The Orphan Drug for Acanthamoeba Keratitis (ODAK) Trial: PHMB 0.08% (Polihexanide) and Placebo versus PHMB 0.02% and Propamidine 0.1.

PURPOSE: To compare topical PHMB (polihexanide) 0.02% (0.2 mg/ml)+ propamidine 0.1% (1 mg/ml) with PHMB 0.08% (0.8 mg/ml)+ placebo (PHMB 0.08%) for Acanthamoeba keratitis (AK) treatment. DESIGN: Prospective, randomized, double-masked, active-controlled, multicenter phase 3 study (ClinicalTrials.gov identifier, NCT03274895). PARTICIPANTS: One hundred thirty-five patients treated at 6 European centers. METHODS: Principal inclusion criteria were 12 years of age or older and in vivo confocal microscopy with clinical findings consistent with AK. Also included were participants with concurrent bacterial keratitis who were using topical steroids and antiviral and antifungal drugs before randomization. Principal exclusion criteria were concurrent herpes or fungal keratitis and use of antiamebic therapy (AAT). Patients were randomized 1:1 using a computer-generated block size of 4. This was a superiority trial having a predefined noninferiority margin. The sample size of 130 participants gave approximately 80% power to detect 20-percentage point superiority for PHMB 0.08% for the primary outcome of the medical cure rate (MCR; without surgery or change of AAT) within 12 months, cure defined by clinical criteria 90 days after discontinuing anti-inflammatory agents and AAT. A prespecified multivariable analysis adjusted for baseline imbalances in risk factors affecting outcomes. MAIN OUTCOME MEASURES: The main outcome measure was MCR within 12 months, with secondary outcomes including best-corrected visual acuity and treatment failure rates. Safety outcomes included adverse event rates. RESULTS: One hundred thirty-five participants were randomized, providing 127 in the full-analysis subset (61 receiving PHMB 0.02%+ propamidine and 66 receiving PHMB 0.08%) and 134 in the safety analysis subset. The adjusted MCR within 12 months was 86.6% (unadjusted, 88.5%) for PHMB 0.02%+ propamidine and 86.7% (unadjusted, 84.9%) for PHMB 0.08%; the noninferiority requirement for PHMB 0.08% was met (adjusted difference, 0.1 percentage points; lower one-sided 95% confidence limit, -8.3 percentage points). Secondary outcomes were similar for both treatments and were not analyzed statistically: median best-corrected visual acuity of 20/20 and an overall treatment failure rate of 17 of 127 patients (13.4%), of whom 8 of 127 patients (6.3%) required therapeutic keratoplasty. No serious drug-related adverse events occurred. CONCLUSIONS: PHMB 0.08% monotherapy may be as effective (or at worse only 8 percentage points less effective) as dual therapy with PHMB 0.02%+ propamidine (a widely used therapy) with medical cure rates of more than 86%, when used with the trial treatment delivery protocol in populations with AK with similar disease severity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Corneal Decompensation in Uveitis Patients: Incidence, Etiology, and Outcome.

Purpose: To identify the prevalence, etiology, management and visual outcomes of treatment in uveitis-related corneal decompensation.Patients and methods: This is a retrospective study of patients with corneal decompensation identified from a large cohort with uveitis in a tertiary referral clinic setting.Results: Between March 1991 and May 2018, 4132 new patients with uveitis were seen in Manchester Uveitis Clinic. Of these, 25 patients (0.6%) were identified with corneal decompensation of which 9 (0.2%) were affected bilaterally (total 34 eyes). The mean interval between uveitis diagnosis and decompensation was 23 months (range 0-117 m). Ten patients (41%) had associated glaucoma. Seventeen eyes (50%) had undergone intraocular surgery prior to decompensation. For eyes with no history of raised intraocular pressure or intraocular surgery, keratouveitis (presumed autoimmune or tuberculous) was the most common cause of corneal decompensation. Fourteen eyes (41%) required corneal graft and of these, five required repeat grafting.Conclusions: Corneal decompensation in eyes with uveitis is a rare but significant complication. Direct endothelial inflammation may alone cause decompensation, but in most eyes with uveitis, prior raised intraocular pressure or intraocular surgery are required to precipitate the cornea into decompensation. Outcomes of corneal transplantation in this group may be disappointing.

Subconjunctival Ab Externo Gel Stent Implantation for Refractory Glaucoma After High-Risk Penetrating Keratoplasty.

This case study reports the successful deployment of the XEN45 gel stent (AbbVie Inc, Chicago, IL) through an ab externo approach in a 73-year-old woman with refractory glaucoma following high-risk penetrating keratoplasty (PK) 10 years prior. The PK was for corneal perforation secondary to peripheral ulcerative keratitis, which required systemic immunosuppression comprising intravenous cyclophosphamide, azathioprine, and corticosteroids to stabilise the disease and prevent corneal graft rejection. The patient's intraocular pressure was reduced from 40 mmHg preoperatively to 12 mmHg six months after surgery, off medication. The patient's visual acuity and visual fields remained stable. The XEN45 gel stent utilising the ab externo approach can be considered as a potential tool to lower intraocular pressure in patients with glaucoma after corneal keratoplasty.

Corneal clarity measurements in patients with keratoconus undergoing either penetrating or deep anterior lamellar keratoplasty.

PURPOSE: To compare the corneal clarity measurement between penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) in patients with keratoconus, using densitometry software for the Oculus Pentacam. METHODS: A retrospective comparative study was carried out at Manchester Royal Eye Hospital. Data were collected 12-18 months after corneal transplantation for keratoconus, including postoperative corneal densitometry, best corrected visual acuity (BCVA), central corneal thickness (CCT), and other relevant clinical details. RESULTS: Analysis of 37 keratoconus eyes from 36 patients found there was a significantly higher corneal densitometry measurement after DALK than PK. This was predominantly in the posterior layer of the concentric zone 0-2 mm of the cornea (P=0.0004). A significant correlation was found between postoperative BCVA and corneal densitometry in DALK groups at full thickness (P=0.03). This correlation was seen in the central 0-2 mm (P=0.03) and posterior 0-2 mm (P=0.04) zones. In addition, within the DALK group, a correlation was found between central corneal thickness and densitometry at full thickness 2-6 mm (P=0.007), central 0-2 (P=0.04), central 2-6 mm (P=0.01), and at posterior 2-6 mm (P=0.01) zones. CONCLUSION: This study showed that corneal densitometry measurement differs depending on the type of corneal transplantation used to treat keratoconus patients. Densitometry may have an important role to play in the final BCVA achieved by patients undergoing corneal transplantation for keratoconus. Analysis of Oculus Pentacam images provides an objective evaluation to monitor the cornea status after the surgery.

Tomographic indices as possible risk factors for progression in pediatric keratoconus.

PURPOSE: To determine whether corneal tomography can help predict the risk of progression of keratoconus in children. METHODS: The medical records of pediatric patients with keratoconus presenting to a large tertiary institution in the UK from 2009 to 2014 were reviewed retrospectively. Patients underwent serial clinical examination and corneal tomography. The minimum follow-up period was 5 months. Patients with a history of eye surgery including corneal crosslinking were excluded. The following tomographic parameters were analyzed: thinnest corneal thickness (TCT), average central corneal keratometry (Km), and maximum central posterior elevation (MCPE). The rate of progressive corneal thinning, in µm/month, was calculated as the difference between TCT on presentation and at the most recent visit divided by the time in months. RESULTS: A total of 36 eyes of 19 patients (10-16 years of age) were included. Mean follow-up was 19 months (range, 5-30 months). Six eyes (17%) developed corneal scarring and 1 eye (3%) developed acute hydrops. Of the 29 eyes that did not develop corneal scarring or hydrops, 24 (83%) demonstrated progressive corneal thinning over the period of the study. Eyes with TCT of <450 µm, Km above 50 D, and MCPE above 50 µm at presentation demonstrated the highest rates of progressive corneal thinning over the study period. CONCLUSIONS: In pediatric keratoconus, lower TCT, higher Km, and higher MCPE on corneal tomography seem to be risk factors for faster rates of progressive corneal thinning.

Regeneration of Corneal Epithelium With Dental Pulp Stem Cells Using a Contact Lens Delivery System.

PURPOSE: The corneal epithelium is sloughed off surface of the eye by the action of blinking and is continually replaced by division and maturation of the limbal stem cells (LSCs). In the case of injury or disease, LSCs can be lost or damaged to a point at which the corneal epithelial layer is no longer maintained. leading to LSC deficiencies (LSCDs). When this occurs, the opaque conjunctiva overgrows the anterior surface of the eye, leading to vision impairment or loss. Dental pulp stem cells (DPSCs) are promising candidates as autologous LSC substitutes. In this study, contact lenses (CLs) are used as a novel medical device to deliver DPSCs onto corneal surface to enhance corneal epithelium regeneration. METHODS: Dental pulp stem cells labeled with green fluorescent Qtracker 525 were seeded onto the pretreated CLs, allowed to adhere, then delivered to debrided human corneas. Expression of KRT3, 12, 13, and 19 was investigated by immunostaining, then standard and confocal microscopy. RESULTS: Dental pulp stem cells were successfully isolated, labeled, and delivered to the corneal surface using CLs. Following removal of CLs, confocal microscopy showed that the DPSCs had migrated onto the cornea. Coexpression of KRT12 and green fluorescent Qtracker 525 confirmed that the DPSCs had transdifferentiated into corneal epithelial progenitors. Delimitation of KRT 19 and green fluorescence provides evidence that Qtracker 525-labeled DPSCs establish a barrier to the invasion of the cornea by conjunctiva. CONCLUSIONS: In this study we show that DPSCs, delivered using CLs, can be used to enhance repair and regeneration of the human corneal epithelium.

Biomechanical Changes of Collagen Cross-Linking on Human Keratoconic Corneas Using Scanning Acoustic Microscopy.

PURPOSE: To assess the biomechanical changes of collagen cross-linking on keratoconic corneas in vitro. METHODS: Six keratoconic corneal buttons were included in this study. Each cornea was divided into two halves, where one half was cross-linked and the other half was treated with riboflavin only and served as control. The biomechanical changes of the corneal tissue were measured across the stroma using scanning acoustic microscopy (SAM). RESULTS: In the cross-linked corneas, there was a steady decrease in the magnitude of speed of sound from the anterior region through to the posterior regions of the stroma. The speed of sound was found to decrease slightly across the corneal thickness in the control corneas. The increase in speed of sound between the cross-linked and control corneas in the anterior region was by a factor of 1.039×. CONCLUSION: A higher speed of sound was detected in cross-linked keratoconic corneal tissue when compared with their controls, using SAM. This in vitro model can be used to compare to the cross-linking results obtained in vivo, as well as comparing the results obtained with different protocols.

The suitability of corneas stored by organ culture for penetrating keratoplasty and influence of donor and recipient factors on 5-year graft survival.

PURPOSE: To determine the impact of donor factors on the suitability of corneas stored by organ culture for penetrating keratoplasty (PK) and the influence of donor and recipient factors on 5-year survival of first PK. METHODS: Logistic regression analyses were carried out to determine the influence of donor factors on, respectively, the risk of microbial contamination during organ culture, the suitability of corneas for PK (endothelial cell density ≥ 2200 cells/mm(2)), and the quality of corneas (endothelial cell density ≥ 2500 cells/mm(2)). Only one cornea, randomly selected, from each donor was included in these analyses. A Cox regression analysis was used to determine the influence of donor and recipient factors on 5-year PK survival. RESULTS: Risk of contamination (n = 8317): Causes of donor death including infection, respiratory disease, and cancer all increased the risk of contamination during organ culture (P < 0.0001). Suitability for PK and endothelial quality (n = 7107): Donor age (P < 0.0001) and storage time in organ culture (P < 0.0001) were the principal factors affecting suitability and quality. Death to enucleation and enucleation to processing times had little influence. Corneas from organ donors were more likely to be suitable for PK (P = 0.0003). Five-year graft survival (n = 3014): Graft survival was dominated by the indication for PK (P < 0.0001). Allograft rejection was also a major risk factor for failure (P < 0.0001). The only donor factor affecting survival was sex (P = 0.008). CONCLUSIONS: Donor age and storage time but not postmortem times influenced the suitability of corneas for PK. The indication for PK and other recipient factors were the main predictors of graft failure.

Trends in the indications for corneal graft surgery in the United Kingdom: 1999 through 2009.

OBJECTIVE: To examine trends in the indications for corneal graft surgery in the United Kingdom. METHODS: National Health Service Blood and Transplant data were analyzed for keratoplasty operations performed in the United Kingdom between April 1, 1999, and March 31, 2009, distinguishing the type of graft and the surgical indication. RESULTS: The total number of annual keratoplasty operations increased from 2090 in 1999-2000 to 2511 in 2008-2009. Among these, the annual number of grafts performed for endothelial failure increased from 743 (35.6%) in 1999-2000 to 939 (37.4%) in 2008-2009. The performance of penetrating keratoplasty (PK) for endothelial failure decreased from 98.3% of all grafts in 1999-2000 to 46.6% of all grafts in 2008-2009, while the performance of endothelial keratoplasty increased from 0.3% of all grafts in 1999-2000 to 51.2% of all grafts in 2008-2009. The annual number of grafts performed for keratoconus increased from 514 (24.6%) in 1999 to 564 (22.5%) in 2008-2009. The performance of PK for keratoconus decreased from 88.4% of all grafts in 1999-2000 to 57.1% of all grafts in 2008-2009, while the performance of deep anterior lamellar keratoplasty increased from 8.8% of all grafts in 1999-2000 to 40.1% of all grafts in 2008-2009. The number of annual regraft operations increased from 249 (11.9%) in 1999-2000 to 401 (16.0%) in 2008-2009, most commonly for endothelial failure. In 2008-2009, PK regrafts (78.1%) far outnumbered endothelial keratoplasty regrafts (17.0%). CONCLUSIONS: Endothelial failure is the most common indication for keratoplasty in the United Kingdom, and endothelial keratoplasty is performed more commonly than PK for this indication. The number of grafts performed for pseudophakic bullous keratopathy has remained stable, while the number of grafts performed for Fuchs endothelial dystrophy is likely to continue increasing. Keratoconus is the second most common indication for keratoplasty, and deep anterior lamellar keratoplasty numbers are approaching those for PK. Regraft surgery is the third most common indication for keratoplasty, required in most cases because of endothelial failure.

Trends in corneal graft surgery in the UK.

AIMS: The aims of this study were to examine trends over time and regional variation in rates of corneal graft surgery in the UK. METHODS: The hospital in-patient enquiry (HIPE) and hospital episode statistics (HES) were analysed for keratoplasty admissions in England from 1971 to 2006. NHS Blood and Transplant (NHSBT) data were analysed for keratoplasty operations in the UK from 1999 to 2009. RESULTS: Annual rates of penetrating keratoplasty (PK) under HIPE and HES increased from 0.7 per 100,000 population (1971) to 3.9 (1992), then decreased to 3.1 (2006). Rates of lamellar keratoplasty (LK) increased from 0.1 (1971) to 0.9 (2006). Annual PK operations under NHSBT decreased from 1901 (1999/00) to 1473 (2008/9). Over the same period, deep anterior lamellar keratoplasty operations increased from 91 to 327 per year, while endothelial keratoplasty operations increased from 2 to 569 per year. Geographical analysis showed a wide variation across local authority areas in rates of keratoplasty around 1998-2004, especially for LK. CONCLUSION: The total number of corneal graft operations performed in the UK has increased slowly over the past decade. The proportion of lamellar versus penetrating keratoplasty has increased, with LK performed at the highest rates in specialist centres distributed across the UK.

Darier disease: beware the cyst that smells.

A 32-year-old woman presented with cystic eyelid lesions accompanied by foul-smelling discharge. Excision biopsy showed that she had Darier disease, and she was referred to dermatology for further management. Despite clinically indolent-looking lesions, biopsy and histology allowed the diagnosis of this rare condition to be made.

Total encapsulation and asymmetric deformation of an intraocular lens.

We report a case of marked anterior capsule contraction after uneventful cataract surgery in an 82-year-old women. The patient had implantation of a single-piece foldable acrylic intraocular lens (IOL) after phacoemulsification through a 3.0 mm superior corneal incision. Between 1 month and 5.5 months after surgery, significant anterior capsule contraction ensued with total encapsulation of the lens. The resultant fibrotic reaction, which had a localized tangential component, caused an asymmetric deformation and mild IOL displacement. The patient was treated on separate occasions with a neodymium:YAG laser anterior capsulotomy and surgical capsulotomy to release tension on the lens and clear the visual axis.