To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting ...from impaired corneal innervation.
Phase II multicenter, randomized, double-masked, vehicle-controlled trial.
Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye.
The REPARO phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat.
Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining).
At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 μg/ml (+35.3%; 97.06% confidence interval CI, 15.88–54.71; P < 0.001) and 58.0% receiving rhNGF 20 μg/ml (+38.4%; 97.06% CI, 18.96–57.83; P < 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 μg/ml (+31.4%; 97.06% CI, 11.25–51.49; P = 0.001) and 74.0% receiving rhNGF 20 μg/ml (+30.9%; 97.06% CI, 10.60–51.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient.
Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK.
In a routine cataract operation cornea tissue may be damaged when an intra-ocular lens (IOL) injector of diameter between 1.467 and 2.011 mm is inserted through an empirically designed 2.2 mm corneal ...incision. We aimed to model and estimate the minimal length of the incision required to avoid wound tear. It was assumed that the damage was caused by tissue fracture at the tips of the incision, and this fracture could be studied using damage and fracture mechanics. The criterion of the damage was caused by a tear governed by the critical energy release rate (ERR)
, which is tissue dependent. Analytical and numerical studies were both conducted indicating the possibility of a safe and effective incision in cataract surgery. Six commonly used IOL injection systems were examined. Our results suggested that the recommended 2.2 mm incision cannot be treated as a universal threshold. Quicker IOL insertion may reduce wound damage. It was also recommended to advance IOL injector
its minor axis, and to cut the tear preferably along the circumferential direction due to tissue orthotropy. This study provides useful information and a deeper insight into the potential for mechanical damage to the corneal wound in cataract surgery.
Alzheimer’s disease (AD) is the leading cause of dementia, which is a growing public health concern. Although there is no curative treatment for established AD, early recognition and modification of ...the known risk factors can reduce both severity and the rate of progression. Currently, an early diagnosis of AD is rarely achieved, as there is no screening for AD. The cognitive decline in AD is gradual and often goes unnoticed by patients and caregivers, resulting in patients presenting at later stages of the disease. Primary care physicians (general practitioners in the UK) can administer a battery of tests for patients presenting with memory problems and cognitive impairment, however final diagnosis of AD is usually made by specialised tertiary level clinics. Recent studies suggest that in AD, visuospatial difficulties develop prior to the development of memory problems and screening for visuospatial difficulties may offer a tool to screen for early stage AD. AD and cataracts share common risk and predisposing factors, and the stage of cataract presentation for intervention has shifted dramatically with early cataract referral and surgical intervention becoming the norm. This presentation offers an ideal opportunity to administer a screening test for AD, and visuospatial tools can be administered at post-operative visits by eye clinics. Abnormal findings can be communicated to primary care physicians for further follow up and assessment, or possible interventions which modify risk factors such as diabetes, hypertension and obesity can be undertaken. We propose that eye clinics and ophthalmology facilities have a role to play in the early diagnosis of AD and reducing the burdens arising from severe dementia.
The aim of this paper was to further develop a previously described finite element model which equates clinical iris billowing movements with mechanical buckling behaviour, simulating floppy iris ...syndrome. We wished to evaluate the impact of pupil dilation and mechanical devices on normal iris and floppy iris models.
Theoretical mathematical modelling and computer simulations were used to assess billowing/buckling patterns of the iris under loading pressures for the undilated and dilated normal iris, the undilated and dilated floppy iris, and additionally with a mechanical ring device.
For the normal iris, billowing/buckling occurred at a critical pressure of 19.92 mmHg for 5 mm pupil size, which increased to 28.00 mmHg (40.56%) with a 7 mm pupil. The Malyugin ring device significantly increased critical initiating buckling pressures in the normal iris scenario, to 34.58 mmHg (73.59%) for 7 mm ring with boundary conditions I (BC I) and 34.51 mmHg (73.24%) with BC II. For the most floppy iris modelling (40% degradation), initiating buckling value was 18.04 mmHg (-9.44%), which increased to 28.39 mmHg (42.52%) with the 7 mm ring. These results were much greater than for normal undilated iris without restrictive mechanical expansion (19.92 mmHg).
This simulation demonstrates that pupil expansion devices inhibit iris billowing even in the setting of floppy iris syndrome. Our work also provides a model to further investigate the impact of pupil size or pharmacological interventions on anterior segment conditions affected by iris position.
Povidone-iodine (PVI) preparations are well known for their microbicidal effect. In ophthalmology, PVI is commonly used to sterilise the ocular surface prior to surgical procedures. It is also used ...uncommonly as treatment for adenoviral conjunctivitis, yet the virucidal benefits of PVI have not been clearly documented in existing clinical management guidelines for ocular surface conditions. The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has challenged traditional healthcare systems. The morbidity and mortality of this highly contagious disease have resulted in fatalities among healthcare workers, including ophthalmologists. The SARS-CoV-2 virus has been identified on conjunctival testing, a potential source of contagious infection which may be unrecognised in asymptomatic carriers. Concern has been raised that ocular procedures may be ‘aerosol-generating’ and the additional wearing of personal protective equipment has been recommended to protect operating theatre staff. This literature review demonstrates that PVI has a broad virucidal activity, including against coronaviruses. It is already used perioperatively as standard of ophthalmic care and has been shown clinically to be effective against adenoviruses on the ocular surface. The current surgical practice of application of 5%–10% PVI applied periocularly for 3 min seems to provide an adequate effective reduction in the patient’s ocular surface viral load. The virucidal benefits of routine PVI use should be included in ophthalmology guidelines regarding safe ocular surgery protocols.
Acanthamoeba keratitis (AK) is a severe infection of the cornea. Prevention and treatment are difficult due to the inefficacy of currently available compounds. The impact of many commonly used ...compounds for routine examinations of Acanthamoeba is unexplored but might offer insight useful in combatting AK. In this study, we demonstrate that sodium metabisulfite, a common preservation constituent of eye care solutions, was found to be active against Acanthamoeba trophozoites at concentrations lower than that commonly found in eye drops (IC50 0.03 mg/mL). We demonstrate that sodium metabisulfite depletes thiamine from growth medium and that Acanthamoeba is a thiamine auxotroph, requiring thiamine salvage for growth. The inhibitory effects of sodium metabisulfite can be overcome by thiamine supplementation. These results are consistent with the lack of key enzymes for thiamine biosynthesis in the genome of Acanthamoeba, an area which might prove exploitable using new or existing compounds. Indeed, this study highlights sodium metabisulfite as a useful inhibitor of Acanthamoeba castellanii trophozoites in vitro and that it acts, at least in part, by limiting available thiamine.
We aimed to test previous predictions that limbal epithelial stem cells (LESCs) are quantitatively deficient or qualitatively defective in Pax6(+/-) mice and decline with age in wild-type (WT) mice. ...Consistent with previous studies, corneal epithelial stripe patterns coarsened with age in WT mosaics. Mosaic patterns were also coarser in Pax6(+/-) mosaics than WT at 15 weeks but not at 3 weeks, which excludes a developmental explanation and strengthens the prediction that Pax6(+/-) mice have a LESC-deficiency. To investigate how Pax6 genotype and age affected corneal homeostasis, we compared corneal epithelial cell turnover and label-retaining cells (LRCs; putative LESCs) in Pax6(+/-) and WT mice at 15 and 30 weeks. Limbal BrdU-LRC numbers were not reduced in the older WT mice, so this analysis failed to support the predicted age-related decline in slow-cycling LESC numbers in WT corneas. Similarly, limbal BrdU-LRC numbers were not reduced in Pax6(+/-) heterozygotes but BrdU-LRCs were also present in Pax6(+/-) corneas. It seems likely that Pax6(+/-) LRCs are not exclusively stem cells and some may be terminally differentiated CD31-positive blood vessel cells, which invade the Pax6(+/-) cornea. It was not, therefore, possible to use this approach to test the prediction that Pax6(+/-) corneas had fewer LESCs than WT. However, short-term BrdU labelling showed that basal to suprabasal movement (leading to cell loss) occurred more rapidly in Pax6(+/-) than WT mice. This implies that epithelial cell loss is higher in Pax6(+/-) mice. If increased corneal epithelial cell loss exceeds the cell production capacity it could cause corneal homeostasis to become unstable, resulting in progressive corneal deterioration. Although it remains unclear whether Pax6(+/-) mice have LESC-deficiency, we suggest that features of corneal deterioration, that are often taken as evidence of LESC-deficiency, might occur in the absence of stem cell deficiency if corneal homeostasis is destabilised by excessive cell loss.
Limbal stem cell deficiency (LSCD) is a disease resulting from the loss or dysfunction of epithelial stem cells, which seriously impairs sight. Autologous limbal stem cell transplantation is ...effective in unilateral or partial bilateral disease but not applicable in total bilateral disease. An allogeneic source of transplantable cells for use in total bilateral disease can be obtained from culture of donated cadaveric corneal tissue. We performed a controlled multicenter study to examine the feasibility, safety, and efficacy of allogeneic corneal epithelial stem cells in the treatment of bilateral LSCD. Patients were randomized to receive corneal epithelial stem cells cultured on amniotic membrane (AM): investigational medicinal product (IMP) or control AM only. Patients received systemic immunosuppression. Primary endpoints were safety and visual acuity, secondary endpoint was change in composite ocular surface score (OSS). Sixteen patients were treated and 13 patients completed all assessments. Safety was demonstrated and 9/13 patients had improved visual acuity scores at the end of the trial, with no significant differences between IMP and control groups. Patients in the IMP arm demonstrated significant, sustained improvement in OSS, whereas those in the control arm did not. Serum cytokine levels were measured during and after the period of immune suppression and we identified strongly elevated levels of CXCL8 in the serum of patients with aniridia, which persisted throughout the trial. This first randomized control trial of allogeneic corneal epithelial stem cells in severe bilateral LSCD demonstrates the feasibility and safety of this approach. Stem Cells Translational Medicine 2019;8:323–331
Patients with severe ocular surface disorder received transplants of amniotic membrane with (black bars) or without (gray bars) cadaveric‐donor‐derived cultured limbal stem cells. All patients received immune suppression. Only patients who received transplants containing limbal stem cells showed sustained significant improvements (reductions) in combined ocular surface scores (5 factors scored 0–3 where 0 is a normal eye score).
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