Peng T. Khaw

Primary open-angle glaucoma

Primary open-angle glaucoma is a progressive optic neuropathy and, perhaps, the most common form of glaucoma. Because the disease is treatable, and because the visual impairment caused by glaucoma is irreversible, early detection is essential. Early diagnosis depends on examination of the optic disc, retinal nerve fibre layer, and visual field. New imaging and psychophysical tests can improve both detection and monitoring of the progression of the disease. Recently completed long-term clinical trials provide convincing evidence that lowering intraocular pressure prevents progression at both the early and late stages of the disease. The degree of protection is related to the degree to which intraocular pressure is lowered. Improvements in therapy consist of more effective and better-tolerated drugs to lower intraocular pressure, and more effective surgical procedures. New treatments to directly treat and protect the retinal ganglion cells that are damaged in glaucoma are also in development.

Characterization of the Limbal Epithelial Stem Cell Niche: Novel Imaging Techniques Permit In Vivo Observation and Targeted Biopsy of Limbal Epithelial Stem Cells

It is anticipated that stem cell (SC) therapy will enable the regeneration of diseased tissues and organs. Understanding SC niches is an essential step toward realizing this goal. By virtue of its optical transparency and physical separation of SC and transient amplifying cell compartments, the human cornea provides a unique opportunity to visualize and observe a population of adult stem cells, limbal epithelial stem cells (LESCs), in their niche environment. To date, the characteristics of the LESC niche have remained unclear. State‐of‐the‐art imaging techniques were used to construct a three‐dimensional (3D) view of the entire human corneal limbus and identify the structural characteristics of the LESC niche. Two distinct candidate LESC niche structures were identified. Cells within these structures express high levels of the putative limbal stem cell markers p63α and ABCG2; however, current methods cannot identify for certain which exact cells within this cell population are truly LESCs. These structures could be located and observed in vivo in normal human subjects, but not in patients with clinically diagnosed corneal LESC deficiency. The distribution of these structures around the corneal circumference is not uniform. Biopsies targeted to limbal regions rich in LESC niche structures yielded significantly higher numbers of LESCs in culture. Our findings demonstrate how adult stem cell niches can be identified and observed in vivo in humans and provide new biological insight into the importance of LESC niche structures in maintaining normal LESC function. Finally, the concept of targeted biopsy of adult SC niches improves stem cell yield and may prove to be essential for the successful development of novel adult stem cell therapies.

Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy : Results from a randomized, double-blind, controlled clinical trial.

PURPOSE To assess the safety and efficacy of adjuvant combination therapy using 5-fluorouracil (5-FU) and low molecular weight heparin (LMWH) for prevention of proliferative vitreoretinopathy (PVR) after vitrectomy and retinal reattachment surgery. DESIGN Prospective randomized, double-masked, placebo controlled trial. PARTICIPANTS One hundred seventy-four high-risk patients were randomized to receive either 5-FU and LMWH therapy or placebo. Patients were selected from all patients undergoing primary vitrectomy for rhegmatogenous retinal detachment. METHOD Results of standard surgery with 5-FU and LMWH therapy or placebo were compared at the 6-month follow-up. MAIN OUTCOME MEASURES Development of postoperative PVR, retinal reattachment at 6 months after surgery, single operation reattachment rate, number of reoperations, and best-corrected visual acuity. RESULTS There were 87 patients in the 5-FU and LMWH therapy group and 87 in the placebo group. The incidence of postoperative PVR was significantly lower (P = 0.02) in the 5-FU and LMWH therapy compared with the placebo group. In 26.4% (23/87) of the placebo group and in 12.6% (11/87) of the 5-FU and LMWH group, postoperative PVR developed. In the 5-FU and LMWH group, the number of patients undergoing more than one operation was 19.5% (17/87) and the number of reoperations resulting from PVR was 52.9% (9/17). In the placebo group, the number of patients undergoing more than one operation was 25.3% (22/87) and the number of reoperations resulting from PVR was 72.7% (16/22). The difference in visual acuity was not statistically different in the two treatment groups, although those patients in whom postoperative PVR developed tended to have poorer vision (P < 0.0001). There were no differences in complication rates between the two groups. CONCLUSIONS There is a significant reduction in the incidence of postoperative PVR in patients receiving the 5-FU and LMWH therapy and in the reoperation rate resulting from PVR. This trial shows that incidence of PVR can be reduced with inexpensive and simple pharmacologic treatment with 5-FU and LMWH and should be used routinely in the treatment of patients at risk of developing PVR.

Cystic bleb formation and related complications in limbus- versus fornix-based conjunctival flaps in pediatric and young adult trabeculectomy with mitomycin C.

OBJECTIVE Comparison of fornix- and limbus-based conjunctival flaps with respect to cystic bleb-related complications of trabeculectomy with high-dose mitomycin C (MMC) in pediatric and young adult glaucoma. DESIGN Retrospective nonrandomized comparative interventional case series. PARTICIPANTS Thirty-seven patients. METHODS Identification of patients aged <30 years from operating theater records from 1995 and 1996 of the Moorfields Pediatric Glaucoma Service who had trabeculectomy with an MMC concentration of >/=0.4 mg/ml. Over a 2-year period, 37 consecutive operations matching these criteria were performed by a single surgeon: 20 with a limbus-based flap and 17 with a fornix-based flap. Except for the conjunctival incision and associated alteration in antimetabolite application and wound closure, the surgical technique was not significantly different between the groups. MAIN OUTCOME MEASURES Bleb evolution and complications. RESULTS The age at time of surgery, MMC concentration, history of one or more previous surgeries, and follow-up were similar in the 2 groups. The risk of cystic bleb formation was greater in the limbus-based flap group (90% in the limbus-based group vs. 29% in the fornix-based group; P<0.001). Late hypotony and bleb-related ocular infection were more common in the limbus-based flap group (P<0.05) and occurred earlier. There were four episodes of bleb-related infection (20%) in the limbus-based group (three of these [15%] were bleb-related endophthalmitis) and none in the fornix-based group. CONCLUSIONS In pediatric and young adult trabeculectomy with high doses of MMC, limbus-based flaps may be more likely to develop serious bleb-related complications and may develop these earlier than fornix-based flaps. The higher rates of complications could be attributable to the differences in bleb morphology, with limbus-based flap cases more likely to develop cystic blebs.

MIO‐M1 Cells and Similar Müller Glial Cell Lines Derived from Adult Human Retina Exhibit Neural Stem Cell Characteristics

Growing evidence suggests that glial cells may have a role as neural precursors in the adult central nervous system. Although it has been shown that Müller cells exhibit progenitor characteristics in the postnatal chick and rat retinae, their progenitor‐like role in developed human retina is unknown. We first reported the Müller glial characteristics of the spontaneously immortalized human cell line MIO‐M1, but recently we have derived similar cell lines from the neural retina of several adult eye donors. Since immortalization is one of the main properties of stem cells, we investigated whether these cells expressed stem cell markers. Cells were grown as adherent monolayers, responded to epidermal growth factor, and could be expanded indefinitely without growth factors under normal culture conditions. They could be frozen and thawed without losing their characteristics. In the presence of extracellular matrix and fibroblast growth factor‐2 or retinoic acid, they acquired neural morphology, formed neurospheres, and expressed neural stem cell markers including βIII tubulin, Sox2, Pax6, Chx10, and Notch 1. They also expressed markers of postmitotic retinal neurons, including peripherin, recoverin, calretinin, S‐opsin, and Brn3. When grafted into the subretinal space of dystrophic Royal College of Surgeons rats or neonatal Lister hooded rats, immortalized cells migrated into the retina, where they expressed various markers of retinal neurons. These observations indicate that adult human neural retina harbors a population of cells that express both Müller glial and stem cell markers and suggest that these cells may have potential use for cell‐based therapies to restore retinal function.

Corneal stem cells in review

The cornea provides the eye with protection and the refractive properties essential for visual acuity. The transparent epithelium is highly specialized with basal and stratified squamous cells that are renewed throughout life from a stem cell population. The stem cells are thought to reside at the corneal limbus and may be maintained by a variety of intrinsic and extrinsic factors such as the local environment, survival factors, and cytokines. A number of markers have been localized to the limbus in an attempt to identify stem cells; however, definite stem cell identification remains elusive. During homeostasis and following injury to the corneal epithelium, the limbal stem cells divide to produce daughter transient amplifying cells that proliferate, migrate, and differentiate to replace lost cells. However, this cannot occur if the stem cell population is depleted. Limbal stem cell deficiency then results in corneal re‐epithelialization by the neighboring conjunctiva, causing pain, poor vision, and even blindness. This review will focus on corneal epithelial stem cells in ocular surface repair and regeneration. The current knowledge of stem cell biology in the corneal epithelium, clinical consequences of stem cell deficiency, and therapeutic strategies aimed at reversing stem cell deficiency will be discussed.

Recent advances in trabeculectomy technique.

Purpose of review Trabeculectomy is an effective operation for lowering intraocular pressure. However, success is limited by complications such as infection, hypotony, and scarring. Recent findings These complications, which are increased by antifibrotic use, can be reduced with attention to surgical technique. We highlight the benefit of sub-Tenon anaesthesia, careful choice of the surgical site, fashioning of the scleral flap to produce diffuse aqueous flow, and better intraocular pressure control, maintenance of intraocular pressure, a formed anterior chamber, with outflow control during surgery using an infusion, optimal method of antimetabolites application, new adjustable sutures, and corneal-conjunctival closure techniques. Summary These techniques reduce hypotony, producing a diffuse noncystic bleb with long-term pressure control.

Human antitransforming growth factor β2 monoclonal antibody—a new modulator of wound healing in trabeculectomy ☆: A randomized placebo controlled clinical study

PURPOSE The human monoclonal antibody that neutralizes the growth factor TGFbeta(2) (CAT-152) safely and effectively inhibits in vitro and in vivo models of conjunctival scarring. This phase I/IIa clinical trial was designed to assess the safety and tolerability of CAT-152 in patients undergoing trabeculectomy. DESIGN Prospective randomized placebo-controlled clinical trial. PARTICIPANTS AND CONTROLS Twenty-four patients who were due to undergo primary trabeculectomy at Moorfields or Western Eye Hospitals in London, England, were recruited for this study and randomly assigned to treatment with either CAT-152 (100 microg in 100 microl) (n = 16) or placebo (n = 8). METHODS The treatment regimen was a series of four 100-microl subconjunctival injections, given immediately before and after surgery, and at 1 day and 1 week postoperatively. Assessment consisted of a full ophthalmic examination with recordings of the logarithm of the minimum angle of resolution visual acuities performed at baseline and at set intervals after surgery. Any adverse events were recorded. MAIN OUTCOME MEASURES Logarithm of the minimum angle of resolution visual acuity, intraocular pressure, complications, and adverse events. RESULTS The results of 12 months follow-up on all patients are documented. There were no statistically significant differences in the incidence of complications between the two groups, and no serious adverse events related to the study drug occurred. Blebs after CAT-152 antibody treatment were diffuse, noncystic, and nonavascular, unlike blebs associated with antimetabolites. The fall in intraocular pressure was greater in the CAT-152 group at 3 and 6 months (P < 0.05) and approached statistical significance at 12 months. There was a trend toward less intervention in those patients treated with CAT-152. The small number of patients included limited the power of the study (34%) to detect a difference between groups. Sixteen patients in each arm of the study would be required to obtain a power of 90% with a 5% significance level. CONCLUSIONS This is the first clinical study of CAT-152 in patients undergoing glaucoma filtration surgery. CAT-152 seems to be well tolerated, and based on these results further multicenter trials are underway.

Matrix Metalloproteinases in Disease and Repair Processes in the Anterior Segment

The pathogenesis of many anterior segment disorders and ocular complications following surgery are secondary to the wound healing response. The extent of clinical damage observed is closely related to the amount of scarring and tissue contraction. Matrix metalloproteinases (MMPs) are a family of enzymes that play a vital role in all stages of the wound healing process. They degrade all extracellular matrix components and also have the ability to synthesize collagen and extracellular matrix members, and are therefore important in the remodeling of a wound. Overexpression of MMPs results in excessive extracellular matrix degradation, leading to tissue destruction and loss of organ function. In the case of the anterior segment, this may mean the loss of visual function. This review focuses on the role MMPs have in the development of various anterior segment disorders. The importance of MMPs in the wound healing response and its potential modulation to manipulate the scarring response is being recognized, and current developments will be described.

Glaucoma drainage devices; past, present, and future

Glaucoma filtration surgery (GFS) has been shown to be more effective at preventing disease progression than other primary treatment modalities in open angle glaucoma.1 2 If it were possible to avoid complications associated with poor flow control, primary GFS would probably be offered more widely. Trabeculectomy, the procedure of choice in conventional GFS, has remained essentially unchanged for over a quarter of a century. Local control over wound healing with antimetabolite agents such as 5-fluorouracil and mitomycin C has improved the prognosis for cases with high risk of filtration failure; but flow control remains inexact despite the introduction of a variety of suture adjustment techniques. Glaucoma drainage devices (GDDs) have the potential to regulate flow consistently, eliminating hypotony after GFS. Design, material, and manufacturing deficiencies have left this potential unfulfilled in existing GDDs, all of which exhibit problems with poor flow control and suboptimal tissue compatibility. The role of GDDs in contemporary GFS remains poorly defined, but possibilities offered by new biomaterials and the goal of accurate flow control have stimulated considerable recent interest in GDD development. This review traces the progress of GDD design through to the present and beyond. In 1906, horse hair3 was placed through a corneal paracentesis in an attempt to drain a hypopyon externally. The same technique was later used to treat two patients with painful absolute glaucoma.4 Sporadic attempts using implants to shunt aqueous to a variety of unconventional sites, including the vortex veins5 and the nasolacrimal duct,6 have since been reported. Results were generally unfavourable or too poorly documented to evaluate, and attention has focused on devices shunting aqueous fluid to the subconjunctival space as with conventional GFS. The first translimbal GDD, reported by Zorab7 in 1912, was silk thread used as a seton to aid drainage …