Visual function and quality of life in patients who had undergone eye removal surgery: a patient survey.

PURPOSE: To measure aspects of self-reported vision-related health status and assess the impact of treatment in patients who have undergone eye removal surgery (evisceration or enucleation), using a patient administered questionnaire. METHODS: In this non-randomised, questionnaire-based cohort study, patients were identified from the Artificial Eye Service referral register from 2003 to 2010. A self-administered questionnaire based upon previously published scales was completed to measure aspects of visual function and the impact of treatment. RESULTS: Thirty-six completed questionnaires were obtained. Mean age at surgery was 54.1 years (range 13-90), with 83% male. Indication for eye-removal was trauma in 14(39%) cases. Ten (28%) had ocular co-morbidity in the fellow-eye. The main reported difficulties were with peripheral vision or distance judgements, in 64% patients. The majority of drivers (66%) had maintained the ability to drive. Self-consciousness was reported in 28(78%) patients, and 56% were able to continue work or activities with no perceived limitations. Overall comfort and aesthetic improvement were noted by the majority. Procedure-specific information leaflets for patients were appreciated. CONCLUSIONS: This survey increases our knowledge of aspects of vision-related health status following ocular pathology or trauma that requires eye removal, and may enable improved pre-operative patient counselling. Effects on peripheral vision may be noted most significantly, but the majority can continue normal activities with little difficulty. Overall improvement in comfort and appearance occurs in most patients, although feelings of self-consciousness are common.

Lacrimal duct cyst (dacryops) following ocular chemical injury.

A 37-year-old man presented with swelling under the lateral aspect of the right upper eyelid. He had sustained an alkali ocular chemical injury 10 years before resulting in persistent lateral canthal webbing. Diagnosis was made of lacrimal duct cyst (dacryops) and webbing of the lateral canthus and the findings were confirmed on computed tomography. He underwent lacrimal duct cyst marsupialisation and lateral canthoplasty with good cosmetic result, and there was no recurrence of symptoms at 2 months post-operatively. Lacrimal duct cyst is a rare clinical entity and has been postulated to result from localized inflammation or trauma to conjunctiva. To the best of our knowledge, this is the first report of dacryops following a chemical injury.

Ophthalmic medicine regulatory approvals through the European Centralised Procedure, 1999-2017: Clinical efficacy considerations.

OBJECTIVES: Regulatory approval of new medicines requires a thorough assessment of the potential clinical benefits and risks. Study end-points are expected to demonstrate a clinically relevant treatment effect that will translate into direct patient benefits. This study sought to review the ophthalmic medicines with European Union-wide approval granted via the Centralised Procedure and characterise the key efficacy end-points underpinning the demonstration of clinical benefit. METHODS: This study was a retrospective review of published data pertaining to the European regulatory authorisation of centrally approved ophthalmic products between 1999 and 2017, inclusive. All sources and data consulted are in the public domain. European Public Assessment Reports published by the European Medicines Agency were consulted for data concerning the pivotal clinical efficacy studies supporting the applications. Data analyses were descriptive. RESULTS: The European Medicines Agency have authorised 30 products via the Centralised Procedure between 1999 and 2017. For these products, a total of 24 additional approvals for line extensions or additional therapeutic indications were granted. Four products have been approved for orphan indications, including one approval 'under exceptional circumstances' and one 'Conditional Marketing Authorisation'. Approvals for products in retina (36%) and glaucoma (28%) indications together accounted for the majority of authorisations, with trial end-points predominantly based on visual acuity and intraocular pressure parameters, respectively. Products were also approved for indications in ocular surface disease, inflammation, optic neuropathy and surgical adjuncts, with a range of functional and anatomical end-points. CONCLUSION: Approvals for ophthalmic medicines have been granted for a range of clinical indications, representing a considerable portion of available major therapeutics for practitioners. Benefit-risk assessments rely on clinical trial data demonstrating a clearly relevant patient benefit.

Trends in licence approvals for ophthalmic medicines in the United Kingdom.

OBJECTIVES: The grant of marketing authorisation (MA) for new medicines requires comprehensive assessment by regulatory authorities. This study sought to identify ophthalmic medicines granted United Kingdom MA and consider trends in licence approvals. METHODS: This retrospective study reviewed published lists of products granted MA by the UK Medicines & Healthcare products Regulatory Agency between January 2001 and December 2018, inclusive. Eye drops and medicinal products intended for ophthalmic use were identified. All regulatory data sources consulted are in the public domain. Data analyses were descriptive. RESULTS: A total of 295 MAs were issued for ophthalmic products between 2001 and 2018, inclusive. Of these 229 (78%) were for single-active substances and 66 (22%) fixed-dose combination (FDC). Approvals for products with single-active substance included ocular hypotensives (115; 50%), antibiotics (48; 22%), allergy medicines (30; 13%), lubricants (18; 8%) and anti-inflammatories (11; 5%). Approvals for FDCs were predominantly ocular hypotensives (56; 85%), with timolol combined with carbonic anhydrase inhibitors (27; 48%) and prostaglandin analogues (26; 46%) accounting for the majority of glaucoma FDCs. Other FDCs were approved for antibiotic/inflammatory (5; 7.5%), pupillary mydriasis (2; 3%), allergy (2; 3%) and ocular surface lubrication (1; 1.5%) products. A median of 16 licences were approved per year (range 7 [2005] to 35 [2011]). CONCLUSIONS: The majority of MAs granted were for single-agent products, particularly ocular hypotensives and antibiotic preparations. Most products were generic versions of well-established active substances. A trend for increased approvals for FDCs is evident, particularly for the treatment of raised IOP.

Effects of siRNA-Mediated Knockdown of GSK3ß on Retinal Ganglion Cell Survival and Neurite/Axon Growth.

There are contradictory reports on the role of the serine/threonine kinase isoform glycogen synthase kinase-3ß (GSK3ß) after injury to the central nervous system (CNS). Some report that GSK3 activity promotes axonal growth or myelin disinhibition, whilst others report that GSK3 activity prevents axon regeneration. In this study, we sought to clarify if suppression of GSK3ß alone and in combination with the cellular-stress-induced factor RTP801 (also known as REDD1: regulated in development and DNA damage response protein), using translationally relevant siRNAs, promotes retinal ganglion cell (RGC) survival and neurite outgrowth/axon regeneration. Adult mixed retinal cell cultures, prepared from rats at five days after optic nerve crush (ONC) to activate retinal glia, were treated with siRNA to GSK3ß (siGSK3ß) alone or in combination with siRTP801 and RGC survival and neurite outgrowth were quantified in the presence and absence of Rapamycin or inhibitory Nogo-A peptides. In in vivo experiments, either siGSK3ß alone or in combination with siRTP801 were intravitreally injected every eight days after ONC and RGC survival and axon regeneration was assessed at 24 days. Optimal doses of siGSK3ß alone promoted significant RGC survival, increasing the number of RGC with neurites without affecting neurite length, an effect that was sensitive to Rapamycin. In addition, knockdown of GSK3ß overcame Nogo-A-mediated neurite growth inhibition. Knockdown of GSK3ß after ONC in vivo enhanced RGC survival but not axon number or length, without potentiating glial activation. Knockdown of RTP801 increased both RGC survival and axon regeneration, whilst the combined knockdown of GSK3ß and RTP801 significantly increased RGC survival, neurite outgrowth, and axon regeneration over and above that observed for siGSK3ß or siRTP801 alone. These results suggest that GSK3ß suppression promotes RGC survival and axon initiation whilst, when in combination with RTP801, it also enhanced disinhibited axon elongation.

Topical Delivery of Anti-VEGF Drugs to the Ocular Posterior Segment Using Cell-Penetrating Peptides.

Purpose: To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection. Methods: CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA. The biological efficacy of topical anti-VEGF + CPP complexes was compared with ivit anti-VEGF injections using an established model of CNV. Results: CPPs were nontoxic in vitro. In vivo, after topical eye drop delivery, CPPs were present in the rat anterior chamber within 6 minutes. A single application of CPP + bevacizumab eye drop delivered clinically relevant concentrations of bevacizumab to the posterior chamber of the rat eye in vivo. Similarly, clinically relevant levels of CPP + ranibizumab and CPP + bevacizumab were detected in the porcine vitreous and retina ex vivo. In an established model of CNV, mice treated with either a single ivit injection of anti-VEGF, twice daily CPP + anti-VEGF eye drops or daily dexamethasone gavage for 10 days all had significantly reduced areas of CNV when compared with lasered eyes without treatment. Conclusions: CPPs are nontoxic to ocular cells and can be used to deliver therapeutically relevant doses of ranibizumab and bevacizumab by eye drop to the posterior segment of mouse, rat, and pig eyes. The CPP + anti-VEGF drug complexes were cleared from the retina within 24 hours, suggesting a daily eye drop dosing regimen. Daily, topically delivered anti-VEGF with CPP was as efficacious as a single ivit injection of anti-VEGF in reducing areas of CNV in vivo.

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms.

PURPOSE: To investigate, using in vivo and in vitro models, retinal ganglion cell (RGC) neuroprotective and axon regenerative effects and underlying mechanisms of siRTP801, a translatable small-interfering RNA (siRNA) targeting the mTOR negative regulator RTP801. METHODS: Adult rats underwent optic nerve (ON) crush (ONC) followed by intravitreal siRTP801 or control siRNA (siEGFP) every 8 days, with Brn3a+ RGC survival, GFAP+ reactive gliosis, and GAP43+ regenerating axons analyzed immunohistochemically 24 days after injury. Retinal cultures, prepared from uninjured animals or 5 days after ONC to activate retinal glia, were treated with siRTP801/controls in the presence/absence of rapamycin and subsequently assessed for RGC survival and neurite outgrowth, RTP801 expression, glial responses, and mTOR activity. Conditioned medium was analyzed for neurotrophin titers by ELISA. RESULTS: Intravitreal siRTP801 enabled 82% RGC survival compared to 45% with siEGFP 24 days after ONC, correlated with greater GAP43+ axon regeneration at 400 to 1200 µm beyond the ONC site, and potentiated the reactive GFAP+ Müller glial response. In culture, siRTP801 had a direct RGC neuroprotective effect, but required GFAP+ activated glia to stimulate neurite elongation. The siRTP801-induced neuroprotection was significantly reduced, but not abolished, by rapamycin. The siRTP801 potentiated the production and release of neurotrophins NGF, NT-3, and BDNF, and prevented downregulation of RGC mTOR activity. CONCLUSIONS: The RTP801 knockdown promoted RGC survival and axon elongation after ONC, without increasing de novo regenerative sprouting. The neuroprotection was predominantly direct, with mTORC1-dependent and -independent components. Enhanced neurite/axon elongation by siRTP801 required the presence of activated retinal glia and was mediated by potentiated secretion of neurotrophic factors.

Opacification of hydrophilic intraocular lenses after Descemet stripping automated endothelial keratoplasty.

PURPOSE: Opacification of hydrophilic acrylic intraocular lenses (IOLs) is an emerging complication following Descemet stripping automated endothelial keratoplasty (DSAEK). We report six cases and review the current literature. METHODS: In this retrospective, noncomparative, observational case series, patients with IOL opacification after previous DSAEK surgery were identified from corneal clinic records. Case notes were reviewed for demographic details, indication for DSAEK, IOL model, incidence of rebubbling, and postoperative course. RESULTS: Six patients developed IOL opacification after DSAEK. All patients had Fuchs' endothelial dystrophy and had previously received hydrophilic acrylic IOL models. Central anterior IOL opacification was noted in all six cases. Five cases (83%) had required rebubbling due to dislocated graft tissue, and one had an early postoperative intraocular pressure (IOP) rise. Five cases (83%) were managed conservatively, and one case with a failed graft underwent redo DSAEK and IOL exchange. CONCLUSION: Repeated exposure to intracameral air, raised IOP, and other patient influences may be major etiological factors for IOL opacification after DSAEK. We advise avoiding hydrophilic acrylic IOL models in patients who may require future endothelial keratoplasty.

Decorin Reduces Intraocular Pressure and Retinal Ganglion Cell Loss in Rodents Through Fibrolysis of the Scarred Trabecular Meshwork.

PURPOSE: To investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis. METHODS: Adult rats had intracameral (IC) injections of human recombinant (hr) TGF-ß over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-ß injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed. RESULTS: Transforming growth factor-ß injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-ß-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss. CONCLUSIONS: Human recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.

Intraocular lens-edge design and material factors contributing to posterior-capsulotomy rates: comparing Hoya FY60aD, PY60aD, and AcrySof SN60WF.

PURPOSE: To compare neodymium-doped yttrium aluminum garnet laser posterior capsulotomy (LPC) rates between the Hoya FY60AD, Hoya PY60AD, and Alcon AcrySof SN60WF intraocular lenses (IOLs) after routine cataract surgery. METHODS: In this retrospective comparative study, patients undergoing uncomplicated cataract surgery over a 3-year period were included, and those subsequently undergoing LPC were identified from laser clinic records. LPC rates at 2 years postoperatively were compared between the round-edged Hoya FY60AD, the newer sharp-edged Hoya PY60AD three-piece IOLs, and the one-piece AcrySof SN60WF IOL. RESULTS: A total of 1,265 cataract operations were included, and 49 eyes (3.9%) underwent LPC within 2 years of surgery. Twenty-eight of 315 eyes (8.9%) implanted with the FY60AD underwent LPC by 2 years, compared to eleven of 254 (4.3%) with the newer sharp square-edged PY60AD and ten of 696 (1.4%) with the one-piece SN60WF (P < 0.05, Chi-squared analyses). CONCLUSIONS: The newer, sharper-edged Hoya PY60AD IOL has a lower LPC rate than the Hoya FY60AD IOL at 2 years post-cataract surgery. The one-piece AcrySof SN60WF has a lower LPC rate than both the three-piece Hoya IOLs in the same time period postoperatively. Variations in IOL-edge design and material effect may have contributed to the different rates observed.

Exploiting mTOR signaling: a novel translatable treatment strategy for traumatic optic neuropathy?

Retinal ganglion cell (RGC) death and a failure of axon regeneration contribute to the profound visual loss experienced by patients after traumatic optic neuropathy (TON), for which there are no effective treatments. Experimental manipulations of cellular signaling pathways in animal models have demonstrated that neuronal survival and axon regeneration in the mature central nervous system (CNS) are possible, and increased understanding of the molecular basis of prosurvival and regenerative signals has led to the identification of candidate targets for novel therapeutic strategies. The axogenic pathway is activated sequentially, after growth factor/receptor binding, through phosphoinositide-3-kinase (PI3K) and the downstream serine/threonine kinase Akt. Akt is a nodal point for the regulation of growth cone dynamics by glycogen synthase kinase (GSK3ß) and axon protein synthesis/RGC survival by the mammalian target of rapamycin (mTOR). The mTOR signaling pathway has a pivotal role in numerous cellular processes. It is active during development, but downregulated in the mature CNS and further suppressed by axonal injury, and experimental upregulation of mTOR signaling promotes RGC survival and axon regeneration after optic nerve crush injury. However, several translational challenges remain, including understanding the regulatory mechanisms of axotomy-induced mTOR and GSK3ß signaling, and the disparity between the RGC survival and axon regenerative effects. In this review, we explore the molecular basis of RGC regenerative failure and assess the potential for manipulations of mTOR signaling as a novel translatable treatment for TON.