The vitreous humor is the most abundant ocular tissue, comprising the majority (4 ml) of the eye’s volume. Often referred to as the “vitreous gel,” a reference to both its consistency and biomechanical composition, the vitreous extends from the posterior lens capsule back to the retina’s internal limiting membrane (ILM). For centuries, ophthalmologists believed that the vitreous could not be safely manipulated, altered, or removed without precipitating catastrophic consequences such as retinal tears, retinal detachments, suprachoroidal hemorrhages, or endophthalmitis. In retrospect, it has become obvious that physicians lacked a sufficient understanding of vitreous anatomy and physiology and did not possess the proper technology with which to safely and effectively handle the vitreous [60].

The gel-like consistency of the vitreous impedes the diffusion of substances such as vascular endothelial growth factor out of the retina and the movement of oxygen from anterior structures into the retina. The high viscosity of the vitreous (up to six times that of water) slows the resorption of hemorrhage that may result from insufficiently treated proliferative diabetic retinopathy (PDR), and it impedes the elimination of intravitreally administered drugs, thereby improving the effectiveness and duration of pharmacologic therapy. Trial designers recognize the importance of an intact vitreous since they routinely exclude eyes that have already undergone vitrectomy from participating in intravitreal drug trials.

An intact vitreous provides a scaffold for fibrovascular growth in various proliferative retinopathies. Vitreomacular traction (VMT) due to partial vitreous contraction and collapse without complete separation of the posterior hyaloid from the ILM upregulates VEGF production, promotes the formation of macular edema, and limits the efficacy of intravitreal pharmacotherapy.

In eyes with diabetic retinopathy (DR), the vitreous is viewed as both an enemy that contributes to the disease and as an ally that potentiates treatment by providing a reservoir for drug placement. Successfully changing the vitreous by inducing a vitreous detachment or removing most of it has become an important therapeutic approach for many retinal and vitreoretinal interface diseases. Pars plana vitrectomy with the removal of VMT has been used for two decades to treat diabetic macular edema (DME) (Chap. 3).

This chapter will discuss pharmacologic approaches to eliminate the adverse effects of VMT on the formation of diabetic retinopathy.

The vitreous comprises about 80% of the ocular volume [82], and its transparent matrix is composed primarily (98–99%) of water [6]. The gel structure is maintained by a complex branching network of collagen fibrils held apart by hyaluronic acid and other macromolecules. Type II collagen is the most common vitreous protein with highest concentrations found at the vitreous base and in the posterior vitreous cortex [41]. The collagen fiber network gives the gel strength and stability, which enables it to absorb shock from blunt trauma and resume its previous shape after being subjected to distorting forces.

Hyaluronic acid, the most common glycosaminoglycan within the vitreous, stabilizes the collagen network [7, 78]. The hyaluronic acid-collagen matrix correctly spaces fibrils to optimize transparency and decrease light scatter, and endows the vitreous with viscoelastic properties [7, 8, 13]. The vitreous is nearly acellular except for a small number of hyalocytes, phagocytic cells found mostly at the vitreous base and posterior pole [4, 8, 78, 94]. Hyalocytes also synthesize collagen fibrils and hyaluronic acid.

The interface between the vitreous and adjacent structures is composed of vitreous cortical fibrils and the basal laminae of the other tissue [30]. Changes at the vitreous base usually result in retinal tears and detachments, but the interface between the posterior hyaloid and macula is more important in patients with DR. The ILM of the retina consists of the footplates or basal laminae of the Müller cells [79] together with types I and IV collagen, proteoglycans, fibronectin, and laminin [36, 47, 52, 53]. It is not clear which of these molecules must be dissolved to facilitate a posterior vitreous detachment, and even “linker molecules” like lectins, integrins, and chondroitin sulfate may ultimately be responsible for the attachment of the vitreous cortex to the ILM. The ILM varies in thickness from 50 μm at the vitreous base to 300 μm at the equator to 1890 μm over the posterior pole before it thins to only 10–20 μm at the fovea [25, 30, 37]. The firmest vitreous adhesions occur where the ILM is thinnest – at the vitreous base and the fovea.

The vitreous both liquefies and aggregates as it ages. Vitreous liquefaction, or syneresis, begins at the age of 4 years, whereas aggregation of fibrils, or synchysis, begins in midlife and continues into old age (Fig. 7.1) [48, 49]. Changes in hyaluronic acid and its interaction with the collagen fibrils create areas of liquefaction that alternate with areas of increased collagen fiber concentration within the residual gel [45, 59]. Liquefaction in the central vitreous overlying the macula enables incident light to produce free radicals that weaken the residual collagen and decrease the concentrations of glycosaminoglycans and chondroitin sulfate [51]. This promotes posterior hyaloid separation from the ILM (posterior vitreous detachment).

Most posterior vitreous detachments (PVDs) result from a combination of vitreous synchysis and weakening of the adhesions between the ILM and posterior hyaloid. Liquefied premacular vitreous slowly migrates into the potential space between the posterior hyaloid and ILM, and since the adhesions have been weakened, the two surfaces slowly begin to separate, beginning in the peripheral macula (Fig. 7.2). Saccadic eye movements and continued loss of adherent molecules cause further cleavage with progressive enlargement of the preretinal space that marches toward the fovea. A final collapse of the vitreous gel with complete separation of the posterior hyaloid from the fovea and optic disc characterizes a PVD [22, 58, 77].

Incomplete separation of the posterior hyaloid because of residual vitreomacular adhesion constitutes an anomalous PVD [84]. If the residual vitreous adhesion causes distortion of the macula by elevating the ILM, this is termed vitreomacular traction. Excessive gel liquefaction is seen in many systemic conditions including diabetes [80] and together with strong vitreomacular adhesion may cause symptomatic vitreomacular traction or even macular holes. In patients with diabetic retinopathy, this can cause diabetic macular edema (DME).

Diagnosing an anomalous vitreous detachment can sometimes be done with slit-lamp biomicroscopy and a magnifying fundus lens (Fig. 7.3), but spectral domain optical coherence tomography (SD-OCT) is an easier and more accurate method of visualizing the partially detached posterior hyaloid [31, 54, 75, 97]. Correctly differentiating between a complete PVD and a completely attached posterior hyaloid can be difficult with OCT, and ultrasound is a more accurate tool to discriminate between these two conditions.

Several studies have investigated the association between integrity of the vitreous and the development and progression of DR. Retinal vessels are normally excluded from the vitreous because development of neovascularization on the retinal surface – proliferative diabetic retinopathy (PVR) – requires a scaffold of collagenous material [21]. Elevated glucose levels in the vitreous induce the formation of advanced glycation end products [85] and promote cross-linking of collagen and the development of excess vitreous liquefaction, without promoting dehiscence of the posterior cortical vitreous. Intravitreal proteins that normally inhibit the development of neovascularization may lose this ability because they undergo nonenzymatic glycation [38, 81]. In eyes with DR, growth factors that are synthesized in the retina diffuse into the vitreous and encourage the development of neovascularization [33, 34, 61]. Oxygen transport from the ciliary body to the inner retina may be impeded, which worsens retinal ischemia and further increases the synthesis of growth factors.

Diabetes-mediated breakdown of the blood-retinal barrier leads to an extracellular accumulation of serum proteins, which increases the concentrations of fibronectin and other chemokines at the vitreoretinal surface by tenfold [53]. These molecules stimulate the migration and adhesion of proliferating vascular endothelial cells [9] and fibroblasts to the posterior hyaloid. Contraction of these cells, in the presence of an anomalous PVD, exerts tangential traction on the retina, further upregulates VEGF, and exacerbates DME [70]. Traction also decreases interstitial pressure, which, according to Starling’s Law, promotes passage of fluid out of the vascular lumens [15].

A complete PVD should provide some protection against the development of neovascularization [65, 66], but since islands of residual cortical vitreous remain attached to the ILM, such protection is generally incomplete. Five studies that included over 2000 eyes have looked at the association of PDR and BDR development according to the status of the posterior hyaloid [2, 46, 69, 90, 91]. A pooled analysis of these data found that eyes with complete PVDs had a significantly lower prevalence of PDR (OR 0.1, 95% CI, 0.05–0.18), and the development of a PVD is frequently followed by resolution of DME [42, 100]. Two of the studies found that eyes with partial PVDs had six times the progression rate as those without a PVD and 15 times the progression rate as those with complete PVDs [2, 46, 69, 90, 91].

Removal of the posterior hyaloid may help resolve DME by relieving traction and releasing trapped preretinal growth factors. A liquefied vitreous may accelerate the removal of vascular endothelial growth factor from the inner retina. When surgeons propose treatments for DR that involve the induction of a PVD, they need to remember that a partial PVD may actually worsen the retinopathy.

Spectral domain OCT imaging has demonstrated that vitreomacular adhesion (VMA) occurs in the majority of patients over the age of 50 years. Vitreomacular adhesion that distorts the inner retinal contour is termed vitreomacular traction (Fig. 7.4). Macular changes may be limited to loss of the foveal depression, to macular splitting or schisis, or to traction foveal detachment. Patients usually experience decreased central visual function though some may be asymptomatic. The natural history of this process is highly variable, as some eyes achieve complete vitreoretinal separation, others progress to partial or full-thickness macular holes, and a third group remains stable for years.

Creating a complete PVD to relieve an anomalous partial vitreous detachment has been a topic of considerable interest to retinal surgeons over the last 5 years. Surgical intervention for eyes with symptomatic VMT can be done in two ways. Pars plana vitrectomy removes the core vitreous, after which the posterior hyaloid is detached with aspiration. Despite what appears to be complete removal of the posterior cortical vitreous, islands of cortex frequently remain attached to the ILM. These may sequester growth factors and promote fibrovascular growth. Many surgeons perform a dye-assisted peeling of the ILM to remove all vitreous fragments and minimize the chance of postoperative angiogenesis or traction.

Vitrectomy with ILM removal effectively and predictably removes traction but not without associated risks. Many phakic patients develop cataracts within 2 years that require removal. The risks of retinal tears, retinal detachments, and endophthalmitis are relatively low but still of concern. If the adhesive forces between the posterior cortical vitreous and the ILM are sufficiently strong, vitrectomy can convert VME into a full-thickness macular hole.

Pharmacologic vitreolysis involves the use of drugs that liquefy the vitreous (synchysis) and weaken the adhesion between the posterior hyaloid and the ILM [83]. Intravitreal hyaluronidase was used as early as 1946 [72] and collagenase was used in 1973 [67]. Chondroitinase, dispase, plasmin, and tissue plasminogen activator (tPA) have all been tested in animals and used sporadically in humans [67, 71, 93, 99]. Results with intravitreal hyaluronidase and dispase were disappointing because of insufficient vitreoretinal separation or partial digestion of the inner retina [32, 44, 50, 55, 56, 68, 93]. Only the fibrinolytic enzymes plasmin and tissue plasminogen activator (tPA) showed some success in PVD induction when injected into human eyes [3, 12, 17, 57, 63, 95]. Successful induction of PVDs has been achieved after intravitreal injections of ocriplasmin (Jetrea®, Thrombogenics, Leuven, Belgium) into eyes with symptomatic vitreomacular traction (Fig. 7.5) or stage 2 macular holes (Fig. 7.6). Eyes that responded best to ocriplasmin had the following characteristics: age >65 years of age, vitreomacular adhesion <1500 μm, phakic lens status. and the absence of epiretinal membrane. Macular holes of <400 μm diameter with persistent vitreomacular adhesion also responded well to ocriplasmin.

Many surgeons believe that pharmacologic vitreolysis produces a more complete and less traumatic PVD than does surgery [3]. Vitreolysis trials with ocriplasmin and other pharmacologic agents in patients with DME are underway. Table 7.1 lists the drugs that have been used to induce posterior vitreous detachments in animals and humans.