Chapter 118 Cystoid Macular Edema and Vitreomacular Traction
Introduction
Macular edema is defined as an abnormal thickening of the macula associated with accumulation of fluid in the extracellular space of the outer plexiform layer and the inner nuclear layer, and occasionally in the intracellular space.1,2 It contributes to vision loss by altering the functional cell relationship in the retina and promoting an inflammatory reparative response. Macular edema associated with vitreous traction represents a particular tissue reaction due to the mechanical distortion of the retina. However, it is often difficult to differentiate whether edema is linked to the fact that the vitreous is pulling actively on the retina or to the fact that it is simply adherent. Furthermore, in certain circumstances, the changes at the vitreoretinal interface may represent the cause and in some others, the effect of vitreoretinal traction.3
The therapeutic approaches to macular edema depend on its pathophysiological mechanisms related to the underlying etiology, and they may be purely surgical or in combination with medial treatments. Therapies have evolved dramatically over the last years, as research has led to enhanced understanding of its causes as well as to the development of new pharmacologic agents and surgical approaches.3 Cystoid macular edema (CME) is considered a leading cause of central vision loss in the developed world, and it is therefore of enormous medical and socioeconomic importance.4
Historical discovery of macular edema
One of the first reports, after the advent of the direct ophthalmoscope, on what would be described as diabetic macular edema today was published by Eduard Jaeger in 1856.5 In 1872, Edward Nettleship provided the first histopathological proof for a “cystoid degeneration of the macula” in patients with diabetes,6 while histological observations on a cystic degeneration unrelated to diabetes were further documented by the Russian ophthalmologist Iwanoff.7
The first description of macular edema with documented vitreomacular traction was published by Irvine in his classical paper on CME after intra- and extracapsular cataract extraction characterizing the vitreous tug syndrome after incarcerated vitreous in the corneal wound.8
Anatomy and pathophysiology of macular edema
Anatomy of cystoid macular edema
Cystoid spaces in macular edema are intracellular or extracellular, or both according to different pathologic studies.9–11 The central area of the retina is predisposed to develop edema due to its unique anatomy, which is characterized by an extremely high cell count with increased metabolic activity and a central avascular zone, creating a watershed arrangement between the choroidal and retinal circulation which decreases resorption of extracellular fluid.12
The classic understanding has been that cystoid spaces form within Henle’s layer, which courses laterally away from the central fovea. In the foveal region, these fibers of the outer plexiform layer demonstrate a loose arrangement allowing accumulation of fluid leaking from perifoveal capillaries. However, it has been shown that the cystoid spaces can also form in the outer nuclear, inner nuclear, inner plexiform, and even the ganglion cell layer.13
The leakage from the perifoveal capillaries may explain the presence of cystoid spaces in the inner nuclear layer and Henle fiber layer. The presence of cystoid spaces in the ganglion cell layer might be explained with the assumption that epiretinal membranes, thickened internal limiting membrane (ILM), and/or adherence of the vitreal cortex to the retina disturbs the water movement between the vitreous and retina.14
Pathophysiology of tractional macular edema
In a normal steady state, several mechanisms prevent an accumulation of extracellular and intraretinal fluid and proteins. These mechanisms are able to maintain a balance of osmotic forces, hydrostatic forces, capillary permeability, and tissue compliance. The result is that the rate of capillary filtration equals the rate of fluid removal from the extracellular retinal tissue. Therefore, the interstitial spaces of the retina can be kept “dry” in physiological conditions.2
Fluid accumulation can be caused by increased water influx into the retinal tissue by decreased fluid clearance through glial and retinal pigment epithelium (RPE) cells.15 The former can be a result of an increase in the hydrostatic pressure (as occurring, e.g., during increased retinal blood flow and vasodilation), and of osmotic imbalances (hypo-osmolarity of the blood/vitreous and/or hyperosmolarity of the retinal tissue, as occurring, e.g., in diabetic retinopathy and cases of hepatic and renal failures). A decreased water clearance through glial and RPE cells occurs when inflammatory conditions impair the transcellular transport of osmolytes, or when the fluid influx through the disrupted blood–retinal barrier (BRB) exceeds the fluid clearance capacity of the cells.
The vitreous has been implicated as a cause of macular edema via several mechanical and physiologic mechanisms. One of the most constructive hypotheses on how vitreomacular traction (VMT) may result in macular edema was given by Schubert in 1989, and was summarized by Bringmann and Wiedemann in 2009.16,17 Vitreous fibers, which adhere to Müller cell end-feet at sites of vitreoretinal attachments after partial detachment of the vitreous, exert tractional forces onto the cells; this activates Müller cells and results in cell hypertrophy, proliferation, and vascular leakage.16,17 Furthermore, long-lasting mechanical stress of astrocytes and Müller cells induced by vitreal fibers adhering to the cells can stimulate the release of inflammatory factors such as basic fibroblast growth factor (bFGF), inducing local inflammation and BRB breakdown promoting vascular leakage and macular edema.18
Vitreoretinal traction can also exert forces at the level of the RPE, which can eventually result in morphological RPE changes.19,20 Furthermore, VMT has been shown to induce pigment epithelial detachment and RPE tearing.21 It is a well-known phenomenon in many retinal vascular diseases that direct traction on the macula or on the RPE may induce not only local inflammation but also increase vascular endothelial growth factor (VEGF) locally, with subsequent macular edema formation.22–24
Mechanical traction can also cause macular edema by direct distortion of the surrounding intraretinal vessels, resulting in leakage due to disturbance of the macular microcirculation with reduced capillary blood flow and a loss of apposition between the retina and the RPE pump.25
Sebag and others have found enzyme-mediated vitreous cross-linking and nonenzymatic glycation in the diabetic vitreous, and they have suggested that the abnormal cross-linking might affect the collagen structure and destabilize the attached vitreous gel strengthening the adhesion of the posterior vitreous cortex to the ILM, which in turn produces stronger vitreoretinal attachment with subsequent macular edema.26,27
Furthermore, the vitreous in various pathologic conditions may act as a sink for factors influencing macular edema themselves. The breakdown of the BRB usually leads to an increased concentration of intravitreal serum-derived chemoattractants, which may provide a stimulus for cellular migration into the attached premacular posterior hyaloid. Cellular contraction may potentially lead to tangential traction with consequent leakage and macular edema.28,29 In turn, leakage from the vascular bed aggravates chemoattractant outflow, thus creating an inexorable vicious circle.
It has also been shown that several growth factors such as VEGF, IL-6, platelet-derived growth factor (PDGF), and others are secreted in large amounts into the vitreous during proliferative vasculopathies such as diabetic retinopathy or retinal vein occlusion30–32 and these factors may increase vasopermeability and promote macular edema. Furthermore, during aging, VEGF is increasingly bound by altered vitreous collagen fibrils at the interface between retina and posterior vitreous cortex potentiating the effects of these growth factors.33
Clinical signs of cystoid macular edema
Clinically, macular edema can be best detected using the slit lamp and either a contact lens (e.g., Goldmann lens) or a handheld, noncontact lens (e.g., +78 D, +60 D). Ophthalmoscopically, the cysts are characterized by an altered light reflex. These changes may be better visible using green light, while retroillumination can help to delineate the polycystic spaces. The lack of sensitivity of the clinical examination for detection of mild edema has been demonstrated for eyes with a foveal center thickness between 201 and 300 µm. Only 14% of eyes were noted to have foveal edema by contact lens biomicroscopy. The term “subclinical foveal edema” describes such cases.34,35 A thorough examination of the anterior segment should always complement the clinical evaluation as incarcerated vitreous or a badly placed intraocular lens may be the underlying cause of macular edema.14 Symptoms range from loss in distance visual acuity, contrast sensitivity, color vision, reading acuity to a reduction in reading speed.36–38 Accompanying symptoms may include metamorphopsia and micropsia. Additionally, a marked reduction in central retinal sensitivity with either a relative or absolute scotoma during active macular edema, but also after the edema has resolved, has been reported.39 Retinal thickness appears to be most closely correlated with visual acuity,40 whereas increased leakage on fluorescein angiography is not directly correlated with reduced visual acuity.
Imaging of cystoid macular edema
Angiography
The fundus fluorescein angiogram has for many years been one of the most useful tests in detecting macular edema of various etiologies.41
In the early phase of the angiogram, capillary dilation can be detected in the perifoveal region. In the late phase, fluorescein pools in cystoid spaces located in the outer plexiform layer (Henle’s layer) displayed as the classic petaloid staining pattern.35,41 The fusiform cystoid spaces are arranged in a radial pattern. In long-standing macular edema, the cystoid spaces enlarge and may merge, representing irreversible damage to the retina. When cystoid spaces occur outside the perifoveal area, fluorescein angiography shows a honeycomb appearance, rather than a petaloid pattern.41,42 The amount of fluorescein leakage depends on the dysfunction of the retinal vascular endothelium and there is a significant correlation between visual acuity and the area covered by these cystoid changes.11,43 So-called “silent” angiograms have also been reported, which correspond to the presence of clinical macular edema, which shows, however, no leakage on fluorescein angiography. One reason for this may be very old changes within the retina, which are characterized by intraretinal cysts, which have become impermeable to the fluorescein dye diffusion.
Furthermore, one should consider that macular edema can also occur without vascular leakage, when the fluid clearance through glial and RPE cells is impaired.15 This may also explain the presence of edema in cases without significant angiographic vascular leakage.
Indocyanine green angiography is not considered a very useful tool for detecting macular edema.35 However, in some cases, particularly for laser scanning, it may provide additional direct signs of macular edema for the delimitation of cystoid spaces progressively filled with the dye and also for precise analysis of RPE alterations.41 The autofluorescence can also depict the cysts as hyperautofluorescent because of the displacement of macular pigments that naturally attenuate the autofluorescent signal.35
Optical coherence tomography
Optical coherence tomography (OCT) is able to accurately measure the retinal thickness, allowing a more precise and reproducible assessment than fluorescein angiography,44–46 with a particular efficacy in the volumetric analysis of macular edema. Several authors have proposed different patterns and classifications of macular edema, according to the underling pathology based on OCT findings.35,47–52
OCT and diabetic macular edema
In diabetic macular edema (DME), there are several broad nonexclusive categories: diffuse retinal thickening; cystoid macular edema; serous retinal detachment, and vitreomacular interface abnormality. It has been demonstrated that the amount of reflectivity within these diabetic cystoid spaces is due to higher concentration of protein associated with the breakdown of the inner blood–retinal barrier in diabetic macular edema.53 OCT identified vitreomacular interface abnormalities including the presence of epiretinal membranes (ERM) and/or VMT. An ERM can be manifested on OCT by the presence of a macular pseudohole, a hyperreflective band along the inner aspect of the retina, or a visible hyperreflective membrane tuft or edge. Vitreomacular traction is identified by a hyperreflective band that is in apposition with the inner surface of the retina at discrete site(s) and elevated above the surface of the retina elsewhere.47,51
Ghazi et al.54 demonstrated that in eyes with persistent DME, vitreomacular interface abnormalities may be found in up to 52–67% on OCT, and concluded that OCT was nearly twice as sensitive as traditional techniques in detecting vitreomacular interface abnormalities.
Kim et al.47 proposed five different morphologic patterns at OCT evaluation of diabetic macular edema in relation to VMT: Pattern I is a diffuse increased retinal thickening, with areas of reduced intraretinal reflectivity; Pattern II is CME as described above; Pattern III shows posterior hyaloidal traction, which appears as a highly reflective band over the retinal surface; Pattern IV exhibits serous retinal detachment not associated with posterior hyaloidal traction, which appears as a dark accumulation of subretinal fluid beneath a highly reflective dome-like elevation of detached retina; Pattern V shows posterior hyaloidal traction and tractional retinal detachment, which appear as a peak-shaped detachment with a highly reflective signal arising from the inner retinal surface and with an area of low signal beneath the highly reflective border of detached retina (Table 118.1). More recent reports have also shown – using immunohistochemistry – unequivocal proof of proliferative changes on the retinal and vitreal surface of the diabetic ILM,55 while others have quantified the frequency of vitreomacular interface pathologies in diabetic macular edema in general.56
A very recent publication showed furthermore, that in eyes with DME, ERM and incomplete posterior vitreous detachment, the posterior cortical vitreous and the membrane appeared as one membrane in most eyes and were typically associated with vitreopapillary adhesion.57
OCT in vitreomacular traction syndrome
Vitreomacular traction syndrome (VMTS) can sometimes be characterized by a particular type of macular edema and OCT represents the most helpful tool for the diagnosis and follow-up of these pathologies. OCT can show perifoveal vitreous detachment, a thickened hyperreflective posterior hyaloid and ERM (Fig. 118.1).35 Koizumi H et al.52 described two different OCT patterns of vitreous attachment in VMT using spectral-domain OCT: foveal cavitation defined as the formation of cystoid cavity located in the inner part of the central fovea secondary to mechanical forces and CME that was defined as intraretinal cyst-like cavities extending beyond the foveal region. Sometimes, a neurosensory retinal detachment occurs while the macular traction may resolve in the formation of a lamellar-macular hole.43
Odrobina et al.50 also advocated that vitreous surface adhesion and persistence of ERM on OCT may be the prognostic factors for the natural course of VMT. They observed spontaneous resolution of VMT in eyes with less vitreous surface adhesion and without ERMs, while in eyes with higher vitreous surface adhesion or coexisting ERM they suggested a surgical intervention.50 Similar observations have been made on VMT in retinal vein occlusion.58
OCT for vitreomacular traction in age-related macular degeneration
The initial observations were made using B-scan ultrasound which showed that ARMD patients have a high rate of persisting vitreous attachment using ultrasound59 and other means of diagnosis.60–62 But more recently, using high-resolution OCT, vitreomacular adhesions and traction have also been associated with the presence of ARMD. OCT-aided studies confirmed a high incidence of attached vitreous of up to 79%.24
Surgical treatment of tractional macular edema
Rationale for vitrectomy
Tractional origin of macular edema
The initial rationale for using vitrectomy in cases of macular edema was entirely structural, i.e. aimed at the removal of vitreous traction on the macula.63,64 The latter becomes understandable by looking at Newton’s third law: to any action there is always an equal reaction in the opposite direction. The force of vitreoretinal traction will thus be met by an equal and opposite force in the retina, resulting in the manifold pathological reactions described previously. Vitrectomy may thus conceptually relieve traction on Müller and RPE cells that had resulted in vascular leakage, and it may also suppress the release of inflammatory factors previously induced by the mechanical stress on these cells. Additionally, vitrectomy may reduce the tractional disturbance of the macular microcirculation and it may restore the apposition between the retina and the RPE pump.
Nontractional origin of macular edema
Recent discoveries have shown that vitrectomy may not only be beneficial in the presence of macular traction, but also in cases where no particular deformation of the macula can be identified. This is particularly true for macular edema of vascular origin, such as diabetes or retinal vein occlusion. The beneficial effect of vitrectomy is thought to be based – at least in part – on two mechanisms. First, it has been found that oxygenation of the posterior segment of the eye is increased after vitrectomy.65–68 Others have shown that pharmacologic vitreolysis also improves vitreal O2 levels and that it increases the rate of O2 exchange within the vitreous cavity.69,70 This may also be the mechanism behind the observation that vitrectomy may reduce the extent of the foveal avascular zone as seen on fluorescein angiography.71 Second, it has been shown that several growth factors such as VEGF, IL-6, platelet-derived growth factor, and others are secreted in large amounts into the vitreous during proliferative vasculopathies such as diabetic retinopathy or retinal vein occlusion31,32,72,73 and it is conceivable that a complete vitrectomy will remove this excess of growth factors mechanically with the desired effect of a restitution of the blood–retinal barrier.19 The rapid clearance of VEGF and other cytokines may thus help to prevent macular edema and retinal neovascularization in ischemic retinopathies, such as diabetic retinopathy and retinal vein occlusions. Vitreous clearance of growth factors may indeed have the same effect as the presence of, e.g., VEGF antibodies in the vitreous cavity.74–76
Rationale for internal limiting membrane peeling
ILM may thicken due to an increased content of extracellular matrices and cellular proliferation on the vitreous surface in cases of diabetic macular edema.77 It has been hypothesized that ILM changes contribute to the structural and functional disturbance of water movement between the vitreous and the retina77 and eventually retain proteins in the interstitial space avoiding diffusion of proteins to the vitreous space leading to macular edema.78 Additionally, the diffusion of oxygen from the fluid in the vitreous cavity into the retina would be retarded by a thickened ILM.79 Also, the absence of the vitreous gel would increase the transport of cytokines, such as VEGF, from the retina into the vitreous cavity, and the absence of ILM would further speed up this clearance of cytokines from the retina.75 The efficacy of ILM delamination may be caused by the removal of a growth factor reservoir, which may have accumulated in the ILM and in cellular elements on its vitreous side. Vitreous remnants may be present even after surgical vitreous separation80 and ILM delamination allows a more complete removal of vitreous elements.77,80 In uveitis and in VMT complicating ARMD, it has been speculated that intraocular inflammation, through the release of chemokines and cytokines into the vitreous, may result in a firmer attachment of the posterior hyaloid to the macula and/or contraction of the ILM creating tangential traction on the retina and the development of macular edema. In such cases, macular edema may be refractive to medical therapy – corticosteroids and anti-VEGF agents – and it may only be relieved by vitrectomy with separation of the posterior hyaloid and/or peeling of the ILM (Fig. 118.2).81
Clinical entities with cystoid macular edema associated with vitreomacular traction
Diabetic macular edema (DME)
Role of vitrectomy in DME
In 1992 Lewis et al. were the first to report the resolution of macular edema in 80% of cases after vitrectomy for diabetic edema associated with posterior hyaloidal traction.63 Other studies have also suggested a beneficial result of vitrectomy for tractional DME.82,83 The functional prognosis was considered to be better when vitrectomy is performed at an early stage.84
In 2010, the Diabetic Retinopathy Clinical Research Network evaluated vitrectomy for diabetic macular edema in eyes with at least moderate vision loss and vitreomacular traction. They found retinal thickening to be reduced in most eyes postoperatively. The median change in visual acuity increased on average at 6 months after surgery by three letters, with visual acuity improving by ≥10 letters from baseline to 6 months in 38% and worsening by ≥10 letters in 22%. Reduction in central macular thickness as shown by OCT to be less than 250 µm occurred in almost half, and most eyes had a thickness reduction of ≥50%.85 Since 1990, several other authors have also reported that vitrectomy is beneficial for diffuse DME combined with a taut thickened posterior hyaloid presumably with tangential hyaloidal traction.86 Pendergast et al.87 reported stability or improvement in 91% of eyes and complete disappearance in 92% of patients after vitrectomy for diffuse DME associated with a taut posterior hyaloid.
Reports in the literature on vitrectomy for DME, in the absence of traction, include mixed visual acuity results. Some studies suggested positive outcomes; others have shown anatomic but not visual improvement after surgery, while some studies suggested that vitrectomy is not beneficial in eyes with DME without traction.83–85
Role of internal limiting membrane peel in DME
Despite several clinical studies over the past few years, the role of ILM peeling in DME is still far from clear. Stolba et al. and Stefaniotou et al. reported a favorable outcome following vitrectomy and ILM peeling opposed to the natural course of DME.88,89 In contrast, others found good anatomical but less impressive visual results. Bahadir et al. found similar degrees of improvement in visual acuity after vitrectomy without ILM peel compared to vitrectomy with ILM peeling in the treatment of DME.90 Patel et al. in a comparative, prospective study of vitrectomy with and without ILM peeling for diffuse clinically significant macular edema, reported structural improvement but with limited visual improvement after ILM peeling.91 Kumar et al. compared the effectiveness of vitrectomy and ILM peeling with grid laser photocoagulation in patients with diffuse DME and found that vitrectomy with ILM peeling was beneficial by inducing a statistically significant reduction of macular thickness and macular volume. However, the comparative visual acuity outcome analysis between the two groups was not significantly different.92
Gentile et al. advocated that a taut ILM can still cause diffuse DME after vitrectomy, and that its removal can restore the normal foveal contour and improve visual acuity.93 In a recent randomized controlled study, Hoerauf et al.79 demonstrated a favorable effect of additional ILM removal in vitrectomy for cystoid DME without evident VMT. They concluded that in the long term, while posterior vitreous detachment (PVD) alone slowly improves the anatomical results, it is markedly less effective than additional ILM removal. However, even though the morphological results were substantial, visual results were unsatisfactory.
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