Topical NSAIDs in Prevention of Postcataract Macular Edema

Ahmed Alnagdy, Ahmed M. Eissa and Amr El-Kannishy

## Abstract

Postoperative macular edema is considered one cause of diminished vision after cataract surgery. It was approved that inflammatory mediators especially prostaglandins play a key role in macular edema formation especially in the presence of risk factors that affect blood-retinal barrier such as diabetes, uveitis, tear of posterior capsule, and vitreous loss. So, anti-inflammatory medications like corticosteroids and NSAIDs are the cornerstone of macular edema managements. In spite of using corticosteroids as gold standard for treatment of ocular inflammation, they cannot be used for prolonged period due to associated adverse effects. Lastly, there were many studies about benefits of NSAIDs in management and prevention of macular edema to avoid the side effects of corticosteroids.

Keywords: NSAIDs, macular edema, phacoemulsification, cataract, blood-retinal barrier

## 1. Introduction

Macula is an important part of the retina, which is responsible for color vision, contrast sensitivity,sharp vision, communications and interpersonal relationships [1].

Macular thickening is well-known postoperative complication after cataract surgery, even with uncomplicated small incision phacoemulsification surgery. Subclinical cystoid macular edema (CME) is diagnosed with fluorescein angiography as leakage from perifoveal dilated capillaries without visual acuity affection [2]. Although fluorescein angiography is considered gold standard for diagnosis of macular edema, quantification of fluorescein leakage is difficult. Optical coherence tomography (OCT) nowadays has an upper hand in diagnosis of macular edema because of its advantages as a noninvasive device and can detect macular edema quantitatively and qualitatively [3].

Clinical CME can be identified on biomicroscopic examination and is associated with decreased visual acuity [4].

The pathogenesis of CME is disruption of blood-retinal barrier (BRB) by inflammatory mediators generated through several cascades as a result of surgical trauma to iris, ciliary body, or lens epithelial cells. Also, preexisting ocular conditions such as diabetes, hypertension, and uveitis, which affect BRB, can increase risk of CME [5].

The blood-retinal barrier in diabetic eyes is impaired to a variable degree, which plays a role in development of postoperative CME. CME in diabetic patients is affected by many factors including duration, severity of the disease, presence of

retinopathy, and previous treatment with photocoagulation [6]. Total ophthalmic payments were documented to be 47% higher in patients who developed postoperative CME [7]. So, prophylactic prevention or even decreased CME severity is cost savings, particularly among diabetic patients.

## 2. Macular anatomy and physiology

Being the main part of clear vision, the macula is located in the heart of the retina between upper and lower arcades measured about 4.5–6 mm in diameter. It can be divided into centralfovea,surrounded by parafovea and outer perifovea (Figure 1) [8].

• Retinal vascular plexus was described simply into two planes: inner one at ganglion cell layer and outer plexus at inner nuclear layer [9] (Figure 2).

Parts of the macula from inside to outside: foveola, fovea, parafovea, and perifovea [8].

#### Figure 2.

Vascular plexus position in layers of retina: inner vascular plexus in ganglion cell layer and deep vascular plexus in inner nuclear layer [9].

• As a whole, the retina blood supply is divided into outer part supplied by choriocapillaris and inner part supplied by retinal vascular plexus branch of posterior ciliary arteries [10].

## 3. The blood-retinal barrier

The blood-retinal barrier (BRB) is a barrier that physiologically establishes and maintains specific substrate and ion concentrations to allow proper neural function. BRB regulates flux of substances in retina such as ion, protein, and water and also regulates infiltration of immune competent cells and blood toxins. BRB is formed at two levels, inner and outer BRB. The inner one is composed of tight junctions between retinal vascular endothelial cells. The outer barrier is composed of tight junction between retinal pigment epithelium cells [11].

Pericytes secrete angiopoietin 1, which induces tight junction protein expression to support endothelial cells barrier [12].

## 3.1 Tight junction

Tight junction is mainly apical junctional complex, which has a barrier function against solute flux and movement of proteins and lipids into retinal parenchyma. This junction is showed as transmembrane proteins and junctional adhesion molecule (JAM) [13].

## 3.2 Adherens junction

Adherens junction is second barrier beneath the tight junction. This junction is important for development of the barrier as it affects formation of tight junction [14].

Tight junction: Transmembrane proteins claudins, occludin, and junctional adhesion molecule (JAM) connected with scaffolding protein ZO to actin.

Adherens junction: Vascular endothelial (VE) cadherin connected to actin through complex of β-catenin, α-catenin, and vinculin.

## 4. Pathophysiology

The macula is responsible for central 30 degrees of sharp vision with color vision, interpersonal relationships, communications, and contrast sensitivity [1]. The retina is very sensitive to fluctuation in blood oxygen levels and intraocular changes, as it consumes oxygen more than other tissues, being highly active tissue. Microchanges not felt by patient visual acuity are also not seen by inspection ophthalmoscopy examination [15].

It has been reported that clinical affection due to CME after uneventful phacoemulsification is between 0 and 9%. Furthermore, clinical affection between 9.1 and 20.4% with angiographic leakage is reported [16]. Interruption of bloodretinal barrier is the most accepted explanation of postoperative macular edema, which causes macular thickening. Surgical trauma disrupts the blood-aqueous barrier, release of prostaglandins, and increase of perifoveal capillaries' permeability of liquid in extracellular spaces, which cause macular thickening and CME [17]. The pathophysiology of these macular changes may be considered consecutively as follows: (1) release of inflammatory mediators into anterior chamber produced by surgical procedures; (2) removal of normally lens barrier, which separate posterior

segment from anterior segment; (3) local effect of inflammatory mediators on macular area; and (4) anterior displacement of vitreous leading to increase traction on macula [18].

Recently, being noninvasive, OCT has been established to be the main method for examining retinal architecture [19]. OCT can measure microhistological retinal changes in difference to fluorescein angiography, which detects it as a leakage that cannot be detected by biomicroscopy [20]. It was reported that subclinical increase in retinal thickness and volume can be found in the early course postoperatively at 4 weeks after phacoemulsification [21].

## 5. Nonsteroidal anti-inflammatory drugs

Surgical trauma stimulates arachidonic acid cascade, which stimulates phospholipase A2 enzyme to release arachidonic acid from membrane phospholipids and produces inflammatory mediators including prostaglandins (PGs) and leukotriene by activation of cyclooxygenase (COX) enzymes. COX-1 and COX-2 isoforms are believed to be the primary mediator of ocular inflammation. PG is an important mediator of postoperative complications, associated with symptoms including pain, ciliary injection, cystoid macular edema, impaired vision, and intraoperative miosis [22].

So, treatment of ocular inflammation depends mainly on stopping of arachidonic cascades by corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). Corticosteroids inhibit the activity of phospholipase A2 enzyme, but NSAIDs inhibit PGs synthesis irreversibly and nonspecifically by direct inhibition of COX-1 and COX-2 activity [23] (Figure 3).

#### 5.1 Corticosteroids

In spite of using corticosteroids as gold standard for treatment of ocular inflammation, they cannot be used for prolonged period due to associated adverse effects.

## Figure 3.

Side effects of corticosteroids include increased susceptibility to infections as a result of suppression of host immune response, retardation of corneal wound healing, and increased intraocular pressure (IOP) [24].

## 5.2 Nonsteroidal anti-inflammatory drugs

NSAIDs are considered as safety option used for treatment of ocular inflammation. NSAIDs inhibit COX activity patently by several chemically heterogeneous classes [25].

Currently, the uses of topical NSAIDs in ophthalmology to reduce pain and discomfort after cataract and refractive surgery prevent intraoperative miosis during cataract surgery and manage postoperative inflammation (Table 1) and are also reported to have a role in prevention of CME after cataract surgery [25, 27].

NSAIDs have beneficial effects over corticosteroids including analgesia effect, maintaining pupillary dilatation if used preoperatively (Figure 4), and also reduce the risk of secondary infections and increased IOP [25].

## 5.3 Pharmacokinetics

Diclofenac: Plasma levels reached (10 ng/mL) during a 4 hours period after instillation of two drops in each eye [29].

Flurbiprofen: No information about systemic absorption was approved.

Ketorolac: The use of ketorolac in 26 patients with one drop in each eye three times daily resulted in 5/26 (= 19.2%) with detectable plasma level of ketorolac (10.7–22.5 ng/mL) after 10 days.

Bromfenac: After topical administration, plasma level is expected to be below the detectable limit (50 ng/mL).

Nepafenac: It is an inactive prodrug, which penetrates corneal epithelium and is converted by ocular tissue hydrolases to active form amfenac. Plasma levels of bromfenac and amfenac were detected 2–3 hours in most patients after installation of nepafenac in both eyes but with low plasma level.


#### Table 1.

Ophthalmic NSAIDs' FDA-approved indications [26].

Figure 4. Comparing pupil poor dilatation in control group (A) and full dilated pupil with NSAIDs (B) [28].

## 5.4. Limitation of NSAIDs

Topical NSAIDs contain some warnings, which include the following:


## 6. Discussion

In the last few years, there were many studies using NSAIDs to prevent postoperative CME in different situations. In Table 2, some studies focus on the effect of NSAIDs in prevention of postoperative CME in diabetic patients. All of them approved significant low macular thickening in diabetic patients receiving NSAID bromfenac only [34], classical postoperative steroid regimen in addition of nepafenac [35] or either nepafenac or ketorolac with classical postoperative steroid regimen [28].

Other studies documented the effect of NSAIDs in a mixed population (nondiabetic and diabetic patients) without cystoid macular edema preoperatively and with no predisposing factors for developing cystoid macular edema (Table 3). Some studies documented that topical steroid medication may not be absolutely essential after uneventful cataract surgery [37, 44]. Topical nonsteroidal started 1 day before surgery and continued for 1 month by Almeida et al. [37], while Nishino et al. [44] started medication postoperatively and continued for 1 month. On the other hand, many studies approved the significant importance of topical NSAIDs in prevention of macular edema [36, 38–43, 45, 46]. topical ketorolac had more effect in decreasing macular edema than prednisolone only, if started 2 days before surgery and continued for 1 month postoperatively in combination with

Topical NSAIDs in Prevention of Postcataract Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.82321


#### Table 2.

Clinical trials using ophthalmic NSAIDs to prevent postoperative macular edema in diabetic patients without cystoid macular edema preoperatively and with no predisposing factors for developing cystoid macular edema.



#### Table 3.

Clinical trials using ophthalmic NSAIDs to prevent postoperative macular edema in a mixed population (nondiabetic and diabetic patients) without cystoid macular edema preoperatively and with no predisposing factors for developing cystoid macular edema.

prednisolone had more effect in decreasing macular edema in comparison to postoperative topical prednisolone alone [36]. Wittpenn et al. approved that starting ketorolac 1 hour before surgery had significant effects in preventing macular edema [46]. Cervantes-Coste et al. documented that diclofenac effectively maintains mydriasis and decreases macular thickness [39]. Also, diclofenac eye drops in Rossetti et al. effectively reduced incidence of angiographic CME and ocular inflammation after cataract surgery [40], while Miyake et al. suggested that diclofenac effectively decreases CME in comparison to fluorometholone [41] and also approved its effect in preventing chronological change in choroidal blood flow and disruption of the blood-aqueous barrier [42]. In 2011, there was another study by

## Topical NSAIDs in Prevention of Postcataract Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.82321

Miyake et al. which approved that nepafenac was more effective than fluorometholone in preventing cystoid macular edema [43]. In other hand, some studies compared the effect of different NSAIDs similar to the study by Cable et al. who suggested that bromfenac is more effective than nepafenac [38] and Weber et al. who suggested that there was no change from baseline in retinal thickness between indomethacin group and ketorolac group.

Nondiabetic patients who have undergone cataract surgery without preoperative macular edema and with no predisposing factors for developing cystoid macular edema were enrolled in studies in Table 4. In glaucoma patients after cataract surgery, Miyake et al. approved that diclofenac seems to prevent macular edema formation enhanced by latanoprost therapy [49], and timolol and its preservative benzalkonium chloride [50].




Topical NSAIDs in Prevention of Postcataract Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.82321

#### Table 4.

Clinical trials using ophthalmic NSAIDs to prevent postoperative macular edema in nondiabetic patients without cystoid macular edema preoperatively and with no predisposing factors for developing cystoid macular edema.

Donnenfeld et al. documented that early started ketorolac 3 days or 1 day preoperatively provided superior outcomes over ketorolac startes only 1 hour preoperatively [47]. Also, preoperative indomethacin drugs decreased the incidence of CME more than postoperative use only in the study of Yavas et al. [55].

In comparative study between different NSAIDs, Capote et al. approved that bromfenac is more effective than diclofenac and nepafenac in reducing macular thickness after phacoemulsification [56]. In other study, bromfenac was more effective and safer in comparison to topical steroid; inspite of using oral prednisones for all patients in the study [54].

In other studies, NSAIDs did not seem to offer any additional benefit after uneventful phacoemulsification of diclofenac in the study of Moschos et al. [52] and ketorolac in the study of Ticly et al. [53]. Miyanaga et al. documented that 2 months' use of topical NSAIDs, different topical steroids, or alternating steroids and NSAIDs had no significant differences [51]. Stock et al. suggested no differences between nepafenac, control, and ketorolac through 45-day follow-up [58].

Mathys et al. told that routine use of preoperative nepafenac may be necessary to achieve excellent visual recovery if continued for 3 weeks postoperatively or not [48].

In the study of McCafferty et al., postoperative topical nepafenac reduces macular edema in patients with preoperative risk (diabetic retinopathy, contralateral CME, or prostaglandin use) compared to placebo, but there were no differences in patients without risk factors [57]. Nepafenac was effective in reducing macular thickness compared with a placebo in fellow eye 5 weeks postoperatively in patients who had bilateral phacoemulsification enrolled in the study of Tzelikis et al. [60].

### 7. Conclusion(s)

The most important line of management of postoperative macular edema is by prevention. NSAIDs have large effects in prevention of postoperative macular edema with minimal side effects. Furthermore, some studies have suggested that NSAIDs may have a greater effect in re-establishment of the blood-aqueous barrier than corticosteroids. The claim about synergistic effects of NSAIDs and corticosteroids is made by several authors. Although several studies may have favored

starting NSAID treatment preoperatively, there are no comparison studies about starting corticosteroids preoperatively.

## Conflict of interest

The authors declare that they have no conflict of interest.

## Author details


<sup>©</sup> 2019 The Author(s). Licensee IntechOpen. This chapteris distributed underthe terms oftheCreative 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.

Topical NSAIDs in Prevention of Postcataract Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.82321

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**65**

**1. Introduction**

**Chapter 4**

**Abstract**

Prevalence and Association

of Diabetic Retinopathy with

Diabetic Foot Ulcer: A Cross-

*Shaista Zafar, Kashif Rahim, Inayat Ullah Khan,* 

examinations for timely diagnosis and management of DR.

**Keywords:** diabetic foot ulcer, diabetic retinopathy, risk factors, Pakistan

Diabetes mellitus (DM) is a metabolic disease, caused by chronic hyperglycemia as a result of defects in secretion of insulin, resistance to insulin action, or a combination of the two. Type 1 and type 2 are two main types of diabetes. Type 1 diabetes mellitus (T1DM) results from absolute deficiency of insulin secretion, and type 2 diabetes mellitus (T2DM) results from combined defects in both relative deficiency of insulin secretion and insulin resistance [1]. T2DM is the dominant form of diabetes which account to approximately >85% of all diabetes cases [2]. Diabetic foot ulcer (DFU) is the most devastating complication of diabetes, with a global prevalence of 6.3%, and is more common in patients with type 2 diabetes [3].

Sectional Observational Study

*Muhammad Yasin, Muhammad Dawood and Shamim Saleha*

We aimed to elucidate prevalence and association of diabetic retinopathy (DR) in patients with diabetic foot ulcer (DFU) from Pakistan. In this cross-sectional study, about 225 DFU patients who underwent ophthalmic examinations within 6 months of diagnosis of foot ulceration were included. The medical records of 305 diabetic patients without DFU were included as controls. The association of DR with DFU was assessed by comparing DFU patients with proliferative DR (PDR) and DFU patients without PDR. Out of 225 DFU patients, 215 patients (95.6%) had DR and 169 patients (75.1%) had PDR. The prevalence of DFU was significantly greater (P = 0.0527) among the male diabetic patients, whereas advanced age of these patients (≥41 years) had a significant effect (P = 0.0286) on development and progression of PDR. A longer duration of diabetes (≥10 years) was identified as a significant contributing factor for the development of both DFU (P = 0.0029) and PDR (P = 0.0299). Moreover, the risk of PDR increased in diabetic patients with higher DFU grades (grade 3 and grade 4). In conclusion, retinopathy was prevalent in DFU patients. Therefore, DFU patients with advancing age and longer duration of diabetes should undergo retinal

## **Chapter 4**

## Prevalence and Association of Diabetic Retinopathy with Diabetic Foot Ulcer: A Cross-Sectional Observational Study

*Shaista Zafar, Kashif Rahim, Inayat Ullah Khan, Muhammad Yasin, Muhammad Dawood and Shamim Saleha* 

## **Abstract**

We aimed to elucidate prevalence and association of diabetic retinopathy (DR) in patients with diabetic foot ulcer (DFU) from Pakistan. In this cross-sectional study, about 225 DFU patients who underwent ophthalmic examinations within 6 months of diagnosis of foot ulceration were included. The medical records of 305 diabetic patients without DFU were included as controls. The association of DR with DFU was assessed by comparing DFU patients with proliferative DR (PDR) and DFU patients without PDR. Out of 225 DFU patients, 215 patients (95.6%) had DR and 169 patients (75.1%) had PDR. The prevalence of DFU was significantly greater (P = 0.0527) among the male diabetic patients, whereas advanced age of these patients (≥41 years) had a significant effect (P = 0.0286) on development and progression of PDR. A longer duration of diabetes (≥10 years) was identified as a significant contributing factor for the development of both DFU (P = 0.0029) and PDR (P = 0.0299). Moreover, the risk of PDR increased in diabetic patients with higher DFU grades (grade 3 and grade 4). In conclusion, retinopathy was prevalent in DFU patients. Therefore, DFU patients with advancing age and longer duration of diabetes should undergo retinal examinations for timely diagnosis and management of DR.

**Keywords:** diabetic foot ulcer, diabetic retinopathy, risk factors, Pakistan

## **1. Introduction**

Diabetes mellitus (DM) is a metabolic disease, caused by chronic hyperglycemia as a result of defects in secretion of insulin, resistance to insulin action, or a combination of the two. Type 1 and type 2 are two main types of diabetes. Type 1 diabetes mellitus (T1DM) results from absolute deficiency of insulin secretion, and type 2 diabetes mellitus (T2DM) results from combined defects in both relative deficiency of insulin secretion and insulin resistance [1]. T2DM is the dominant form of diabetes which account to approximately >85% of all diabetes cases [2]. Diabetic foot ulcer (DFU) is the most devastating complication of diabetes, with a global prevalence of 6.3%, and is more common in patients with type 2 diabetes [3]. The lifetime risk of foot ulceration in patients with diabetes lies somewhere in the range of 15 and 25% [4, 5], with a yearly rate of around 2–3% [6].

 Diabetic is associated with microvascular complications, including retinopathy, neuropathy, and nephropathy, and macrovascular complications, including ischemic coronary illness, stroke, and peripheral vascular disease [7]. Diabetic retinopathy (DR) is a common complication of diabetes that affects vision. DR damages the blood vessels of the light-sensitive tissue at the back of the eye (retina) that results in blindness if left undiagnosed and untreated. It is estimated that 20 years after diagnosis, those with type 1 diabetes and 60% of those with type 2 diabetes will have some level of retinopathy [8]. Approximately 4 million individuals around the globe are estimated to losing their sight from diabetic retinopathy, the main source of visual impairment in patients aged 20–74 years [9]. The risk of development and progression of DR is closely associated with the type 1 diabetes [8], longer duration of diabetes [10], advancing age [11], poor glycemic control [12], high blood pressure [13] and elevated serum lipids [14].

The descriptive analytical studies have demonstrated that diabetic retinopathy (DR) is among one of the major contributing factors in the development of foot ulceration and subsequent lower limb amputation in diabetic patients [11, 15–17]. Importantly, DFU patients with PAD are less likely to heal and more likely to require amputation compared to patients without PAD. Moreover, retinal screening in people with diabetic foot ulceration, followed by treatment of sight-threatening retinopathy, may prevent severe vision loss or blindness [18]. It is therefore essential that DR is diagnosed in all diabetic patients with a foot ulcer. There is a significant rise in the prevalence of diabetes and its complications in Pakistan, causing a major social and economic burden [19, 20]. Therefore, this study was conducted with an aim to investigate the prevalence of DR in patients with a DFU in Pakistan and to elucidate the potential association between DR and DFU.

## **2. Materials and methods**

 This was a cross-sectional observational study conducted in the diabetology clinic at Pakistan Institute of Medical Sciences (PIMS), located in federal capital of Pakistan, which is the largest tertiary care referral hospital. This study was conducted between March 2017 and February 2018 as per the guidelines of the Declaration of Helsinki, and the Institutional Ethical Committee approval was obtained before initiation. The study was explained, and written informed consent of the patients was obtained before their recruitment. Inclusion criteria were as follows: (1) all type 2 diabetic patients and only those type 1 diabetes patients with diabetes duration of more than 5 years, diagnosed with foot ulcers based on the Wagner ulcer classification, were included in this study. (2) Patients were included in the study only if they underwent ophthalmic examinations particularly funduscopy of the retina within 6 months after DFU diagnosis.

Participated DFU patients were classified into Wagner's grades [21] as follows: grade 1 (superficial ulcer), grade 2 (deep ulcer), grade 3 (ulcer with osteomyelitis), grade 4 (forefoot gangrene), and grade 5 (mid foot or hind foot gangrene). Moreover, the presence and severity of DR among DFU patients were assessed based on the grading of the Global Diabetic Retinopathy Project Group [22]. A five-stage disease severity classification for DR includes no apparent retinopathy (no DR), proliferative DR (PDR), and mild, moderate, or severe non-proliferative DR (NPDR). Clinical information and demographic details were obtained from medical records of participating patients. The medical records of diabetic patients without a DFU who also visited the diabetology clinic at PIMS for a health checkup were included as control.

*Prevalence and Association of Diabetic Retinopathy with Diabetic Foot Ulcer: A Cross-Sectional… DOI: http://dx.doi.org/10.5772/intechopen.82667* 

Analysis of recruitment data was performed by using SPSS-PC version 16.0, and then tables and graphs were constructed to display characteristics of studied patients. The association between DR and DF was determined by using the Chisquare test. P-values <0.05 were considered significant.

## **3. Results**

 Data of patients recruited in the study was analyzed and summarized in **Table 1**. Among 225 patients with foot ulceration, majority of them were male (62.7%) and had type 2 (60%) diabetes. Most DFU patients were aged 41 years old and over (88.4%) and had diabetes since ≥10 years (65.8%), high HbA1c ≥ 7% (77.3%), and higher level of systolic blood pressure (72.4%). Statistically, significant differences were observed among diabetic patients with a foot ulcer or without a foot ulcer in relation to gender (P = 0.0527) and diabetes duration (P = 0.0029) only.

Additionally, DFU patients with PDR were compared with DFU patients without PDR as shown in **Table 1**. The PDR was less prevalent in diabetic males with foot ulcers (53.8%) in comparison to those without foot ulcers (66.1%). The DFU patients with PDR had type 2 diabetes (66.9%), advanced age (82.8%), longer


#### **Table 1.**

*Basic characteristics of diabetic patients with or without diabetic foot ulcer (DFU).* 


**Table 2.** 

*Prevalence of DR in patients with a DFU and in diabetic patients without a DFU .* 

duration of diabetes (85.8), high HbA1c ≥ 7% (82.2%), and elevated systolic blood pressure (72.2%) than DFU patients without PDR. The significant contributing factors of PDR among DFU patients were advanced age (p = 0.0286) and longer duration of diabetes (0.0299).

 In terms of DR among diabetic patients with foot ulceration, 215 patients (95.6%) had DR and 169 patients (75.1%) had PDR. 11 patients (4.9%) had mild NPDR, 26 patients had moderate NPDR (11.6%), and 9 patients had severe NPDR (4.0%), as shown in **Table 2** and **Figure 1**. Moreover, the common ulcer grades were 3 (41.8%) and 4 (31.6%), among DFU patients with DR (**Table 3**).

#### **Figure 1.**

*Fundus photographs of some studied patients show clinical grades of DR. (A) Mild NPDR phenotypes based on the presence of only two microaneurysms and the absence of macular edema. (B) Moderate NPDR phenotypes based on the presence of scattered microaneurysms, dot-blot hemorrhages, hard exudates, and diffuse macular edema. (C) Severe NPDR phenotypes based on the presence of scattered microaneurysms, dot-blot hemorrhages, hard exudates, cotton wool spots, and clinically significant macular edema. (D) PDR phenotypes based on the presence of new vessels on the disc (NVD), new vessels elsewhere (NVE), preretinal hemorrhage, retinal hemorrhages, tractional bands, and laser marks of the previous pan retinal photocoagulation (PRP).* 

*Prevalence and Association of Diabetic Retinopathy with Diabetic Foot Ulcer: A Cross-Sectional… DOI: http://dx.doi.org/10.5772/intechopen.82667* 


**Table 3.** 

*Distribution of diabetic patients with DR according to ulcer grades.* 

## **4. Discussion**

Diabetes is a common disease, associated with microvascular and macrovascular diseases that contribute to an increased risk of foot ulcers and subsequent lower extremity amputations in diabetic patients [7]. Population-based studies identified that DR is among one of the contributing diseases that significantly increased risk for foot ulceration in diabetic populations of Saudi Arabia [23], Korea [11], Spain [15], Iran [16] and India [17]. However, data is limited about contribution of DR in development of foot ulceration in diabetic population of Pakistan.

 The present study revealed that the majority (95.7%) of DFU patients had DR, with 71.9% demonstrated PDR. A similar study reported that DR was prevalent (90%) in the US diabetic patients with foot ulcers, and about more than half of these patients had PDR [11]. Pemayun et al. in a hospital-based case-control study found PAD to be a major predictive factor for poor outcome among hospitalized DFU patients [24]. Previously, Nwanyanwu et al. in a retrospective cohort study assessed that chronic foot ulcers might contribute to retinopathy progression due to the reason that a significant proportion of diabetic chronic ulcer patients with NPDR who progressed to PDR in their analysis [25]. Among DFU patients with PDR, 73.4% had advanced Wagner's grades (grades 3 and 4) of foot ulceration in the present study. Hwang et al. found association of PDR with DFU and speculated that elevated oxidative stress and endothelial dysfunction can cause PDR in the advanced stages of diabetes [11].

 The cross-sectional diabetes studies reported that prevalence of foot complications increases among diabetic males with advanced age and longer duration of diabetes [10, 11, 19, 23]. In the current study, diabetic patients with foot ulcers were compared with those without foot ulcers to find significant determinants for foot ulcer in diabetic patients, and it was found that a significant number of diabetic males were at a greater risk for the development of foot ulcers. Higher average height, higher plantar pressure, inadequate self-care practices, inappropriate shoes, and frequent exposure to traumatic events and frequently found peripheral insensate neuropathy have been identified as risk factors contributing to foot ulceration in diabetic males [26, 27]. Additionally, DFU patients were classified into the PDR or NPDR group; our results showed that diabetic males with foot ulcers had a higher prevalence of PDR comparatively to females, but this difference was not significant. Similarly, a diabetes study from the United Kingdom reported that PDR was more prevalent in males than in females [28]. In contrast, a community-based study in China showed that diabetic females were associated with increased risk of PDR [29]. This gender difference observed in present and previous studies could not identify it as a risk factor contributing to PDR in diabetic patients with foot ulceration.

Importantly, advancing age has been observed as a contributing factor to foot ulceration in diabetic patients in many studies [11, 23]. Although prevalence of foot ulcers was determined high among advanced age diabetic patients in current study, a statistically significant difference was not observed in terms of increasing age (≥41 years) of diabetic patients with and without foot ulceration. On the other hand, our study demonstrated statistically significant correlation between PDR and advanced age of DFU patients. In contrast to this observation, Hwang et al. [11] in a recent study failed to show a correlation between PDR and advanced age of DFU patients. Similarly, Li and Wang reported lower prevalence of DR in elderly diabetic patients and suggested that favorable control of blood glucose, blood pressure, and blood lipids effectively prevented the occurrence of DR in diabetic patients [30]. Therefore, it seems that high blood glucose levels and elevated systolic blood pressure have contributed to the developing of PDR in elderly DFU patients in current study.

 Comparatively high prevalence of foot ulcers was observed among diabetic patients with diabetes duration more than 10 years in the current study, and this observation was significant. A previous study from Sudan supported our observation [10]. In two different previously conducted diabetic foot studies, the average duration of diabetes in DFU patients was 13.2 [31] and 8.2 years [32]. Based on current and previous observations, we hypothesize that the lengthy duration of diabetes is a significant risk factor for the development of diabetic foot ulceration. In addition, Chawla et al. in a study reported that chronic hyperglycemia and diabetes duration are among the main contributing factors to development and progression of DR in diabetic patients with foot ulcer [33]. The results of the present study also showed that lengthy duration of diabetes was a significant risk factor in progression of PDR among patients with DFU. In agreement with our results, Hwang et al. also reported that the foot ulcer patients with PDR had a longer duration of diabetes compared to those with NPDR [11].

#### **5. Conclusion**

In summary, the present study showed that a large proportion of advanced age patients with longer duration of diabetes had retinopathy and were at substantial risk of developing foot ulceration. Therefore, in advanced age DFU patients, and particularly those with longer duration of diabetes, early detection of DR and timely treatment may decrease the risk of severe vision loss or blindness.

### **Acknowledgements**

This study was financially supported by the Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology. The authors acknowledge all those patients who participated in the study.

### **Conflict of interest**

The author(s) declare that they have no competing interests.

*Prevalence and Association of Diabetic Retinopathy with Diabetic Foot Ulcer: A Cross-Sectional… DOI: http://dx.doi.org/10.5772/intechopen.82667* 

## **Author details**

Shaista Zafar1 , Kashif Rahim<sup>2</sup> , Inayat Ullah Khan1 , Muhammad Yasin3 , Muhammad Dawood3 and Shamim Saleha<sup>3</sup> \*

1 Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan

2 Beijing Key Laboratory of Genetic Engineering Drug and Biotechnology, Institute of Biochemistry and Biotechnology, College of Life Sciences, Beijing Normal University, Beijing, China

3 Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Khyber Pakhtunkhwa, Pakistan

\*Address all correspondence to: shamimsaleha@yahoo.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.

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## **Chapter 5**
