Efficacy and safety of 0.05% micellar nano-particulate (MNP) cyclosporine ophthalmic emulsion in the treatment of moderate-to-severe keratoconjunctivitis sicca: a 12-week, multicenter, randomized, active-controlled trial.

BACKGROUND: Keratoconjunctivitis sicca or dry eye disease (DED) is a multifactorial disorder underpinned by a complex inflammatory cycle. Introduction of topical cyclosporine has been a significant advance in the management of DED. In recent years advancements in formulation technology have led to development of micellar nano-particulate (MNP) cyclosporine formulations that promise better penetration into ocular target tissues and potential for reduced ocular surface irritation. METHODS: We compared two dosing regimes of a proprietary MNP cyclosporine emulsion with the widely marketed topical cyclosporine formulation Restasis™ in a multicenter parallel-group randomised trial in patients with DED. Patients were randomised to one of 3 treatment groups with 90 patients eligible for the per protocol analysis: 30 in the higher dose test arm A; 32 in the lower dose test arm B; and 28 in the Restasis™ control arm C. All scored efficacy endpoints were tested for significance by comparing the mean change in scores from baseline in the test groups with that in the control group at 12 weeks, using the Student's t test. Wilcoxon's rank sum test was used to test individual symptom scores and clinician's global evaluation of treatment grades. RESULTS: Corneal fluorescein staining score, the primary efficacy endpoint, decreased by 6.8 ± 4.0, 5.7 ± 3.9, and 4.6 ± 3.6 points in the 3 groups respectively, indicating superior efficacy in test arm A in comparison to control arm C (p = 0.0026). Schirmer's tear test, conjunctival lissamine staining score, ocular surface disease index, and individual dry eye symptom scores also favoured higher dose MNP cyclosporine over Restasis™. The study failed to differentiate the treatment arms in terms of clinician's global evaluation of treatment, use of tear substitutes, best corrected visual acuity or safety and toleration. CONCLUSION: The results indicate that the dose of 1 drop of a 0.05% w/v ophthalmic emulsion of MNP cyclosporine administered topically twice daily yields better outcomes at 12 weeks than the lower dose tested in the study, and is more efficacious than an equivalent dose of Restasis™, the active control used in the study. TRIAL REGISTRATION: This trial was registered in the Clinical Trials Registry of India on 29/03/2019, and was assigned registration number CTRI/2019/03/018319.

Cosmetic iris implants - double edge sword.

Iris implants were originally described as an option to treat photophobia and glare associated with aniridia, coloboma, corectopia or any other causes of acquired or congenital iris defects. They are not designed to be used in healthy phakic eyes and not approved by regulatory bodies anywhere in the world for cosmesis. However, widespread publicity and the compulsive need for beautification has popularised the use of these implants illicitly. Implantation into phakic eyes causes mechanical irritation of angle structures leading to chronic inflammation, pigment dispersion, prolonged endothelial cell loss and compression of the trabecular meshwork. The consequences are dire, leading to presentation of such patients with serious complications involving the cornea, angle, and lens. Here we give an extensive review of available literature on cosmetic iris implants and also describe a case with bilateral cosmetic iris implants (New-ColorIris). The patient presented with corneal decompensation, glaucoma, and cataract in both eyes, seven years after the implantation and was successfully managed with explantation of the device followed by a DMEK Triple procedure.

Biomarkers of in vivo limbal stem cell function.

PURPOSE: To evaluate in vivo parameters as biomarkers of limbal stem cell function and to establish an objective system that detects and stage limbal stem cell deficiency (LSCD). METHODS: A total of 126 patients (172 eyes) with LSCD and 67 normal subjects (99 eyes) were included in this observational cross-sectional comparative study. Slit-lamp biomicroscopy, in vivo laser scanning confocal microscopy (IVCM), and anterior segment optical coherence tomography (AS-OCT) were performed to obtain the following: clinical score, cell morphology score, basal cell density (BCD), central corneal epithelial thickness (CET), limbal epithelial thickness (LET), total corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), and tortuosity coefficient. Their potential correlations with the severity of LSCD were investigated, and cutoff values were determined. RESULTS: An increase clinical score correlated with a decrease in central cornea BCD, limbal BCD, CET, mean LET, maximum LET, CNFL, CNFD, CNBD, and tortuosity coefficient. Regression analyses showed that central cornea BCD, CET and CNFL were the best parameters to differentiate LSCD from normal eyes (Coef = 3.123, 3.379, and 2.223; all p < 0.05). The rank correlation analysis showed a similar outcome between the clinical scores and the central cornea BCD (ρ = 0.79), CET (ρ = 0.82), and CNFL (ρ = 0.71). A comprehensive LSCD grading formula based on a combination of these parameters was established. CONCLUSIONS: A comprehensive staging system combining clinical presentation, central cornea BCD, CET, and CNFL is established to accurately and objectively diagnose LSCD and stage its severity.

Cell Morphology as an In Vivo Parameter for the Diagnosis of Limbal Stem Cell Deficiency.

PURPOSE: The aim of this study was to investigate basal epithelial cell morphology (CM) in the central cornea and limbal areas of eyes with limbal stem cell deficiency (LSCD). METHODS: This was a prospective, cross-sectional comparative study. We developed a CM scoring system based on basal epithelial cell phenotypes graded from 0 (normal) to 3 (severe morphologic alterations); this system was evaluated by 2 independent masked observers. The CM score was compared with the LSCD clinical score, mean best-corrected visual acuity, and in vivo laser scanning confocal microscopy parameters used to stage LSCD (ie, basal epithelial cell density, basal epithelial thickness, and subbasal corneal nerve fiber length density). RESULTS: One hundred sixty-eight eyes with LSCD and 63 normal eyes were included. Compared with the control group, the LSCD group had significantly higher mean (±SD) CM scores in the central cornea (1.8 ± 0.7 vs. 0.5 ± 0.4, respectively; P = 0.01) and limbal areas (1.6 ± 0.2 vs. 1.3 ± 0.0, respectively; P < 0.05). The mean CM score in the central cornea was positively correlated with the clinical score ( P < 0.01, r = 0.66) and negatively correlated with the best-corrected visual acuity ( P < 0.01, r = 0.42). The CM scores were positively correlated with all other in vivo laser scanning confocal microscopy parameters in the central cornea and limbal areas (all P < 0.001). CONCLUSIONS: Basal epithelial CM is altered in the central cornea and limbus of eyes with LSCD and thus can be used to stage the clinical severity of the disease.

Sequence of events leading to diagnosis of keratoconus and its impact on quality of life.

PURPOSE: Early diagnosis of keratoconus (KCN) and corneal collagen cross-linking can ensure that best-corrected visual acuity is preserved. We report the sequence of events leading to the diagnosis of KCN, as well as its impact on quality of life. METHODS: This survey-based study included patients diagnosed with KCN for the first time at our center. Their corneal tomography was analyzed, and they were provided with a proforma and the NEI-VFQ-25 questionnaire and were asked to answer the given set of questions. RESULTS: The study included 328 eyes of 164 patients. At the time of diagnosis, 112 (68.3%) patients were not aware of a disease called "keratoconus." VKC was present in 56 patients, and 92 patients were not aware of the need to avoid eye rubbing. In total, 101 patients gave a history of sleeping more often on the side with worse KCN. The preferred primary point of contact was an optometrist for 45.1% of patients; 51.2% of patients reported never having visited an ophthalmologist. Sixty-four (39%) patients were advised a screening test to rule out KCN before presenting to our center; 42 (71.8%) of these patients did not get it done. Vision-targeted score showed a significant negative correlation with grade of KCN (r value: -0.471) and positive correlation (r value: 0.534) with LogMAR vision. CONCLUSION: KCN is a disease of the young and severely affects the quality of life. Improving awareness of the general public, ensuring timely referral by optometrists, and keeping a high index of suspicion is emphasized.

Diagnostic criteria for limbal stem cell deficiency before surgical intervention-A systematic literature review and analysis.

An accurate diagnosis of limbal stem cell deficiency (LSCD) is the premise of an appropriate treatment; however, there is no consensus about the diagnostic criteria for LSCD. We performed a systematic literature search of the peer-reviewed articles on PubMed, Medline, and Ovid to investigate how LSCD was diagnosed before surgical intervention. The methods used to diagnose LSCD included clinical presentation, impression cytology, and in vivo confocal microscopy. Among 131 eligible studies (4054 eyes), 26 studies (459 eyes, 11.3%) did not mention the diagnostic criteria. In the remaining 105 studies, the diagnosis of LSCD was made on the basis of clinical examination alone in 2398 eyes (62.9%), and additional diagnostic tests were used in 1047 (25.8%) eyes. Impression cytology was used in 981 eyes (24.2%), in vivo confocal microscopy was used in 29 eyes (0.7%), and both impression cytology and in vivo confocal microscopy were used in 37 eyes (0.9%). Our findings suggest that only a small portion of patients underwent a diagnostic test to confirm the diagnosis of LSCD. Treating physicians should be aware of the limitations of clinical examination in diagnosing LSCD and perform a diagnostic test whenever possible before surgical intervention.

Pigment dispersion syndrome diagnosed after photorefractive keratectomy-A case report.

Pigment dispersion syndrome predominantly affects young myopes. It is not uncommon for such patients to seek refractive surgery. It may also be encountered after an uneventful refractive surgery. We report a case of a young myopic male who presented with bilateral pigment dispersion syndrome 9 months after an uneventful photorefractive keratectomy. A meticulous ocular examination is the cornerstone of a successful refractive surgery. Through this report, we highlight the need for gonioscopy to be included as a routine examination in screening for refractive surgery.

Outcomes of Limbal Stem Cell Transplant: A Meta-analysis.

Importance: Limbal stem cell transplant (LSCT) can be categorized as direct autologous limbal transplant (AULT), direct allogenic limbal transplant (ALLT), cultivated autologous limbal stem cells transplant (cAULT), and cultivated allogenic limbal stem cells transplant (cALLT). To our knowledge, there is no study directly comparing the outcomes and complications of these procedures. Objective: To evaluate the outcomes of different LSCT procedures. Data Source: We searched PubMed, EMBASE, Web of Science, and Cochrane without language filter for peer-reviewed articles about LSCT. The latest search was performed on June 30, 2019. Study Selection: Clinical studies with the outcome of at least 20 eyes after LSCT were included. Animal studies and studies of other surgical interventions were excluded. Data Extraction and Synthesis: Two reviewers independently abstracted the data from each study. Heterogeneity was evaluated with the I2 statistic, and a meta-analysis was performed using the random-effects model. Main Outcomes and Measures: Outcome measures included the improvement of ocular surface, visual acuity (VA), and adverse events of recipient eyes and donor eyes. Results: Forty studies (2202 eyes) with a mean (SD) follow-up of 31.3 (20.9) months met the inclusion criteria. The mean (SD) age of study participants was 38.4 (13.1) years, and men accounted for 74%. The number of eyes that underwent AULT, ALLT, cAULT, and cALLT were 505, 742, 771, and 184, respectively. Improvement of the ocular surface was achieved in 74.5% of all eyes, 85.7% of eyes after AULT (95% CI, 79.5%-90.3%), 84.7% after cAULT (95% CI, 77.2%-90.0%), 57.8% after ALLT (95% CI, 49.0%-66.1%), and 63.2% after cALLT (95% CI, 49.3%-75.2%). Autologous limbal transplantation resulted in a greater VA improvement rate (76%) than did the other 3 procedures (cAULT: 56.4%; ALLT: 52.3%; cALLT: 43.3%; all P < .001). The most common adverse events in all recipient eyes were recurrent/persistent epithelial erosion (10.5%; 95% CI, 7.2%-23.3%) and elevated intraocular pressure (intraocular pressure, 1.7%; 95% CI, 0.5%-7.8%). Patients who underwent ALLT had the highest rate of recurrent epithelial erosion (27.8%; 95% CI, 17.1%-41.9%) and intraocular pressure elevation (6.3%; 95% CI, 1.8%-19.4%). Conclusions and Relevance: These findings suggest LSCT can improve or stabilize the corneal surface with a low rate of severe ocular complications and that autologous LSCT may have a higher success rate and fewer complications than allogenic LSCT.

Corneal Perforation After Corneal Cross-Linking in Keratoconus Associated With Potentially Pathogenic ZNF469 Mutations.

PURPOSE: To report a case of bilateral and repetitive corneal perforations after corneal cross-linking (CXL) for keratoconus in a woman harboring potentially pathogenic variants in the ZNF469 gene and to characterize the keratoconus phenotype in this woman and her daughter who shared the same ZNF469 mutations. METHODS: Clinical characterization of the proband and her daughter followed by sequencing of the genes associated with brittle cornea syndrome, ZNF469 and PRDM5, in both individuals. RESULTS: An Ashkenazi Jewish woman in her sixth decade presented with diffuse corneal thinning and progressive steepening consistent with keratoconus. After CXL, epithelium-off in the first eye and epithelium-on in the second, she developed spontaneous corneal perforations in each eye. Her daughter in her fourth decade demonstrated a similar pattern of diffuse corneal thinning and progressive corneal steepening but did not undergo CXL and did not develop corneal perforation. Screening of the ZNF469 and PRDM5 genes revealed 3 missense ZNF469 variants (c.2035G>A, c.10244G>C, and c.11119A>G) in cis arrangement on 1 allele of ZNF469 in both proband and her daughter. Although the 3 variants share low (<0.01) global minor allele frequencies, each has significantly higher minor allele frequencies (0.01-0.03) in the Ashkenazi Jewish population, leading to uncertainty regarding a pathogenic role for the identified variants. CONCLUSIONS: CXL may be associated with the development of corneal perforation in particular at-risk individuals with keratoconus. Identifying clinical and genetic risk factors, including screening of ZNF469 and PRDM5, may be useful in the prevention of significant complications after CXL.

Phakic Intraocular Lenses and their Special Indications.

Phakic intraocular lenses revolutionize refractive surgery and continue to serve as an excellent option for vision correction in patients who are not ideal candidates for laser vision correction. This article will review special indications of phakic intraocular lenses in the clinical practice.