: Overall, 132 patients were randomized and received treatment (PVP-I/DEX, n=66; vehicle, n=66); 38 patients continued into the open-label portion of the study. Not enough patients with confirmed adenoviral conjunctivitis (n=32/132) were enrolled to assess the primary endpoint, although there were some efficacy trends in the PVP-I/DEX group for global clinical score (sum of watery conjunctival discharge and bulbar conjunctival redness). There were no serious treatment-emergent adverse events (TEAEs) and no patients discontinued due to a TEAE. In the masked phase, 56.1% of patients receiving PVP-I/DEX experienced at least one TEAE vs 43.9% in the vehicle group; 78.9% of patients in the open-label phase experienced at least one TEAE. Most TEAEs were mild in severity. CONCLUSION: PVP-I/DEX ophthalmic suspension administered for ≤14 days had a favorable safety profile and was generally well tolerated.

Longitudinal changes in dry eye symptoms and signs following lifitegrast therapy and relationship to tear osmolarity.

BACKGROUND: This study measured longitudinal changes in dry eye disease (DED) symptoms and signs following lifitegrast therapy and assessed their relationship to tear osmolarity to test the hypothesis that a decline in tear osmolarity is a reliable leading indicator of subsequent improvement in DED symptoms and signs after initiating lifitegrast treatment. METHODS: This phase IV, prospective, single-arm, open-label, 12-week study enrolled subjects aged ≥18 years with eye dryness score ≥40 (0-100 VAS) and tear osmolarity ≥308 mOsm/L. Subjects were prescribed lifitegrast ophthalmic solution 5%, twice daily in each eye. DED symptoms were assessed via VAS at baseline and 2, 6, and 12 weeks. Signs included tear osmolarity, meibomian gland dysfunction, tear breakup time, and fluorescein corneal staining. In post-hoc analysis, subjects with ≥5 mOsm/L decrease in osmolarity over 12 weeks were Responders. RESULTS: Of 26 subjects in the intent-to-treat population, 23 were female; mean age was 67.4 years. Baseline mean±SD eye dryness was 68.7±16.5 and tear osmolarity was 317.8±8.5 mOsm/L. All seven symptoms (dryness, burning, foreign body sensation, pain, photophobia, itching, blurred vision) declined significantly (P<0.01) from baseline to 6 and 12 weeks. Signs did not change significantly. For 13 Responders, tear osmolarity decreased from baseline to 12 weeks (319.2±8.5 to 300.6±12.3 mOsm/L, P<0.001) and corneal staining trended toward improvement (1.1±0.9 to 0.6±0.7, P=0.136). Among Nonresponders, osmolarity increased from 316.4+8.7 to 329.6+13.9 (P<0.01) and corneal staining showed no change (1.3±0.8 to 1.0±0.7 at 12 weeks, P=0.293). CONCLUSIONS: Lifitegrast reduced DED symptoms among subjects with moderate-to-severe disease (severity defined by VAS for eye dryness). Potential reasons that may underlie the dichotomous effect of drug treatment on tear osmolarity are discussed.

Evaluation of the small-aperture intracorneal inlay: Three-year results from the cohort of the U.S. Food and Drug Administration clinical trial.

PURPOSE: To evaluate the safety and effectiveness of the Kamra small-aperture intracorneal inlay. SETTING: Centers in North America, Europe, Asia, and Australia. DESIGN: Prospective clinical trial. METHODS: Patients with emmetropic presbyopia had intracorneal implantation of the inlay in the nondominant eye. RESULTS: The study comprised 507 patients with emmetropic presbyopia who were aged 45 to 60 years old. The implanted eyes exhibited 3.5 diopters of defocus range above 20/40, with 363 (87.1%) of 417 patients and 391 (93.8%) of 417 patients having 20/40 or better monocular and binocular uncorrected near visual acuity (UNVA) at 36 months, respectively. Patients implanted via a femtosecond laser pocket procedure using a spot/line setting of 6 µm × 6 µm demonstrated further improved near vision, with 131 (90.3%) of 145 patients and 137 (94.5%) of 145 of patients having 20/40 or better monocular and binocular UNVA, respectively. Uncorrected distance visual acuity 20/25 or better was maintained in 135 (93.1%) of 145 of implanted eyes and 100% (145) of 145 of implanted eyes binocularly at 36 months. Less than 1.5% of eyes had a loss of 2 or more lines of corrected distance visual acuity for 3 months or more at any time after surgery. Forty-four inlays (8.7%) were removed from the full cohort over 3 years. The removal rate was significantly less in the 6 × 6 pocket group (3.0% for visual complaints) and further reduced with deeper implantation (0%). Less than 1.0% of the patients reported severe glare or halos postoperatively. CONCLUSION: The small-aperture corneal inlay was found to be safe and effective, improving near vision both monocularly and binocularly with minimal effect on distance visual acuity.

Randomized, Controlled, Phase 2 Trial of Povidone-Iodine/Dexamethasone Ophthalmic Suspension for Treatment of Adenoviral Conjunctivitis.

PURPOSE: To evaluate the efficacy/safety of an ophthalmic suspension of povidone-iodine (PVP-I) 0.6% and dexamethasone 0.1% in patients with acute adenoviral conjunctivitis. DESIGN: Multicenter, randomized, vehicle-controlled, double-masked trial. METHODS: Adults with a positive Rapid Pathogen Screening Adeno-Detector Plus test were randomized 1:1:1 to PVP-I 0.6%/dexamethasone 0.1%, PVP-I 0.6%, or vehicle, bilaterally 4 times daily for 5 days (days 1-5). Patients were evaluated on days 3, 6, and 12 (+1-day window). Efficacy measures included clinical resolution and adenoviral eradication. RESULTS: Overall, 144 patients were included in the efficacy analysis (PVP-I/dexamethasone, n = 48; PVP-I, n = 50; vehicle, n = 46). The proportion of patients with clinical resolution (primary study eye with last observation carried forward [LOCF]) at the day 6 visit was higher with PVP-I/dexamethasone (31.3%) than with vehicle (10.9%; P = .0158) and PVP-I (18.0%; P = nonsignificant). The proportion with adenoviral eradication (primary study eye with LOCF) was higher with PVP-I/dexamethasone than with vehicle at the day 3 (35.4% vs 8.7%; P = .0019) and day 6 (79.2% vs 56.5%; P = .0186) visits and vs PVP-I (day 3 visit, 32.0%; day 6 visit, 62.0%; each P = nonsignificant). Treatment-emergent adverse events (AEs) occurred in 69.0% (vehicle), 62.7% (PVP-I), and 53.4% (PVP-I/dexamethasone) of patients in the safety dataset. Discontinuation owing to AEs occurred in 37 patients (vehicle, n = 16; PVP-I, n = 12; PVP-I/dexamethasone, n = 9). CONCLUSION: PVP-I/dexamethasone appeared safe and well tolerated, and significantly improved clinical resolution and adenoviral eradication in patients with acute adenoviral conjunctivitis.

TFOS DEWS II iatrogenic report.

Dry eye can be caused by a variety of iatrogenic interventions. The increasing number of patients looking for eye care or cosmetic procedures involving the eyes, together with a better understanding of the pathophysiological mechanisms of dry eye disease (DED), have led to the need for a specific report about iatrogenic dry eye within the TFOS DEWS II. Topical medications can cause DED due to their allergic, toxic and immuno-inflammatory effects on the ocular surface. Preservatives, such as benzalkonium chloride, may further aggravate DED. A variety of systemic drugs can also induce DED secondary to multiple mechanisms. Moreover, the use of contact lens induces or is associated with DED. However, one of the most emblematic situations is DED caused by surgical procedures such as corneal refractive surgery as in laser-assisted in situ keratomileusis (LASIK) and keratoplasty due to mechanisms intrinsic to the procedure (i.e. corneal nerve cutting) or even by the use of postoperative topical drugs. Cataract surgery, lid surgeries, botulinum toxin application and cosmetic procedures are also considered risk factors to iatrogenic DED, which can cause patient dissatisfaction, visual disturbance and poor surgical outcomes. This report also presents future directions to address iatrogenic DED, including the need for more in-depth epidemiological studies about the risk factors, development of less toxic medications and preservatives, as well as new techniques for less invasive eye surgeries. Novel research into detection of early dry eye prior to surgeries, efforts to establish appropriate therapeutics and a greater attempt to regulate and oversee medications, preservatives and procedures should be considered.

Accommodating Intraocular Lenses.

With an explosive increase in the worldwide prevalence of presbyopia, development of an accommodating intraocular lens (IOL) with expansive accommodative amplitude remains the holy grail in lens-based refractive surgery. A dynamic change in the dioptric power of the eye can be accomplished by various strategies alone or in combination, including changes in the position, shape, or refractive index of a single- or dual- optic IOL. This article reviews the cumulative advances in these various lens designs, along with clinical outcomes and complications of those that have been implanted. The challenges that remain in each cat-egory are also highlighted.

Benefits and barriers of accommodating intraocular lenses.

PURPOSE OF REVIEW: Presbyopia and cataract development are changes that ubiquitously affect the aging population. Considerable effort has been made in the development of intraocular lenses (IOLs) that allow correction of presbyopia postoperatively. The purpose of this review is to examine the benefits and barriers of accommodating IOLs, with a focus on emerging technologies. RECENT FINDINGS: True accommodation of an IOL involves a dynamic increase in dioptric power to affect a shift from distance to intermediate or near focus. The Crystalens (Crystalens Bausch and Lomb, Inc., Rochester, NY, USA) was the first IOL labeled by the FDA as an accommodating IOL. Further studies have suggested that the Crystalens and several other single optic presbyopia-correcting IOLs may be providing improved intermediate or near vision predominantly through pseudoaccommodative mechanisms, in addition to small changes in axial translation. In light of these findings, a more objective demonstration of accommodation is now required for an IOL to have an accommodative label. Newer technology accommodating IOLs in development have embraced design strategies using dual optics, shape-changing optics, and IOLs with dynamic changes in refractive index. Prevention and treatment algorithms for capsular contraction syndromes unique to Crystalens and Trulign IOL designs will be discussed. SUMMARY: Accommodating IOLs that are in current use are constrained by their low and varied amplitude of accommodation. Such limitations may be circumvented in the future by accommodative design strategies that rely more on shape-related changes in the surfaces of the IOLs or in dynamic changes in refractive index than by forward translation alone.

Contrast Sensitivity in Patients With Emmetropic Presbyopia Before and After Small-Aperture Inlay Implantation.

PURPOSE: To develop a normative contrast sensitivity function and examine the postoperative contrast sensitivity outcomes for emmetropic patients with presbyopia implanted with a KAMRA intracorneal inlay (AcuFocus Inc., Irvine, CA) in their non-dominant eyes. METHODS: A prospective, non-randomized, multicenter clinical trial was conducted on 507 patients between 45 and 60 years of age who were monocularly implanted with the KAMRA inlay. A predetermined subgroup of 335 patients in the contrast sensitivity substudy were measured preoperatively and postoperatively with the Functional Acuity Contrast Test (FACT) chart in the Optec 6500 Vision Tester (Stereo Optical Co., Chicago, IL) under monocular and binocular, photopic and mesopic without glare, and binocular mesopic with glare conditions each over four spatial frequencies (3, 6, 12, and 18 cycles per degree for photopic conditions and 1.5, 3, 6, and 12 cycles per degree for mesopic conditions). Normative ranges were developed using 1.96 standard deviations from the preoperative mean logCS (log10 unit of contrast sensitivity). RESULTS: The preoperative contrast sensitivity measurements were used to develop the normative contrast sensitivity curves. Postoperatively, contrast sensitivity was stable both monocularly and binocularly and average contrast sensitivity remained within the normative ranges. Postoperative contrast sensitivity was mildly reduced monocularly but not binocularly, and the ratio of area under logCS function comparing postoperative to preoperative values was above 90% for all but one condition. CONCLUSIONS: Normative contrast sensitivity curves for a presbyopic population are established to provide a referent in the investigation of the impact of other presbyopia-correcting ophthalmic procedures on contrast sensitivity. [J Refract Surg. 2016;32(6):386-393.].