Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

laser occlusion of retinal veins resulted in increased levels of VEGF in the aqueous and was associated with NVI.34 Furthermore, intravitreal injection of VEGF in monkeys has been shown to induce the development of NVI and neovascular glaucoma, similar to that seen in humans with advanced PDR.35

Pigment epithelium-derived factor

PEDF inhibits endothelial cell proliferation and migration and to date appears to be the most potent endogenous angiogenic inhibitor in the eye.36 PEDF levels are decreased by hypoxia. Animal studies have demonstrated that decreased levels of PEDF are associated with the development of retinal neovascularization,33 and laser photocoagulation produces increased levels of PEDF.37 In humans, PEDF levels in the vitreous have been found to be significantly lower in patients with PDR as compared to individuals without diabetes.38 Also, lower levels of PEDF have been found to be predictive of progression of diabetic retinopathy.39 These studies demonstrate that PEDF likely plays a significant role in the pathogenesis of PDR. Ongoing studies are examining the potential utility of exogenous PEDF in the treatment of neovascular disease.

Endostatin

Endostatin also acts to inhibit proliferation of vascular endothelial cells. Patients with diabetic retinopathy have been demonstrated to have decreased levels of endostatin in the aqueous and vitreous.40 Lower levels of endostatin have been found to be predictive of a higher risk of progression of PDR after vitreous surgery as compared to patients with high endostatin levels.41 Recent animal studies using adenoviral vectors for delivery of endostatin into the eye have demonstrated reduction and/or inhibition of neovascularization.42 Ongoing studies will further evaluate the potential uses for endostatin in the treatment of neovascular disease.

Treatment

Treatment for early stages of diabetic retinopathy has been covered in previous chapters. The gold standard of treatment for PDR is panretinal photocoagulation (PRP). The utility of PRP was demonstrated in the Diabetic Retinopathy Study which determined that PRP for high-risk PDR, defined as neovascularization of the disc greater than one-third disc diameters, neovascularization elsewhere plus vitreous hemorrhage, or any neovascularization of the disc plus vitreous hemorrhage, reduces the risk of severe vision loss by 50%.43 The role of vitrectomy in the management of PDR was first evaluated by the Diabetic Retinopathy Vitrectomy Study (DRVS).44 The study proved a role for vitrectomy in the management of vitreous hemorrhage in individuals with type 1 diabetes or in all cases if there is significant fibrovascular proliferation and/or incomplete PRP. Vitreoretinal surgical techniques advanced rapidly immediately after the DRVS, and with even more recent progress, most surgeons currently maintain much broader indications for surgery. Vitrectomy will be considered in all cases of nonclearing vitreous hemorrhage persisting longer than 3 months,

Conclusions

Box 66.4  Treatment considerations

•Laser photocoagulation

•Vitrectomy

•Needs further study:

Antivascular endothelial growth factor agents

Aldose reductase inhibitors

Protein kinase C inhibitors

Antioxidants

tractional retinal detachment, and select cases of cystoid macular edema.

Recent research has focused on developing therapeutic modalities which target the biochemical alterations which precipitate diabetic retinopathy (Box 66.4). These new agents, including aldose reductase inhibitors, PKC inhibitors, and antioxidants have the potential to prevent the biochemical sequela of hyperglycemia. Furthermore, angiogenesis inhibitors appear to have a role in the treatment of diabetic retinopathy. Although no angiogenesis inhibitor is yet approved for the treatment of diabetic retinopathy, many agents are currently in clinical trials. Several nonrandomized trials have demonstrated a role for antiVEGF agents in the management of both DME and PDR, and these agents are being used off-label in select cases. See Chapter 65 for a discussion of the uses of these agents with respect to DME. Specific to PDR, anti-VEGF agents have been used as a preoperative adjunct to vitrectomy for vitreous hemorrhage and appear to facilitate surgery and reduce the rate of intraoperative and postoperative hemorrhage.45 Anti-VEGF agents may also obviate the need for vitrectomy in PDR with vitreous hemorrhage by inducing closure of active vessels and clearance of hemorrhage, and allowing PRP to be performed.46 Furthermore, anti-VEGF agents cause quicker regression of active vessels when compared to PRP.47 Expedient resolution of vessels has shown particular importance in the management of neovascular glaucoma. One study demonstrated complete resolution of NVI in 82% of treated cases, and all cases showed decreased leakage on fluorescein within 24 hours of injection.48

Conclusions

The role of hyperglycemia in the pathogenesis of diabetic retinopathy has been well described. However, the underlying biochemical mechanisms which precipitate this visually devastating disease are complex. Recent studies have revealed that an altered balance between angiogenic stimuli and inhibitors contributes to the development of diabetic retinopathy. Laser photocoagulation, although beneficial, is most useful only in the late stages of disease, after irreversible pathology has already occurred. Similarly, surgery is primarily useful in the treatment of late complications of disease. Research investigating the mechanisms of diabetic retinopathy has led to the development of many new potential therapeutic options. The gold standard of laser photocoagulation

in the treatment of diabetic retinopathy is now supplemented and may ultimately be supplanted by the availability and utility of vasoactive pharmaceuticals. Anti-VEGF agents are already being used in the management of select cases of both DME and proliferative retinopathy. Ongoing studies will clarify their particular indications and optimal regi-

mens. Future work will further elucidate the mechanisms of diabetic retinopathy, allowing for the development of new therapeutic options. By targeting the specific metabolic byproducts that produce vascular injury and hypoxia, it may ultimately be possible to curb the disease at a preproliferative state.

7.Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factorinduced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997;46:1473–1480.

10.Kamiuchi K, Hasegawa G, Obayashi H, et al. Intercellular adhesion molecule-1 (ICAM-1) polymorphism is associated with diabetic retinopathy in type 2 diabetes mellitus. Diabetic Med 2002;19: 371–376.

11.Beranek M, Kankova K, Benes P, et al. Polymorphism R25P in the gene encoding transforming growth factor-beta is a newly identified risk factor for proliferative diabetic retinopathy. Am J Med Genet 2002;109:278–283.

19.Joussen AM, Murata T, Tsujikawa A, et al. Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 2001;158:147–152.

27.Tripathi RC, Li J, Tripathi BJ, et al. Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology 1998;105:232–237.

30.Dvorak HF, Brown LF, Detmar M, et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995;146:1029–1039.

31.Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with

diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480– 1487.

32.Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994;118:445–450.

34.Miller JW, Adamis AP, Shima DT, et al. Vascular endothelial growth factor/ vascular permeability factor is temporally and spatially correlated with ocular angiogenesis in a primate model. Am J Pathol 1994;145:574–584.

35.Tolentino MJ, Miller JW, Gragoudas ES, et al. Vascular endothelial growth factor is sufficient to produce iris neovascularization and neovascular glaucoma in a nonhuman primate. Arch Ophthalmol 1996;114:964–970.

40.Noma H, Funatsu H, Yamashita H, et al. Regulation of angiogenesis in diabetic retinopathy: possible balance between vascular endothelial growth factor and endostatin. Arch Ophthalmol 2002;120: 1075–1080.

42.Auricchio A, Behling KC, Maguire AM, et al. Inhibition of retinal neovascularization by intraocular

viral-mediated delivery of anti-angiogenic agents. Mol Ther: J Am Soc Gene Ther 2002;6:490–494.

45.Rizzo S, Genovesi-Ebert F, DiBartolo E, et al. Injection of intravitreal bevacizumab as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR). Graefes Arch Clin Exp Ophthalmol 2008;246:837–842

46.Minnella AM, Savastano CM, Ziccardi L, et al. Intravitreal bevacizumab in proliferative diabetic retinopathy. Acta Ophthalmol Scand 2007;86:683–687.

48.Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab in the treatment of proliferative diabetic retinopathy.

Ophthalmology 2006;113:1695.e1–1695. e15.

Box 67.1  Risk factors for diabetic macular edema

•Duration of diabetes

•Diabetic retinopathy severity level

•Hyperglycemia

•Hypertension

•Dyslipidemia

•Nephropathy

taking insulin (8.4% and 26% respectively) compared to those not taking insulin (2.9% and 14% respectively). Risk factors that contribute to the progression of DME include increasing levels of hyperglycemia, diabetes duration, severity of DR at baseline, diastolic blood pressure, and the presence of gross proteinuria.7,9–12 The UK Prospective Diabetes Study Group clearly demonstrated the beneficial effect of tight blood pressure control on DME in type 2 diabetic patients as it showed, at 9 years of follow-up, a 47% reduced risk of visual loss due to reduced incidence of macular edema.13 Lastly, several studies found a correlation

Box 67.2  Diagnosis and follow-up of diabetic

macular edema

Diagnosis

•Slit-lamp biomicroscopy

•Stereoscopic photography

•Fluorescein angiography

•Optical coherence tomography (OCT)

Follow-up

•Slit-lamp biomicroscopy

•Stereoscopic photography

•OCT

between elevated rate of serum lipids and the amount of lipid exudates.7,14,15

Diagnostic workup (Box 67.2)

Until recently, the clinical detection and evaluation methods currently used have been limited to slit-lamp biomicroscopy

Box 67.3  Contribution of optical coherence tomography to the management of diabetic macular edema (DME)

•Accurate measurement of macular thickness

•Detection of intraretinal cysts and serous retinal detachment

•Analysis of the vitreomacular relationship:

Tractional DME with thickening of the posterior hyaloid

Early posterior vitreous detachment

•Neuronal remodeling, including loss of outer-segment reflectance

and stereoscopic photography. However, both methods are subjective and insensitive to small changes in retinal thickness.

Fluorescein angiography facilitates the visualization of the breakdown of the inner blood–retinal barrier, demonstrating leakage of fluorescein from the macular capillaries or microaneurysms into the retinal tissue; it may also show its accumulation within cystoid spaces. However, fluorescein leakage alone does not necessarily indicate the presence of macular edema. Fluorescein angiography is also useful to identify macular capillary nonperfusion, which may be combined with DME.

Profound change in the diagnosis and management of DME has occurred since the advent of OCT in the late 1990s (Box 67.3). OCT was first described by Huang et al in 1991.16 Since it became commercially available in 1995, there has been tremendous progress in this technology. OCT provides both cross-sectional imaging of the retina and reliable quantitative measurement of macular thickness. First OCT devices were based on the principle of low-coherence interferometry, which measures the time-of-flight delay of light reflected from ocular structures. To date, time domain OCT using the Stratus OCT instrument (Carl Zeiss Meditec, Dublin, CA) has been the most widely used tool. This instrument acquires images at a rate of 400 axial scans per second, with an axial resolution of 10 m. Recently, a new class of OCT instruments employing spectral (Fourier) domain technology has been developed, with a scan rate of at least 20 000 axial scans per second and an improved axial resolution of 5 m.

In the case of DME, OCT demonstrates increased retinal thickness with areas of low intraretinal reflectivity prevailing in the outer retinal layers, and loss of foveal depression. Hard exudates are detected as spots of high reflectivity, and are found primarily in the outer retinal layers (Figure 67.1); intraretinal cysts appear as small round intraretinal hyporeflective lacunae (Figure 67.2). OCT seems particularly useful to detect a feature combined with macular edema that is not easily seen on biomicroscopy – serous retinal detachment (Figure 67.3). It is seen in 15% of eyes with DME.17 The pathogenesis and prognostic value of serous retinal detachment are not clearly established, but it does not appear to have any negative prognostic value.18,19 OCT may also show a disruption in the line of the inner/outer-segment photoreceptors, which is an indicator of poor visual prognosis (Figure 67.4).

OCT seems particularly relevant to analyze the vitreomacular relationship. Perifoveal detachment of the posterior

522

A

B

Figure 67.3  Evolution after intravitreal injection of triamcinolone acetonide. (A) Diffuse cystoid diabetic macular edema with serous detachment of the fovea, which appears as an optically clear space between the retina and the retinal pigment epithelium. (B) Four weeks after triamcinolone injection, diabetic macular edema has completely resolved. The posterior hyaloid is detached from the macula.

hyaloid, which appears slightly reflective, is quite common, and corresponds to early posterior vitreous detachment.20 But, in some cases of DME, the posterior hyaloid on OCT is thick and hyperreflective, and is partially detached from the posterior pole, but remains attached to the disk and to the top of the raised macular surface, on which it exerts traction (Figure 67.5). In these cases, vitrectomy is beneficial.21,22

One major advantage of OCT is that it allows measurement of retinal thickness from tomograms by means of computer image-processing techniques. Several studies have shown the reliability and good reproducibility of such meas- urements.23–25 OCT is thus an accurate tool to follow the spontaneous evolution of DME, as well as its response to treatments.

Treatment (Table 67.2)

It is now widely accepted that control of systemic factors, which may worsen DME, is essential. These factors include glycemic and blood pressure control, as well as anemia, hyperlipidemia, and all causes of intravascular fluid overload (congestive heart failure, renal failure, hypoalbuminemia).26

Randomized studies have clearly demonstrated the efficacy of laser photocoagulation to prevent vision loss from DME.1,27,28 In the ETDRS, eyes with nonproliferative DR and macular edema were randomly assigned to early focal/grid photocoagulation or nonphotocoagulation. After 3 years of follow-up, 24% of the control group lost three lines of the ETDRS visual acuity chart compared with 12% of the treated

A

B

Figure 67.5  Tractional diabetic macular edema (DME). (A) Before vitrectomy: diffuse DME with a thickened and highly reflective posterior hyaloid which is partially detached from the posterior pole, but remains attached to the top the fovea, on which it exerts traction. (B) DME has completely resolved after vitrectomy.

Table 67.2  Treatment for diabetic macular edema (DME)

eye. However, this beneficial effect was only observed in eyes with clinically significant DME, for which prompt photocoagulation is thus highly recommended. In addition, laser photocoagulation was more effective for focal than diffuse DME. In eyes with diffuse DME, more than 15% of patients

go on losing vision despite previous laser photocoagulation.29 Laser photocoagulation may also be associated with severe side-effects such as laser burns to the fovea, enlargement of laser scars over time, choroidal neovascularization, and subretinal fibrosis.

The exact mechanism of action of laser photocoagulation is not known. It may be due to an enhanced proliferation of RPE and endothelial cells, leading to a restoration of the blood–retinal barrier,30,31 or a better oxygenation of the inner retina from the choriocapillary after destruction of oxygen-consuming photoreceptors.32 A retinal vasoconstriction has indeed been observed after grid laser photocoagulation for DME.33

The drawbacks and side-effects of laser photocoagulation have led to the search for alternative treatments for DME. They include vitrectomy and intravitreal injection of steroids or anti-vascular endothelial growth factor (VEGF) drugs.

A benefical effect of vitrectomy to reduce DME and improve visual acuity has been demonstrated in eyes with DME associated with a taut and thickened posterior hyaloid exerting macular traction21,22,34,35 (Figure 67.5). In cases of DME without any vitreomacular traction, the effect of vitrectomy remains unclear.36–38

Several studies have shown the efficacy of intravitreal injections of triamcinolone acetonide (IVTA) to reduce DME temporarily and increase visual acuity (Figure 67.5).3,39–41 The mean reduction in macular thickening reaches 85% 3 months after injection with a mean two lines of improvement of visual acuity.4,41 However, recurrence of DME occurs 3–6 months after injection. Side-effects of IVTA include ocular hypertension in up to 50% of patients, glaucoma requiring surgery in 2%, and cataract surgery in 54% within 2 years of injection.4 Recently, the Diabetic Retinopathy Clinical Research network (DRCR.net), comparing the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone in comparison with focal/grid laser photocoagulation in patients with DME, showed that, over a 2-year period, focal/grid laser photocoagulation is more effective and has fewer sideeffects than triamcinolone.42

Steroids act by reducing vascular permeability: indeed, steroids stabilize endothelial tight junctions and increase their numbers. They may also inhibit production of

VEGF.43–45 Steroids also suppress inflammation and inhibit the migration of leukocytes.

Extensive data have established that VEGF is involved in the vascular permeability observed in DR.46,47 These data support the use of anti-VEGF therapy for diffuse DME. Pegaptanib is an anti-VEGF aptamer, binds to VEGF165, sequestering it and preventing VEGF receptor activation. A phase II trial evaluating the efficacy and safety of injections of three doses (0.3, 1, and 3 mg) of pegaptanib versus placebo every 6 weeks has shown interesting results, with better median visual acuity at 6 months in the group treated with 0.3 mg as compared with sham. Phase III trial is under way.48 Ranibizumab, which is a recombinant humanized monoclonal antibody fragment with specificity for all isoforms of human VEGF, is also under investigation for DME. A phase II trial investigating the efficacy and safety of two concentrations of intravitral ranibizumab (0.3 and 0.5 mg) in patients with DME with center involvement, compared with sham, showed a significant improvement of visual acuity in patients who received ranibizumab, with a mean average change in visual acuity from baseline to month 1 through month 12 of 7.6 letters, versus 1.2 letters in the sham group. Treatment with both doses of ranibizumab was associated with a significant decrease in central retinal thickness on OCT (Massin P and the RESOLVE Study Group, presented at the American Academy of Ophthalmology, Atlanta, 2008). Encouraging results were also observed in the phase II READ II trial (Nguyen, presented at the American Academy of Ophthalmology, 2008). Finally, comparing the results of intravitreal bevacizumab injection alone or in combination with intravitreal triamcinolone acetonide versus macular photocoagulation as a primary treatment for DME, Soheilian et al49 found that intravitreal bevacizumab injection in patients with DME yielded a better visual outcome at 24 weeks compared with macular photocoagulation, although its effect on decreasing retinal edema was transient.

Pathophysiology

The breakdown of the inner blood–retinal barrier is the most important mechanism leading to visual loss, but capillary nonperfusion and possibly direct neuronal damage are also major actors. Macular edema thus represents the result of multiple processes affecting a number of interdependent cell populations. The dominant paradigm attributes a major role to the interaction of a variety of factors, including overproduction of VEGF, inflammation, and endothelial dysfunction. Yet, because of its complexity and the lack of a convenient animal model, the pathophysiology of the onset and complications of DME remains still largely uncertain.

Inner blood–retinal barrier dysfunction (Box 67.4)

The blood–retinal barrier isolates the neural elements of the retina from the circulation in order to facilitate the control of the extracellular milieu. The inner blood–retinal barrier schematically comprises intercellular barrier (tight junctions between adjacent endothelial cells) and transcellular barrier (as shown by the relative paucity of intracellular vesicles).50 Plasma may flow between endothelial cells, suggesting opening of tight junctions, or through endothelial cells, due to increased membrane permeability or vesicular trans-

524

Box 67.4  Factors possibly involved in blood–retinal

barrier breakdown during diabetic retinopathy

•Vascular endothelial growth factor overproduction

•Activation of protein kinase C

•Hepatocyte growth factor

•Histamine

•Activation of bradykinin by carbon anhydrase released by erythrocytes

•Impaired vascular autoregulation

•Endothelial dysfunction

•Inflammation, including leukostasis

port.51,52 Dysfunctional blood–retinal barrier is always present in visible manifestations of microvascular remodeling such as microaneurysms, but normal-appearing capillaries may also leak fluorescein, suggesting that barrier dysfunction precedes morphological changes of capillaries.

Tight junctions are made of a complex aggregate of proteins, among them occludin claudins, zonula occludens-1 (ZO-1), zonula occludens (ZO-2), and zonula occludens-3 (ZO-3). Experimental diabetes causes disorganization of the tight junction proteins, as shown by the reduction of occludin content in retinal endothelial cells,53,54 resulting in reversibly increased permeability. Both VEGF and hepatocyte growth factor administration in vitro reduce occludin content and lead to tight junction complex internalization in vascular endothelial cells.47,55–57 The effect of VEGF on tight junction is partly mediated by occludin phosphorylation, and indeed activation of protein kinase C (PKC) participates in the mechanism of VEGF-induced vascular permeability.46,58

In vivo, it is likely that macular edema results at least in part from the action of VEGF on vascular endothelial tight junction proteins and transcellular flow. Increased expression of VEGF in the retina is indeed an early change observed in experimental diabetes. It may result from local tissue ischemia due to microcapillary occlusions, or may be due to an inflammatory response, possibly through activation of the receptor for advanced glycation end-products.59 There is evidence that VEGF exerts neuroprotective effects on neurons and thus may be a response of neurons and glia to physiological stresses imposed by chronic hyperglycemia.53 Yet, as clinical experience shows, the effect of specific anti-VEGF therapy is often partial, suggesting the involvement of other crucial partners in the maintenance of DME. Other biochemical pathways may be involved in the breakdown of the blood–retinal barrier, such as PKC activation.46 The effect of ruboxistaurine, a tissue-specific PKC-ß inhibitor, has now been evaluated in several trials.60 The PKC-Diabetic Retinopathy Study evaluated the effects of three different doses of oral ruboxistaurin versus a placebo on the progression of DR, while the PKC-Diabetic Macular Edema Study evaluated the effect of the same doses of ruboxistaurine versus a placebo on the progression of macular edema.60,61 Neither of these studies demonstrated any significant changes in primary endpoint. However, in the PKC-DRS, compared to placebo, 32 mg/day ruboxistaurine was associated with a delayed occurrence of vision loss, probably due to less progression of macular edema. And in the PKC-DME Study, a subgroup analysis showed a slower progression of DME in

Clinical background

many cases of macular edema there is no detectable leakage of fluorescein, and Müller cells are known to increase their cytoplasmic volume in response to some stimuli such as ischemia–reperfusion. Thus, cytotoxic edema from ischemia may participate in retinal thickening. Increased volume of Müller cells may also be a consequence of their role in the water homeostasis of the retina; they are indeed known to express AQP4 aquaporine channels.64 Dysfunction or death of Müller cells is also a likely explanation for the formation of large cystoid spaces, which are similar to some extent to the cyst seen in retinoschisis. It may also cause impairment of outflow from the retina, but experimental demonstrations of such a phenomenon are as yet lacking.

It is likely that there is dysfunction of the outer blood– retinal barrier in diabetic retinopathy, although there have been few investigations of it; it seems that in response to inner blood–retinal barrier rupture, the RPE cells increase their pumping activity, but this increase cannot ensure complete clearing of plasma molecules beyond a certain point.

The cause of the preferential accumulation of fluid in the fovea may be due to its specific architecture, especially the absence of astrocytes and of a dense vascular bead; thus, the fovea is a weak point mechanistically speaking, and fluid easily accumulates there because there is less restriction to retinal distension than elsewhere in the retina.

Vascular dysfunction and inflammation

The retina controls its own blood flow in response to local and systemic influences by means of a variety of cellular and chemical factors. Such autoregulation is crucial for the maintenance of a constant blood flow despite strong, minute-to- minute changes in perfusion pressure and metabolic needs. Diabetic patients have an impaired endothelial function that occurs very early in the course of the disease. Recent experiments have shown that the vasodilatory effect of flicker light is impaired before the onset of clinically detectable DR.65 Diabetic patients are also known to have chronically dilated retinal vessels, possibly due to chronic ischemia.66 This may locally increase hydrostatic pressure and hence aggravate retinal edema. Interestingly, steroids, which are known to reduce macular edema, are also potent vasoconstrictors of retinal vessels,67 as well as anti-VEGF molecules. The therapeutic effect of oxygen on macular edema has also been attributed to vasoconstriction.68

Endothelial dysfunction also provides a basis for the chronic, low-grade inflammation observed in experimental and clinical diabetes. Increased leukocyte adherence, or leukostasis, has been shown to occur early in DR, and may account for both capillary closure and blood–retinal barrier rupture.69 Another aspect of chronic inflammation is related to microglial cells, which are chronically activated during diabetes.70 Because activated microglia release proinflammatory cytokines and chemokines, such as VEGF and tumor necrosis factor, it is likely that they further exacerbate retinal vascular permeability in diabetes.

Role of systemic factors (Box 67.5)

When the blood–retinal barrier is open, Starling’s laws influence the net movement of water and solutes out of capillaries, leading to macular edema formation.71 Starling’s law

Box 67.5  Aggravating factors of diabetic

macular edema

Systemic factors

•Hypertension

•Intravascular fluid overload (congestive heart failure, renal failure, hypoalbuminemia)

Mechanical factors

•Vitreomacular traction

•Epiretinal membrane

states that the net movement of fluid out of capillaries is determined by the sum of hydrostatic and oncotic pressures. Therefore, changes in accumulation of water and solutes in the retina may be due either to changes in hydrostatic (e.g., arterial pressure) or oncotic (e.g., protein content) pressure. Thus, systemic mechanisms leading to increased hydrostatic pressure such as hypertension, or intravascular fluid overload, as observed in cases of congestive heart failure, or renal failure, as well as decreased oncotic pressure (hypoalbuminemia) may worsen DME, and should be actively managed.

Mechanical factors (Box 67.5)

Several observations have suggested that the vitreous may play a role in the pathogenesis of DME. Indeed, Hikichi et al

observed a more frequent spontaneous resolution of DME when the posterior hyaloid was completely detached from the posterior pole.72 Sebag observed increased levels of early glycation products, as well as advanced glycation endproducts in the vitreous of diabetic patients compared to controls.73 These alterations may lead to liquefaction and destabilization of the vitreous gel. Furthermore, the vitreo­ retinal adhesion often remains strong despite gel liquefaction.74 Destabilization of the central vitreous cortex together with the persistent attachment of the vitreous cortex to the retina may thus lead to traction on the macula, and contribute to the development of DME. Such mechanism is obvious in cases of diffuse DME combined with a taut and thickened posterior hyaloid, for which the beneficial effect of vitrectomy has been demonstrated.21 Mechanical traction by epiretinal membranes may also aggravate edema, which is relieved by surgical ablation.

Conclusion

If the treatment of DME is still mainly based on laser photocoagulation, the control of systemic factors seems crucial to prevent its worsening. Pharmacological approaches, including anti-VEGF therapy and steroids, are under investigation. The increased understanding of the complex mechanisms which are involved in the pathogenesis of DME will further enhance our therapeutic possibilities.

1.Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. ETDRS report number 1. Arch Ophthalmol 1985;103:1796–1806.

4.Gillies MC, Sutter FK, Simpson JM, et al. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology 2006;113:1533–1538.

6.Wilkinson CP, Ferris FL 3rd, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110:1677– 1682.

9.Klein R, Klein BE, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. Ophthalmology 1995;102:7–16.

13.UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular

complications in type 2 diabetes: UKPDS 38. Br Med J 1998;317:703–713.

26.Gardner TW, Antonetti DA, Barber AJ, et al. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol 2002;47(Suppl. 2):S253–S262.

32.Bresnick GH. Diabetic macular edema. A review. Ophthalmology 1986;93:989– 997.

42.A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008;115:1447– 1449, e1441–1410.

46.Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factorinduced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997;46:1473–1480.

53.Antonetti DA, Barber AJ, Khin S, et al. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group. Diabetes 1998;47:1953–1959.

57.Jiang WG, Martin TA, Matsumoto K, et al. Hepatocyte growth factor/scatter factor decreases the expression of

occludin and transendothelial resistance (TER) and increases paracellular permeability in human vascular endothelial cells. J Cell Physiol 1999; 181:319–329.

62.Gao BB, Clermont A, Rook S, et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 2007;13:181–188.

69.Joussen AM, Murata T, Tsujikawa A, et al. Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 2001;158:147–152.

70.Rungger-Brandle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci 2000;41:1971– 1980.

71.Stefansson E. Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol 2006;51:364–380.