Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009
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254 Diabetes and Ocular Disease
below 7% in order to reduce the risk and progression of retinopathy, which may translate to preservation of vision among individuals with diabetes.
Hypertension and Serum Lipids. In addition to glycemic control, blood pressure control also plays an important role in diabetic retinopathy. The UKPDS demonstrated that intensive blood pressure control was associated with a decreased risk of retinopathy progression and resulted in a 37% reduction in microvascular diseases [5]. Control of hypertension is essential in the management of diabetic retinopathy and collaboration with an internist is recommended.
Observational studies have also shown that elevated levels of serum lipids are associated with increased severity of hard exudates and decreased visual acuity. Among the participants in the DCCT, triglyceride levels were associated with severity of retinopathy while high-density lipoprotein cholesterol levels were inversely associated [6,7]. Data from the DCCT also revealed that, in models controlling for randomized treatment assignment, HbA1c levels and other factors (both total-to- high density lipoprotein (HDL) cholesterol ratio and low density lipoprotein (LDL) predicted the development of clinically significant macular edema (CSME) [8]. Lowering of lipid levels, recommended to prevent cardiovascular disease, may also reduce the risk of CSME, which is an important cause of vision loss.
Pregnancy. Several studies have demonstrated that diabetic retinopathy may be accelerated during pregnancy [9,10]. This increase in retinopathy severity may be due to changes in metabolic control during pregnancy or to the pregnancy itself. In addition to optimizing metabolic control, women with diabetes who are planning a pregnancy should have a baseline ophthalmic examination before attempting to conceive, and have a follow-up examination during the first trimester. Depending on the level of diabetic retinopathy, additional examinations throughout the pregnancy are recommended.
Other less common systemic entities such as sleep apnea, which may impact on the diabetic patient’s ocular status, should also be evaluated and treated as necessary [11].
STEP 3: EXCLUDE OTHER TREATABLE CAUSES
OF MACULAR EDEMA
Although most cases of macular edema among diabetic individuals are due to the effect of their systemic disease, a thorough ophthalmic examination may reveal other treatable causes of central retinal thickening. There may be coexisting ocular disorders that are the primary, or a contributing secondary, cause of decreased visual acuity. Vitreomacular interface abnormalities such as an epiretinal membrane (ERM) or vitreomacular traction (VMT) may cause retinal edema and distorted vision (Figs. 13.1C and D and 13.2A). These conditions can be diagnosed with careful biomicroscopic fundus examination, but additional imaging modalities are helpful. Optical coherence tomography (OCT) imaging in particular is valuable in identifying DME due to traction from an ERM or from a partially detached
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posterior hyaloid, both conditions that may benefit from surgical intervention (Fig. 13.2B) [12]. OCT is also more accurate than clinical examination in grading macular edema, and can detect the thickening earlier [13]. Particularly in situations where the degree of edema and visual loss seem out of proportion to the amount of leakage seen on fluorescein angiography, vitreomacular interface abnormalities should be suspected. Patients with suspected vitreomacular interface abnormalities may benefit from OCT imaging to evaluate the macula. If ERM or VMT is at least in part responsible for the macular edema and decreased vision, pars plana vitrectomy may be an initial therapy to be considered.
Another possible cause of vision loss among individuals with diabetes is postsurgical cystoid macular edema (CME). Postsurgical CME has a characteristic petalloid pattern of leakage on fluorescein angiography and is accompanied by optic disc staining. Although diffuse DME may also present in a cystoid pattern on angiography, postsurgical CME should be suspected in diabetic patients who have undergone recent ocular surgery. Treatment with topical nonsteroidal and/or steroidal anti-in- flammatory eye drops may help resolve all or some component of the CME without
A
B
Figure 13.2. (A) Fundus photograph of an eye with mild nonproliferative diabetic retinopathy and suspected diabetic macular edema. (B) Corresponding optical coherence tomography (OCT) image demonstrated vitreomacular traction as the cause of the macular edema.
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the need for more invasive therapy. Similarly, eyes with vitreous incarcerated in a cataract surgical incision, patients with mobile anterior chamber intraocular lenses, or patients with retained posteriorly dislocated lens fragments potentially responsible for low-grade inflammation and macular edema may benefit from correction of these anatomic problems as a first step before other therapies are instituted.
STEP 4: LASER PHOTOCOAGULATION
Laser photocoagulation has been the gold standard for treatment of DME since the ETDRS [14]. This type of photocoagulation has been adjusted in clinical practice over the years since the trial results were initially published, so that the type of treatment commonly applied employs lighter burns. This “modified ETDRS” laser photocoagulation is the type used in the Diabetic Retinopathy Clinical Research (DRCR) Network protocols (Table 13.1) [15].
Two strategies for laser treatment are used in this type of therapy. Focal laser involves direct treatment of individual microaneurysms in the areas of retinal edema. A spot size of 50 to 100 microns is typically used with an exposure time of 0.05 to 0.1 s. The power is set low and increased to obtain a mild whitening or darkening of the microaneurysm, or subjacent retinal pigment epithelium (RPE) effect. Grid laser is commonly used in areas of retinal thickening, particularly if the fluorescein angiogram demonstrates a diffuse leakage pattern and few microaneurysms. The laser burns, usually 50 to 100 microns in size, are equally spaced and placed more than one burn-width apart to produce light intensity laser marks in edematous retina.
STEP 5: CAREFUL FOLLOW-UP AND REASSESSMENT
Following focal laser therapy, patients are, in general, followed at approximately 3-month intervals to assess their response to therapy. Tools used to evaluate this response include clinical examination with biomicroscopy, OCT imaging, and fluorescein angiography, although all of these are not always necessary. At the time of evaluation, the level of retinopathy is also carefully assessed for progression, and the overall state of the eye and the patient’s metabolic control reviewed.
STEP 6: FURTHER TREATMENT IF INDICATED
Re-treatment with Laser. Eyes with diminishing edema may continue to be followed even if they still have some degree of persistent thickening, or re-treatment may be considered. Eyes with no response to laser photocoagulation are, in general, retreated with further laser photocoagulation. Eyes unresponsive to laser photocoagulation, or eyes in which further laser photocoagulation is considered relatively contraindicated (such as eyes with leaking microaneuryms very close to the foveal center or eyes with extensive fibrotic or pigmentary reaction to previous laser) may be considered for other types of therapy.
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Table 13.1. Laser Treatment Techniques for Diabetic Macular Edema |
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Burn Characteristic |
Focal/Grid Photocoagulation |
Mild Macular Grid |
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(modified ETDRS technique) |
Photocoagulation Technique |
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Focal Treatment |
Focally treat all leaking MAs |
Not applicable |
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in areas of retinal thickening |
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between 500 and 3000 microns |
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from center of macula (but not |
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within 500 microns of disk) |
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Change in MA Color |
Not required, but at least a |
Not applicable |
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with Focal Treatment |
mild gray-white burn should |
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be evident beneath all MAs |
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Burn Size for Focal |
50 microns |
Not applicable |
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Treatment |
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Burn Duration for |
0.05 to 0.10 s |
Focal Treatment |
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Grid Treatment |
Applied to all areas with diffuse |
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leakage or nonperfusion within |
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area described below for |
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treatment |
Area Considered for |
500 to 3000 microns from |
Grid Treatment |
center of macula (no burns |
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placed within 500 microns |
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of disk) |
Burn Size for Grid |
50 microns |
Treatment |
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Not applicable
Applied to entire area described below for treatment (including unthickened retina) 500 to 3000 microns superiorly, nasally, and inferiorly from center of
macula (no burns placed within 500 microns of disk) 50 microns
Burn Duration for |
0.05 to 0.10 s |
0.05 to 0.10 s |
Grid Treatment |
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Burn Intensity for |
Barely visible (light gray) |
Barely visible (light gray) |
Grid Treatment |
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Burn Separation |
2 visible burn widths apart |
200–300 total burns evenly |
for Grid Treatment |
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distributed over the |
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treatment area outlined |
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above (approximately 2–3 |
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burn widths apart) |
Wavelength (Grid and |
Green to yellow wavelengths |
Green to yellow wavelengths |
Focal Treatment) |
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Adapted from the Diabetic Retinopathy Clinical Research Network Protocol #1A: A Pilot Study of Laser Photocoagulation for Diabetic Macular Edema.
MA = microaneurysm
Other Options: Pharmacological Agents, Combination Therapy, Referral to Prospective Clinical Trials. Options for eyes unresponsive to laser photocoagulation continue to expand, and any list is bound to become out of date rapidly. At this writing, all drugs are used off-label for DME, and include the anti-vascular endothelial growth factor (VEGF) agents pegaptanib, ranibizumab, and bevacizumab, and steroids that can be introduced in and around the eye, specifically triamcinolone acetonide (Kenalog) and the fluocinolone implant Retisert. Finally, numerous new drugs in the investigational pipeline offer promise for DME treatment in the future.
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Trials of these drugs as monotherapy or in combination with other pharmacological agents and/or laser photocoagulation and/or surgery are frontiers that remain to be fully and carefully explored. Referral of the appropriately informed, eligible, motivated diabetic patient to a prospective study is an important and beneficial option for the management of DME.
Anti-VEGF Agents. Several studies have shown that VEGF plays an important role in vascular permeability and contributes to diabetic retinopathy and DME [16,17]. Pegaptanib (Macugen, Eyetech Pharmaceuticals Inc.), an aptamer that blocks the effects of the 165 isomer of VEGF and has already been approved for use in neovascular age-related macular degeneration (AMD), is being evaluated for the treatment of DME. A phase 2 study has shown that subjects assigned to intravitreal injections of pegaptanib had better visual acuity outcomes, were more likely to show reduction in central retinal thickness, and were deemed less likely to need additional therapy with photocoagulation compared to subjects assigned to sham injections at 36 weeks of follow-up [18].
In addition to pegaptanib, several studies are underway to investigate other antiVEGF agents for the treatment of DME. Ranibizumab (Lucentis, Genentech Inc.), a humanized monoclonal antibody to VEGF which has been approved for the treatment of neovascular AMD, has also shown promise for the treatment of DME in a small single center study [19]. Bevacizumab (Avastin, Genentech, Inc.), a fulllength monoclonal antibody to VEGF, which is Food and Drug Administration (FDA) approved as an intravenous therapy for patients with metastatic colorectal cancer, has been reported to effect resolution of DME in some eyes when injected intravitreally [20]. VEGF-Trap (Regeneron, Inc.), a humanized protein against the VEGF molecule, and other novel agents are also being tested in phase 1 clinical trials for efficacy and safety in DME [21]. Results from these and other randomized clinical trials will help determine the safety and efficacy of anti-VEGF agents and other novel therapies in the treatment of DME.
Steroids and Other Pharmacologic Agents. Several studies have also investigated the role of intraocular steroids for DME. Steroids have a host of effects on processes that result in leakage from retinal blood vessels, notably stabilizing tight junctions between vascular endothelial cells. Intravitreal and posterior sub-Tenon’s injection of steroids, principally the commercially available formulation of triamcinolone acetonide, Kenalog, have been widely used to treat DME that has not responded to laser therapy [20,22]. Although results from these case series have shown a beneficial effect of intraocular steroids in the treatment of DME, steroids are also known to have significant side effects, including cataract progression and an increase in IOP with development of glaucoma (Fig. 13.3). In addition, the beneficial effects of intraocular steroids when given as an intravitreal or sub-Tenon’s injection often wane several months after the injection.
The DRCR Network has investigated the role of a new ocular-specific formulation of triamcinolone administered in the sub-Tenon’s space in a pilot study as well as that of the drug injected intravitreally in a larger randomized study to help elucidate the role of these drugs in treating DME [15]. In a phase 2 study of
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Figure 13.3. Fundus photograph of an optic disc with significant glaucomatous cupping due to increased intraocular pressure after intravitreal injection of triamcinolone acetonide.
sub-Tenon’s injections of triamcinolone either alone or in combination with focal photocoagulation in the treatment of mild DME [23], 129 eyes with mild DME and a visual acuity of 20/40 or better were randomized to receive either focal photocoagulation, a 20-mg anterior sub-Tenon’s injection of triamcinolone, a 20-mg anterior sub-Tenon’s injection followed by focal photocoagulation after 4 weeks, a 40-mg posterior sub-Tenon’s injection of triamcinolone, or a 40-mg posterior subTenon’s injection followed by focal photocoagulation after 4 weeks. Changes in visual acuity and OCT retinal thickness were not significantly different among the five treatment groups at 34 weeks (P = 0.94 and P = 0.46, respectively). Elevated IOP and ptosis were adverse effects related to the injections. On the basis of these results, the DRCR investigators concluded that peribulbar triamcinolone, with or without focal photocoagulation, is unlikely to be of substantial benefit in eyes with DME and good visual acuity comparable to those studied.
The DRCR also conducted a phase 3 clinical trial evaluating the efficacy and safety of 1- and 4-mg doses of preservative-free intravitreal triamcinolone in comparison with focal/grid photocoagulation for the treatment of DME [24]. The primary outcome of this study was ETDRS visual acuity at 2 years. Eight hundred forty study eyes of 693 subjects with DME with visual acuity of 20/40 to 20/320 were randomized to focal/grid photocoagulation, 1 mg intravitreal triamcinolone, or 4 mg intravitreal triamcinolone. Re-treatment was given for persistent or new edema at 4-month intervals. Although at 4 months, the mean visual acuity was better in the 4-mg triamcinolone group than in either the laser group (P < 0.001) or the 1-mg triamcinolone group (P = 0.001), this benefit was not sustained, and at 1 year, there were no significant differences among the three treatment groups in mean visual acuity. At the primary outcome visit at 2 years, mean visual acuity was better in the laser group than in the other two groups (P = 0.02 comparing
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the laser and 1-mg groups, P = 0.002 comparing the laser and 4-mg groups, and P = 0.49 comparing the 1- and 4-mg groups). The mean change ± standard deviation in visual acuity letter score from baseline was +1 ± 17 in the laser group, −2 ± 18 in the 1-mg triamcinolone group, and −3 ± 22 in the 4-mg triamcinolone group. Although cataract progression was more common in eyes randomized to triamcinolone injection, the differences in the 2-year visual acuity outcome could not be attributed solely to cataract formation. Cataract surgery was performed in 13%, 23%, and 51% of eyes in the three treatment groups. In addition, IOP increased from baseline by 10 mmHg or more at any visit in 4%, 16%, and 33% of eyes in the three treatment groups, respectively. This phase 3 randomized clinical trial has shown that focal/grid photocoagulation is more effective and has fewer side effects than 1- or 4-mg doses of preservative-free intravitreal triamcinolone for eyes with DME through 2 years of follow-up for eyes similar to those included in this study.
In order to increase the duration of steroid effects, scientists have developed sustained delivery devices that release steroids into the eye at a constant rate over months to years. A fluocinolone acetonide sustained delivery device sutured intravitreally to the sclera at the pars plana has been shown to decrease macular edema and improve visual acuity in patients with diabetic retinopathy, although its use was associated with significant risks of cataract and glaucoma [25]. In a randomized controlled trial, 97 patients were assigned to receive either a fluocinolone implant or standard care (defined as laser treatment or observation). At 3 years, 58% of implanted eyes had no evidence of edema compared to 30% of standard-of-care eyes (p < 0.001) and 45% of implanted eyes had 2 steps of retinal thickness improvement relative to 24% of standard-of-care eyes. In addition, 28% of implanted eyes experienced visual acuity improvements of 3 or more lines compared to 15% of standard of care eyes (P < 0.05). Of interest was the finding that steroid implant-treated eyes had a reduced rate of retinopathy progression compared with the standard-of-care- group. However, the intravitreal fluocinolone acetonide-implanted eyes were at higher risk of developing serious adverse events than non-implanted eyes; 95% of phakic implanted eyes underwent cataract surgery over the three year study period. In addition 35% of implanted eyes developed intraocular pressure elevation, among whom 28% required a filtering procedure and 5% required removal of the implant to manage the increased intraocular pressure.
A dexamethasone sustained-release biodegradable implant currently being evaluated in a phase 3 trial for DME was shown in a phase 2 study to significantly improve visual acuity, fluorescein angiographic leakage, and OCT-measured macular thickness when compared to placebo. In a 6-month, phase 2 randomized controlled trial, 315 patients with persistent macular edema (55% of whom had macular edema secondary to diabetic retinopathy, 45% had macular edema secondary to retinal vein occlusion, Irvine-Gass syndrome, or uveitis) were randomized to treatment with 350 μg or 700 μg dexamethasone implant or observation [26]. At 3 months (primary end point of the study), an improvement of 10 letters or more was achieved by a greater proportion of patients treated with the dexamethasone implant, 700 μg (35%) or 350 μg (24%), than observed patients (13%; P < .001 vs 700 μg group; P = .04 vs 350 μg group). In addition, an improvement
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of 15 letters or more was achieved in 18% of patients treated with dexamethasone implant, 700 μg versus 6% of observed patients (P = .006). Of note, 33% of implanted patients within the diabetic retinopathy subgroup had at least a 10-letter improvement compared to 12% in the observation group. The improvements from dexamethasone treatment relative to observation were also significant on the physiologic and anatomic levels. Twenty percent, and 34% of the 350 and 700 μg dexamethasone groups, respectively, had reductions of 2 or more levels of improvement on fluorescein leakage (an indication of vascular permeability) compared to 5% from the observation group. In addition, OCT-analyses revealed a mean reduction of −53.19 and –106.57 microns respectively in the 350 and 700 μg dexamethasone groups, respectively, compared to a mean increase in thickness of +20.67 microns in the observation group. At 6 months, 12% and 17% of the 350 and 700 μg dexamethasone groups developed an increase in intraocular pressure of 10 mmHg or more from baseline, relative to 3% in the observation arm. All subjects with intraocular pressure increases were managed with observation or topical IOP-lowering medications, and no significant increase in cataract formation was observed in the treatment group versus, the control at 6 months.
In addition to the fluocinolone and dexamethasone implants mentioned here, other sustained delivery steroid devices are in development. Results from randomized clinical trials with long-term follow-up are needed to better evaluate the potential role and safety of steroids in macular edema.
Vitrectomy surgery is an option for the treatment of DME not uncommonly proposed in situations where the edema is resistant to other therapies. Maneuvers including peeling of epiretinal membranes, peeling of internal limiting membrane, concomitant injection of pharmacological agents, and supplementary endolaser have all been advocated, although none proven to be valuable. In cases where clearcut traction on the macula is observed, whether from epiretinal membrane contracture or vitreomacular traction, the rationale for this approach is much more straightforward than in cases where no such traction is documented. Although numerous papers, many in the preOCT era and most retrospective, have been published on this topic [27–29], the reported results are variable and in many cases contradictory, and this treatment modality remains at this point one of last resort, with incompletely understood indications, benefits and longterm risks.
Because of the changing landscape in the DME therapy field, new options and new data are emerging continually. The most accurate statement seems to be that our approach to this disease requires continual reevaluation. Although pharmacologic therapy appears promising, laser photocoagulation remains the standard treatment for DME and our armamentarium will still require close collaboration with our medical colleagues.
SUMMARY
Optimal treatment of DME requires a multipronged battle plan with both systemic and ocular fronts (Table 13.2). An algorithm for approaching these patients includes a complete ocular evaluation, maximization of metabolic control, and
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Table 13.2. Algorithm for Managing Diabetic Macular Edema
1.Complete Ocular Evaluation
2.Metabolic Control
3.Exclude Other Treatable Causes of Edema
4.Start with ETDRS Laser Photocoagulation
5.Follow the patient carefully
6.Re-treat with laser or consider other options: New drugs, combination of drugs and laser photocoagulation, referral to clinical trial
identification and correction of other treatable causes of macular edema. This is typically followed by ETDRS-type laser photocoagulation with subsequent careful follow-up and reassessment. Options for further treatment, if indicated, include additional laser photocoagulation, use of adjuvant pharmacological therapy, combined photocoagulation and pharmacological intervention, vitrectomy, or referral of appropriate patients to clinical trials.
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