Ординатура / Офтальмология / Английские материалы / Glaucoma Surgery_Trope_2005

1.INTRODUCTION

Obstruction of aqueous outflow causing raised intraocular pressure (IOP) following trabeculectomy is usually regarded as a surgical complication. Although undesired, it is in fact the normal and appropriate response to a penetrating eye injury. Wound healing is a fundamental biological process that is critical for survival. In most living organisms, wound-healing systems are very well developed. Establishment of prolonged trans-scleral aqueous flow sufficient to maintain a steady-state pressure gradient of just the right size represents a highly abnormal state and can only be achieved by inducing a partial failure of normal wound-healing responses.

2.WOUND HEALING FOLLOWING PENETRATING OCULAR INJURIES

Trabeculectomy creates a penetrating wound between the anterior chamber and the subconjunctival space. From the moment the conjunctiva is incised, a complex cascade of protective and reparative processes is set in motion. These are detailed in Chapter 4 and the subject of numerous reviews and studies (1 4). It is essential to understand the dynamic nature of wound healing in order to adequately diagnose and manage both the risk factors for failure and the scarring process itself.

The basic process is probably similar to that seen after a penetrating skin wound, with the exceptions of the presence of aqueous humor and the trans-scleral pressure gradient. The initial phase is principally hematological with coagulation and formation of platelet/fibrin clot within minutes. White blood cells recruited to the wound secrete a number of growth factors that transform quiescent fibrocytes in the surrounding tissue into fibroblasts, the primary cells responsible for the production and contraction of the ubiquitous collagen scar.

Activated fibroblasts migrate to the wound and begin to proliferate after 5 days, their numbers peaking after 2 weeks (5,6). In skin and probably also in subconjunctival tissue, migrating fibroblasts exert traction forces on the collagen matrix of the tissue surrounding the wound and remodel it along the lines of stress (7). The tissue stress induces the fibroblasts to secrete growth factors for which they also express receptors and produce collagen, which further increases traction. This autocrine (self-stimulating) process is fundamental to wound contraction and usually results in closure of the wound (8).

The third phase is characterized by a relatively rapid reduction in the number of T-cells, small blood vessels, and fibroblasts from the wound site by apoptosis (9,10).

It is coincident with a maturation of the collagen scar (replacement of type III collagen with type I) (11). Little is known about the factors that initiate or regulate this phase. However, there is some evidence that reduction in tissue tension (12) and T-Cells (13) play key roles.

3.IMPACT OF SURGICAL TECHNIQUE ON WOUND HEALING

Given the strength of the healing forces, it is a little surprising that external fistularizing surgery for glaucoma could have long-term success. Although good surgical technique plays a role, it is most likely the flow of aqueous through the sclerostomy that retards wound closure (14). Unguarded full thickness sclerostomies allow the greatest initial outflow rates. It was the associated complications of early over-filtration that lead to the adoption of the trabeculectomy with a scleral flap even though pressure control was not as good (14). Until relatively recently, hypotony with significant shallowing of the anterior chamber was considered a reasonable trade-off for adequate flow in the early postoperative period.

In an attempt to reduce the complications of early over-filtration and with the understanding of the inflammatory response to hypotony, controlling initial flow with increased scleral flap suture tension has been advocated (15). The microperforating trabeculectomy procedures such as deep sclerectomy producing lower initial flow rates than trabeculectomy are notable for their low rates of hypotony and stable early IOPs (16 19). As the anterior chamber is not entered and no iridectomy is performed, the damage to the blood eye barrier is presumably less. However, published trials show higher IOPs than standard trabeculectomy with longer follow-up (16 18). The trade-off for more stable eyes with better vision in the early postoperative period may be an increased ability for scar tissue to bridge the scleral flap. However, the increasing use of antimetabolites in trabeculectomy has shifted the balance once again towards wound-healing failure.

4.NATURAL HISTORY OF THE BLEB

Although bleb morphology is recognized as important to the outcome of trabeculectomy (3,14), there is no clear agreement as to what constitutes the best appearance of a bleb. This may be due to the effect of preoperative risk factors on bleb morphology, variations in surgical technique (including the use of antimetabolites), and changes in bleb appearance over time (3,14,20,21). It is also due to the design of many published studies that define success as an absolute IOP level (sometimes higher than the preoperative IOP) and after relatively short follow-up periods.

The ideal trabeculectomy bleb allows aqueous to pass from the bleb (into the vascular system or transconjunctivally) at a rate which lowers IOP to the target range. Its structure and function should maximize its life while minimizing symptoms.

In an eye with a functioning bleb, aqueous outflow from the bleb is a major determinant of IOP. Normally, the flow rate is determined by inflow to the bleb (scleral flap resistance), local tissue resistance (bleb wall thickness), and total area of drainage. Several studies have suggested an additional direct toxic effect of Mitomycin C (MMC) on the ciliary body (22 25). This raises the possibility that part of the pressure-lowering effect of MMC trabeculectomy is also due to an MMC-induced decrease in aqueous production. The degree to which bleb outflow is pressure dependant or involves significant active cellular transport is uncertain.

Histopathological studies have shown late failed blebs to have dense, thick, organized, but acellular collagen walls (26,27). In blebs that failed early, large numbers of inflammatory cells and fibroblasts were present (27). In contrast, functioning blebsexcised postmortem showed loose connective tissue with histologically clear spaces thought to contain aqueous and to correspond to clinically visible microcysts (26,28). In addition, mitomycin-treated blebs excised for hypotony showed abnormally arranged and developed collagen fibrils (29).

These studies are consistent with our ideas of the wound-healing process and the clinical observation that drainage over a large surface area or through a very thin bleb wall is associated with lower IOPs. Very thin-walled bleb are, however, at risk of manifest leak and the potentially blinding complications of hypotony and infection. Although the precise mechanism leading to this morphology is unknown, it does not appear to be solely antimetabolites, as increasing antimetabolite treatment area has been reported in an animal model to increase bleb survival without leading to the bleb morphology associated with infection or late leak (30).

5.PREOPERATIVE RISK FACTORS FOR BLEB FAILURE

The first step in the management of the failing bleb is the preoperative identification of risk factors for failure and the preparation of a detailed management plan focused on inducing an appropriate degree of wound-healing failure.

Trabeculectomy success rates vary greatly and most studies examining risk factors for failure suffer from small numbers, limited follow-up, and an overly optimistic definition of success. However, reports from large studies with long follow-up periods and a concurrence of risk factors from small studies can help to define eyes which are more likely to fail and which require more aggressive suppression of wound-healing.

5.1.Larger Studies

The Advanced Glaucoma Intervention Study (AGIS) followed 789 eyes of 591 patients aged 35 80 years with advanced glaucoma between recruitment (1988 1992) and 2001. Eyes were randomized to the treatment sequences of either argon laser trabeculoplasty (ALT) trabeculectomy trabeculectomy or trabeculectomy ALT trabeculectomy. Preintervention factors associated with failure of trabeculectomy were higher IOP and diabetes. Any postoperative complication but especially marked inflammation or elevated IOP was also associated with increased risk of failure. Younger age was found to be a risk factor. However, this effect was predominantly due to increased risk amongst young subjects with poor preoperative visual acuity. Associations of borderline significance included “black” race (31). Another report from the same group (32) found male gender to be associated with bleb encapsulation which itself was associated with higher IOP. It did not find a statistically significant association with previous laser trabeculoplasty, suggesting that this previously reported risk factor (33) may be relatively unimportant.

The fluorouracil filtering surgery study (FFSS) (34) followed 213 patients with previous cataract surgery or failed filtering surgery, for 5 years. Subjects were randomized to either trabeculectomy alone or trabeculectomy with postoperative subconjunctival 5-fluorouracil injections. All procedures used a limbus-based conjunctival flap. Fiftyfour (51%) of the 105 eyes in the 5-fluorouracil group and 80 (74%) of the 108 eyes in the standard filtering surgery group were classified as failures on the basis of IOP .21 mmHg (P , 0.001, Mantel Cox survival analysis). Risk factors for failure

included high IOP, a short time interval after the last procedure involving a conjunctival incision, the number of procedures with conjunctival incisions, and Hispanic ethnicity. Patients in the 5-fluorouracil group had a higher risk of late-onset bleb leaks (9%) than those in the standard filtering surgery group (2%).

5.2.Smaller Studies

There are many reports from small studies of risk factors for trabeculectomy failure. As expected, the strength of individual risk factors varies widely. However, several factors have been consistently reported to increase risk of failure. Almost all smaller studies define failure as IOP .21 mmHg. This very conservative definition tends to underestimate failure rates, as do the generally short follow-up times.

5.2.1.Cataract Surgery

Cataract surgery prior to trabeculectomy has been identified as a risk factor for bleb failure when associated with a conjunctival incision (34). Pseudophakia without conjunctival incisions or posterior capsule loss has also been suggested to be a risk factor for failure (33,35,36) although the strength of the published evidence is relatively poor (37).

5.2.2.Aphakia

The largest study of aphakia followed 82 patients for 6 months to 10 years (38). Fiftyone percent of patients either required further glaucoma surgery or lost light perception. A further 10% could not maintain IOP of ,21 mmHg with medication or 25 mmHg without. In a subgroup of 20 eyes of patients younger than 50 years, 95% failed. In other reports, failure rates as low as 20% have been reported at 1 year (39,40).

5.2.3.Younger Age

In addition to the AGIS (31), several smaller studies have suggested reduced success with younger patient age (41), particularly when comparing adults with children (20,42 45). Other small series showed quite good results at up to 2 years (46) particularly when children with other associated ocular conditions were excluded (47). Because open-angle glaucoma prevalence is strongly associated with age (48), studies of trabeculectomy in younger patients have almost always included complex and secondary glaucomas. This has led to the suggestion that the primary reason for poorer results in younger adults and children is not age itself (35), but associated risk factors.

5.2.4.Long-Term Use of Glaucoma Medications

One of the most important risk factors for bleb failure identified to date is the conjunctival cellular profile, originally reported in association with the long-term use of some topical glaucoma medications. In a cohort study of trabeculectomy on 106 patients, preoperative treatment with miotic or sympathomimetic topical glaucoma medications for 3 years or more substantially reduced success (93% for beta-blockers vs. 72% for miotics and 45% for miotics and sympathomimetics) (49). Failure was associated with increased numbers of inflammatory cells (macrophages and lymphocytes) and fibroblasts in the conjunctiva. In another study, treatment with fluoromethalone 1% for 1 month preoperatively reduced cell numbers in these tissues and improved success rate of trabeculectomy compared with matched controls (82% vs. 50%) (50). The same author also reported that a number of other conditions thought to be independent risk factors for bleb

failure, such as age, race, and uveitis, are characterized by conjunctival histology that is likely to increase the chance of failure (35).

5.2.5.Skin Color and Race

Several studies, including the AGIS, have reported lower trabeculectomy success rates amongst residents of the United States of America described as “black.” Although the meaning of the term is not clear, it is generally considered to describe subjects with a significant proportion of their ancestry from Africa. Similarly, the FFSS reported increased failure in a subgroup identified as “Hispanic ethnicity.” Race or ethnicity is usually used as a socio-economic measure, which by acting as a surrogate for a number of environmental risk factors is associated with different health problems and outcomes. It has also been held to have some biological value on the basis of an increased prevalence of dermal keloid formation, thicker tenon’s capsule, or conjunctival cell population (51). However, the biological relationship to race is tenuous (52). The few reports of bleb failure rates from Africa do not appear to support the assertion of a large difference from studies in other populations (53 55).

5.2.6.Other Risk Factors

Neovascular Glaucoma and Diabetes. Neovascular glaucomas are generally considered to reduce the success of trabeculectomy although the state of active neovascularization at the time of surgery is important (56). Diabetes (non-neovascular) has been reported to be an independent risk factor for bleb failure (57,58).

Uveitis. The results of trabeculectomy in uveitis are generally thought to be poor and antimetabolites are frequently used. However, published reports on trabeculectomy outcome in uveitis with 5FU and MMC or with no antimetabolites are surprisingly good (59 63). Application of results is made difficult by the wide variety and intensity of uveitic disease and IOP rise secondary to chronic corticosteroid use.

Angle Closure. There are few reports of trabeculectomy outcome in primary angle-closure glaucoma (PACG). Aung (64) reported only 56% of blebs maintained IOP ,21 mmHg over a mean of 22 months in 57 Singaporeans unresponsive with PACG to medical therapy. However, a retrospective case review of combined phacotrabeculectomy for PACG in Singaporeans found a much higher 81% bleb survival over a similar time (65).

6.PERIOPERATIVE RISK FACTORS FOR FAILURE

6.1.Conjunctival Wound Position

Conjunctival wound position may influence bleb failure. Most published studies failed to find a difference although their power was low (66 71). The largest reported study (of 100 trabeculectomies) found a higher failure with limbus-based conjunctival flaps compared with fornix-based flaps (72). Similar results have recently been reported in MMC trabeculectomy in children and young adults (73).

6.2.Combined Surgery

A relatively large number of studies have examined the effect of combined cataract and glaucoma surgery. Some have reported this as risk factor for bleb failure. However, as with many studies in this area, methodological rigor is somewhat lacking (74). Two

systematic reviews of published studies examined evidence for an effect of technique in combined surgery (37) and different methods of dealing with cataract in the presence of glaucoma (75). In both studies, IOP was the main outcome measure. Studies of combined surgery vs. trabeculectomy alone consistently suggested relatively reduced bleb function in eyes undergoing the combined procedure. In this group, cataract extraction by nucleus expression was associated with higher IOPs than phacoemulsification. Studies examining wound site suggested slightly reduced bleb function when the cataract extraction and trabeculectomy components of the procedure were performed through the same site compared to separate sites.

7.POSTOPERATIVE RISK FACTORS FOR BLEB FAILURE

Any disease that increases intraocular or conjunctival inflammation can lead to an increase in wound healing and bleb failure. Uveitis and intraocular hemorrhage in particular may lead to a rapid increase in wound-healing response. Ocular procedures can have the same effect.

Reports of the impact of cataract surgery on functioning trabeculectomies are contradictory with some studies failing to find a difference in IOP and one reporting needle revision or additional IOP-lowering medications were needed in 30% of cases (76). A recent prospective study examined 47 eyes with pre-existing functioning blebs which underwent clear corneal approach phacoemulsification and posterior chamber implantation of a copolymer acrylic intraocular lens (77). After 1 month, 76% of eyes had increased IOP. A failure rate of 44% after 2 years was also reported despite the use of topical steroids for twice the duration of isolated cataract surgery.

Table 18.1 summarizes the principal risk factors for bleb failure along with an estimation of their strength based on published studies.

Table 18.1 Risk Factors for Bleb Failure

8.POSTOPERATIVE SIGNS OF REDUCING BLEB FUNCTION

8.1.Intrascleral Obstruction

Any intraocular material drawn into the sclerostomy can occlude aqueous flow and cause bleb failure. This includes blood or fibrin clot, iris, vitreous, ciliary processes, and even

lens capsule. With surgical techniques now placing the entry point in the cornea rather than sclera (the opening should be called a keratotomy; however, the term sclerostomy is more widely understood and is used here for historical reasons), the most common causes of obstruction are posterior corneal tissue from an incomplete sclerostomy and iris tissue which may remain intrascleral after iridectomy. Forward rotation of the ciliary body and iris root in aqueous misdirection syndrome or suprachoroidal hemorrhage can also occlude a sclerostomy. Although such obstruction can be the primary cause of trabeculectomy failure, fibrosis of the bleb will cause a secondary failure unless the obstruction is promptly removed. Intraocular viscoelastic material can also transiently obstruct the sclerostomy. Although sodium hyaluronate may have anti-inflammatory properties, injection of viscoelastic material into the anterior chamber may be associated with early postoperative pressure rises (78 80).

8.2.Bleb Fibrosis

Bleb fibrosis is the most common cause of bleb failure. Preoperative glaucoma medications, surgical trauma and inflammation can frequently cause aqueous hypo-secretion in the early postoperative period. Thus, low IOP in the early postoperative period is not always an indicator of good bleb development. In the absence of techniques to directly measure cellular activity in human trabeculectomy, bleb appearance is used as an indicator of wound healing. A number of clinical signs have been suggested as risk factors for bleb failure (see Table 18.2). They include increased bleb vascularity, presence of hemorrhage, corkscrew-shaped vessels, bleb height and extent, bleb wall thickness and conjunctival transparency, presence of tenon’s cysts or bleb encapsulation, suture-line contraction in limbus-based conjunctival flaps, bleb leak with and without pressure, and presence of microcysts. Most of these are signs of wound healing or aqueous flow. As wound healing is a dynamic process, these signs change over time. Unfortunately, there are relatively few published studies on the relationship between such clinical signs and bleb outcome and grading is mostly subjective (81 87). Recently, two groups have independently published standardized bleb-grading protocols. The Indiana Bleb Appearance Grading Scale (88) (Fig. 18.1) has been devised for slit-lamp assessment and the Moorfields Bleb Grading System (81) (Fig. 18.2) for grading from bleb photographs. Neither group has published the relationship between grading and outcomes as yet but both systems represent a significant advance in standardization of bleb assessment.

Table 18.2 Signs of Bleb Failure

Figure 18.1 The Indiana bleb appearance grading scale.

8.2.1.Bleb Vascularity, Corkscrew Vessels, and Hemorrhage

Bleb vascularity is the most commonly described sign reported to influence bleb failure and is graded in both the Indiana (Fig. 18.1) and Moorfields (Fig. 18.2) bleb grading systems. It reflects dilatation, migration, and possibly neovascularization within the conjunctiva and subconjunctival tissues. Increased vascularity both reflects increased woundhealing activity (vessel dilatation, angiogenesis, and contraction) and increases delivery of many cellular and chemical constituents of the wound-healing process. Picht and Grehn (87,89) reported a retrospective review of 55 trabeculectomies (76% primary trabeculectomy without antimetabolites) and classified them according to favorable or unfavorable outcome. Increased vascularity within the first month was associated with an increased failure rate at 3 months. Other authors have made similar clinical observations (85).

In a prospective observational study of MMC trabeculectomy (0.1 mg/mL MMC for 5 min under a limbus-based conjunctival flap), Sacu et al. (90) reported that all 49 eyes studied had exactly the same grade of vascularity throughout the study period (postoperative weeks 1 and 2) despite differences in IOP at 1, 3, 6, and 12 months. The use of MMC may have confounded this assessment. Compared with 5FU or nonantimetabolite trabeculectomies, MMC blebs tend to appear more inflamed or have greater vascularity in the early postoperative period. The same study reported the presence of corkscrew vessels in weeks 1 or 2 to be associated with higher IOP at 1, 3, 6, and 12 months. Of the eight eyes that developed encapsulated blebs, four had corkscrew vessels (90). Picht and Grehn (87,89) also found corkscrew vessels more prevalent in blebs with a poorer outcome. The corkscrew appearance of vessels is probably due to

Figure 18.2 (See color insert) The Moorfields bleb grading system.

contraction of surrounding tissue. As such it is an important sign of fibroblast function. Suture-line contraction in limbus-based blebs and conjunctival retraction in fornixbased blebs are signs of the same process.

Avascular areas may also develop in filtering blebs. In a mature bleb, marked conjunctival thinning may be present and diffuse transconjunctival aqueous flow (“bleb sweating”) apparent with fluoroscein staining. This “polycystic” bleb morphology was categorized many years prior to antimetabolite trabeculectomy (91). In antimetabolite trabeculectomy,