Deficient Autophagy Contributes to the Development of Diabetic Retinopathy

*Jacqueline M. Lopes de Faria and Marcella Neves Dátilo*

## **Abstract**

Autophagy is a self-degradation process essential to maintain intracellular homeostasis and cell survival, controlling elimination of pathogens, damage to organelles, and nutrient recycling to generate energy. Alterations in autophagic flux have been reported in the mechanisms of several diseases such as neurodegenerative diseases, cancer, diabetes mellitus, and its associated complications. Diabetic retinopathy (DR) is a microvascular complication of diabetes, affecting nearly 30% of diabetic patients. Several pathways are triggered and repressed in the development of DR, and autophagy showed to be relevant in the pathogenesis of this devastating complication. In this chapter, autophagy's involvement in the development and progression of DR will be discussed, mainly in retinal pigmented epithelial cells and retinal microvascular endothelial cells, as well as in Müller cells—the more prominent retinal glial cell.

**Keywords:** retina, diabetic retinopathy, autophagy, ARPE-19, endothelial cell, Müller cell

## **1. Introduction**

Autophagy (from Greek, meaning "self-eating") refers to a highly conserved process in eukaryotic cells, which coordinates the degradation of intracellular components and nutrient recycling. This process is essential for cellular homeostasis, survival, and differentiation. In basal conditions, the autophagic process happens in low levels to maintain cellular homeostasis. However, in such conditions as low levels of adenosine triphosphate (ATP) or depletion of essential amino acids and glucose, autophagic flux can increase to generate energy and raise basal levels. More recently, the understanding of this process has gained attention due to its pivotal role in cellular physiology and a variety of diseases from cancer, chronic degenerative diseases, and immune diseases (**Table 1**).

Autophagy is a primary cell response to stress and can be induced by starvation, endoplasmic reticulum (ER) stress, hypoxia, cytotoxicity, and infection (**Figure 1**). Sensation, initiation, and regulation of the autophagy–lysosomal pathway is controlled by the heterotrimeric serine/threonine kinase AMP (AMPK) and rapamycin complex 1 (mTORC1), either triggering or repressing autophagy and mitophagy. Unc-51-like kinase 1 (ULK1) is a primary initiating protein, as is mTORC1 supressed transcription factor EB (TFEB), which coordinates the synthesis of


#### **Table 1.**

*In this table, some examples of genetic diseases associated with autophagic impairment [1–8].*

#### **Figure 1.**

*Several cellular sensors regulate autophagic flux to maintain homeostasis.*

lysosomes and other essential proteins maintaining the autophagic flux [9–12]. In addition, sirtuin-1—a class III deacetylase dependent on nicotinamide adenine dinucleotide (NAD+)—becomes a positive autophagy regulator, since it may also be considered a cellular sensor [13].

This process is mainly regulated at a post-translational level, increasing mRNA expression of autophagy genes [14]. Under stress conditions, TFEB is translocated from cytosol to the nucleus, activating transcription of ATG genes and coordinating upregulation of the entire autophagy–lysosomal pathway [15].

**15**

*Deficient Autophagy Contributes to the Development of Diabetic Retinopathy*

or 5 genes leads to postnatal neurodegeneration [16, 17].

pathways that similarly modulate AMPK and mTOR [20–22].

autophagy-related genes (ATG). For example, deletion of specific neurons of ATG7

leads to an increase in the AMP/ADP ratio, activating the AMPK α subunit [10].

This discussion includes a short overview of the more common types of autophagy and will highlight the role of autophagy in retinal diseases, with special

There are three forms of autophagy previously described in the literature: macroautophagy, chaperone-mediated autophagy, and microautophagy (**Figure 2**).

Usually known as autophagy, this intracellular pathway includes cytosolic components such as proteins, lipids, organelles, and parts of the nucleus [23, 24]. Autophagy was first described by Christian du Duve 50 years ago and has been highly preserved across the species. From beginning to end, the whole process is controlled by the ATG protein family, and more than 35 genes have been identified

Autophagosome formation is the hallmark of this process. The well-coordinated process begins with an initiation phase, when ULK1 kinase forms a complex with ATG13, ATG10, and FIP200 (known as RB1CC1) at a specific cell site located in the perivacuolar region known as the phagophore assembly site (PAS). ULK1 kinase activity triggers the formation of the phosphoinositide 3-kinase (PI3K) complex, which favors the formation of phosphatidylinositol 3-phosphate, initiating the nucleation phase [26]. Ubiquitin-like conjugation systems are then activated, catalyzed by ATG7. ATG12 is conjugated to ATG5, then phosphatidylethanolamine to microtubule-associated protein 1A/1B-light chain 3 (LC3) through ATG7 kinase, forming an autophagosome bound to LC3 (also called LC3-II) [27, 28]. The late stage of autophagy is controlled by molecules that regulate maturation of the autophagosome, fusion with lysosomes, acidification of the inside compartment of the autophagosome components, and recycling of metabolites from the lysosomal compartment. This coordinated process—including a sequence of protein–protein and protein–lipid interaction—is a dynamic process, where the autophagosome formation, fusion to the lysosome, and digestion of the inside components occur in less than 10 minutes. Therefore, any sort of autophagy dysfunction (such as blockage of lysosomal fusion or lysosomal function impairment) may lead to accumulation of harmful damaged organelles and protein aggregates inside the cell [29] (**Figure 2**).

In chaperone-mediated autophagy, there is no reorganization of the lysosomal membrane. This selective autophagy is only described in mammals [30], which

Intrinsically, cellular sensors detect changes in levels of glucose, cytosolic Ca++, reactive oxygen species (ROS), and metabolic intermediates. Therefore, a decrease in glucose availability or impairment of mitochondrial respiration-compromising ATP production

An example of extrinsic sensing occurs via drug-targetable mechanisms at the plasma membrane level. Tyrosine kinase receptors converge on mTOR, AMPK, or Beclin-1-Vps complex by modulating autophagy following growth factors [18, 19]. Even G-protein-coupled receptors (GPCRs) control autophagy via intracellular

*DOI: http://dx.doi.org/10.5772/intechopen.89339*

attention to diabetic retinopathy.

**2. Types of autophagy**

**2.1 Macroautophagy**

to orchestrate the process [25].

**2.2 Chaperone-mediated autophagy**

Autophagy can be constitutive or inducible, rapidly adjusting to alterations within the internal and external environment of the cells. Autophagy serves as a housekeeping system, demonstrated by animal models deficient in

#### *Deficient Autophagy Contributes to the Development of Diabetic Retinopathy DOI: http://dx.doi.org/10.5772/intechopen.89339*

autophagy-related genes (ATG). For example, deletion of specific neurons of ATG7 or 5 genes leads to postnatal neurodegeneration [16, 17].

Intrinsically, cellular sensors detect changes in levels of glucose, cytosolic Ca++, reactive oxygen species (ROS), and metabolic intermediates. Therefore, a decrease in glucose availability or impairment of mitochondrial respiration-compromising ATP production leads to an increase in the AMP/ADP ratio, activating the AMPK α subunit [10].

An example of extrinsic sensing occurs via drug-targetable mechanisms at the plasma membrane level. Tyrosine kinase receptors converge on mTOR, AMPK, or Beclin-1-Vps complex by modulating autophagy following growth factors [18, 19]. Even G-protein-coupled receptors (GPCRs) control autophagy via intracellular pathways that similarly modulate AMPK and mTOR [20–22].

This discussion includes a short overview of the more common types of autophagy and will highlight the role of autophagy in retinal diseases, with special attention to diabetic retinopathy.

## **2. Types of autophagy**

*The Eye and Foot in Diabetes*

**14**

**Figure 1.**

**Table 1.**

*Several cellular sensors regulate autophagic flux to maintain homeostasis.*

upregulation of the entire autophagy–lysosomal pathway [15].

considered a cellular sensor [13].

lysosomes and other essential proteins maintaining the autophagic flux [9–12]. In addition, sirtuin-1—a class III deacetylase dependent on nicotinamide adenine dinucleotide (NAD+)—becomes a positive autophagy regulator, since it may also be

*In this table, some examples of genetic diseases associated with autophagic impairment [1–8].*

Autophagy can be constitutive or inducible, rapidly adjusting to alterations within the internal and external environment of the cells. Autophagy serves as a housekeeping system, demonstrated by animal models deficient in

This process is mainly regulated at a post-translational level, increasing mRNA expression of autophagy genes [14]. Under stress conditions, TFEB is translocated from cytosol to the nucleus, activating transcription of ATG genes and coordinating

There are three forms of autophagy previously described in the literature: macroautophagy, chaperone-mediated autophagy, and microautophagy (**Figure 2**).

#### **2.1 Macroautophagy**

Usually known as autophagy, this intracellular pathway includes cytosolic components such as proteins, lipids, organelles, and parts of the nucleus [23, 24]. Autophagy was first described by Christian du Duve 50 years ago and has been highly preserved across the species. From beginning to end, the whole process is controlled by the ATG protein family, and more than 35 genes have been identified to orchestrate the process [25].

Autophagosome formation is the hallmark of this process. The well-coordinated process begins with an initiation phase, when ULK1 kinase forms a complex with ATG13, ATG10, and FIP200 (known as RB1CC1) at a specific cell site located in the perivacuolar region known as the phagophore assembly site (PAS). ULK1 kinase activity triggers the formation of the phosphoinositide 3-kinase (PI3K) complex, which favors the formation of phosphatidylinositol 3-phosphate, initiating the nucleation phase [26]. Ubiquitin-like conjugation systems are then activated, catalyzed by ATG7. ATG12 is conjugated to ATG5, then phosphatidylethanolamine to microtubule-associated protein 1A/1B-light chain 3 (LC3) through ATG7 kinase, forming an autophagosome bound to LC3 (also called LC3-II) [27, 28]. The late stage of autophagy is controlled by molecules that regulate maturation of the autophagosome, fusion with lysosomes, acidification of the inside compartment of the autophagosome components, and recycling of metabolites from the lysosomal compartment. This coordinated process—including a sequence of protein–protein and protein–lipid interaction—is a dynamic process, where the autophagosome formation, fusion to the lysosome, and digestion of the inside components occur in less than 10 minutes. Therefore, any sort of autophagy dysfunction (such as blockage of lysosomal fusion or lysosomal function impairment) may lead to accumulation of harmful damaged organelles and protein aggregates inside the cell [29] (**Figure 2**).

#### **2.2 Chaperone-mediated autophagy**

In chaperone-mediated autophagy, there is no reorganization of the lysosomal membrane. This selective autophagy is only described in mammals [30], which

#### **Figure 2.**

*Types of autophagy. (1) Macroautophagy: initiation of autophagy through isolation membrane, extension of membrane, and closure forming the autophagosome. Finally, the autophagosome merges with lysosome. Lysosomal hydrolases digest the contents to recycling nutrients. (2) Chaperone-mediated autophagy: identification of KFERQ-motif by Hsc70. Transportation of damage protein to lysosome. Recognition and multimerization of LAMP-2. Damage proteins are translocated to inside of the lysosome to suffer the action of lysosomal hydrolases. (3) Microautophagy: recognition and internalization of cytoplasmatic component.*

mediates delivery of specific proteins to the lysosome. The distinction occurs because the cytosolic proteins need to be degraded by the presence of a pentapeptide amino acid sequence, KFERQ. This sequence permits recognition of the target protein by a family of chaperones and co-chaperones: the heat shock cognate, 70-kDa (Hsc70)—the most abundant in the family. After recognition of the KFERQ sequence, Hsc70 presents the unfolded proteins to the lysosome, one by one, where they are recognized by the transmembrane domain of lysosome-associated membrane protein type 2A (LAMP2-A). After this, the multimerization of LAMP2-A occurs, allowing transportation of the substrate into the lysosome for degradation. At the end of this process, the LAMP2-A complex is disassembled, and the chaperone Hsp70 is released to start a new cycle [31].

## **2.3 Microautophagy**

Microautophagy is not well described in mammalian cells. However, recent evidence has shown that there is recognition and internalization of small cytoplasmatic components in late endosomes. This type of autophagy requires the chaperone Hsc70. However, the microautophagy process is independent of the unfolding of KFERQ and the multimerization of LAMP2-A [32, 33].

## **2.4 Role of autophagy in disease development**

Since the primary function of autophagy is to eliminate harmful components from cells (aggregated proteins, damaged organelles, and pathogens), malfunctioning of this mechanism implicit in diseases—such as Huntington's and Parkinson's diseases [34, 35]—results in protein accumulation.

**17**

as DR [71].

*Deficient Autophagy Contributes to the Development of Diabetic Retinopathy*

In physiological conditions, autophagy is involved in cellular homeostasis, as demonstrated in heart diseases, as seen in heart failure and ischemia–reperfusion injuries [36]. In the pancreas, autophagy is required to maintain function of β cells, revealing significance in the pathogenesis of diabetes. Alterations in autophagy have also been described in a more complex model in cancer research: it can suppress tumors but also helps the tumor adapt to metabolic stress in its late

Diabetes mellitus is a public health issue, estimated to affect about 500 million people by 2035 [38]. Nearly 30% of patients are likely to suffer from retinal microvascular complications and 10% may experience visual threatening due to macular

Multiple mechanisms are triggered under hyperglycemic conditions (hexosamine and polyol pathways [41], synthesis de novo of diacylglycerol-PKC [42, 43], low grade oxidative stress [44–46], inflammation [47–51], and advanced glycation end products [52, 53]). Although vascular changes are presumed to be the hallmarks of DR, abnormalities in retinal function are detected in patients with diabetes who

The characteristics of retinal neurodegeneration are apoptosis of neuro cells and dysfunction of glial cells—mainly Müller cells [29, 50, 60]. In microvascular disease of diabetic retinopathy, both inner and outer blood retinal barrier break down [61].

Since their pioneering studies, Remé et al. —describing the presence of active autophagy in photoreceptors during hibernation with a decreased number of mitochondria and organelles compared to animals in non-hibernating conditions observed an increased number of autophagosomes [62]. These data show the pivotal role of autophagy in the retina, degrading cellular components (such as mitochon-

Implications of autophagy in retinal ganglion cells (RGCs) attracted interest as a potential tool for neuroprotection in glaucoma. The first evidence of the cytoprotective role of autophagy in RGCs was shown by Rodríguez-Muela et al. using autophagy-deficient mice, which displayed increased axonal damage following

The main function of the blood-retina barrier (BRB) is maintenance of retinal homeostasis, regulating the transport of blood stream molecules to provide an appropriate supply for the neuroretina and to protect neural tissue against harmful agents present in the blood. The BRB is formed by two types of barriers: the inner blood-retina barrier (iBRB) and the outer blood-retina barrier (oBRB) [66].

Both outer and inner retinal barriers are affected by the toxic metabolic effects of hyperglycemia [67]. Alterations in the iBRB are more studied than the oBRB among the mechanisms of development and progression of DR [68–70]. The appropriated function of autophagy flux is important for maintenance of cellular viability and confers stress tolerance in retinal cells under adverse conditions such

optic nerve transection (ONT) models of optic neuropathy [63–65].

**3.2 Autophagy in blood retinal barriers and implications on diabetic** 

*DOI: http://dx.doi.org/10.5772/intechopen.89339*

edema or proliferative diabetic retinopathy [39, 40].

stages [37].

**3. Diabetic retinopathy**

have good visual acuity [54–59].

dria) during hibernation.

**retinopathy**

**3.1 Autophagy in diabetic retinopathy**

*Deficient Autophagy Contributes to the Development of Diabetic Retinopathy DOI: http://dx.doi.org/10.5772/intechopen.89339*

In physiological conditions, autophagy is involved in cellular homeostasis, as demonstrated in heart diseases, as seen in heart failure and ischemia–reperfusion injuries [36]. In the pancreas, autophagy is required to maintain function of β cells, revealing significance in the pathogenesis of diabetes. Alterations in autophagy have also been described in a more complex model in cancer research: it can suppress tumors but also helps the tumor adapt to metabolic stress in its late stages [37].

## **3. Diabetic retinopathy**

*The Eye and Foot in Diabetes*

mediates delivery of specific proteins to the lysosome. The distinction occurs because the cytosolic proteins need to be degraded by the presence of a pentapeptide amino acid sequence, KFERQ. This sequence permits recognition of the target protein by a family of chaperones and co-chaperones: the heat shock cognate, 70-kDa (Hsc70)—the most abundant in the family. After recognition of the KFERQ sequence, Hsc70 presents the unfolded proteins to the lysosome, one by one, where they are recognized by the transmembrane domain of lysosome-associated membrane protein type 2A (LAMP2-A). After this, the multimerization of LAMP2-A occurs, allowing transportation of the substrate into the lysosome for degradation. At the end of this process, the LAMP2-A complex is disassembled, and the chaperone Hsp70 is released to start a new cycle [31].

*Types of autophagy. (1) Macroautophagy: initiation of autophagy through isolation membrane, extension of membrane, and closure forming the autophagosome. Finally, the autophagosome merges with lysosome. Lysosomal hydrolases digest the contents to recycling nutrients. (2) Chaperone-mediated autophagy: identification of KFERQ-motif by Hsc70. Transportation of damage protein to lysosome. Recognition and multimerization of LAMP-2. Damage proteins are translocated to inside of the lysosome to suffer the action of lysosomal hydrolases. (3) Microautophagy: recognition and internalization of cytoplasmatic component.*

Microautophagy is not well described in mammalian cells. However, recent evidence has shown that there is recognition and internalization of small cytoplasmatic components in late endosomes. This type of autophagy requires the chaperone Hsc70. However, the microautophagy process is independent of the unfolding

Since the primary function of autophagy is to eliminate harmful components from cells (aggregated proteins, damaged organelles, and pathogens), malfunctioning of this mechanism implicit in diseases—such as Huntington's and Parkinson's

of KFERQ and the multimerization of LAMP2-A [32, 33].

**2.4 Role of autophagy in disease development**

diseases [34, 35]—results in protein accumulation.

**16**

**2.3 Microautophagy**

**Figure 2.**

Diabetes mellitus is a public health issue, estimated to affect about 500 million people by 2035 [38]. Nearly 30% of patients are likely to suffer from retinal microvascular complications and 10% may experience visual threatening due to macular edema or proliferative diabetic retinopathy [39, 40].

Multiple mechanisms are triggered under hyperglycemic conditions (hexosamine and polyol pathways [41], synthesis de novo of diacylglycerol-PKC [42, 43], low grade oxidative stress [44–46], inflammation [47–51], and advanced glycation end products [52, 53]). Although vascular changes are presumed to be the hallmarks of DR, abnormalities in retinal function are detected in patients with diabetes who have good visual acuity [54–59].

The characteristics of retinal neurodegeneration are apoptosis of neuro cells and dysfunction of glial cells—mainly Müller cells [29, 50, 60]. In microvascular disease of diabetic retinopathy, both inner and outer blood retinal barrier break down [61].

#### **3.1 Autophagy in diabetic retinopathy**

Since their pioneering studies, Remé et al. —describing the presence of active autophagy in photoreceptors during hibernation with a decreased number of mitochondria and organelles compared to animals in non-hibernating conditions observed an increased number of autophagosomes [62]. These data show the pivotal role of autophagy in the retina, degrading cellular components (such as mitochondria) during hibernation.

Implications of autophagy in retinal ganglion cells (RGCs) attracted interest as a potential tool for neuroprotection in glaucoma. The first evidence of the cytoprotective role of autophagy in RGCs was shown by Rodríguez-Muela et al. using autophagy-deficient mice, which displayed increased axonal damage following optic nerve transection (ONT) models of optic neuropathy [63–65].

### **3.2 Autophagy in blood retinal barriers and implications on diabetic retinopathy**

The main function of the blood-retina barrier (BRB) is maintenance of retinal homeostasis, regulating the transport of blood stream molecules to provide an appropriate supply for the neuroretina and to protect neural tissue against harmful agents present in the blood. The BRB is formed by two types of barriers: the inner blood-retina barrier (iBRB) and the outer blood-retina barrier (oBRB) [66].

Both outer and inner retinal barriers are affected by the toxic metabolic effects of hyperglycemia [67]. Alterations in the iBRB are more studied than the oBRB among the mechanisms of development and progression of DR [68–70]. The appropriated function of autophagy flux is important for maintenance of cellular viability and confers stress tolerance in retinal cells under adverse conditions such as DR [71].

Retinal endothelial cells of microcirculation of the retina form the iBRB. This barrier selectively allows passage of molecules from systemic circulation to retinal tissue. As a constituent of this barrier, there are tight junctions and adherens junctions such as zonula occludens-1 (ZO-1), occludin, VE-cadherin, and N-cadherin [72]. Endothelial cells are warped by pericytes, which are highly specialized. Pericytes play an essential role in the structure and stability of the iBRB, coordinating angiogenesis and vascular remodeling [73, 74].

Few articles have highlighted the autophagic process in retinal endothelial cells under diabetic conditions [75, 76]. Exposure to high glucose leads to an increase in retinal endothelial cell apoptosis, and this mechanism is mediated by the enhancement of ROS production. This phenomenon is correlated with a reduction in the AMPK pathway [76], which is well described as a direct activator of ULK-1 in the autophagy process [77]. Reestablishing the level of AMPK using specific activators—such as AICAR or antioxidant treatment—is effective in the protection of endothelial retinal cells from damage caused by diabetic conditions [75, 76]. A recent study from Niu et al. described the importance of the protective properties of metformin on retinal endothelial cells and human umbilical vascular endothelial cells (HUVECs) via autophagy in diabetic conditions. In this work, the authors showed that there was an increased LC3 puncta formation, which is an indicative of autophagy, in retinal vascular endothelium from db/db (diabetic) mice compared with control (non-diabetic) mice. This is indicative that metformin protects the retinal microvascular cells by diminishing LC3 formation. To further understand this mechanism, HUVECs were exposed to high levels of glucose and treated with metformin, resulting in a clear increase of LC3 formation. In HUVECs transfected with sh-PRKAA1/2 (AMP catalytic subunit), the protective effect of metformin was abrogated, indicating that metformin acts via AMPK activation [78] and improving autophagy in these cells.

The oBRB is a monolayer formed by retinal pigment epithelial cell layer that separates the neuro retina from choriocapillaris. Impairment of this barrier is implicated in diabetic retinopathy development [79–81]. The major functions of the oBRB are to provide glucose, fatty acids, and retinol to photoreceptors from choriocapillaris and reisomerise all-trans-retinal in 11-cis-retinal after photon absorption of the photoreceptor [66, 82, 83]. Therefore, any disturbance in this structure may have detrimental effects on the retina. A number of sight-threatening diseases display RPR dysfunction, such as age-related macular degeneration, proliferative vitreoretinopathy, and diabetic retinopathy [84].

It is well described in the literature that human retinal pigmented epithelial (RPE) immortalized cells (ARPE-19) exposed to high concentrations of glucose present molecular changes, including a decrease of proliferation, an increase in oxidative stress mediated by ROS production, and augmented lipid droplets and inflammation [85–88]. These alterations can activate or repress the autophagic flux in RPE cells. Studies have shown that, until 48 hours of exposure to high glucose levels, ARPE-19 cells present an increase in lipid droplets, which can contribute to ROS production [71, 85, 89]. This increase in ROS production can initiate autophagy, enhancing the numbers of autophagosomes, increasing conversion of LC3-I to LC3-II, and decreasing levels of p62/SQSTM1 as a defense mechanism against damage caused by high glucose. However, Chen et al. found that an increase in autophagic flux promoted by high glucose cannot be maintained long-term. After 7 days in high glucose, ARPE-19 presented impairment in the degradation of p62/ SQSTM1 and an increase in apoptotic cells. These findings indicated that autophagy was the first defense against oxidative stress in high-glucose conditions. In the longterm, this protective pathway became saturated and inefficient, thus contributing to RPE degeneration in DR [87].

**19**

*Deficient Autophagy Contributes to the Development of Diabetic Retinopathy*

because the biogenesis of mitochondria becomes compromised [90].

Zhang et al. have shown that high glucose concentrations can attenuate the PINK1 and parkin pathways involved in controlling cellular mitophagy. Downregulation of mitophagy can lead to an increase in cellular stress levels

**3.3 Autophagy in Müller glial cells and implications in diabetic retinopathy** 

Müller cells are the predominant glial cell in the retina. Its unique morphology allows the Müller cell to directly interact with neighboring neural and vascular cells, expanding through the entire retina from the inner limiting membrane to the photoreceptor layer. Müller cells are closely related with vitreous, blood vessels, and sub retinal space. Each Müller cell interacts with one cone and 10 rods [91]. This configuration of Müller cells inside the retina explains the diversity of its function, responsible for the metabolic, functional, and structural support of the retina [92]. There are several functions attributed to Müller cells, such as the release of trophic factors [93, 94], neurotransmitter recycling [95], and phagocytosis of external photoreceptor segments [96, 97]. Müller cells, depending upon the stimulus (trauma, vascular, or metabolic), may react with phenotype changes called gliosis, which consist in adaptive morphological, biochemical, and physiological alterations. Among the more interesting biochemical changes in Müller cells are increased vascular endothelial growth factor (VEGF) [98] and glial fibrillary acidic protein (GFAP) production, both with pro-angiogenic and pro-inflammatory effects. Massive VEGF release is present in the proliferative stages of DR and diabetic macular edema, representing a major therapeutic target for pharmacological treatment of

There are few studies showing the effects of high glucose on autophagy in retinal

In the previously published work addressing the mechanism by which Müller cells exposed to high glucose release high amounts of VEFG and trigger increased apoptosis, it was shown that the autophagic process was defective in Müller cells among diabetic conditions. In cells exposed to high glucose, autophagy markers both early Beclin and late LC3-I and LC3-II—were increased, but p62/SQSTM1 accumulated in the cytosol compartment of Müller cells, accompanied by an increased apoptotic rate. To further understand how p62/SQSTM1 could modulate the autophagy and apoptosis in Müller cells exposed to high glucose, p62/SQSTM1 was suppressed. In this condition, there was less endoplasmic reticulum stress, lowering the interaction with caspase-8 and, by extension, less apoptosis. The presence of rapamycin, an mTOR blocker, triggered the formation of autophagosome

Müller cells. Devi et al. described the implications of autophagy dysfunction in the mechanisms of DR [99]. In their study, Müller cells exposed to high glucose conditions for 5 days displayed an increase of autophagosome and mitophagosome in the cytosol, suggesting high glucose conditions activated the autophagy process. Despite activation of the protective process (autophagy), they observed an association with an increased proapoptotic caspase-3, leading to programmed cell death. This scenario elucidates that diabetic conditions induce activation of autophagy

The role of autophagy in retinal diabetic complications is not simply a matter of inhibiting its initiation or progression. Inhibition of autophagy in ARPE-19 during its initial phase with 3-methyladenine (3-MA) or during the fusion of autophagosome and lysosome using bafilomycin aggravates oxidative stress and exacerbates secretion of the pro-inflammatory interleukin-1β promoted by high glucose [88]. The appropriated autophagic process is important as a mechanism of cell homeosta-

*DOI: http://dx.doi.org/10.5772/intechopen.89339*

sis in diabetic conditions.

these devastating complications.

followed by dysfunction, leading to cellular death.

**pathogenesis**

#### *Deficient Autophagy Contributes to the Development of Diabetic Retinopathy DOI: http://dx.doi.org/10.5772/intechopen.89339*

Zhang et al. have shown that high glucose concentrations can attenuate the PINK1 and parkin pathways involved in controlling cellular mitophagy. Downregulation of mitophagy can lead to an increase in cellular stress levels because the biogenesis of mitochondria becomes compromised [90].

The role of autophagy in retinal diabetic complications is not simply a matter of inhibiting its initiation or progression. Inhibition of autophagy in ARPE-19 during its initial phase with 3-methyladenine (3-MA) or during the fusion of autophagosome and lysosome using bafilomycin aggravates oxidative stress and exacerbates secretion of the pro-inflammatory interleukin-1β promoted by high glucose [88]. The appropriated autophagic process is important as a mechanism of cell homeostasis in diabetic conditions.

## **3.3 Autophagy in Müller glial cells and implications in diabetic retinopathy pathogenesis**

Müller cells are the predominant glial cell in the retina. Its unique morphology allows the Müller cell to directly interact with neighboring neural and vascular cells, expanding through the entire retina from the inner limiting membrane to the photoreceptor layer. Müller cells are closely related with vitreous, blood vessels, and sub retinal space. Each Müller cell interacts with one cone and 10 rods [91]. This configuration of Müller cells inside the retina explains the diversity of its function, responsible for the metabolic, functional, and structural support of the retina [92].

There are several functions attributed to Müller cells, such as the release of trophic factors [93, 94], neurotransmitter recycling [95], and phagocytosis of external photoreceptor segments [96, 97]. Müller cells, depending upon the stimulus (trauma, vascular, or metabolic), may react with phenotype changes called gliosis, which consist in adaptive morphological, biochemical, and physiological alterations. Among the more interesting biochemical changes in Müller cells are increased vascular endothelial growth factor (VEGF) [98] and glial fibrillary acidic protein (GFAP) production, both with pro-angiogenic and pro-inflammatory effects. Massive VEGF release is present in the proliferative stages of DR and diabetic macular edema, representing a major therapeutic target for pharmacological treatment of these devastating complications.

There are few studies showing the effects of high glucose on autophagy in retinal Müller cells. Devi et al. described the implications of autophagy dysfunction in the mechanisms of DR [99]. In their study, Müller cells exposed to high glucose conditions for 5 days displayed an increase of autophagosome and mitophagosome in the cytosol, suggesting high glucose conditions activated the autophagy process. Despite activation of the protective process (autophagy), they observed an association with an increased proapoptotic caspase-3, leading to programmed cell death. This scenario elucidates that diabetic conditions induce activation of autophagy followed by dysfunction, leading to cellular death.

In the previously published work addressing the mechanism by which Müller cells exposed to high glucose release high amounts of VEFG and trigger increased apoptosis, it was shown that the autophagic process was defective in Müller cells among diabetic conditions. In cells exposed to high glucose, autophagy markers both early Beclin and late LC3-I and LC3-II—were increased, but p62/SQSTM1 accumulated in the cytosol compartment of Müller cells, accompanied by an increased apoptotic rate. To further understand how p62/SQSTM1 could modulate the autophagy and apoptosis in Müller cells exposed to high glucose, p62/SQSTM1 was suppressed. In this condition, there was less endoplasmic reticulum stress, lowering the interaction with caspase-8 and, by extension, less apoptosis. The presence of rapamycin, an mTOR blocker, triggered the formation of autophagosome

*The Eye and Foot in Diabetes*

autophagy in these cells.

ing angiogenesis and vascular remodeling [73, 74].

vitreoretinopathy, and diabetic retinopathy [84].

Retinal endothelial cells of microcirculation of the retina form the iBRB. This barrier selectively allows passage of molecules from systemic circulation to retinal tissue. As a constituent of this barrier, there are tight junctions and adherens junctions such as zonula occludens-1 (ZO-1), occludin, VE-cadherin, and N-cadherin [72]. Endothelial cells are warped by pericytes, which are highly specialized. Pericytes play an essential role in the structure and stability of the iBRB, coordinat-

Few articles have highlighted the autophagic process in retinal endothelial cells under diabetic conditions [75, 76]. Exposure to high glucose leads to an increase in retinal endothelial cell apoptosis, and this mechanism is mediated by the enhancement of ROS production. This phenomenon is correlated with a reduction in the AMPK pathway [76], which is well described as a direct activator of ULK-1 in the autophagy process [77]. Reestablishing the level of AMPK using specific activators—such as AICAR or antioxidant treatment—is effective in the protection of endothelial retinal cells from damage caused by diabetic conditions [75, 76]. A recent study from Niu et al. described the importance of the protective properties of metformin on retinal endothelial cells and human umbilical vascular endothelial cells (HUVECs) via autophagy in diabetic conditions. In this work, the authors showed that there was an increased LC3 puncta formation, which is an indicative of autophagy, in retinal vascular endothelium from db/db (diabetic) mice compared with control (non-diabetic) mice. This is indicative that metformin protects the retinal microvascular cells by diminishing LC3 formation. To further understand this mechanism, HUVECs were exposed to high levels of glucose and treated with metformin, resulting in a clear increase of LC3 formation. In HUVECs transfected with sh-PRKAA1/2 (AMP catalytic subunit), the protective effect of metformin was abrogated, indicating that metformin acts via AMPK activation [78] and improving

The oBRB is a monolayer formed by retinal pigment epithelial cell layer that separates the neuro retina from choriocapillaris. Impairment of this barrier is implicated in diabetic retinopathy development [79–81]. The major functions of the oBRB are to provide glucose, fatty acids, and retinol to photoreceptors from choriocapillaris and reisomerise all-trans-retinal in 11-cis-retinal after photon absorption of the photoreceptor [66, 82, 83]. Therefore, any disturbance in this structure may have detrimental effects on the retina. A number of sight-threatening diseases display RPR dysfunction, such as age-related macular degeneration, proliferative

It is well described in the literature that human retinal pigmented epithelial (RPE) immortalized cells (ARPE-19) exposed to high concentrations of glucose present molecular changes, including a decrease of proliferation, an increase in oxidative stress mediated by ROS production, and augmented lipid droplets and inflammation [85–88]. These alterations can activate or repress the autophagic flux in RPE cells. Studies have shown that, until 48 hours of exposure to high glucose levels, ARPE-19 cells present an increase in lipid droplets, which can contribute to ROS production [71, 85, 89]. This increase in ROS production can initiate autophagy, enhancing the numbers of autophagosomes, increasing conversion of LC3-I to LC3-II, and decreasing levels of p62/SQSTM1 as a defense mechanism against damage caused by high glucose. However, Chen et al. found that an increase in autophagic flux promoted by high glucose cannot be maintained long-term. After 7 days in high glucose, ARPE-19 presented impairment in the degradation of p62/ SQSTM1 and an increase in apoptotic cells. These findings indicated that autophagy was the first defense against oxidative stress in high-glucose conditions. In the longterm, this protective pathway became saturated and inefficient, thus contributing

**18**

to RPE degeneration in DR [87].

and ameliorated the degradation of p62/SQSTM1. Rapamycin showed to improve proteolytic activity of the lysosome, reducing the release of VEGF. Corresponding findings were also demonstrated in models using diabetic animals. In the retinas of diabetic rats, there was a significant increase in p62/SQSTM1 accumulation, particularly in cells located in the inner nuclear layer [29]. Lysosomal impairment and autophagic flux dysfunction are early indicators of the pathogenesis of DR.

## **4. Conclusion**

Diabetic retinopathy is a neurodegenerative disease presenting vascular changes in its late stages. Multiple factors are associated with the development and progression of DR. Recently, better understanding at cellular and molecular levels of its process has been identified through the pathways and intracellular signaling involved in cells exposed to diabetic conditions. This has allowed identification of new therapeutic approaches. Recent concepts of this disease have been analyzed here, with special focus on the process of autophagy using experimental models in different retinal cells targeted by hyperglycemia in the developmental stages of the disease.

## **Author details**

Jacqueline M. Lopes de Faria\* and Marcella Neves Dátilo Faculty of Medical Sciences, State University of Campinas, São Paulo, Brazil

\*Address all correspondence to: lopesdefariajm@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**21**

*Deficient Autophagy Contributes to the Development of Diabetic Retinopathy*

[7] Sumpter R, Sirasanagandla S,

cell.2016.04.006

immuni.2016.05.007

10.1038/s41586-018-0162-7

DOI: 10.4161/auto.3636

[10] Melendez A. Autophagy genes are essential for Dauer development and life-span extension in C. elegans. Science. 2003;**301**(5638):1387-1391. DOI: 10.1038/s41586-018-0162-7

[11] Hars ES, Qi H, Jin SV, Cai L, Hu C, Liu LF. Autophagy Regulates Ageing in C. elegans. Autophagy. 2007;**3**(2):93-95.

[12] Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon CA. Role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genetics. 2008;**4**(2):e24. DOI: 10.1371/journal.pgen.0040024.

Neufeld TP. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in drosophila. Genes & Development. 2007;**21**(23):3061-3066. DOI: 10.1101/

[14] Feng Y, Yao Z, Klionsky DJ. How to control self-digestion: Transcriptional,

[13] Juhasz G, Erdi B, Sass M,

gad.1600707

Fernández ÁF, Wei Y, Dong X, Franco L, et al. Fanconi anemia proteins function in Mitophagy and immunity. Cell. 2016;**165**(4):867-881. DOI: 10.1016/j.

[8] Lassen KG, McKenzie CI, Mari M, Murano T, Begun J, Baxt LA, et al. Genetic coding variant in GPR65 alters Lysosomal pH and links Lysosomal dysfunction with colitis risk. Immunity. 2016;**44**(6):1392-1405. DOI: 10.1016/j.

[9] Fernández ÁF, Sebti S, Wei Y, Zou Z, Shi M, McMillan KL, et al. Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice. Nature. 2018;**558**(7708):136-140. DOI:

*DOI: http://dx.doi.org/10.5772/intechopen.89339*

[1] Schapira AHV. Glucocerebrosidase and parkinson disease: Recent advances. Molecular and Cellular Neurosciences.

2015;**66**:37-42. DOI: 10.1016/j.

[2] Kim MJ, Deng H-X, Wong YC, Siddique T, Krainc D. The Parkinson's disease-linked protein TMEM230 is required for Rab8a-mediated secretory vesicle trafficking and retromer

[3] Lee J-H, Yu WH, Kumar A,

trafficking. Human Molecular Genetics. 2017;**26**(4):729-741. DOI: 10.1093/hmg/

Lee S, Mohan PS, Peterhoff CM, et al. Lysosomal proteolysis and autophagy require Presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010;**141**(7):1146-1158. DOI: 10.1016/j.

[4] Reddy PH, Yin X, Manczak M, Kumar S, Pradeepkiran JA, Vijayan M, et al. Mutant APP and amyloid betainduced defective autophagy,

mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease. Human Molecular Genetics. 2018;**27**(14):2502-2516. DOI:

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Becker HM, Fischbeck A, Frei P, Arikkat J, et al. Protein tyrosine phosphatase nonreceptor type 2 regulates Autophagosome formation in human intestinal cells. Inflammatory Bowel Diseases. 2012;**18**(7):1287-1302.

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*Deficient Autophagy Contributes to the Development of Diabetic Retinopathy DOI: http://dx.doi.org/10.5772/intechopen.89339*

## **References**

*The Eye and Foot in Diabetes*

**4. Conclusion**

stages of the disease.

**Author details**

Jacqueline M. Lopes de Faria\* and Marcella Neves Dátilo

provided the original work is properly cited.

\*Address all correspondence to: lopesdefariajm@gmail.com

Faculty of Medical Sciences, State University of Campinas, São Paulo, Brazil

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

and ameliorated the degradation of p62/SQSTM1. Rapamycin showed to improve proteolytic activity of the lysosome, reducing the release of VEGF. Corresponding findings were also demonstrated in models using diabetic animals. In the retinas of diabetic rats, there was a significant increase in p62/SQSTM1 accumulation, particularly in cells located in the inner nuclear layer [29]. Lysosomal impairment and autophagic flux dysfunction are early indicators of the pathogenesis of DR.

Diabetic retinopathy is a neurodegenerative disease presenting vascular changes in its late stages. Multiple factors are associated with the development and progression of DR. Recently, better understanding at cellular and molecular levels of its process has been identified through the pathways and intracellular signaling involved in cells exposed to diabetic conditions. This has allowed identification of new therapeutic approaches. Recent concepts of this disease have been analyzed here, with special focus on the process of autophagy using experimental models in different retinal cells targeted by hyperglycemia in the developmental

**20**

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[2] Kim MJ, Deng H-X, Wong YC, Siddique T, Krainc D. The Parkinson's disease-linked protein TMEM230 is required for Rab8a-mediated secretory vesicle trafficking and retromer trafficking. Human Molecular Genetics. 2017;**26**(4):729-741. DOI: 10.1093/hmg/ ddw413

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[5] Scharl M, Wojtal KA, Becker HM, Fischbeck A, Frei P, Arikkat J, et al. Protein tyrosine phosphatase nonreceptor type 2 regulates Autophagosome formation in human intestinal cells. Inflammatory Bowel Diseases. 2012;**18**(7):1287-1302. DOI: 10.1002/ibd.21891

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[8] Lassen KG, McKenzie CI, Mari M, Murano T, Begun J, Baxt LA, et al. Genetic coding variant in GPR65 alters Lysosomal pH and links Lysosomal dysfunction with colitis risk. Immunity. 2016;**44**(6):1392-1405. DOI: 10.1016/j. immuni.2016.05.007

[9] Fernández ÁF, Sebti S, Wei Y, Zou Z, Shi M, McMillan KL, et al. Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice. Nature. 2018;**558**(7708):136-140. DOI: 10.1038/s41586-018-0162-7

[10] Melendez A. Autophagy genes are essential for Dauer development and life-span extension in C. elegans. Science. 2003;**301**(5638):1387-1391. DOI: 10.1038/s41586-018-0162-7

[11] Hars ES, Qi H, Jin SV, Cai L, Hu C, Liu LF. Autophagy Regulates Ageing in C. elegans. Autophagy. 2007;**3**(2):93-95. DOI: 10.4161/auto.3636

[12] Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon CA. Role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genetics. 2008;**4**(2):e24. DOI: 10.1371/journal.pgen.0040024.

[13] Juhasz G, Erdi B, Sass M, Neufeld TP. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in drosophila. Genes & Development. 2007;**21**(23):3061-3066. DOI: 10.1101/ gad.1600707

[14] Feng Y, Yao Z, Klionsky DJ. How to control self-digestion: Transcriptional, post-transcriptional, and posttranslational regulation of autophagy. Trends in Cell Biology. 2015;**25**(6):354- 363. DOI: 10.1016/j.tcb.2015.02.002

[15] Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, et al. A gene network regulating Lysosomal biogenesis and function. Science. 2009;**325**(5939):473- 477. DOI: 10.1126/science.1174447

[16] Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, et al. Genomewide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proceedings of the National Academy of Sciences. 2010;**107**(32):14164-14169. DOI: 10.1016/j.cellsig.2013.06.013

[17] Chen Y, Sawada O, Kohno H, Le YZ, Subauste C, Maeda T, et al. Autophagy protects the retina from light-induced degeneration. The Journal of Biological Chemistry. 2013;**288**(11):7506-7518. DOI: 10.1074/jbc.M112.439935

[18] Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, et al. FoxO3 coordinately activates protein degradation by the Autophagic/ Lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metabolism. 2007;**6**(6):472-483. DOI: 10.1016/j.cmet.2007.11.004

[19] Sarkis GJ, Ashcom JD, Hawdon JM, Jacobson LA. Decline in protease activities with age in the nematode caenorhabditis elegans. Mechanisms of Ageing and Development. 1988;**45**(3):191-201. DOI: 10.1016/0047-6374(88)90001-2

[20] Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;**432**(7020):1032-1036. DOI: 10.1038/nature03029

[21] Kapahi P, Kaeberlein M, Hansen M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Research Reviews. 2017;**39**:3-14. DOI: 10.1016/j.arr.2016.12.005

[22] Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, et al. Caloric restriction improves health and survival of rhesus monkeys. Nature Communications. 2017;**8**(1):14063. DOI: 10.1038/ ncomms14063

[23] Boya P, Reggiori F, Codogno P. Emerging regulation and functions of autophagy. Nature Cell Biology. 2013;**15**(7):713-720. DOI: 10.1038/ ncb2788

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[25] Ktistakis NT, Tooze SA. Digesting the expanding mechanisms of autophagy. Trends in Cell Biology. 2016;**26**(8):624-635. DOI: 10.1016/j. tcb.2016.03.006

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[27] Choi AMK, Ryter SW, Levine B. Mechanisms of disease: Autophagy in human health and disease. The New England Journal of Medicine. 2013;**368**(7):651-662. DOI: 10.1056/ NEJMra1205406

[28] Suzuki H, Osawa T, Fujioka Y, Noda NN. Structural biology of the core autophagy machinery. Current Opinion in Structural Biology. 2017;**43**:10-17. DOI: 10.1016/j.sbi.2016.09.010

**23**

*Deficient Autophagy Contributes to the Development of Diabetic Retinopathy*

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64. DOI: 10.1172/JCI73943

DOI: 10.1016/j.tcb.2015.11.001

diacare.27.5.1047

dc11-1909

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[37] Galluzzi L, Bravo-San Pedro JM, Kroemer G. Autophagy mediates tumor suppression via cellular senescence. Trends in Cell Biology. 2016;**26**(1):1-3.

[38] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;**27**(5):1047-1053. DOI: 10.2337/

[39] Yau JWY, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;**35**(3):556-564. DOI: 10.2337/

[40] Kempen JH, O'Colmain BJ, Leske MC, Haffner SM, Klein R, Moss SE, et al. The prevalence of diabetic retinopathy among adults in the United States. Archives of Ophthalmology. 2004;**122**(4):552-563. DOI: 10.1001/archopht.122.4.552

[41] Berrone E, Beltramo E, Solimine C, Ape AU, Porta M. Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. The Journal of Biological Chemistry. 2006;**281**(14):9307-9313. DOI: 10.1074/

[42] Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circulation Research. 2010;**106**(8):1319-1331. DOI: 10.1161/CIRCRESAHA.110.217117

[43] Lee TS, Saltsman KA, Ohashi H, King GL. Activation of protein kinase C

jbc.M600418200

*DOI: http://dx.doi.org/10.5772/intechopen.89339*

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Ophthalmology & Visual Science. 2016;**57**(10):4356. DOI: 10.1167/

[30] Arias E, Cuervo AM. Chaperonemediated autophagy in protein quality control. Current Opinion in Cell Biology. 2011;**23**(2):184-189. DOI:

10.1016/j.ceb.2010.10.009

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Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone. The Journal of Biological Chemistry. 2018;**293**(15):5414-5424.

[34] Moloudizargari M, Asghari MH, Ghobadi E, Fallah M, Rasouli S, Abdollahi M. Autophagy, its mechanisms and regulation: Implications in neurodegenerative diseases. Ageing Research Reviews. 2017;**40**:64-74. DOI: 10.1016/j.

iovs.16-19197

R117.818237

devcel.2010.12.003

arr.2017.09.005

[33] Tekirdag K, Cuervo AM.

DOI: 10.1074/jbc.R117.818237

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Caricasole A, Bento CF, Andrews SP, Ashkenazi A, et al. Autophagy and Neurodegeneration: Pathogenic mechanisms and therapeutic

opportunities. Neuron. 2017;**93**(5):1015- 1034. DOI: 10.1016/j.neuron.2017.01.022

*Deficient Autophagy Contributes to the Development of Diabetic Retinopathy DOI: http://dx.doi.org/10.5772/intechopen.89339*

[29] Lopes de Faria JM, Duarte DA, Montemurro C, Papadimitriou A, Consonni SR, Lopes de Faria JB. Defective autophagy in diabetic retinopathy. Investigative Ophthalmology & Visual Science. 2016;**57**(10):4356. DOI: 10.1167/ iovs.16-19197

*The Eye and Foot in Diabetes*

post-transcriptional, and posttranslational regulation of autophagy. Trends in Cell Biology. 2015;**25**(6):354- 363. DOI: 10.1016/j.tcb.2015.02.002

[21] Kapahi P, Kaeberlein M, Hansen M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Research Reviews. 2017;**39**:3-14. DOI:

Beasley TM, Allison DB, Kemnitz JW, Roth GS, et al. Caloric restriction improves health and survival of rhesus monkeys. Nature Communications. 2017;**8**(1):14063. DOI: 10.1038/

[23] Boya P, Reggiori F, Codogno P. Emerging regulation and functions of autophagy. Nature Cell Biology. 2013;**15**(7):713-720. DOI: 10.1038/

[24] Dou Z, Xu C, Donahue G, Shimi T, Pan JA, Zhu J, et al. Autophagy mediates degradation of nuclear lamina. Nature. 2015;**527**(7576):105-109. DOI: 10.1038/

[25] Ktistakis NT, Tooze SA. Digesting

[26] Bento CF, Renna M, Ghislat G, Puri C, Ashkenazi A, Vicinanza M, et al. Mammalian autophagy: How does it work? Annual Review of Biochemistry. 2016;**85**(1):685-713. DOI: 10.1146/ annurev-biochem-060815-014556

[27] Choi AMK, Ryter SW, Levine B. Mechanisms of disease: Autophagy in human health and disease. The New England Journal of Medicine. 2013;**368**(7):651-662. DOI: 10.1056/

[28] Suzuki H, Osawa T, Fujioka Y, Noda NN. Structural biology of the core autophagy machinery. Current Opinion in Structural Biology. 2017;**43**:10-17. DOI: 10.1016/j.sbi.2016.09.010

the expanding mechanisms of autophagy. Trends in Cell Biology. 2016;**26**(8):624-635. DOI: 10.1016/j.

10.1016/j.arr.2016.12.005

ncomms14063

ncb2788

nature15548

tcb.2016.03.006

NEJMra1205406

[22] Mattison JA, Colman RJ,

[15] Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, et al. A gene network regulating Lysosomal biogenesis and function. Science. 2009;**325**(5939):473- 477. DOI: 10.1126/science.1174447

[16] Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, et al. Genomewide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proceedings of the National Academy of Sciences. 2010;**107**(32):14164-14169. DOI: 10.1016/j.cellsig.2013.06.013

[17] Chen Y, Sawada O, Kohno H, Le YZ, Subauste C, Maeda T, et al. Autophagy protects the retina from light-induced degeneration. The Journal of Biological Chemistry. 2013;**288**(11):7506-7518. DOI: 10.1074/jbc.M112.439935

[18] Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, et al. FoxO3 coordinately activates protein degradation by the Autophagic/ Lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metabolism. 2007;**6**(6):472-483. DOI:

10.1016/j.cmet.2007.11.004

of Ageing and Development. 1988;**45**(3):191-201. DOI: 10.1016/0047-6374(88)90001-2

DOI: 10.1038/nature03029

[20] Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;**432**(7020):1032-1036.

[19] Sarkis GJ, Ashcom JD, Hawdon JM, Jacobson LA. Decline in protease activities with age in the nematode caenorhabditis elegans. Mechanisms

**22**

[30] Arias E, Cuervo AM. Chaperonemediated autophagy in protein quality control. Current Opinion in Cell Biology. 2011;**23**(2):184-189. DOI: 10.1016/j.ceb.2010.10.009

[31] Orenstein SJ, Cuervo AM. Chaperone-mediated autophagy: Molecular mechanisms and physiological relevance. Seminars in Cell & Developmental Biology. 2010;**21**(7):719-726. DOI: 10.1074/jbc. R117.818237

[32] Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, et al. Microautophagy of cytosolic proteins by late endosomes. Developmental Cell. 2011;**20**(1):131-139. DOI: 10.1016/j. devcel.2010.12.003

[33] Tekirdag K, Cuervo AM. Chaperone-mediated autophagy and endosomal microautophagy: Jointed by a chaperone. The Journal of Biological Chemistry. 2018;**293**(15):5414-5424. DOI: 10.1074/jbc.R117.818237

[34] Moloudizargari M, Asghari MH, Ghobadi E, Fallah M, Rasouli S, Abdollahi M. Autophagy, its mechanisms and regulation: Implications in neurodegenerative diseases. Ageing Research Reviews. 2017;**40**:64-74. DOI: 10.1016/j. arr.2017.09.005

[35] Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, et al. Autophagy and Neurodegeneration: Pathogenic mechanisms and therapeutic opportunities. Neuron. 2017;**93**(5):1015- 1034. DOI: 10.1016/j.neuron.2017.01.022

[36] Lavandero S, Chiong M, Rothermel BA, Hill JA. Autophagy in cardiovascular biology. The Journal of Clinical Investigation. 2015;**125**(1):55- 64. DOI: 10.1172/JCI73943

[37] Galluzzi L, Bravo-San Pedro JM, Kroemer G. Autophagy mediates tumor suppression via cellular senescence. Trends in Cell Biology. 2016;**26**(1):1-3. DOI: 10.1016/j.tcb.2015.11.001

[38] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;**27**(5):1047-1053. DOI: 10.2337/ diacare.27.5.1047

[39] Yau JWY, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;**35**(3):556-564. DOI: 10.2337/ dc11-1909

[40] Kempen JH, O'Colmain BJ, Leske MC, Haffner SM, Klein R, Moss SE, et al. The prevalence of diabetic retinopathy among adults in the United States. Archives of Ophthalmology. 2004;**122**(4):552-563. DOI: 10.1001/archopht.122.4.552

[41] Berrone E, Beltramo E, Solimine C, Ape AU, Porta M. Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. The Journal of Biological Chemistry. 2006;**281**(14):9307-9313. DOI: 10.1074/ jbc.M600418200

[42] Geraldes P, King GL. Activation of protein kinase C isoforms and its impact on diabetic complications. Circulation Research. 2010;**106**(8):1319-1331. DOI: 10.1161/CIRCRESAHA.110.217117

[43] Lee TS, Saltsman KA, Ohashi H, King GL. Activation of protein kinase C by elevation of glucose concentration: Proposal for a mechanism in the development of diabetic vascular complications. Proceedings of the National Academy of Sciences. 2006;**86**(13):5141-5145. DOI: 10.1073/ pnas.86.13.5141

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[45] Rosales MAB, Silva KC, Duarte DA, Rossato FA, Lopes de Faria JB, Lopes de Faria JM. Endocytosis of tight junctions Caveolin Nitrosylation dependent is improved by cocoa via opioid receptor on RPE cells in diabetic conditions. Investigative Ophthalmology & Visual Science. 2014;**55**(9):6090. DOI: 10.1167/ iovs.14-14234

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**26**

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[94] Powell C, Grant AR, Cornblath E, Goldman D. Analysis of DNA methylation reveals a partial reprogramming of the Muller glia genome during retina regeneration. Proceedings of the National Academy of Sciences. 2013;**110**(49):19814-19819. DOI: 10.1073/pnas.1312009110

[95] Schütte M, Werner P. Redistribution of glutathione in the ischemic rat retina. Neuroscience Letters. 1998;**246**(1):53-56. DOI: 10.1016/ S0304-3940(98)00229-8

[96] Long KO, Fisher SK, Fariss RN, Anderson DH. Disc shedding and autophagy in the cone-dominant ground squirrel retina. Experimental Eye Research. 1986;**43**(2):193-205. DOI: 10.1016/S0014-4835(86)80087-2

[97] Wang JS, Kefalov VJ. The conespecific visual cycle. Progress in Retinal and Eye Research. 2011;**30**(2):115-128. DOI: 10.1016/j.preteyeres.2010.11.001

#### *The Eye and Foot in Diabetes*

[98] Bai Y, Ma J, Guo J, Wang J, Zhu M, Chen Y, et al. Müller cell-derived VEGF is a significant contributor to retinal neovascularization. The Journal of Pathology. 2009;**219**(4):446-454. DOI: 10.1002/path.2611

[99] Devi TS, Lee I, Hüttemann M, Kumar A, Nantwi KD, Singh LP. TXNIP links innate host defense mechanisms to oxidative stress and inflammation in retinal Muller glia under chronic hyperglycemia: Implications for diabetic retinopathy. Experimental Diabetes Research. 2012;**2012**:1-19. DOI: 10.1155/2012/438238

**29**

**Chapter 3**

**Abstract**

*Ogugua N. Okonkwo*

offer even more benefit.

**1. Introduction**

treatment [5–8].

should be done on a case-by-case basis.

Diabetic Vitrectomy

Diabetic retinopathy (DR) in its advanced stage is a leading cause of blindness and visual impairment. Despite efforts at early detection of DR, disease monitoring, and medical therapy, significant proportions of people living with diabetes still progress to develop the advanced proliferative disease, which is characterized by neovascularization, actively proliferating fibrovascular membranes, and retinal traction. The surgical removal of this proliferating tissue and the treatment of the retinal ischemic drive can be very rewarding, providing significant stability of the retina and in several cases improved retinal anatomy and vision. Diabetic vitrectomy comprises a broad range of surgical techniques and maneuvers, which offer the surgeon and patient opportunity to reverse deranged vitreoretinal anatomy and improve or stabilizes vision. Advances in vitreoretinal technology have contributed greatly to more recent improved outcomes; it is expected that future advances will

**Keywords:** diabetic retinopathy, vitreous hemorrhage, proliferative diabetic retinopathy, tractional retinal detachment, macular edema, vitrectomy

Global estimates of diabetes have been on the rise [1]. Diabetic retinopathy (DR) is a leading cause of blindness among the working age group, with increasing numbers of persons being affected worldwide [2, 3]. It is a microvascular complication of diabetes which progresses to advanced disease in several cases. It is a global concern as indicated by a recent review published in Lancet [4]. The microvascular complications of diabetes result in macular leakage or exudation and vasoproliferative retinal disease, which are the hallmarks of advanced DR. Despite treatment of earlier stages of DR with medical therapy, which include intravitreal injection of anti-vascular endothelial growth factor (VEGF), intravitreal injection of steroids, and retinal laser photocoagulation, several eyes will progress to require surgical

Surgical treatment for the advanced complications of DR can range from more straightforward cases involving the removal of a non-clearing vitreous hemorrhage from an eye in which vitreous separation has already occurred, to more complicated surgical techniques such as in dealing with a combined tractional and rhegmatogenous retinal detachment (TRD/RRD) or tractional retinal detachment (TRD) involving the macula [9, 10]. The preoperative considerations, intraoperative techniques, and the postoperative outcome, including the complications of surgery, could vary considerably, depending on the risk factors and complexity of the vitreoretinal presentation associated with each case. Therefore surgical planning

## **Chapter 3** Diabetic Vitrectomy

*Ogugua N. Okonkwo*

## **Abstract**

*The Eye and Foot in Diabetes*

10.1002/path.2611

10.1155/2012/438238

[98] Bai Y, Ma J, Guo J, Wang J, Zhu M, Chen Y, et al. Müller cell-derived VEGF is a significant contributor to retinal neovascularization. The Journal of Pathology. 2009;**219**(4):446-454. DOI:

[99] Devi TS, Lee I, Hüttemann M, Kumar A, Nantwi KD, Singh LP. TXNIP links innate host defense mechanisms to oxidative stress and inflammation in retinal Muller glia under chronic hyperglycemia: Implications for diabetic retinopathy. Experimental Diabetes Research. 2012;**2012**:1-19. DOI:

**28**

Diabetic retinopathy (DR) in its advanced stage is a leading cause of blindness and visual impairment. Despite efforts at early detection of DR, disease monitoring, and medical therapy, significant proportions of people living with diabetes still progress to develop the advanced proliferative disease, which is characterized by neovascularization, actively proliferating fibrovascular membranes, and retinal traction. The surgical removal of this proliferating tissue and the treatment of the retinal ischemic drive can be very rewarding, providing significant stability of the retina and in several cases improved retinal anatomy and vision. Diabetic vitrectomy comprises a broad range of surgical techniques and maneuvers, which offer the surgeon and patient opportunity to reverse deranged vitreoretinal anatomy and improve or stabilizes vision. Advances in vitreoretinal technology have contributed greatly to more recent improved outcomes; it is expected that future advances will offer even more benefit.

**Keywords:** diabetic retinopathy, vitreous hemorrhage, proliferative diabetic retinopathy, tractional retinal detachment, macular edema, vitrectomy

## **1. Introduction**

Global estimates of diabetes have been on the rise [1]. Diabetic retinopathy (DR) is a leading cause of blindness among the working age group, with increasing numbers of persons being affected worldwide [2, 3]. It is a microvascular complication of diabetes which progresses to advanced disease in several cases. It is a global concern as indicated by a recent review published in Lancet [4]. The microvascular complications of diabetes result in macular leakage or exudation and vasoproliferative retinal disease, which are the hallmarks of advanced DR. Despite treatment of earlier stages of DR with medical therapy, which include intravitreal injection of anti-vascular endothelial growth factor (VEGF), intravitreal injection of steroids, and retinal laser photocoagulation, several eyes will progress to require surgical treatment [5–8].

Surgical treatment for the advanced complications of DR can range from more straightforward cases involving the removal of a non-clearing vitreous hemorrhage from an eye in which vitreous separation has already occurred, to more complicated surgical techniques such as in dealing with a combined tractional and rhegmatogenous retinal detachment (TRD/RRD) or tractional retinal detachment (TRD) involving the macula [9, 10]. The preoperative considerations, intraoperative techniques, and the postoperative outcome, including the complications of surgery, could vary considerably, depending on the risk factors and complexity of the vitreoretinal presentation associated with each case. Therefore surgical planning should be done on a case-by-case basis.

Furthermore, in recent times, there have been significant improvements in preoperative care and evaluation, and intraoperative surgical technique, including the administration of preoperative intravitreal pharmacotherapy, development of small-gauge transconjunctival instrumentation [11–13], and availability of multifunctional vitrectomy probes with high cut rates [14]. These advances have made surgical outcome more predictable and have resulted in an expansion of the indication for vitrectomy in the management of the tractional complications seen in DR. This review will focus on highlighting the indications, pathophysiology and principles of surgery, preoperative considerations, intraoperative surgical techniques, and outcome of diabetic vitrectomy in contemporary times.

## **2. Indications for surgery**

The indications for vitrectomy in advanced DR have increased over the years from the situation in the early years of diabetic vitrectomy, when surgery was used for removing non-clearing vitreous hemorrhage. The first vitrectomy performed by Machemer was for the removal of non-clearing vitreous hemorrhage in a patient living with diabetes, and suffering from proliferative diabetic retinopathy (PDR) [15]. The Diabetic Retinopathy Vitrectomy Study (DRVS) was the first randomized, large series study evaluating the outcome of early versus deferral of vitrectomy in eyes with vitreous hemorrhage secondary to advanced DR [16]. It highlighted the benefit of early vitrectomy especially in type 1 diabetics with more severe disease. The DRVS also demonstrated that the benefit of surgery was maintained over a 4-year study period. Since then, the indications for diabetic vitrectomy (DV) are now known to include non-clearing vitreous hemorrhage, TRD, combined RRD/TRD, vitreomacular traction, traction-induced diabetic macular edema (DME), rubeosis iridis, and macular distortion (including dragging of the macula), to mention a few [17–21].


**31**

glaucoma.

*Diabetic Vitrectomy*

*DOI: http://dx.doi.org/10.5772/intechopen.91360*

advanced tractional complications.

**3. Preoperative systemic considerations**

neovascular tuft.

Surgery is indicated when the traction occurs in the macula or if there is obvious progression of an extra macular TRD towards the macula. In some cases the retinal traction is significant and creates a retinal tear. This adds a rhegmatogenous component to the already existing TRD. In combined TRD/RRD, progression to

In these situations of significant traction involving the macula or threatening the macula, surgery is indicated to relieve the traction and reattach the retina or to prevent progression of TRD to the macula. However, there are several cases in which extra macular TRD remains stable after adequate panretinal laser photocoagulation (PRP) and good control of systemic parameters have been achieved. Such cases can be observed since there is no progression. In one review comparing African-Americans with Caucasians requiring diabetic vitrectomy, patients of African-American descent were found to be more likely to have TRD/RRD than Caucasians, and it was concluded that African-Americans might have a greater risk of developing this advanced complication [24]. In the light of this, African-Americans and others at increased risk could benefit from earlier vitrectomy, before the onset of vision damaging

3.Persistent retinal neovascularization despite adequate laser PRP may result in recurrent VH and requires surgical removal of the vitreous scaffolding on which such neovascularization would progress. In such cases, adequate retinal laser fails to cause a complete regression of neovascularization. The vascular tuft invades the vitreous scaffold and forms neovascular pegs. This vitreous attachment to the neovascular peg has to be removed to prevent the recurrent VH, which recurs whenever there is significant vitreous traction on the

4.Severe FVP, especially if associated with significant traction involving or threatening the macula, or if obscuring the macula, may require surgical removal. In some instances, FVP occurs in the retina periphery and may be associated with proliferation extending from sclerotomy sites. This was more common in the era of large sclerotomies using the 20-gauge vitrectomy systems. Residual postoperative peripheral vitreous and significant untreated ischemia in the peripheral retina using either endoretinal laser photocoagulation or cryotherapy predispose to the formation of this complication better known as anterior hyaloidal fibrovascular proliferation (AHFVP) [25]. This is a known complication of diabetic vitrectomy which has also been reported to occur after cataract surgery in poorly controlled diabetic patients [25, 26].

Other indications for diabetic vitrectomy include macular ectopia and rubeotic

Diabetes is a multisystem disease. The presence of DR suggests microvascular affectation, which may include an effect on the microvasculature in other organs, especially the kidney resulting in diabetic nephropathy. Advanced retinopathy requiring surgery has been found to be associated with reduced life expectancy [27]. Also patients with diabetic macular edema have been noted to have a higher

incidence of cerebrovascular accidents and myocardial infarcts [28].

involve the macula could be rapid, and early surgery is advised.

#### *Diabetic Vitrectomy DOI: http://dx.doi.org/10.5772/intechopen.91360*

*The Eye and Foot in Diabetes*

**2. Indications for surgery**

ultrasound, which will reveal the TRD.

Furthermore, in recent times, there have been significant improvements in preoperative care and evaluation, and intraoperative surgical technique, including the administration of preoperative intravitreal pharmacotherapy, development of small-gauge transconjunctival instrumentation [11–13], and availability of multifunctional vitrectomy probes with high cut rates [14]. These advances have made surgical outcome more predictable and have resulted in an expansion of the indication for vitrectomy in the management of the tractional complications seen in DR. This review will focus on highlighting the indications, pathophysiology and principles of surgery, preoperative considerations, intraoperative surgical tech-

The indications for vitrectomy in advanced DR have increased over the years from the situation in the early years of diabetic vitrectomy, when surgery was used for removing non-clearing vitreous hemorrhage. The first vitrectomy performed by Machemer was for the removal of non-clearing vitreous hemorrhage in a patient living with diabetes, and suffering from proliferative diabetic retinopathy (PDR) [15]. The Diabetic Retinopathy Vitrectomy Study (DRVS) was the first randomized, large series study evaluating the outcome of early versus deferral of vitrectomy in eyes with vitreous hemorrhage secondary to advanced DR [16]. It highlighted the benefit of early vitrectomy especially in type 1 diabetics with more severe disease. The DRVS also demonstrated that the benefit of surgery was maintained over a 4-year study period. Since then, the indications for diabetic vitrectomy (DV) are now known to include non-clearing vitreous hemorrhage, TRD, combined RRD/TRD, vitreomacular traction, traction-induced diabetic macular edema (DME), rubeosis iridis, and macular distortion (including dragging of the macula), to mention a few [17–21].

1.Vitreous hemorrhage (VH): vitrectomy for vitreous hemorrhage removal, in several studies, remains the most common indication for diabetic vitrectomy [20, 22, 23]. The scope of this will depend on the surgeon's personal experience, state of the fellow eye, previous retinal laser, recurrence of VH, and systemic control of glycemic levels. Non-clearing vitreous hemorrhage cases with complete separation of the posterior hyaloid are rather uncommon and the vitreous can be easily removed with expectation of improved vision in a majority of eyes. Vitrectomy for a case in which prior retinal laser photocoagulation has been applied also tends to progress quite well as the prior laser would have reduced the activity of the retinopathy, treated the retinal ischemia, and slowed the momentum of the disease. Moreover, in eyes with prior preoperative retinal laser, the occurrence of iatrogenic breaks within the areas of retinal laser scars prevents progression to retinal detachment. VH can at times be associated with more severe proliferative retinal disease such as a macula involving TRD. In this case both VH and TRD are indications for surgery and eventual visual outcome will be affected by the occurrence of TRD. This situation can be identified using a preoperative B scan

2.Retinal traction involving the macula can be an important indication for vitrectomy. This can occur as a result of an epiretinal membrane (ERM), TRD, TRD/ RRD and vitreomacular traction (VMT). Fibrovascular proliferation (FVP) in the sub-hyaloid space is responsible for the retinal traction, which could initially occur in an extra macular site, and then progress to involve the macular area. Also, TRD could develop primarily in the macula and have an early impact on vision.

niques, and outcome of diabetic vitrectomy in contemporary times.

**30**

Surgery is indicated when the traction occurs in the macula or if there is obvious progression of an extra macular TRD towards the macula. In some cases the retinal traction is significant and creates a retinal tear. This adds a rhegmatogenous component to the already existing TRD. In combined TRD/RRD, progression to involve the macula could be rapid, and early surgery is advised.

In these situations of significant traction involving the macula or threatening the macula, surgery is indicated to relieve the traction and reattach the retina or to prevent progression of TRD to the macula. However, there are several cases in which extra macular TRD remains stable after adequate panretinal laser photocoagulation (PRP) and good control of systemic parameters have been achieved. Such cases can be observed since there is no progression.

In one review comparing African-Americans with Caucasians requiring diabetic vitrectomy, patients of African-American descent were found to be more likely to have TRD/RRD than Caucasians, and it was concluded that African-Americans might have a greater risk of developing this advanced complication [24]. In the light of this, African-Americans and others at increased risk could benefit from earlier vitrectomy, before the onset of vision damaging advanced tractional complications.


Other indications for diabetic vitrectomy include macular ectopia and rubeotic glaucoma.

## **3. Preoperative systemic considerations**

Diabetes is a multisystem disease. The presence of DR suggests microvascular affectation, which may include an effect on the microvasculature in other organs, especially the kidney resulting in diabetic nephropathy. Advanced retinopathy requiring surgery has been found to be associated with reduced life expectancy [27]. Also patients with diabetic macular edema have been noted to have a higher incidence of cerebrovascular accidents and myocardial infarcts [28].

As the patient for diabetic vitrectomy could be ill before or after the surgery, careful review by the internist and anesthesia team is required before the decision to proceed to surgery is taken. If the patient is on routine dialysis, heparin-free dialysis may be beneficial in reducing the incidence of intraoperative and postoperative hemorrhage. Preoperative administration of intravitreal VEGF injection has become popular in recent times and has been shown to decrease the rate of intraoperative and postoperative hemorrhage; it also improves intraoperative visibility and reduces surgery time.

Importantly, an internist clearance is required before preoperative adjunctive anti-VEGF is administered to avoid a situation in which following the administration of anti-VEGF, surgery is postponed due to the patient's ill health. This may result in an overactivity of the anti-VEGF with severe contraction of the fibrous component of the fibrovascular membrane resulting in a worsening TRD (and perhaps more retinal ischemia); this is known as a "Crunch." The use of anti-VEGF will be discussed in more detail later on.

## **4. Preoperative ocular considerations**


**33**

*Diabetic Vitrectomy*

*DOI: http://dx.doi.org/10.5772/intechopen.91360*

5.Lens: the presence of significant cataract may require that a combined vitrectomy and cataract removal be performed during the same surgery. The cataract is first removed using a phacoemulsification technique, then the diabetic vitrectomy is performed. The intraocular lens (IOL) could be inserted before or at the conclusion of the vitrectomy. This combined procedure has become a popular technique in recent years. It provides a clearer view and lends itself to improved access to the retina periphery with the use of a wide-angle viewing lens. However, it can also be associated with significant complications of the anterior segment, since there could be enhanced diffusion of the growth factors including VEGF from the posterior segment to the anterior segment of the

eye, resulting in the formation of rubeosis iridis and its sequelae.

ing its presence is essential for good outcome.

**5. Relevant pathophysiology and surgical principles**

Advanced stages of DR are characterized by retina edema and ischemia, consequent to vascular hyperpermeability and vascular occlusion, respectively. The chronic hyperglycemia results in progressive damage to the retinal capillary network resulting in retinal hypoxia and release of hypoxia-inducible factor (HIF) from the affected areas of the retina. The resultant ischemic retina due to the action of HIF then releases pro angiogenesis growth factors which include basic fibroblast growth factor (FGF), insulinlike growth factor 1 (IGF 1), erythropoietin, and, the most known growth factor, VEGF [29]. Also, cytokines such as IL-6, IL-8, and MCP-1 are released. The interaction of these growth factors and cytokines stimulate angiogenesis. VEGF-mediated new blood vessels sprout out from the surrounding vessels, i.e., capillaries and venules, and invade the vitreous. Progressive vasoproliferation occurs in response to increasing levels of the growth factors; and this is associated with proliferation of fibrous tissue resulting in the characteristic fibrovascular membranes. The fibrovascular tissue proliferates and extends across the retina in the preretinal space (or sub hyaloid space). In eyes with PVD, fibrovascular membranes can only grow on the surface of the retina; therefore, retinal detachments do not tend to occur. However in eyes without a PVD (which is often the case), the posterior hyaloid acts as a scaffold that allows the fibrovascular tissue to grow, leading to traction on the retina and retinal detachments. Tractional forces within the vitreous exert effect on these rather brittle new blood vessels resulting in different degrees of hemorrhage. The resulting hemorrhage can range from a small leakage of blood on the surrounding retina to larger preretinal hemorrhage (**Figure 1a**) and to a more severe break through intragel vitreous hemorrhage.

6.A B scan ultrasound is a useful ocular investigation to have, especially in situations in which there is limited or no view of the retina as a result of vitreous hemorrhage, opacities in the vitreous, and cataract. A B scan can detect the presence or absence of posterior vitreous detachment (PVD) and provide information useful for preparing the eye for diabetic vitrectomy. For instance, some surgeons would give preoperative intravitreal anti-VEGF in eyes without a PVD and refrain from doing so in eyes in which a PVD already exists. Also a B scan can detect the presence of vitreoschisis (aka second membrane). Vitreoschisis is common in diabetic retinopathy eyes, and for this reason re-staining using multiple intravitreal triamcinolone injections is important to detect the residual vitreous layer when vitreoschisis is present. Vitreoschisis is thought to be due to vitreous hemorrhage in the gel splitting the vitreous fibers. Recogniz-

#### *Diabetic Vitrectomy DOI: http://dx.doi.org/10.5772/intechopen.91360*

*The Eye and Foot in Diabetes*

reduces surgery time.

will be discussed in more detail later on.

**4. Preoperative ocular considerations**

obscure the view of the macula.

tation such as using iris hooks.

As the patient for diabetic vitrectomy could be ill before or after the surgery, careful review by the internist and anesthesia team is required before the decision to proceed to surgery is taken. If the patient is on routine dialysis, heparin-free dialysis may be beneficial in reducing the incidence of intraoperative and postoperative hemorrhage. Preoperative administration of intravitreal VEGF injection has become popular in recent times and has been shown to decrease the rate of intraoperative and postoperative hemorrhage; it also improves intraoperative visibility and

Importantly, an internist clearance is required before preoperative adjunctive anti-VEGF is administered to avoid a situation in which following the administration of anti-VEGF, surgery is postponed due to the patient's ill health. This may result in an overactivity of the anti-VEGF with severe contraction of the fibrous component of the fibrovascular membrane resulting in a worsening TRD (and perhaps more retinal ischemia); this is known as a "Crunch." The use of anti-VEGF

1.Visual acuity: preoperative acuity has been shown to be an important factor in determining the eventual postoperative visual outcome, with eyes having better preoperative vision tending to have improved postoperative vision. Also, TRD involving the macula will have poorer preoperative vision than a "macular sparing" TRD. Therefore surgery should be performed once the macula is perceived to be threatened. Macular ischemia remains an important reason for poor preoperative and postoperative vision; this can be determined by the use of fundus fluorescein angiography (FFA) to assess for macular non-perfusion. Optical coherence angiography (OCT angiography or OCTA) can also be used and has the advantage of repeatability of the test. However, in several cases, it is not possible to perform this FFA assessment of the macular vasculature before surgery because of opacities in the medium, including VH and FVP, which

2.Intraocular pressure (IOP): this may be normal or elevated. When IOP is elevated, it is important to assess the anterior chamber angles and anterior uvea carefully, in search of rubeosis. The finding of rubeosis suggests very significant retinal ischemia and further worsens the prognosis for recovery of vision. The rise in IOP may also have damaging effects on the cornea, including cornea

3.Cornea: the clarity of this structure is required for proper access and visibility required for diabetic vitrectomy. The use of contact lens viewing systems significantly increases the incidence of cornea opacity and may require the removal of cornea epithelium during the surgery. Such scrapping off of cornea epithelium could result in postoperative cornea defects, which could take some time to heal. The aforementioned situation has been greatly reduced with the

4.Pupil: it is vital to assess for adequate pupillary dilatation prior to surgery. A poorly dilating pupil may require more than pharmacological mydriasis. In some instances pupillary synechiae may exist and will require mechanical dila-

edema, and result in decreased visibility during surgery.

more frequent use of non-contact lens viewing systems.

**32**


## **5. Relevant pathophysiology and surgical principles**

Advanced stages of DR are characterized by retina edema and ischemia, consequent to vascular hyperpermeability and vascular occlusion, respectively. The chronic hyperglycemia results in progressive damage to the retinal capillary network resulting in retinal hypoxia and release of hypoxia-inducible factor (HIF) from the affected areas of the retina. The resultant ischemic retina due to the action of HIF then releases pro angiogenesis growth factors which include basic fibroblast growth factor (FGF), insulinlike growth factor 1 (IGF 1), erythropoietin, and, the most known growth factor, VEGF [29]. Also, cytokines such as IL-6, IL-8, and MCP-1 are released. The interaction of these growth factors and cytokines stimulate angiogenesis. VEGF-mediated new blood vessels sprout out from the surrounding vessels, i.e., capillaries and venules, and invade the vitreous. Progressive vasoproliferation occurs in response to increasing levels of the growth factors; and this is associated with proliferation of fibrous tissue resulting in the characteristic fibrovascular membranes. The fibrovascular tissue proliferates and extends across the retina in the preretinal space (or sub hyaloid space). In eyes with PVD, fibrovascular membranes can only grow on the surface of the retina; therefore, retinal detachments do not tend to occur. However in eyes without a PVD (which is often the case), the posterior hyaloid acts as a scaffold that allows the fibrovascular tissue to grow, leading to traction on the retina and retinal detachments. Tractional forces within the vitreous exert effect on these rather brittle new blood vessels resulting in different degrees of hemorrhage. The resulting hemorrhage can range from a small leakage of blood on the surrounding retina to larger preretinal hemorrhage (**Figure 1a**) and to a more severe break through intragel vitreous hemorrhage.

#### **Figure 1.**

*Fundus photograph of PDR. (a) Left eye showing diffuse vitreous hemorrhage and preretinal hemorrhage in an eye diagnosed to have PDR. Notice also the absence of retinal laser marks and presence of macula hard exudates, with some significant cataract. (b) Same eye as in 1a after vitrectomy; view of the fundus is clearer and some hard exudates persist in the macular area.*

This hemorrhage can often be removed using vitrectomy technique (**Figure 1b**). The fibrous component of the fibrovascular tissue contracts, due to a myofibroblastic effect [30], and causes traction on the inner retina, resulting in a TRD that may initially involve an extra macular site, and then subsequently progresses to the macula and damages vision. In some cases the traction results in a split in the layers of the retina (retinoschisis or foveoschisis) that can be appreciated on optical coherence tomography (OCT) scan. Similarly, ERM may be present in the macular area and result in considerable macular traction, worsening already existing macular edema. Since such diabetic macular edema (DME) has a traction-induced component as its causation, surgery will be required to remove the traction if resolution of the edema is to be achieved. VEGF suppression alone is unlikely to achieve complete resolution of this sort of DME, and this needs to be recognized.

The surgical principles of diabetic vitrectomy include performing a core vitrectomy. In some cases, a posterior vitreous separation already exists preoperatively and the goal of surgery is simply vitreous hemorrhage removal. This is a rather uncommon presentation. In cases of vitreous hemorrhage removal, in addition to the hemorrhage (since the vitreous cavity acts as a reservoir of several proinflammatory and pro-angiogenic factors that result in macular edema, neovascularization, and proliferation of fibrous tissue), diabetic vitrectomy also achieves immediate removal of these factors and cytokines. It facilitates access to the retina and permits release of the posterior hyaloid and further dissection of the tractional fibrotic membranes that create the TRD.

Separation of the anterior vitreous from the more posterior cortical vitreous can be easily accomplished using any standard vitreous cutter, allowing the release of the anteroposterior traction induced by the vitreous. Careful dissection of the posterior vitreous cortex from the underlying retina and the removal of proliferating fibrovascular membranes and fibrous bands from the retina surface (and at times from the subretinal space) are the highlights of the surgery. This should be done, avoiding the creation of iatrogenic breaks and creation of false passages. Identification of the right plane of vitreoretinal separation is the key to proper dissection and avoiding unnecessary iatrogenic breaks. One tip to achieve entry into the right vitreoretinal plane in difficult situations is to commence dissection from the optic disc and then move out towards the macula and retina periphery, the "inside out approach." In

**35**

*Diabetic Vitrectomy*

*DOI: http://dx.doi.org/10.5772/intechopen.91360*

complete TRD repair using only the vitreous cutter [33, 34].

to ensure maximum obliteration of the ischemic drive.

tive status over some weeks.

**6. Intraoperative considerations**

are as enumerated and discussed below:

practice, it is possible to detach the vitreous at the optic disc with gentle traction on the adjoining vitreous or fibrous tissue close to the optic disc using an intraocular forceps or the aspiration port of a vitreous cutter. This lifts the vitreous off the disc and ensures a safe entry into the vitreoretinal space, from where dissection can continue outward. In some cases a moderate to large amount of retrohyaloid blood already exists; this provides a useful entry point into the desired vitreoretinal space. Techniques for fibrovascular proliferation removal have been well described and include en bloc dissection in which vitreous and proliferating tissue is removed as one, segmentation of fibrovascular tissue into islands of tissue using straight scissors or small-gauge cutter, and delamination involving careful removal of the islands of tissue using a small-gauge cutter or a curved intraocular scissors [31, 32]. Various ancillary instrumentation including picks, vertical and horizontal scissors, blades, membrane peeler cutters, forceps, scrapers, and other instruments can be used for the removal of proliferating fibrovascular membranes. However the use of newer high cut rate multifunctional vitreous cutters enables surgeons to often

Upon completion of membrane dissection, ERM in the macular area may require

There may be a need for longer acting tamponade such as silicone oil in the more complex retina detachments such as in TRD cases with the occurrence of significant iatrogenic breaks, TRD/RRD situation, or in cases with existing traction [36]. Silicone oil is also used in monocular patients and patients who cannot position or who have to undertake air travel soon. Otherwise air, saline or shorter acting tamponade such as SF6 is sufficient in cases of low to medium complexity, especially if there are no iatrogenic breaks and release of traction is considered adequate. C3F8 can be used if longer duration of tamponade is required. It is important to ensure that sclerotomy ports are well closed, with no leakage. If required and judged to be necessary, sclerotomy sites should be sutured using, e.g., 8-0 vicryl suture, to prevent hypotony and reduce the risk of postoperative vitreous hemorrhage. A reported disadvantage of the sutured sclerotomy is postoperative patient discomfort and induction of cornea astigmatism, which tends to settle and return to preopera-

Diabetic vitrectomy has benefited from the overwhelming advances that have occurred in vitrectomy over the past decade. This includes advances in surgical technique, instrumentation, improved preoperative patient work-up, and case selection. All this has resulted in improved surgical outcome, which has further increased surgeon confidence in performing surgery, even in the more complex vitreoretinal cases. Some of these advances in diabetic vitrectomy and their impact

1.Improvements in vitrectomy machines and probes, which includes faster cutting rates and smaller gauges (27 G, 25 G, and 23 G) trans conjunctival vitrectomy

identification and removal. Subretinal fluid drainage may be required. Existing retinal ischemia is treated with the application of laser panretinal photocoagulation [35]. PRP should be done up to the extreme retinal periphery, i.e., ora serrata. Scleral indentation is performed in search of iatrogenic retina breaks (which if undetected and treated can result in postoperative RRD and need for re-vitrectomy). Indentation is also done to ensure PRP has been extended to all areas of peripheral ischemia. Some surgeon will apply cryotherapy to the peripheral retina,

#### *Diabetic Vitrectomy DOI: http://dx.doi.org/10.5772/intechopen.91360*

*The Eye and Foot in Diabetes*

**Figure 1.**

This hemorrhage can often be removed using vitrectomy technique (**Figure 1b**). The fibrous component of the fibrovascular tissue contracts, due to a myofibroblastic effect [30], and causes traction on the inner retina, resulting in a TRD that may initially involve an extra macular site, and then subsequently progresses to the macula and damages vision. In some cases the traction results in a split in the layers of the retina (retinoschisis or foveoschisis) that can be appreciated on optical coherence tomography (OCT) scan. Similarly, ERM may be present in the macular area and result in considerable macular traction, worsening already existing macular edema. Since such diabetic macular edema (DME) has a traction-induced component as its causation, surgery will be required to remove the traction if resolution of the edema is to be achieved. VEGF suppression alone is unlikely to achieve complete

*Fundus photograph of PDR. (a) Left eye showing diffuse vitreous hemorrhage and preretinal hemorrhage in an eye diagnosed to have PDR. Notice also the absence of retinal laser marks and presence of macula hard exudates, with some significant cataract. (b) Same eye as in 1a after vitrectomy; view of the fundus is clearer* 

The surgical principles of diabetic vitrectomy include performing a core vitrectomy. In some cases, a posterior vitreous separation already exists preoperatively and the goal of surgery is simply vitreous hemorrhage removal. This is a rather uncommon presentation. In cases of vitreous hemorrhage removal, in addition to the hemorrhage (since the vitreous cavity acts as a reservoir of several proinflammatory and pro-angiogenic factors that result in macular edema, neovascularization, and proliferation of fibrous tissue), diabetic vitrectomy also achieves immediate removal of these factors and cytokines. It facilitates access to the retina and permits release of the posterior hyaloid and further dissection of the tractional

Separation of the anterior vitreous from the more posterior cortical vitreous can be easily accomplished using any standard vitreous cutter, allowing the release of the anteroposterior traction induced by the vitreous. Careful dissection of the posterior vitreous cortex from the underlying retina and the removal of proliferating fibrovascular membranes and fibrous bands from the retina surface (and at times from the subretinal space) are the highlights of the surgery. This should be done, avoiding the creation of iatrogenic breaks and creation of false passages. Identification of the right plane of vitreoretinal separation is the key to proper dissection and avoiding unnecessary iatrogenic breaks. One tip to achieve entry into the right vitreoretinal plane in difficult situations is to commence dissection from the optic disc and then move out towards the macula and retina periphery, the "inside out approach." In

resolution of this sort of DME, and this needs to be recognized.

fibrotic membranes that create the TRD.

*and some hard exudates persist in the macular area.*

**34**

practice, it is possible to detach the vitreous at the optic disc with gentle traction on the adjoining vitreous or fibrous tissue close to the optic disc using an intraocular forceps or the aspiration port of a vitreous cutter. This lifts the vitreous off the disc and ensures a safe entry into the vitreoretinal space, from where dissection can continue outward. In some cases a moderate to large amount of retrohyaloid blood already exists; this provides a useful entry point into the desired vitreoretinal space.

Techniques for fibrovascular proliferation removal have been well described and include en bloc dissection in which vitreous and proliferating tissue is removed as one, segmentation of fibrovascular tissue into islands of tissue using straight scissors or small-gauge cutter, and delamination involving careful removal of the islands of tissue using a small-gauge cutter or a curved intraocular scissors [31, 32]. Various ancillary instrumentation including picks, vertical and horizontal scissors, blades, membrane peeler cutters, forceps, scrapers, and other instruments can be used for the removal of proliferating fibrovascular membranes. However the use of newer high cut rate multifunctional vitreous cutters enables surgeons to often complete TRD repair using only the vitreous cutter [33, 34].

Upon completion of membrane dissection, ERM in the macular area may require identification and removal. Subretinal fluid drainage may be required. Existing retinal ischemia is treated with the application of laser panretinal photocoagulation [35]. PRP should be done up to the extreme retinal periphery, i.e., ora serrata. Scleral indentation is performed in search of iatrogenic retina breaks (which if undetected and treated can result in postoperative RRD and need for re-vitrectomy). Indentation is also done to ensure PRP has been extended to all areas of peripheral ischemia. Some surgeon will apply cryotherapy to the peripheral retina, to ensure maximum obliteration of the ischemic drive.

There may be a need for longer acting tamponade such as silicone oil in the more complex retina detachments such as in TRD cases with the occurrence of significant iatrogenic breaks, TRD/RRD situation, or in cases with existing traction [36]. Silicone oil is also used in monocular patients and patients who cannot position or who have to undertake air travel soon. Otherwise air, saline or shorter acting tamponade such as SF6 is sufficient in cases of low to medium complexity, especially if there are no iatrogenic breaks and release of traction is considered adequate. C3F8 can be used if longer duration of tamponade is required. It is important to ensure that sclerotomy ports are well closed, with no leakage. If required and judged to be necessary, sclerotomy sites should be sutured using, e.g., 8-0 vicryl suture, to prevent hypotony and reduce the risk of postoperative vitreous hemorrhage. A reported disadvantage of the sutured sclerotomy is postoperative patient discomfort and induction of cornea astigmatism, which tends to settle and return to preoperative status over some weeks.

## **6. Intraoperative considerations**

Diabetic vitrectomy has benefited from the overwhelming advances that have occurred in vitrectomy over the past decade. This includes advances in surgical technique, instrumentation, improved preoperative patient work-up, and case selection. All this has resulted in improved surgical outcome, which has further increased surgeon confidence in performing surgery, even in the more complex vitreoretinal cases. Some of these advances in diabetic vitrectomy and their impact are as enumerated and discussed below:

1.Improvements in vitrectomy machines and probes, which includes faster cutting rates and smaller gauges (27 G, 25 G, and 23 G) trans conjunctival vitrectomy

systems, now means that these probes can be used as multifunctional tools. They can be inserted carefully beneath tractional membranes during surgery and used effectively for segmentation and delamination of the membranes without the need for intraocular scissors in several cases. Also the high cut rates provide for less traction on the retina, reduce the mobility of the retina, and reduce the rate of iatrogenic breaks. The presence of the vitrectomy cutting port closer to the tip of the probes means that membranes on the retina can be easily engaged. Indeed many complex cases can be safely completed with the use of only the vitreous cutter and no other ancillary instruments required. Similarly the protection conferred by the cannula system at the sclerotomy entry site provides for reduced incidence of entry sight breaks, vitreous incarceration at the wound edge, and leaking sclerotomies.


**37**

**Figure 2.**

*Diabetic Vitrectomy*

*DOI: http://dx.doi.org/10.5772/intechopen.91360*

limiting membrane (ELM) and ellipsoid zone (EZ) layers (as in **Figure 2a**) have been demonstrated to have better postoperative vision than eyes without, since a preserved EZ and ELM are also expected after surgery (**Figure 2b**). The postoperative presence of EZ and ELM, which are outer retinal layers, are es-

*OCT images of same patient whose fundus picture is shown above. (a) Preoperative crossline OCT images of the same eye as in Figure 1a. Notice the presence of localized macular edema and vitreous hemorrhage with PVD. (b) Postoperative OCT images with normal subfoveal thickness but some intraretinal cystic spaces.*

Fairly decent OCT images can be obtained in eyes with a limited amount of vitreous hemorrhage as in **Figure 2a**. Unfortunately in some of the eyes with an obscured view of the retina, OCT is not possible. However, the successful incorporation of OCT technology into the operating microscope provides the intraoperative OCT (iOCT), which has shown usefulness in intraoperative

sential predictors of postoperative recovery of vision.

## *Diabetic Vitrectomy DOI: http://dx.doi.org/10.5772/intechopen.91360*

*The Eye and Foot in Diabetes*

wound edge, and leaking sclerotomies.

section and relief of traction.

systems, now means that these probes can be used as multifunctional tools. They can be inserted carefully beneath tractional membranes during surgery and used effectively for segmentation and delamination of the membranes without the need for intraocular scissors in several cases. Also the high cut rates provide for less traction on the retina, reduce the mobility of the retina, and reduce the rate of iatrogenic breaks. The presence of the vitrectomy cutting port closer to the tip of the probes means that membranes on the retina can be easily engaged. Indeed many complex cases can be safely completed with the use of only the vitreous cutter and no other ancillary instruments required. Similarly the protection conferred by the cannula system at the sclerotomy entry site provides for reduced incidence of entry sight breaks, vitreous incarceration at the

2.The introduction of intraoperative self-retaining lighting systems, such as the chandelier illuminating system, provides a free hand which can be used to grasp and stabilize intraocular tissue with a forceps while a fibrovascular membrane (FVM) is being dissected away. This led to the use of bimanual surgical technique. Bimanual surgery provides a very useful means of membrane dissection in difficult TRD and TRD/RRD cases, with broad attachment of fibrovascular membrane to the retina. Also various illuminated instruments, such as the lighted peaks, can provide considerable support in membrane dis-

3.During the early days of diabetic vitrectomy, as the era of the DRVS, the ability to perform endoretinal photocoagulation was lacking. The presence of endoretinal photocoagulation probes has provided additional stabilization to the surgery outcome, since panretinal laser photocoagulation can now be done during the surgery irrespective of the occurrence of postoperative vitreous cavity hemorrhage. Supplemental retinal laser photocoagulation may be required in addition to already existing retinal laser marks. PRP should be adequate and done up to the retina periphery to cover the ischemic retina and prevent postoperative complications such as recurrent hemorrhage or AHFVP.

4.The intraoperative use of triamcinolone crystals to highlight the posterior vitreous cortex has helped visualization and improves complete removal of the vitreous. In some cases vitreoschisis is present, and this can be detected if the additional triamcinolone is used. Also vital dyes such as brilliant blue G (BBG) and membrane blue (MB) have been found to help in highlighting ERM and ILM, therefore facilitating its removal. While the removal of ILM is justified in the macula to prevent re-proliferation of membranes, in some cases this can be quiet difficult, especially in the presence of significant macular edema, with pathologically adherent ILM. In such cases with a risk of further trauma to the macula, ILM peel is best avoided. Injection of PFCL, which acts to stabilize the retina during the ILM peel, in some cases, may improve the chances of success-

5.Obtaining a preoperative OCT has become a standard work-up procedure for eyes with diabetic retinopathy (**Figure 2a**). Aside from providing useful histological overview of the retina and vitreous, it can be used to provide three-dimensional overlay including showing areas of vitreoretinal adhesion, pegs as they are called, and areas of vitreous separation, which is important for surgical planning. Also it provides additional information on prognosis for postoperative vision, since eyes with more preoperative preserved external

**36**

ful ILM peel.

#### **Figure 2.**

*OCT images of same patient whose fundus picture is shown above. (a) Preoperative crossline OCT images of the same eye as in Figure 1a. Notice the presence of localized macular edema and vitreous hemorrhage with PVD. (b) Postoperative OCT images with normal subfoveal thickness but some intraretinal cystic spaces.*

limiting membrane (ELM) and ellipsoid zone (EZ) layers (as in **Figure 2a**) have been demonstrated to have better postoperative vision than eyes without, since a preserved EZ and ELM are also expected after surgery (**Figure 2b**). The postoperative presence of EZ and ELM, which are outer retinal layers, are essential predictors of postoperative recovery of vision.

Fairly decent OCT images can be obtained in eyes with a limited amount of vitreous hemorrhage as in **Figure 2a**. Unfortunately in some of the eyes with an obscured view of the retina, OCT is not possible. However, the successful incorporation of OCT technology into the operating microscope provides the intraoperative OCT (iOCT), which has shown usefulness in intraoperative

decision-making. The iOCT can help in determining the intraoperative presence of unremoved traction inducing ERM in the macula or the occurrence of a macular hole, which requires to be addressed during the surgery, since this can significantly affect postoperative visual outcome.

6.Timing of surgery: there is considerable interest in improving the visual outcome of eyes undergoing diabetic vitrectomy. This has resulted in some advocacy for earlier surgery in the category of patients with proliferative disease, instead of waiting for progression to more advanced TRD. Also efforts at inducing a pharmacologic separation of the vitreous from the retina using enzymatic vitreolysis have not been rewarding. Much of diabetic vitrectomy has to do with the separation of the attached vitreous. Induction of posterior vitreous separation could significantly halt the progression of PDR, since the attached vitreous is required for continued FVP.

On the other hand, there are advocates for caution in diabetic vitrectomy, who argue for the more aggressive use of a combination of intravitreal anti-VEGF and retinal laser photocoagulation. They argue that the outcome of diabetic vitrectomy could be unpredictable and that even in seemingly straightforward cases, intra- and postoperative complications was not uncommon. Diabetic vitrectomy according to them should be undertaken only when necessary and other medical options exhausted.

7.Pharmacologic adjuvants: In recent times the use of pharmacological therapy has been introduced as adjuvant for use preoperatively and intraoperatively in diabetic vitrectomy. Intravitreal Injection of anti-VEGFs including Macugen, Avastin, and Lucentis has been used preoperatively and postoperatively, while steroid implants such as Ozurdex have been used pre- and intraoperatively.

Bevacizumab (Avastin, Genentech, South San Francisco, CA, USA) appears to be the most commonly used preoperative anti-VEGF injection [37, 38]. Preoperative injection of anti-VEGF agents is known to considerably shrink neovascular fronds and has been shown to reduce intraoperative and postoperative bleeding and result in improved visual outcome [38–42]. However, an overaction of anti-VEGF can cause contraction of fibrovascular membrane and could exacerbate the traction and cause progression of TRD, in some cases causing a macular sparing TRD to involve the macula. This has been called the "crunch syndrome" which is characterized by a worsening tractional retinal detachment and development of denser fibrotic connections between the retina and overlying tissue, which makes it harder to identify tissue planes and results in more difficult dissection of the fibrous membranes [43].

Therefore the optimum time for anti-VEGF injection preoperatively should be enough time to cause the desired effect, which is reduction in neovascularization, and not long enough to induce severe fibrotic contraction and worsening of TRD. It is generally thought that the ideal time frame is somewhere between 3 and 5 days prior to surgery, with considerable variation among surgeons. This time frame enables neovascular regression while limiting fibrovascular membrane contraction.

Pegaptanib (Macugen, Bausch, and Lomb, Bridgewater, NJ, USA) has been used as an adjunct, when injected preoperatively. Pegaptanib is a PEGylated aptamer and only inhibits the VEGF isoform 165 [44]. It therefore has been suggested to have a more selective effect on the neovascularization component of the fibrovascular membrane and less tractional effect with lower systemic risks [44].

**39**

*Diabetic Vitrectomy*

pathologies.

*DOI: http://dx.doi.org/10.5772/intechopen.91360*

Therefore it can be used to induce regression of neovascularization, in a way similar to bevacizumab, and therefore reduces the risk of intraoperative bleeding, but does not have a similar tractional effect as seen with the use of bevacizumab [45]. This may allow for injection of Pegaptanib at any given time prior to surgery, even in the form of multiple injections, awaiting physician clearance, and good timing for surgery. There is however no wide spread use of Pegaptanib for this purpose, and comparison with bevacizumab has not been done. It may also be systemically advantageous due to the lower risk of vascular accidents in these high-risk patients [44]. It is instructive to mention that Pegaptanib is rarely used as an anti-VEGF of choice for suppression of VEGF in other neovascular ocular

Ozurdex (Allergan, Dublin, Ireland) is a biodegradable 0.7 mg dexamethasone implant that is injected intravitreally via a 22-gauge needle and has been approved by the Food and Drug Administration (FDA) for the treatment of DME. It has been used in the pre- and postoperative control of the neovascularization process and tissue edema. As noted by Mahmoud et al., it can be injected preoperatively in an eye with extensive TRD in which it facilitates regression and consolidation of neovascularization in addition to inhibiting other inflammatory cytokines [45]. Unlike anti-VEGF agents, it is not known to increase risk of systemic complications, and there is no associated fibrovascular membrane or retinal tractional response. Tissue planes were found to be more distinct and not changed into flat fibrovascular tissue, making them more difficult to dissect, as was seen following administration of anti-VEGF agents. Due to these properties, it provides for flexibility with operative physician clearance planning (there is adequate time for preoperative clearance when Ozurdex is being used). In addition, the effect of Ozurdex can continue well into the postoperative period, since the Ozurdex implant can remain in position in the postoperative period under silicone oil [45]. Ozurdex implant releases the active drug over a period of 6 months and therefore keeps the eyes quiet, and the neovascular process is inactive during the postoperative period.

8.Techniques and tips for fibrovascular membrane dissection. Certain techniques are useful in the safe removal of fibrovascular tissue. The following are

a.Smaller-gauge (25 G and 27 G) transconjunctival surgery can provide opportunity for the vitrectomy probe to be inserted between the membrane and the retina. Using an aspiration mode, the membrane is lifted up with the cutting edge of the probe facing superiorly. As soon as resistance to the membrane lifting is encountered, the membrane is cut with the cutter. In this way the fibrovascular membrane is segmented; then the islands of fibrovascular tissue are removed from the retina using a delamination technique. Using the probe in this fashion, it can also serve as a blunt dissector and can be used without the need for additional instrumentation

b.Viscodissection is a very useful technique in cases of very adherent membranes [46, 47]. It was born from the idea that the use of liquid or fluid instead of metal or other materials to separate membranes from normal retina would have safety advantages. The use of small tip retractable cannulas, which can be inserted into small spaces between fibrovascular membranes and detached or attached retina, enables injection of hyaluronic acid (HA). The HA serves to separate the membrane from the retina,

by no means exhaustive and are at best suggestions:

such as scissors or pick.

*The Eye and Foot in Diabetes*

decision-making. The iOCT can help in determining the intraoperative presence of unremoved traction inducing ERM in the macula or the occurrence of a macular hole, which requires to be addressed during the surgery, since this

On the other hand, there are advocates for caution in diabetic vitrectomy,

who argue for the more aggressive use of a combination of intravitreal anti-VEGF and retinal laser photocoagulation. They argue that the outcome of diabetic vitrectomy could be unpredictable and that even in seemingly straightforward cases, intra- and postoperative complications was not uncommon. Diabetic vitrectomy according to them should be undertaken only when

7.Pharmacologic adjuvants: In recent times the use of pharmacological therapy has been introduced as adjuvant for use preoperatively and intraoperatively in diabetic vitrectomy. Intravitreal Injection of anti-VEGFs including Macugen, Avastin, and Lucentis has been used preoperatively and postoperatively, while steroid implants such as Ozurdex have been used pre- and intraoperatively.

to be the most commonly used preoperative anti-VEGF injection [37, 38]. Preoperative injection of anti-VEGF agents is known to considerably shrink neovascular fronds and has been shown to reduce intraoperative and postoperative bleeding and result in improved visual outcome [38–42]. However, an overaction of anti-VEGF can cause contraction of fibrovascular membrane and could exacerbate the traction and cause progression of TRD, in some cases causing a macular sparing TRD to involve the macula. This has been called the "crunch syndrome" which is characterized by a worsening tractional retinal detachment and development of denser fibrotic connections between the retina and overlying tissue, which makes it harder to identify tissue planes and

results in more difficult dissection of the fibrous membranes [43].

fibrovascular membrane contraction.

Bevacizumab (Avastin, Genentech, South San Francisco, CA, USA) appears

Therefore the optimum time for anti-VEGF injection preoperatively should be enough time to cause the desired effect, which is reduction in neovascularization, and not long enough to induce severe fibrotic contraction and worsening of TRD. It is generally thought that the ideal time frame is somewhere between 3 and 5 days prior to surgery, with considerable variation among surgeons. This time frame enables neovascular regression while limiting

Pegaptanib (Macugen, Bausch, and Lomb, Bridgewater, NJ, USA) has been used as an adjunct, when injected preoperatively. Pegaptanib is a PEGylated aptamer and only inhibits the VEGF isoform 165 [44]. It therefore has been suggested to have a more selective effect on the neovascularization component of the fibrovascular membrane and less tractional effect with lower systemic risks [44].

6.Timing of surgery: there is considerable interest in improving the visual outcome of eyes undergoing diabetic vitrectomy. This has resulted in some advocacy for earlier surgery in the category of patients with proliferative disease, instead of waiting for progression to more advanced TRD. Also efforts at inducing a pharmacologic separation of the vitreous from the retina using enzymatic vitreolysis have not been rewarding. Much of diabetic vitrectomy has to do with the separation of the attached vitreous. Induction of posterior vitreous separation could significantly halt the progression of PDR, since the

can significantly affect postoperative visual outcome.

attached vitreous is required for continued FVP.

necessary and other medical options exhausted.

**38**

Therefore it can be used to induce regression of neovascularization, in a way similar to bevacizumab, and therefore reduces the risk of intraoperative bleeding, but does not have a similar tractional effect as seen with the use of bevacizumab [45]. This may allow for injection of Pegaptanib at any given time prior to surgery, even in the form of multiple injections, awaiting physician clearance, and good timing for surgery. There is however no wide spread use of Pegaptanib for this purpose, and comparison with bevacizumab has not been done. It may also be systemically advantageous due to the lower risk of vascular accidents in these high-risk patients [44]. It is instructive to mention that Pegaptanib is rarely used as an anti-VEGF of choice for suppression of VEGF in other neovascular ocular pathologies.

Ozurdex (Allergan, Dublin, Ireland) is a biodegradable 0.7 mg dexamethasone implant that is injected intravitreally via a 22-gauge needle and has been approved by the Food and Drug Administration (FDA) for the treatment of DME. It has been used in the pre- and postoperative control of the neovascularization process and tissue edema. As noted by Mahmoud et al., it can be injected preoperatively in an eye with extensive TRD in which it facilitates regression and consolidation of neovascularization in addition to inhibiting other inflammatory cytokines [45]. Unlike anti-VEGF agents, it is not known to increase risk of systemic complications, and there is no associated fibrovascular membrane or retinal tractional response. Tissue planes were found to be more distinct and not changed into flat fibrovascular tissue, making them more difficult to dissect, as was seen following administration of anti-VEGF agents. Due to these properties, it provides for flexibility with operative physician clearance planning (there is adequate time for preoperative clearance when Ozurdex is being used). In addition, the effect of Ozurdex can continue well into the postoperative period, since the Ozurdex implant can remain in position in the postoperative period under silicone oil [45]. Ozurdex implant releases the active drug over a period of 6 months and therefore keeps the eyes quiet, and the neovascular process is inactive during the postoperative period.

	- a.Smaller-gauge (25 G and 27 G) transconjunctival surgery can provide opportunity for the vitrectomy probe to be inserted between the membrane and the retina. Using an aspiration mode, the membrane is lifted up with the cutting edge of the probe facing superiorly. As soon as resistance to the membrane lifting is encountered, the membrane is cut with the cutter. In this way the fibrovascular membrane is segmented; then the islands of fibrovascular tissue are removed from the retina using a delamination technique. Using the probe in this fashion, it can also serve as a blunt dissector and can be used without the need for additional instrumentation such as scissors or pick.
	- b.Viscodissection is a very useful technique in cases of very adherent membranes [46, 47]. It was born from the idea that the use of liquid or fluid instead of metal or other materials to separate membranes from normal retina would have safety advantages. The use of small tip retractable cannulas, which can be inserted into small spaces between fibrovascular membranes and detached or attached retina, enables injection of hyaluronic acid (HA). The HA serves to separate the membrane from the retina,

and the viscodissection cannula can be used for blunt dissection as well. In addition, the HA provides hemostasis and improves visibility in the area of the dissection. Care should be taken to ensure adequate removal of the HA after the surgery to prevent a rise in IOP.


## **7. Complications of surgery**

Vitrectomy in an eye that suffers from PDR can have significant complications. This ought to be considered and the risk for these intra- and postoperative complication considered before the decision to perform surgery is taken. Some of these complications include intra- and postoperative vitreous cavity hemorrhage (early or delayed), recurrent vitreous hemorrhage, hypotony, progression of diabetic retinopathy, iatrogenic retinal breaks (commonly occurring during fibrovascular tissue dissection), cornea edema, sclerotomy-related complications including vitreous incarceration (not as common with small-gauge vitrectomy compared to 20 G era), vascular ingrowths and AHFVP, rapid progression of cataract, phototoxicity (associated with chandelier illumination placement close to the retina), rubeosis and rubeotic glaucoma (more common in pseudophakia and aphakia), and severe loss of vision. Rubeotic glaucoma is a troublesome disease to manage and will require the use of intravitreal anti-VEGF, retinal laser photocoagulation, or cryotherapy. In some cases additional cyclodestructive procedure or glaucoma drainage tube surgery may be indicated. Fortunately the incidence of this complication is on the decline due to the use of laser endo photocoagulation, which enables more aggressive management of the peripheral ischemia.

**41**

*Diabetic Vitrectomy*

**8. Outcome**

vitrectomy.

suggestions.

None.

**Acknowledgements**

**Conflict of interest**

*DOI: http://dx.doi.org/10.5772/intechopen.91360*

Much of the complications can be avoided with meticulous attention to currently

In recent times due to improvements witnessed in vitrectomy technology and technique as previously discussed, the anatomical and visual outcome of diabetic vitrectomy has generally improved. Compared to the earlier era, when endoretinal laser photocoagulation for treating retinal ischemia intraoperatively was not available (retinal ischemia is the main drive for the proliferative retinal changes), we now have a host of retinal laser photocoagulation probes available for use during vitrectomy. There have been reports of improvements in visual acuity in 75% and 87% of TRD eyes and vitreous hemorrhage eyes, respectively [50, 51]. With continued improvements and probably earlier timing of surgery, success rates will likely continue to improve and may exceed the 90% rates. Some of the poor prognostic factors include poor pre-op visual acuity, rubeosis, ectopia or displacement, and macula involving TRD. Significant fovea ischemia, which can be recognized with the use of fundus fluorescein angiography and OCTA, has a poor prognosis.

To conclude, diabetic vitrectomy has benefited from the advances in the sphere of vitreoretinal surgery. Though presentation of proliferative DR is very variable and can be complex, modern tools and technique can in most cases improve or stabilize vision. There is an ongoing discussion on possible identification of eyes at risk for progression and offering earlier surgery. This may result in further improvements. Perhaps the development of an ideal pharmacologic vitreolytic agent which will induce a PVD in eyes known to have PDR will usher in a new era in diabetic

I wish to expresses my thanks to Dr Vipin Vig, vitreoretinal surgeon in Amritsar,

India, who took the time to read through my manuscript and made useful

available surgical techniques. For instance, the rate of intra- and postoperative hemorrhage can be reduced by the use of preoperative intravitreal anti-VEGF as previously described and careful hemostasis during surgery either by the elevation of intraocular pressure, cautious diathermy, direct application of pressure to bleeding vessels, or application of viscoelastic to the point of bleeding. Also preoperative discontinuation of blood thinners and attention to the systemic blood pressure

during and after surgery to ensure it is not elevated can be helpful.

#### *Diabetic Vitrectomy DOI: http://dx.doi.org/10.5772/intechopen.91360*

Much of the complications can be avoided with meticulous attention to currently available surgical techniques. For instance, the rate of intra- and postoperative hemorrhage can be reduced by the use of preoperative intravitreal anti-VEGF as previously described and careful hemostasis during surgery either by the elevation of intraocular pressure, cautious diathermy, direct application of pressure to bleeding vessels, or application of viscoelastic to the point of bleeding. Also preoperative discontinuation of blood thinners and attention to the systemic blood pressure during and after surgery to ensure it is not elevated can be helpful.

## **8. Outcome**

*The Eye and Foot in Diabetes*

**7. Complications of surgery**

sive management of the peripheral ischemia.

and the viscodissection cannula can be used for blunt dissection as well. In addition, the HA provides hemostasis and improves visibility in the area of the dissection. Care should be taken to ensure adequate removal of the HA

c.In the extremely difficult cases of TRD and TRD/RRD, characterized by thickened fibrotic membranes strongly adherent to the retina, a combination of forceps with curved scissors is a good option. With the use of a bimanual technique using a chandelier illumination placed at 12 O clock position (or any other position as chosen by the surgeon) and wide-angle viewing, the edge of thickened fibrovascular membranes can be engaged using a good gripping tissue forceps and then separated from the retina with scissors. After the separation, the membrane or clot can then be cut

d.Proportional reflux is a feature of the Constellation vitrectomy machine and other machines that have been used in the safe dissection of membranes from the normal retina [48]. The Constellation Vision System (Alcon Laboratories, Fort Worth, TX) has the pulse reflux mode, which allows a jet of fluid to be ejected from the port and is useful for ejecting accidentally incarcerated tissue during vitrectomy. In addition to this, it also has a proportional reflux mode. The proportional reflux mode allows for fluid to be ejected from the vitrectomy probe port in a gradual and controlled manner with foot pedal control, thus the term proportional reflux. The concurrent development of microincisional vitrectomy surgery with a smaller gauge and the port being closer to the tip as well as the development of proportional reflux has allowed for a new surgical technique known as "proportional reflux hydrodissection" [48, 49]. In this technique, credited to Dugel, the port of the cutter is placed between the fibrovascular tissue and the normal retinal tissue. Thereafter, with the foot pedal, the surgeon has complete control over fluid extrusion in a proportional fashion to create a separation between the fibrous tissue and the normal retina.

Vitrectomy in an eye that suffers from PDR can have significant complications. This ought to be considered and the risk for these intra- and postoperative complication considered before the decision to perform surgery is taken. Some of these complications include intra- and postoperative vitreous cavity hemorrhage (early or delayed), recurrent vitreous hemorrhage, hypotony, progression of diabetic retinopathy, iatrogenic retinal breaks (commonly occurring during fibrovascular tissue dissection), cornea edema, sclerotomy-related complications including vitreous incarceration (not as common with small-gauge vitrectomy compared to 20 G era), vascular ingrowths and AHFVP, rapid progression of cataract, phototoxicity (associated with chandelier illumination placement close to the retina), rubeosis and rubeotic glaucoma (more common in pseudophakia and aphakia), and severe loss of vision. Rubeotic glaucoma is a troublesome disease to manage and will require the use of intravitreal anti-VEGF, retinal laser photocoagulation, or cryotherapy. In some cases additional cyclodestructive procedure or glaucoma drainage tube surgery may be indicated. Fortunately the incidence of this complication is on the decline due to the use of laser endo photocoagulation, which enables more aggres-

off with the small-gauge cutter using reduced cut rates.

after the surgery to prevent a rise in IOP.

**40**

In recent times due to improvements witnessed in vitrectomy technology and technique as previously discussed, the anatomical and visual outcome of diabetic vitrectomy has generally improved. Compared to the earlier era, when endoretinal laser photocoagulation for treating retinal ischemia intraoperatively was not available (retinal ischemia is the main drive for the proliferative retinal changes), we now have a host of retinal laser photocoagulation probes available for use during vitrectomy. There have been reports of improvements in visual acuity in 75% and 87% of TRD eyes and vitreous hemorrhage eyes, respectively [50, 51]. With continued improvements and probably earlier timing of surgery, success rates will likely continue to improve and may exceed the 90% rates. Some of the poor prognostic factors include poor pre-op visual acuity, rubeosis, ectopia or displacement, and macula involving TRD. Significant fovea ischemia, which can be recognized with the use of fundus fluorescein angiography and OCTA, has a poor prognosis.

To conclude, diabetic vitrectomy has benefited from the advances in the sphere of vitreoretinal surgery. Though presentation of proliferative DR is very variable and can be complex, modern tools and technique can in most cases improve or stabilize vision. There is an ongoing discussion on possible identification of eyes at risk for progression and offering earlier surgery. This may result in further improvements. Perhaps the development of an ideal pharmacologic vitreolytic agent which will induce a PVD in eyes known to have PDR will usher in a new era in diabetic vitrectomy.

## **Acknowledgements**

I wish to expresses my thanks to Dr Vipin Vig, vitreoretinal surgeon in Amritsar, India, who took the time to read through my manuscript and made useful suggestions.

## **Conflict of interest**

None.

*The Eye and Foot in Diabetes*

## **Author details**

Ogugua N. Okonkwo Eye Foundation Retina Institute, Lagos, Nigeria

\*Address all correspondence to: o\_okonkwo@yahoo.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**43**

*Diabetic Vitrectomy*

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*DOI: http://dx.doi.org/10.5772/intechopen.91360*

[1] Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Research and Clinical Practice.

[8] Newman DK. Surgical management of the late complications of proliferative diabetic retinopathy. Eye (London).

[9] Qamar RM, Saleem MI, Saleem MF. The outcomes of pars plana vitrectomy without endotamponade for tractional retinal detachment secondary to proliferative diabetic retinopathy. International Journal of Ophthalmology. 2013;**6**(5):671-674. DOI: 10.3980/j.

2010;**24**(3):441-449

issn.2222-3959.2013.05.23

[10] Shen YD, Yang CM. Extended silicone oil tamponade in primary vitrectomy for complex retinal detachment in proliferative diabetic retinopathy: A long-term follow-up study. European Journal of Ophthalmology. 2007;**17**(6):954-960

[11] Fujii GY, De Juan E Jr, Humayun MS,

et al. A new 25-gauge instrument system for transconjunctival sutureless vitrectomy surgery. Ophthalmology.

[12] Eckardt C. Transconjunctival sutureless 23-gauge vitrectomy. Retina.

[13] Oshima Y, Wakabayashi T, Sato T, Ohji M, Tano Y. A 27-gauge instrument system for transconjunctival sutureless microincision vitrectomy surgery. Ophthalmology. 2010;**117**(1):93-102.e2. DOI: 10.1016/j.ophtha.2009.06.043

Performance comparison of high-speed dual-pneumatic vitrectomy cutters during simulated vitrectomy with balanced salt solution. Translational Vision Science & Technology.

[15] Machemer R. Reminiscences after 25 years of pars plana vitrectomy. American Journal of Ophthalmology. 1995;**119**(4):505-510. DOI: 10.1016/

[14] Abulon DJ, Buboltz DC.

s0002-9394(14)71238-3

2015;**4**(1):6

2002;**109**(10):1807-1812

2005;**25**(2):208-211

[2] Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care.

[3] Leasher JL, Bourne RR, Flaxman SR, et al. Global estimates on the number of people blind or visually impaired by diabetic retinopathy: A meta-analysis from 1990 to 2010. Diabetes Care.

[4] Sabanayagam C, Banu R, Chee ML, et al. Incidence and progression of diabetic retinopathy: A systematic review. The Lancet Diabetes &

Endocrinology. Feb 2019;**7**(2):140-149. DOI: 10.1016/s2213-8587(18)30128-1

[5] Wirkkala J, Bloigu R, Hautala NM. Intravitreal bevacizumab improves the clearance of vitreous haemorrhage and visual outcomes in patients with proliferative diabetic retinopathy. BMJ Open Ophthalmology. 2019;**4**(1):e000390. DOI: 10.1136/

[6] Zhou AY, Zhou CJ, Yao J, Quan YL,

2016;**9**(12):1772-1778. DOI: 10.18240/

[7] Someya H, Takayama K, Takeuchi M, et al. Outcomes of 25-gauge vitrectomy for tractional and nontractional diabetic macular edema with proliferative diabetic retinopathy. Journal

of Ophthalmology. 2019;**2019**:5304524.

bmjophth-2019-000390

Ren BC, Wang JM. Panretinal photocoagulation versus panretinal photocoagulation plus intravitreal bevacizumab for high-risk proliferative diabetic retinopathy. International

Journal of Ophthalmology.

DOI: 10.1155/2019/5304524

ijo.2016.12.12

## **References**

*The Eye and Foot in Diabetes*

**42**

**Author details**

Ogugua N. Okonkwo

Eye Foundation Retina Institute, Lagos, Nigeria

provided the original work is properly cited.

\*Address all correspondence to: o\_okonkwo@yahoo.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Research and Clinical Practice. 2017;**128**:40-50

[2] Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;**35**:556-564

[3] Leasher JL, Bourne RR, Flaxman SR, et al. Global estimates on the number of people blind or visually impaired by diabetic retinopathy: A meta-analysis from 1990 to 2010. Diabetes Care. 2016;**39**:1643-1649

[4] Sabanayagam C, Banu R, Chee ML, et al. Incidence and progression of diabetic retinopathy: A systematic review. The Lancet Diabetes & Endocrinology. Feb 2019;**7**(2):140-149. DOI: 10.1016/s2213-8587(18)30128-1

[5] Wirkkala J, Bloigu R, Hautala NM. Intravitreal bevacizumab improves the clearance of vitreous haemorrhage and visual outcomes in patients with proliferative diabetic retinopathy. BMJ Open Ophthalmology. 2019;**4**(1):e000390. DOI: 10.1136/ bmjophth-2019-000390

[6] Zhou AY, Zhou CJ, Yao J, Quan YL, Ren BC, Wang JM. Panretinal photocoagulation versus panretinal photocoagulation plus intravitreal bevacizumab for high-risk proliferative diabetic retinopathy. International Journal of Ophthalmology. 2016;**9**(12):1772-1778. DOI: 10.18240/ ijo.2016.12.12

[7] Someya H, Takayama K, Takeuchi M, et al. Outcomes of 25-gauge vitrectomy for tractional and nontractional diabetic macular edema with proliferative diabetic retinopathy. Journal of Ophthalmology. 2019;**2019**:5304524. DOI: 10.1155/2019/5304524

[8] Newman DK. Surgical management of the late complications of proliferative diabetic retinopathy. Eye (London). 2010;**24**(3):441-449

[9] Qamar RM, Saleem MI, Saleem MF. The outcomes of pars plana vitrectomy without endotamponade for tractional retinal detachment secondary to proliferative diabetic retinopathy. International Journal of Ophthalmology. 2013;**6**(5):671-674. DOI: 10.3980/j. issn.2222-3959.2013.05.23

[10] Shen YD, Yang CM. Extended silicone oil tamponade in primary vitrectomy for complex retinal detachment in proliferative diabetic retinopathy: A long-term follow-up study. European Journal of Ophthalmology. 2007;**17**(6):954-960

[11] Fujii GY, De Juan E Jr, Humayun MS, et al. A new 25-gauge instrument system for transconjunctival sutureless vitrectomy surgery. Ophthalmology. 2002;**109**(10):1807-1812

[12] Eckardt C. Transconjunctival sutureless 23-gauge vitrectomy. Retina. 2005;**25**(2):208-211

[13] Oshima Y, Wakabayashi T, Sato T, Ohji M, Tano Y. A 27-gauge instrument system for transconjunctival sutureless microincision vitrectomy surgery. Ophthalmology. 2010;**117**(1):93-102.e2. DOI: 10.1016/j.ophtha.2009.06.043

[14] Abulon DJ, Buboltz DC. Performance comparison of high-speed dual-pneumatic vitrectomy cutters during simulated vitrectomy with balanced salt solution. Translational Vision Science & Technology. 2015;**4**(1):6

[15] Machemer R. Reminiscences after 25 years of pars plana vitrectomy. American Journal of Ophthalmology. 1995;**119**(4):505-510. DOI: 10.1016/ s0002-9394(14)71238-3

[16] The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Archives of Ophthalmology. 1990;**108**:958-964

[17] Diabetic Retinopathy Clinical Research Network Writing Committee, Haller JA, Qin H, Apte RS, et al. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology. 2010;**117**:1087-1093

[18] Stewart MW, Browning DJ, Landers MB. Current management of diabetic tractional retinal detachments. Indian Journal of Ophthalmology. 2018;**66**(12):1751-1762. DOI: 10.4103/ijo. IJO\_1217\_18

[19] Yau GL, Silva PS, Arrigg PG, Sun JK. Postoperative complications of pars plana vitrectomy for diabetic retinal disease. Seminars in Ophthalmology. 2018;**33**(1):126-133. DOI: 10.1080/08820538.2017.1353832

[20] Berrocal MH, Acaba LA, Acaba A. Surgery for diabetic eye complications. Current Diabetes Reports. 2016;**16**(10):99. DOI: 10.1007/ s11892-016-0787-6

[21] Vaziri K, Schwartz SG, Relhan N, Kishor KS, Flynn HW Jr. New therapeutic approaches in diabetic retinopathy. The Review of Diabetic Studies. 2015;**12**:196-210

[22] Cruz-Iñigo YJ, Acabá LA, Berrocal MH. Surgical management of retinal diseases: PROLIFERATIVE diabetic retinopathy and traction retinal detachment. Developments in Ophthalmology. 2014;**54**:196-203. DOI: 10.1159/000360467

[23] Okonkwo ON, Lewis K, Hassan AO, Gyasi ME, Oluyadi B, et al. Indications

and outcomes of vitrectomy surgery in a series of 1000 black African eyes. BMJ Open Ophthalmology. 2019;**4**(1):e000083. DOI: 10.1136/ bmjophth-2017-000083

[24] Law JC, Sharma AG, Eliott D. Indications for diabetic vitrectomy in African Americans versus Caucasians. Investigative Ophthalmology & Visual Science. 2006;**47**:3835

[25] Aylward B, Tadayoni R, Arevalo F, Karkhaneh R. Anterior hyaloid fibrovascular proliferation. Journal of Ophthalmic & Vision Research. 2010;**5**(1):61-64

[26] Hassan AO, Okonkwo ON, Oderinlo O, Oluyadi F, Ogunro A, Harriman A, et al. Anterior hyaloidal fibrovascular proliferation (AHFVP) in a diabetic after cataract extraction, resulting in hyphaema and vitreous haemorrhage during YAG laser capsulotomy. Nigerian Journal of Ophthalmology. 2009;**17**(1):23-26

[27] Helbig H, Kellner U, Bornfeld N, Foerster MH. Life expectancy of diabetic patients undergoing vitreous surgery. The British Journal of Ophthalmology. 1996;**80**:640-643

[28] Nguyen-Khoa BA, Goehring EL, Werther W, et al. Hospitalized cardiovascular events in patients with diabetic macular edema. BMC Ophthalmology. 2012;**12**:11. DOI: 10.1186/1471-2415-12-11

[29] Abcouwer SF. Angiogenic factors and cytokines in diabetic retinopathy. Journal of Clinical and Cellular Immunology. 2013;Suppl 1(11):1-12

[30] Tamaki K, Usui-Ouchi A, Murakami A, Ebihara N. Fibrocytes and fibrovascular membrane formation in proliferative diabetic retinopathy. Investigative Ophthalmology & Visual Science. 2016;**57**:4999-5005

**45**

*Diabetic Vitrectomy*

2001;**52**:54-57

*DOI: http://dx.doi.org/10.5772/intechopen.91360*

proliferative retinopathy (PDR). Graefe Archive for Clinical and Experimental Ophthalmology.

[39] da R Lucena D, Ribeiro JA, Costa RA, Barbosa JC, Scott IU, de Figueiredo-Pontes LL, et al. Intraoperative bleeding during vitrectomy for diabetic tractional detachment with versus without preoperative intravitreal bevacizumab. British Journal of Ophthalmology. 2009;**93**:688-691

[40] Modarres M, Nazari H, Falavarjani KG, Naseripour M,

injection of bevacizumab before vitrectomy for proliferative diabetic retinopathy. European Journal of Ophthalmology. 2009;**19**:848-852

[41] Gupta A, Bansal R, Gupta V, Dogra MR. Six-month visual outcome

after pars plana vitrectomy in proliferative diabetic retinopathy with or without a single postoperative injection of intravitreal bevacizumab.

International Ophthalmology.

[42] Ushida H, Kachi S, Asami T, Ishikawa K, Kondo M, Terasaki H. Influence of preoperative intravitreal bevacizumab on visual function in eyes with proliferative diabetic retinopathy. Ophthalmic Research. 2013;**49**:30-36

[43] Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. The British Journal of Ophthalmology.

[44] Nagpal M, Nagpal K, Nagpal PN. A comparative debate on the various anti-vascular endothelial growth factor drugs: Pegaptanib sodium (Macugen),

ranibizumab (Lucentis) and

2012;**32**:135-144

2008;**92**:213-216

Hashemi M, Parvaresh MM. Intravitreal

2008;**246**:837-842

[31] Gafencu O. Surgical principles and techniques in severe proliferative diabetic retinopathy. Oftalmologia.

[32] Miller SA, Butler JB, Myers FL, Bresnick GH. Pars plana vitrectomy. Treatment for tractional macula detachment secondary to proliferative diabetic retinopathy. Archives of Ophthalmology. 1980;**98**:659-664

[33] Celik E, Sever O, Horozoglu F, Yanyalı A. Segmentation and removal of fibrovascular membranes with highspeed 23 G transconjunctival sutureless vitrectomy, in severe proliferative diabetic retinopathy. Clinical

Ophthalmology. 2016;**10**:903-910. DOI:

Belting C. Comparative study between a standard 25-gauge vitrectomy system and a new ultrahigh-speed 25-gauge system with duty cycle control in the treatment of various vitreoretinal diseases. Retina. 2011;**31**(10):2007-2013

10.2147/OPTH.S95145

[34] Rizzo S, Ebert-Genovesi F,

[35] Gupta V, Arevalo JF. Surgical management of diabetic retinopathy. Middle East African Journal of Ophthalmology. 2013;**20**(4):283-292. DOI: 10.4103/0974-9233.120003

[36] Falkner C, Binder S, Kruger A. Outcome after silicone oil removal. The British Journal of Ophthalmology.

[37] Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin)

preoperative adjunct before vitrectomy surgery in the treatment of severe

in the treatment of proliferative diabetic retinopathy. Ophthalmology.

[38] Rizzo S, Genovesi-Ebert F, Di Bartolo E, Vento A, Miniaci S, Williams G. Injection of intravitreal

bevacizumab (Avastin) as a

2001;**85**:1324-1327

1695;**2006**(113):e1-e15

### *Diabetic Vitrectomy DOI: http://dx.doi.org/10.5772/intechopen.91360*

*The Eye and Foot in Diabetes*

1990;**108**:958-964

2010;**117**:1087-1093

IJO\_1217\_18

[16] The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Archives of Ophthalmology.

and outcomes of vitrectomy surgery in a series of 1000 black African eyes. BMJ Open Ophthalmology. 2019;**4**(1):e000083. DOI: 10.1136/

[24] Law JC, Sharma AG, Eliott D. Indications for diabetic vitrectomy in African Americans versus Caucasians. Investigative Ophthalmology & Visual

[25] Aylward B, Tadayoni R, Arevalo F,

Karkhaneh R. Anterior hyaloid fibrovascular proliferation. Journal of Ophthalmic & Vision Research.

[26] Hassan AO, Okonkwo ON, Oderinlo O, Oluyadi F, Ogunro A, Harriman A, et al. Anterior hyaloidal fibrovascular proliferation (AHFVP) in a diabetic after cataract extraction, resulting in hyphaema and vitreous haemorrhage during YAG laser capsulotomy. Nigerian Journal of Ophthalmology. 2009;**17**(1):23-26

[27] Helbig H, Kellner U, Bornfeld N, Foerster MH. Life expectancy of diabetic patients undergoing vitreous surgery. The British Journal of Ophthalmology.

[28] Nguyen-Khoa BA, Goehring EL, Werther W, et al. Hospitalized cardiovascular events in patients with diabetic macular edema. BMC Ophthalmology. 2012;**12**:11. DOI:

[29] Abcouwer SF. Angiogenic factors and cytokines in diabetic retinopathy. Journal of Clinical and Cellular Immunology. 2013;Suppl 1(11):1-12

[30] Tamaki K, Usui-Ouchi A, Murakami A, Ebihara N. Fibrocytes and fibrovascular membrane formation in proliferative

diabetic retinopathy. Investigative Ophthalmology & Visual Science.

2016;**57**:4999-5005

bmjophth-2017-000083

Science. 2006;**47**:3835

2010;**5**(1):61-64

1996;**80**:640-643

10.1186/1471-2415-12-11

[17] Diabetic Retinopathy Clinical Research Network Writing Committee, Haller JA, Qin H, Apte RS, et al. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthalmology.

[18] Stewart MW, Browning DJ, Landers MB. Current management of diabetic tractional retinal detachments. Indian Journal of Ophthalmology. 2018;**66**(12):1751-1762. DOI: 10.4103/ijo.

2018;**33**(1):126-133. DOI: 10.1080/08820538.2017.1353832

Current Diabetes Reports. 2016;**16**(10):99. DOI: 10.1007/

s11892-016-0787-6

[19] Yau GL, Silva PS, Arrigg PG, Sun JK. Postoperative complications of pars plana vitrectomy for diabetic retinal disease. Seminars in Ophthalmology.

[20] Berrocal MH, Acaba LA, Acaba A. Surgery for diabetic eye complications.

[21] Vaziri K, Schwartz SG, Relhan N,

[23] Okonkwo ON, Lewis K, Hassan AO, Gyasi ME, Oluyadi B, et al. Indications

Kishor KS, Flynn HW Jr. New therapeutic approaches in diabetic retinopathy. The Review of Diabetic

[22] Cruz-Iñigo YJ, Acabá LA, Berrocal MH. Surgical management of retinal diseases: PROLIFERATIVE diabetic retinopathy and traction retinal detachment. Developments in Ophthalmology. 2014;**54**:196-203. DOI:

Studies. 2015;**12**:196-210

10.1159/000360467

**44**

[31] Gafencu O. Surgical principles and techniques in severe proliferative diabetic retinopathy. Oftalmologia. 2001;**52**:54-57

[32] Miller SA, Butler JB, Myers FL, Bresnick GH. Pars plana vitrectomy. Treatment for tractional macula detachment secondary to proliferative diabetic retinopathy. Archives of Ophthalmology. 1980;**98**:659-664

[33] Celik E, Sever O, Horozoglu F, Yanyalı A. Segmentation and removal of fibrovascular membranes with highspeed 23 G transconjunctival sutureless vitrectomy, in severe proliferative diabetic retinopathy. Clinical Ophthalmology. 2016;**10**:903-910. DOI: 10.2147/OPTH.S95145

[34] Rizzo S, Ebert-Genovesi F, Belting C. Comparative study between a standard 25-gauge vitrectomy system and a new ultrahigh-speed 25-gauge system with duty cycle control in the treatment of various vitreoretinal diseases. Retina. 2011;**31**(10):2007-2013

[35] Gupta V, Arevalo JF. Surgical management of diabetic retinopathy. Middle East African Journal of Ophthalmology. 2013;**20**(4):283-292. DOI: 10.4103/0974-9233.120003

[36] Falkner C, Binder S, Kruger A. Outcome after silicone oil removal. The British Journal of Ophthalmology. 2001;**85**:1324-1327

[37] Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 1695;**2006**(113):e1-e15

[38] Rizzo S, Genovesi-Ebert F, Di Bartolo E, Vento A, Miniaci S, Williams G. Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe

proliferative retinopathy (PDR). Graefe Archive for Clinical and Experimental Ophthalmology. 2008;**246**:837-842

[39] da R Lucena D, Ribeiro JA, Costa RA, Barbosa JC, Scott IU, de Figueiredo-Pontes LL, et al. Intraoperative bleeding during vitrectomy for diabetic tractional detachment with versus without preoperative intravitreal bevacizumab. British Journal of Ophthalmology. 2009;**93**:688-691

[40] Modarres M, Nazari H, Falavarjani KG, Naseripour M, Hashemi M, Parvaresh MM. Intravitreal injection of bevacizumab before vitrectomy for proliferative diabetic retinopathy. European Journal of Ophthalmology. 2009;**19**:848-852

[41] Gupta A, Bansal R, Gupta V, Dogra MR. Six-month visual outcome after pars plana vitrectomy in proliferative diabetic retinopathy with or without a single postoperative injection of intravitreal bevacizumab. International Ophthalmology. 2012;**32**:135-144

[42] Ushida H, Kachi S, Asami T, Ishikawa K, Kondo M, Terasaki H. Influence of preoperative intravitreal bevacizumab on visual function in eyes with proliferative diabetic retinopathy. Ophthalmic Research. 2013;**49**:30-36

[43] Arevalo JF, Maia M, Flynn HW Jr, Saravia M, Avery RL, Wu L, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. The British Journal of Ophthalmology. 2008;**92**:213-216

[44] Nagpal M, Nagpal K, Nagpal PN. A comparative debate on the various anti-vascular endothelial growth factor drugs: Pegaptanib sodium (Macugen), ranibizumab (Lucentis) and

#### *The Eye and Foot in Diabetes*

bevacizumab (Avastin). Indian Journal of Ophthalmology. 2007;**55**:437-439

[45] Oellers P, Mahmoud TH. Surgery for proliferative diabetic retinopathy: New tips and tricks. Journal of Ophthalmic & Vision Research. 2016;**11**(1):93-99. DOI: 10.4103/2008-322X.180697

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**47**

Section 2

The Foot in Diabetes

Section 2
