Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

Figure 10.2. Fluorescein angiogram demonstrating a grid pattern of prior laser therapy applied to an area of diffuse macular edema.

barrier and is defined as two or more disc areas of retinal thickening involving the foveal avascular zone [11] (Fig. 10.2). The treatment approach for diabetic macular edema may be altered, depending on whether there is localized or diffuse edema. Focal laser photocoagulation for diabetic macular edema, as described by the ETDRS, includes focal (direct) photocoagulation, directed at specific areas of focal leakage, and grid photocoagulation, in which a grid pattern of burns is applied to areas of diffuse macular edema or nonperfusion (Table 10.1).

Although recovery of reduced vision is relatively unlikely after treatment, the goal of focal laser photocoagulation is to achieve modest improvement or stabilization of vision. Accordingly, even patients with macular edema and excellent visual function should be considered for treatment before visual acuity is affected [4,12,13].

Management recommendations, as prescribed by the American Academy of Ophthalmology, Preferred Practice Patterns, for patients with diabetes, including those with diabetic macular edema, are summarized in Table 10.2 and are more fully described in the following sections.

Indications for Treatment. The ETDRS demonstrated a 50% reduction in moderate visual loss (a loss of 15 or more letters, or a doubling of the visual angle) in eyes with CSME. CSME was defined by any one of the following: (1) Retinal thickening within 500 microns of the center of the macula (Fig. 10.3), (2) hard exudates within 500 microns of the center of the macula with associated thickening (Fig. 10.4), or (3) zone or zones of thickening larger than one disc area in size, any part of which is within one disc diameter of the center of the macula (Fig. 10.5). The three-year risk of moderate visual loss was 24% in untreated eyes compared with 12% in photocoagulation-treated eyes (p = 0.01) [4,14]. Adverse effects on

Source: From: American Academy of Ophthalmology, Preferred Practice Patterns, 2008.

a Exceptions include: hypertension or fluid retention associated with heart failure, renal failure, pregnancy, or any other causes that may aggravate macular edema. Deferral of photocoagulation for a brief period of medical treatment may be considered in these cases. Also, deferral of CSME treatment is an option when the center of the macula is not involved, visual acuity is excellent, close follow-up is possible, and the patient understands the risks.

Focal photocoagulation refers to focal laser to leaking microaneurysms or grid photocoagulation to areas of diffuse leakage or nonperfusion seen on fluorescein angiography.

b Deferring focal photocoagulation for CSME is an option when the center of the macula is not involved, visual acuity is excellent, close follow-up is possible, and the patient understands the risks. However, initiation of treatment with focal photocoagulation should also be considered because although treatment with focal photocoagulation is less likely to improve the vision, it is more likely to stabilize the current visual acuity.

c Scatter (panretinal) photocoagulation surgery may be considered as patients approach high-risk PDR. The benefit of early scatter photocoagulation at the severe nonproliferative or worse stage of retinopathy is greater in patients with type 2 diabetes than in those with type 1. Treatment should be considered for patients with severe NPDR and type 2 diabetes. Other factors, such as poor compliance with follow-up, impending cataract extraction or pregnancy, and status of the fellow eye will help in determining the timing of the scatter photocoagulation.

d Some experts feel that it is preferable to perform focal photocoagulation first, prior to scatter photocoagulation, to minimize scatter laser-induced exacerbation of the macular edema.

e Vitrectomy is indicated in selected cases.

Note: The Diabetic Retinopathy Clinical Research Network study (Arch Ophthalmol 2009; 127:132–140) showed that outcomes were similar following application of PRP in one sitting compared with four sittings in eyes with no or mild center involved macular edema.

low rates of visual improvement in the ETDRS may be due to the fact that a large number of treated patients had 20/20 vision or better at the time of treatment [4]. Based on the reduced rates of moderate visual loss by 50%, and the low complication rate with laser treatment, the ETDRS recommended that focal laser photocoagulation be considered for all eyes with CSME [14].

It is important to note that retinal thickening is an ophthalmoscopic, not an angiographic finding (Fig. 10.6). In addition, hard exudates may be found without associated retinal thickening and are not necessarily indicative of CSME, as defined by the ETDRS.

Figure 10.6. Clinically significant macular edema with a circinate ring of hard exudate formation.

Many clinicians choose to follow patients with 20/20 vision, unless the center of the macula is threatened or involved. An additional analysis of ETDRS data considering only eyes with macular edema and 20/20 or better vision, demonstrated that photocoagulation reduced the occurrence of moderate visual loss from 23% to 11% at 3 years among eyes in which the edema involved the center of the macula. If the edema did not involve the center of the macula, rates of moderate visual loss were low in both the treated and the untreated groups (2.5% and 7%, respectively) [13]. While not statistically significant, this data suggests that involvement of the central macula favors treatment. When treatment is deferred for such patients, close follow-up (every 3–4 months) is warranted to monitor for disease progression [15]. Although the ETDRS only included eyes with vision of 20/200 or better, eyes with lower levels of visual acuity may be considered for treatment because resolution of macular edema may stabilize or improve whatever visual function remains.

Treatment. Mechanism of Action. There are several postulated mechanisms by which laser photocoagulation decreases macular edema. The precise mechanism is unknown and may be a combination of the following: (1) direct closure of retinal vascular anomalies, (2) photocoagulation debridement of dysfunctional (or replacement with newly proliferated) pigment epithelium resulting in an enhanced outer blood–retinal barrier, (3) destruction of photoreceptors leading to improved inner retinal oxygenation and compensatory vasoconstriction with decreased blood flow and decreased vascular leakage, (4) stimulation of vascular endothelial proliferation resulting in restoration of the inner blood–retinal barrier, and (5) reduction of the total surface area of leaking retinal vessels (by their destruction) [16–19].

Wavelength Considerations. Yellow and blue wavelengths have several theoretical advantages including high absorption by hemoglobin that may make them useful for closing microaneurysms in the treatment of diabetic macular edema. Blue

190 Diabetes and Ocular Disease

light, in addition to being absorbed well by hemoglobin, is also absorbed well by macular xanthophyll and may cause neurosensory retinal damage not only to the patient, but also to the treating physician [20,21]. Both argon green and argon blue-green wavelengths were used in the ETDRS trials. While there was no direct evidence that one was preferable to the other, many investigators switched to argon green, particularly when treating near the fovea, to avoid excess uptake of the blue wavelengths by macular xanthophylls in the inner retina. Krypton red was not used because it makes direct photocoagulation of microaneurysms diff icult [4]. With these considerations, argon green is the wavelength of choice in most cases of diabetic macular edema.

Focal (Direct) Photocoagulation. Focal (direct) photocoagulation involves application of laser spots to all leaking microaneurysms between 500 and 3000 microns (two disc diameters) from the center of the macula (Table 10.3). Although the ETDRS did not require fluorescein angiographic confirmation of CSME, treating physicians used a baseline angiogram at the time of treatment to facilitate identification of focal points of leakage, usually microaneurysms, and to identify perifoveal capillary dropout with enlarged foveal avascular zones. Treatment of focal points of leakage in the retina farther than two disc diameters from the center of the macula is optional, but it was recommended if they leak prominently and were associated with retinal thickening or hard exudates rings that extended into the area of the retina within two disc diameters of the center of the macula [2].

Individual microaneurysms are treated with a spot size of 50 to 100 microns, and an exposure time of 0.1 s or less. Power is set low and titrated upward until a therapeutic effect is obtained. The ETDRS recommended increasing power until a whitening of the microaneurysm was observed. However, this often required energy sufficient to cause rupture of Bruch’s membrane. Whitening the microaneurysm is not necessary to achieve the goal of leakage cessation. In general, a very low intensity burn is required to affect microaneurysm closure (Fig. 10.7).

Treatment of focal leaks between 300 and 500 microns from the center of the macula can be performed if (1) previous treatment has been applied and CSME persists, (2) vision is less than 20/40, and (3) treatment is not likely to destroy the remaining perifoveal capillary network. For these lesions closer to the center of the macula, a smaller spot size of 50 microns and a shorter exposure time of 0.05 s were

Table 10.3. Parameters for Focal (Direct) Photocoagulation

Figure 10.7. Immediate posttreatment photograph of focal (direct) photocoagulation to leaking microaneurysms.

recommended by the ETDRS [2]. Effective laser intensity (i.e., uptake) is increased by decreasing spot size and exposure time without decreasing power, so great care must be taken not to rupture Bruch’s membrane by decreasing the power to the lowest level required to observe mild retinal whitening.

Grid Photocoagulation. Grid photocoagulation is used for diffuse macular edema and involves the application of uniformly spaced laser burns to areas of diffuse leakage and occasionally to areas of capillary nonperfusion associated with areas of leakage (Table 10.4). Angiographic leakage does not always correspond to ophthalmoscopically evident retinal thickening. To avoid over treatment, only clinically observable thickening should be treated. ETDRS guidelines for grid photocoagulation consist of placing light burns, 50 to 200 microns in size, at the level of the retinal pigment epithelium in areas of diffuse leakage that are more than 500 microns from the center of the macula and more than 500 microns from the temporal edge of the optic nerve. The spacing of the spots is dependent on the amount of leakage and should be one burn width apart for areas of intense leakage and slightly farther for areas of less intense leakage. Exposure time should be 0.1 s or less. Power should be started low and titrated upward until a barely visible light gray outer retinal lesion is visualized (Fig. 10.8). This helps to avoid over treatment and “spread” of laser burns over time, which can lead to coalescence of the laser scars in the macula (retinal pigment epithelial creep) with resultant paracentral scotomas.

Other Treatment Strategies. The ETDRS technique of meticulous focal (direct) photocoagulation of individual microaneurysms combined with grid photocoagulation to areas of diffuse leakage has been proven beneficial. Other techniques may also be beneficial, but have not been proven in large clinical trials. One technique

Figure 10.8. Example of diffuse macular edema prior to treatment (A), and 4 days after grid laser photocoagulation (B).

involves the application of two to three rows of grid laser around the fovea, as well as grid laser to all areas of thickened retina, followed by confluent laser to all areas of focal leakage [11]. This technique, termed modified grid photocoagulation, has not been shown to be favorable to ETDRS guidelines and may lead to over treatment.

The Diabetic Retinopathy Clinical Research Network, funded by the National Eye Institute, conducted a randomized controlled clinical trial to compare two laser photocoagulation techniques for treatment of diabetic macular edema: the modified ETDRS direct/grid photocoagulation technique and a potentially milder (but potentially more extensive) mild macular grid (MMG) laser technique in which microaneurysms were not treated directly and small mild burns were placed throughout the macula, whether or not edema was present [22]. At 12 months after treatment, the MMG technique was reported to be less effective at reducing optical coherence tomography-measured retinal thickening than the more extensively evaluated current modified ETDRS laser photocoagulation approach. However, the visual acuity outcome with both approaches was not substantially different.

Many pharmacologic treatments for diabetic macular edema have been proposed in recent years. The pathogenesis of diabetic macular edema has been attributed in part to inflammation, making corticosteroids a potential therapeutic option. The Diabetic Retinopathy Clinical Research Network conducted a randomized, prospective clinical trial to compare the efficacy of intravitreal triamcinolone to focal/grid laser photocoagulation for diabetic macular edema [23]. At 4 months, mean visual acuity was better in the intravitreal triamcinolone treated eyes. This was not sustained however, and at 1 year, there was no difference between treatment groups. At the end of the 2-year follow-up period, the focal/grid laser photocoagulation treatment group had better visual acuity outcomes. In addition, complications including cataract formation and glaucoma, were less frequent in the laser-treated group. The investigators concluded that focal/grid laser photocoagulation for diabetic macular edema remains the benchmark against which other treatments should be compared.

Follow-up and Re-treatment. It may take 3 to 4 months for the maximum effect of edema resorption to occur after a session of focal (direct) or grid photocoagulation. Therefore, follow-up intervals of 2 to 4 months are recommended for most patients. If there is persistent CSME present at 4 months, angiography should be repeated and additional treatment offered for selected areas of new or persistent leakage. These consist of leaking microaneurysms 500 to 3000 microns from the center of the macula, leaking microaneurysms 300 to 500 microns from the center of the macula if vision is less than 20/40 and there is no perifoveal capillary dropout. Grid treatment can be administered to areas of diffuse leakage 500 microns from the center of the macula if not treated previously. Treatment over areas of prior laser photocoagulation is not recommended as excessive spread and coalescence of laser scars can ensue.

Multiple laser sessions over many months are often necessary to accomplish the goals of treatment. In fact, most patients require three to four sessions 2 to 4 months apart for macular edema to resolve [12]. While ophthalmoscopically evident thickening was the treatment criterion subjected to the definitive clinical trial, optical coherence tomography may be a useful adjunct to monitor resolution of macular edema or to identify vitreomacular traction in patients with macular edema caused by a taut posterior hyaloid who are unresponsive to laser treatment [24–26].

Prognosis. The goal of laser photocoagulation treatment for diabetic macular edema is modest improvement or stabilization of vision. Patients should be counseled to avoid unrealistic expectations of visual improvement. Visual prognosis or response to treatment is related to several factors. Young age and diet-controlled diabetes mellitus have been associated with a more favorable prognosis [27]. Eyes that exhibit diffuse leakage appear to have a worse prognosis [4,28–32]. Additional factors associated with a worse prognosis include ischemic maculopathy, extensive perifoveal capillary nonperfusion, cystoid changes, hard exudates in the fovea, older age of the patient, and systemic treatment for hypertension [27,28].