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Understanding and controlling the scarring response: the contribution of histology and microscopy.

In response to injury, the body usually initiates a full and swift wound healing response resulting in reconstructed, repaired tissue. In certain instances, due to a variety of factors, this may not happen, an example being chronic granulating venous leg ulcers. At the other extreme, the wound may heal excessively, producing disabling hypertrophic scarring such as can occur following large, deep burn injuries. Our group is interested in the surgical treatment of the eye disease glaucoma. As will be explained, the successful surgical treatment of this disease depends on a reduced scarring response at the end of wound healing. The purpose of this article is to give an overview of our microscopic and histological experimental work which has furthered our understanding of tissue repair, particularly the scarring response and its potential modification for successful glaucoma surgery.

Antimetabolites↗

Cataract after glaucoma filtration surgery.

PURPOSE: We reviewed the evidence regarding cataract incidence and progression after glaucoma surgery. DESIGN: Evidence-based review of available literature. METHODS: We performed a systematic review of relevant studies published in English. RESULTS: Reports of visually significant cataract after glaucoma surgery are supported by data from randomized clinical trials and large case series. CONCLUSIONS: Patients undergoing glaucoma surgery are at increased risk for the development and progression of cataract.

Cataract↗

Sublingual lorazepam as premedication in peribulbar anesthesia.

PURPOSE: To assess the efficacy of sublingual lorazepam in inducing amnesia when used as a premedication for peribulbar anesthesia. SETTING: Department of Ophthalmology in a large district general hospital. METHODS: Following local ethical committee approval, a prospective, randomized, placebo-controlled, double-blind study of patients having routine cataract or glaucoma surgery under local anesthetic was undertaken. Patients older than 90 years of age or who were frail, confused, or unfit for surgery were excluded, as were those who weighed less than 50 kg, swallowed the tablet, or had missing data. Sixty volunteer patients were randomly given 1 mg of lorazepam or a placebo tablet by sublingual route 1 hour preoperatively. All patients were assessed for sedation, akinesia, intraoperative analgesia, and patient response including amnesia. RESULTS: There was no significant difference between groups in sedation, analgesia, or akinesia. Overall patient response was better in the lorazepam group (P = .05). Patient-reported incidence of amnesia was significantly higher in the lorazepam than in the placebo group (P < .05). CONCLUSIONS: Sublingual lorazepam improved patient comfort by inducing amnesia, and in the low dose used in this study, did not adversely affect surgery by undue heavy sedation.

Administration, Sublingual↗

Inhibition of Tenon's fibroblast proliferation and enhancement of filtration surgery in rabbits with cytosine arabinoside.

Our purpose was to study the antiproliferative effect of cytosine arabinoside (Ara-C) on rabbit Tenon's fibroblasts and the efficacy of Ara-C as an adjunctive antifibrosis treatment for glaucoma filtration surgery in the rabbit eye. Rabbit Tenon's fibroblasts were exposed to 1 microg/ml of Ara-C for various time intervals, then cell number and viability was assessed at different time points. Following posterior lip sclerectomy, rabbit eyes were treated with 10 mg subconjunctival Ara-C daily for 7 days, then every other day for 7 days. Rabbit fibroblasts exposed to 1 microg/ml Ara-C for 1 hour showed no significant decrease in cell number compared with control. Continuous or 24-hour incubation of fibroblasts with Ara-C was lethal to the cells. Exposure of cells to Ara-C for 3-, 6-, and 9-hour intervals caused significant reduction of cell proliferation. Pulsed treatment of cells with 6 hour exposure to 1 microg/ml Ara-C every 3 days caused prolonged suppression of cell proliferation. Following posterior lip sclerectomy in rabbits, topical instillation of Ara-C drops at varying concentrations and dosing intervals did not cause any significant lowering of intraocular pressure compared with control eyes, although bleb survival was prolonged in eyes treated with Ara-C (P < 0.01). In rabbit eyes treated postoperatively with subconjunctival injections of 10 mg Ara-C every other day for two weeks, the mean intraocular pressure was significantly decreased and the bleb survival time was significantly prolonged (P < 0.0067) compared with control eyes. In conclusion, Ara-C inhibits rabbit Tenon's fibroblast proliferation in vitro. Postoperative subconjunctival injection of Ara-C results in improved bleb function after filtration surgery in the rabbit.

Animals↗

Trends in glaucoma surgery before and after the introduction of new topical glaucoma pharmacotherapies.

OBJECTIVE: Recent advances in pharmacotherapy that have improved the ability to effect sustained reductions in intraocular pressure may delay or obviate the need for surgery for open-angle glaucoma. This analysis explored this possibility by evaluating the frequency of surgeries for open-angle glaucoma in the US Medicare population before and after the 1996 introduction of latanoprost, a topical prostaglandin analogue with potent ocular antihypertensive efficacy and a better safety profile than older topical glaucoma medications. METHODS: Data from the Medicare 5% Standard Analytical File were used to develop national estimates of the frequency of glaucoma surgeries in the US yearly from 1994 through 1999. RESULTS: While the number of US Medicare patients with a diagnosis of glaucoma remained constant from 1994 through 1999, the number of inpatient and outpatient glaucoma surgeries declined with a particularly sharp drop between 1996 and 1997. In 1999 relative to 1994, the number of annual glaucoma surgeries among unique patients with a diagnosis of glaucoma was reduced by 72% for inpatient procedures and 42% for outpatient procedures. CONCLUSIONS: The number of glaucoma surgeries among US Medicare patients markedly decreased from 1994 to 1999, during which time the prevalence of glaucoma remained stable in this population. The decrease in surgeries coincided with the introduction of improved topical pharmacotherapies for the management of glaucoma. Although the ability to infer a causal relationship between introduction of new pharmacotherapy and the decrease in surgeries is limited, the consistency of these data with those of several other studies renders the findings compelling.

Administration, Topical↗

Annual predictions of adverse outcomes after glaucoma surgery in the United States.

PURPOSE: To predict the number of adverse outcomes or additional ocular surgeries after glaucoma surgery in each year from 1990 to 1994 with ordinary and hierarchical logistic regression models developed with 1989 Medicare data. METHODS: We obtained data on all intraocular and laser glaucoma surgery claims (for example, laser trabeculoplasty, full-thickness and partial-thickness procedures, and cycloablation) to the Health Care Finance Administration (HCFA) in 1989 and developed an ordinary (non-hierarchical) logistic regression model and two hierarchical logistic regression models. The two hierarchical models smoothed state-level effects to different degrees in an effort to improve the precision of model predictions. RESULTS: The hierarchical logistic regression models predicted the number of adverse outcomes or additional ocular surgeries, including repeat glaucoma surgery, from 1990 to 1994 significantly better than the ordinary model. None of the models predicted the downward trend in adverse outcomes in 1990 and 1992, although all three models were able to predict the increase in adverse outcomes in 1991 and the downward trend in adverse outcomes in 1993 and 1994. CONCLUSION: Although systematic changes over time in physician practice or billing patterns affected the ability of both ordinary and hierarchical regression models to predict the number of adverse outcomes in 1990 and 1992, hierarchical logistic regression provides a useful framework for analyzing adverse event rates when the model contains many covariates with imprecisely estimated coefficients. The greater accuracy of predicted adverse event rates from ophthalmic surgeries obtained with hierarchical logistic regression will be useful for future planning and budgeting purposes.

Aged↗

Excimer laser filtration surgery.

PURPOSE: In order to remove precisely scleral tissue overlying Schlemm's canal with minimal trauma as an outpatient procedure under local anesthetic, we used a VisX Twenty/Twenty excimer laser. METHODS: We performed excimer laser filtration in three enucleated pig eyes, seven enucleated human eyes, and seven eyes of seven patients with severe glaucoma. Precise ablation to Schlemm's canal was confirmed by scanning electron microscopy in the enucleated eyes. For the patients, a local anesthetic was used, and a custom-made holder was used to mobilize the conjunctiva and fix the eye. RESULTS: A functional sclerostomy was obtained with 1,780 to 5,965 pulses, using a 2 x 1-mm slit. In our mean follow-up of nine months (range, six to 12 months) the excimer laser filtration technique achieved controlled filtration in five of seven patients and minimized conjunctival trauma. One patient subsequently underwent cataract extraction. CONCLUSIONS: This study indicates that excimer laser filtration is an effective technique for achieving filtration in glaucoma. It may reduce the complications of glaucoma filtration surgery, particularly the incidence of shallow anterior chamber postoperatively, as it leaves the trabecular meshwork intact.

Aged↗

Prolonged antiscarring effects of ilomastat and MMC after experimental glaucoma filtration surgery.

PURPOSE: To determine the long-term antiscarring effect of ilomastat treatment after experimental glaucoma filtration surgery (GFS). METHODS: In a randomized, prospective, masked-observer study, 21 New Zealand White rabbits underwent modified GFS. The animals were allocated to receive either intraoperative mitomycin-C (MMC) at a concentration of 0.2 mg/mL or postoperative subconjunctival injections of either ilomastat or phosphate-buffered saline (PBS). Fifteen injections were given to each animal during the study period. The animals were killed 60 days after surgery. Bleb morphology and intraocular pressures were recorded. Tissue sections were immunohistochemically stained for signs of scarring. RESULTS: Ilomastat significantly improved surgical outcome compared with vehicle (P < 0.0163) and length of bleb survival was similar to the MMC group. The mean day of failure was 46.2 (range, 42-60) with ilomastat, 51.3 (range, 49-60) with MMC, and 16 (range, 15-21) with vehicle. IOP maintenance with ilomastat was similar to that in the MMC group. Histologically, minimal scar tissue was seen with MMC and ilomastat. MMC-treated tissue demonstrated subconjunctival hypocellularity associated with peripheral fibrosis. Ilomastat resulted in normal-appearing conjunctival morphology. CONCLUSIONS: Ilomastat successfully prolongs bleb survival. MMP inhibition may provide an additional, potentially safer method of controlling intraocular pressure, thus preventing failure of glaucoma surgery, and may also act as a potential adjuvant treatment when MMC alone is inadequate.

Animals↗

The management of secondary glaucoma in nanophthalmic patients.

PURPOSE: To investigate the clinical characteristcs, management of secondary glaucoma in nanophthalmos, and the prevention of its complications. METHODS: Retrospectively, 9 cases (17 eyes) with nanophthalmic glaucoma were studied. RESULTS: The axial length of the eyes ranged (14.36 - 19.33) mm; All of the cases combined with hyperopia ranged (+7.00 +/- 16.00) D. All 17 eyes had the manifestation like angle-closure glaucoma. The glaucoma was controlled in 9 of 17 eyes at the early stage, which underwent laser iridotomy (4 of 9 eyes also underwent laser iridoplasty). 1 eye underwent ciliary photocoagulation because its visual acuity was lost and the patient complained of pain. The other 7 eyes underwent filtration surgery and 3 of them had permanent loss of vision caused by disastrous complications after the surgery. CONCLUSIONS: Management of secondary glaucoma in nanophthalmos is complicated. The laser iris surgery is safe and effective in glaucoma at the early stage. Vortex vein decompression, sclerotectomy or anterior sclerotomy may be performed to reduce disastrous complications.

Adolescent↗

Focus on triamcinolone acetonide as an adjunct to glaucoma filtration surgery.

Glaucoma is one of the most common causes of irreversible blindness worldwide. Despite continued advances in medical and laser therapy, incisional surgery still appears to be an important and for many cases the only option by which intraocular pressure is controlled. Unlike many other types of surgery in which complete healing of tissue would be a desirable outcome, glaucoma surgery seeks to achieve incomplete healing to allow aqueous humor to escape the eye. Pharmacologic modulation of wound healing is a hot topic in glaucoma filtration surgery. Although routine antifibrotic medications are associated with good results in modulating wound healing in glaucoma surgery, they carry with them the possibility for significant morbidity due to the adverse effects of treatment. Challenge continues to be to find a safe and effective agent for this purpose. Because of beneficial effects of triamcinolone acetonide in some conditions which are associated with secondary glaucoma and also potential effects of this agent in modulating wound healing process, we propose it as a useful adjunct to glaucoma filtration surgery. This approach may allow modulation of wound healing with less of the toxicity associated with commonly used antifibrotics (5-FU and mitomycin C).

Anti-Inflammatory Agents↗

Glaucoma surgery: are there new perspectives in perioperative pharmacology?

The literature directed at perioperative pharmacologic advances in relation to glaucoma filtration surgery is reviewed. The successful use of subconjunctival anesthesia demonstrates a new alternative in preoperative glaucoma surgical anesthesia. The intraoperative use of the antimetabolites mitomycin C and 5-fluorouracil in both traditional filtration and glaucoma drainage implantation surgery has been expanded. The use of the antifibrinolytic agents urokinase and recombinant tissue plasminogen activator adds a new and controversial dimension to postoperative pharmacologic therapy.

Antimetabolites↗

Management of coincident glaucoma and cataract.

Phacoemulsification for visually significant cataract and trabeculectomy for uncontrolled glaucoma are two of the most commonly performed ophthalmic surgeries. Many articles pertaining to cataract extraction in the glaucoma patient have been published during the 1-year scanning period of this periodical. This discussion reviews the recent literature as it pertains to the management of coincident cataract and glaucoma. Important topics addressed by the recent literature include long-standing controversies such as limbus-based versus fornix-based approaches to trabeculectomy and one-site versus two-site approaches to combined surgery, as well as innovative techniques in cataract and glaucoma surgery. This article also addresses perhaps the most controversial issue with regard to coincident cataract and glaucoma surgery, that is, the indications for the procedure. It should be noted that this article is not a comprehensive review but rather discusses the literature published within the 1-year scanning period.

Cataract↗

Recent developments in glaucoma drainage implant surgery.

Refractory glaucoma remains a challenging problem for the ophthalmologist. Drainage implant surgery is a valuable and effective option for its treatment. Recent developments in implant design and surgical technique have decreased the incidence and severity of postoperative complications while increasing the efficacy of glaucoma drainage implant devices.

Filtering Surgery↗

Endoscopic surgery in glaucoma management.

Endoscopically-controlled intraocular surgery has been evolving rapidly since the introduction of thinner endoprobes with increasing resolving power and higher image quality. Currently, anti-glaucomatous surgery is also beginning to take advantage of this exciting new technology. This article discusses the two main approaches to glaucoma management using microendoscopic techniques-decreasing aqueous humor production by means of laser endoscopic cyclophotocoagulation and increasing outflow facility through endoscopically-controlled selective trabecular surgery. Besides presenting clinical results, emphasis is placed on different surgeons' accounts of intraoperative endoscopic maneuverability and the spectrum of complications that may be attributed to the endoscopic nature of the surgical intervention.

Endoscopy↗

Determinants of bleb morphology in minimally invasive, clear-cornea micropenetrating glaucoma surgery with mitomycin C.

PURPOSE: Antimetabolites, especially mitomycin C (MMC), increase the incidence of late bleb-related endophthalmitis in trabeculectomy. This is related to a higher incidence of avascular, thin, cystic, translucent blebs, which may be caused by a toxic effect on conjunctival tissue. An MMC dose-response study was carried out focusing on bleb morphology and function. PATIENTS AND METHODS: In a retrospective, comparative case series study, 2 successive groups of patients with complicated glaucoma were compared 2 years after a special, minimally invasive, filtering procedure (intrastromal holmium laser keratostomy). Preoperative local subconjunctival injections of a fixed MMC dose (4 microg) were used in group A, and lower MMC doses, calculated individually (1 or 2 microg), were used in group B. Bleb vascularity and morphology were evaluated by masked grading of photomicrographs. Bleb function was evaluated by intraocular pressure (IOP). RESULTS: Total bleb avascularity occurred in 63% of the blebs in group A and 0% in group B (P < 0.01). In eyes with IOP < or = 20 mmHg without medical treatment, the mean IOP was significantly lower in group 1 (8 vs 15 mm Hg, P < 0.002). A translucent cystic bleb without conjunctival stroma was observed in only 1 eye in group A. An optimal spongy stromal bleb was observed in all other eyes (96%) despite the different MMC doses. The numbers of complications in the 2 groups were nearly equal. CONCLUSIONS: Bleb avascularity after 4 microg MMC could be avoided by the use of 1 or 2 microg MMC on the basis of preoperative prognosticators for failure, but at the expense of some of the IOP-lowering effect. This indicates that the therapeutic index (clinical safety margin) of MMC seems to be narrow. An MMC dose-response relation was not observed for the thin, cystic, and translucent bleb. The low incidence of this bleb (4%) indicates that the operative technique, apart from the vascularity, may be the most essential determinant of bleb morphology.

Adolescent↗

Long-term outcome of pediatric aphakic glaucoma.

PURPOSE: To determine the long-term outcome in pediatric patients with aphakic glaucoma. METHODS: A retrospective analysis of 130 patients diagnosed with aphakic glaucoma between 1969 and 2004 was performed. A total of 36 patients (55 eyes) were included in this study after excluding those who had cataract extraction after age 10 and those patients with other ocular conditions, systemic syndromes, traumatic cataracts, congenital glaucoma, or inadequate follow-up (less than 1 year). Outcome variables studied included visual acuity, number of medication changes required over the course of the follow-up, maximum number of medications used at a time for more than 6 months to control intraocular pressures, and surgical interventions required. Mean follow-up period was 18.7 years (range, 6.9-35 years). RESULTS: At the time of last follow-up, 54.5% of the patients had visual acuity 20/40 or better, 34.5% had 20/50 to 20/200, and 11% had acuity worse than 20/200. During the course of follow-up, 34% required 1 to 2 medication changes for controlling glaucoma, 33% required 3 to 5 medication changes, and 33% required 6 or more medication changes. Thirty-six percent of the eyes required a maximum of 1 to 2 medications for more than 6 months during the course of follow-up, 33% required 3, and 31% required 4 or more medications for controlling intraocular pressure. Of the 55 eyes, 15 eyes (27%) required surgical intervention. Six of the 15 eyes (40%) required 1 surgery, 8 eyes (53%) required 2 to 3 surgeries, and 1 eye (7%) required 4 to 6 surgeries. CONCLUSION: Patients with glaucoma after pediatric cataract surgery can have a good visual outcome although multiple medications and surgical interventions may be required to control the glaucoma.

Adolescent↗

Enhancement of filtration surgery with cytosine arabinoside and reversal of toxicity with 2'-deoxycytidine.

Antifibrosis agents have improved the success of glaucoma filtration surgery, although undesired side effects are not readily reversible and may present a major limitation in the use of these agents. Our purpose was to study the efficacy of cytosine arabinoside (Ara-C) as an adjunctive antimetabolite in glaucoma surgery in the rabbit, and reversal of toxicity due to this agent with the competitive inhibitor 2'-deoxycytidine. Posterior lip sclerectomy was performed in rabbit eyes treated with 15 mg subconjunctival Ara-C daily for 7 d then every other day for 7 d. Mean intraocular pressure was lower in eyes treated with Ara-C compared with controls at all time points following filtration surgery. On the 10th postoperative day, the mean intraocular pressure of control eyes (25.0 +/- 1.9 mm Hg) had returned to baseline levels, whereas the intraocular pressure of eyes treated with Ara-C was significantly lower (16.0 +/- 1.7 mm Hg) (P < 0.001). Bleb survival was also prolonged in the Ara-C-treated eyes. The major ocular side effect of Ara-C was corneal toxicity, with epithelial defects in 40% of eyes after 8 daily injections of 15 mg Ara-C. Reversal of toxicity was enhanced with 2'-deoxycytidine, with complete resolution of epithelial toxicity after 6.5 +/- 1.7 d following daily topical 10% 2'-deoxycytidine compared with 12.7 +/- 0.58 for control (P < 0.002). These results demonstrate that postoperative subconjunctival injection of Ara-C results in improved bleb function after filtration surgery in the rabbit. Recovery from corneal epithelial toxicity due to Ara-C is markedly enhanced with the competitive inhibitor 2'-deoxycytidine.

Animals↗