Recent Advances in Management of Diabetic ... - Ingenta Connect

Send Orders for Reprints to [email protected] Current Diabetes Reviews, 2015, 11, 79-97

79

Recent Advances in Management of Diabetic Macular Edema Koushik Tripathy*, Yog Raj Sharma, Karthikeya R, Rohan Chawla, Varun Gogia, Subodh Kumar Singh, Pradeep Venkatesh and Rajpal Vohra Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi, India-110029 Abstract: Diabetic macular edema (DME) is the leading cause of moderate vision loss in diabetics. Modalities to image and monitor DME have evolved much in the last decade. Systemic control is the most important part of management. Available ocular management options include intravitreal antivascular endothelial growth factor (anti-VEGF) agents, laser, steroids (intravitreal or peribulbar), vitrectomy, topical medications and others. Anti-VEGF agents are increasingly being used in clinical practice with good clinical response and are currently the preferred mode of treatment worldwide.

Keywords: Aflibercept, aspirin, bevacizumab, diabetic retinopathy, glitazones, iluvien, i-vation, mecamylamine, medidur, midostaurin, nepafenac, ozurdex, PASCAL, ranibizumab, retisert, ruboxistaurin, selective retina therapy (SRT), sorbinil, subthreshold micropulse diode laser photocoagulation, VEGF. INTRODUCTION Epidemiology Diabetes mellitus (DM) is characterized by hyperglycemia due to relative or absolute deficiency of insulin. Microvascular complications of DM include diabetic retinopathy (DR), nephropathy and neuropathy. Currently more than 170 million persons in the world have DM (2000AD) and DM is estimated to affect 366 million by 2030 [1]. The number of diabetics is rapidly increasing in low and middleincome countries, and among populations of working age [2]. DR causes 4.8% of the 37 million cases of blindness in the world [2]. Diabetic macular edema (DME) is the commonest cause of diminution of vision in DM, and is the leading cause of moderate vision loss in diabetics [3,4]. Overall prevalence of DME is 6.81% (6.74–6.89) in people with diabetes worldwide, accounting for 12% of new cases of blindness annually [5,6]. According to the natural history of DME, 24% of eyes with DME will lose at least three lines of vision within 3 years [7]. The frequency of DME increases with the duration and the severity of DM [8]. Compared to those with less severe nonproliferative diabetic retinopathy (NPDR), relative risk for diffuse macular edema (ME) is 6.2 times more in very severe NPDR and 7.7 times more in proliferative diabetic retinopathy (PDR) [9]. Pathophysiology The pathophysiology of DME has not been fully elucidated since it involves various complex pathological processes and many contributing factors. Various metabolic

changes lead to functional and structural alterations which ultimately increases vascular endothelial growth factor (VEGF) or cause traction on the macula in the form of vitreomacular traction (VMT) (Fig. 1). Dysfunction of the inner and outer retinal barriers leads to accumulation of subretinal and intraretinal fluid, thus causing deterioration in the visual acuity. Hypoxia, ischemia, reactive oxygen species and inflammatory mediators are all involved in breakdown of the retinal blood barrier (BRB). The breakdown of the BRB results in accumulation of plasma proteins (e.g. albumin) which exert a high oncotic pressure in the neural interstitium, which tends to produce interstitial edema. VEGF released secondary to hypoxia is considered as the main factor that disrupts the inner BRB function, making it an important target for pharmaceutical intervention [10]. Though DR involves a complex pathophysiology, hyperglycemia has been accepted as the major pathological factor. A recent meta-analysis (Meta-Eye) analysed the effect of various factors on DR end points which included DME, any DR, PDR, and vision threatening DR (VTDR). The DR end points were increased with duration of DM, hemoglobin A1c (HbA1c), and blood pressure levels [5]. The DR prevalence end points were higher in people with type 1 DM compared to type 2 DM [5]. Hyperglycemia stimulates various pathways including Diacylglycerol (DAG)–protein kinase C (PKC) pathway, advanced glycation end products (AGE) and receptor of AGE (AGEs/RAGE) interaction, Polyol (sorbitol) pathway and Hexosamine pathway (Fig. 1) causing DME and DR. The most important factor amenable to treatment interventions in pathogenesis of DME is VEGF. METHOD OF LITERATURE SEARCH

*Address correspondence to this author at the C/o-Prof. Yog Raj Sharma, Chief, Room 488, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi, India- 110029; Tel: +919013644243; Fax: +911126588919; E-mail: [email protected] 1875-6417/15 $58.00+.00

We searched PubMed and Google Scholar using the phrases Aflibercept, Aspirin, Bevacizumab, Clinically significant macular edema, Diabetic retinopathy, Diabetic macular edema, Glitazones, Iluvien, I-vation, Mecamy© 2015 Bentham Science Publishers

80

Current Diabetes Reviews, 2015, Vol. 11, No. 2

Tripathy et al.

Fig. (1). The pathophysiology of diabetic macular edema (NADPH= reduced nicotinamide dinucleotide phosphate, GSH= glutathione, DAG= Diacyl glycerol, VEGF= vascular endothelial growth factor, AGE= advanced glycation end products, RAGE= receptor of AGEs, RAS= Renin angiotensin system, MMP-9= matrix metalloproteinase 9, b-FGF= basic fibroblast growth factor, PEDF= pigment epithelium derived factor, ICAM 1= intercellular adhesion molecule 1, IL 6= interleukin 6, IGF 1= insulin like growth factor 1, PDGF= platelet derived growth factor, PVD= posterior vitreous detachment, TTPH= thick and taut posterior hayloid, VMT=vitreomacular traction).

lamine, Medidur, Midostaurin, Nepafenac, Ozurdex, PASCAL, Ranibizumab, Retisert, Ruboxistaurin, Selective retina therapy (SRT), Sorbinil, Subthreshold Micropulse Diode Laser Photocoagulation, and VEGF. Search was made for articles dating 1980 to March, 2015. Articles in English were reviewed; articles in other languages were reviewed using their English abstracts. Definitions According to the ‘International clinical diabetic macular edema disease severity scale’ DME is proposed to be ‘apparently present’ when some apparent retinal thickening or hard exudates exist in the posterior pole [11]. DME is proposed to be ‘apparently absent’ otherwise. When DME is present, it has been classified into mild, moderate or severe if the retinal thickening or hard exudate is distant from the center of the macula, approaching the center of the macula but not involving the center and involving the center of the macula respectively. Clinically significant macular edema (CSME) was defined by the ETDRS (Early treatment diabetic retinopathy study) to satisfy any of three criteria: 1) retinal edema located 500 m from the center of the macula, or 2) hard exudates 500 m from the center if associated with thickening of adjacent retina, or 3) a zone of retinal thickening > 1 disc area if located within 1 disc diameter of the center of the macula (Fig. 2) [12]. The studies on efficacy of laser in DME had been reported using CSME definition. However, modern studies evaluating pharmacotherapy most commonly utilize the qualitative and quantitative

measurement of central subfield macular thickness (CSMT) using optical coherence tomography (OCT) along with visual acuity to determine the response of DME to treatment. MANAGEMENT OF DIABETIC MACULAR EDEMA Investigations Systemic Investigations All diabetics should receive expert care from an endocrinologist or primary care physician. Several blood investigations may help monitoring the systemic status of such patients including fasting blood sugar (FBS), postprandial blood sugar (PPBS), glycosylated hemoglobin levels (HbA1C), hemoglobin, urea, creatinine, and lipid profile. Other investigations may be required as per systemic complaints or examination. Proper management of diabetes requires optimal collaboration of various medical specialties including medicine, ophthalmology, endocrinology, nephrology, neurology, cardiology, physical medicine and others. Increased blood pressure is a common co-morbidity in diabetics. Ocular Investigations Clinical Photograph Mydriatic stereoscopic color photographs of 7 standard fields (7SF) of fundus has been considered the gold standard for detection and classification of DR (Fig. 3) [13,14]. The Diabetic retinopathy study (DRS) developed the 7 standard

Advances in DME


81

Fig. (2). The ETDRS (Early treatment diabetic retinopathy study) defined clinically significant macular edema (CSME) by either of three criteria: 1) retinal edema located 500 m from the center of the macula (Fig. 2a), or 2) hard exudates 500 m from the center if associated with thickening of adjacent retina (Fig. 2b), or 3) a zone of retinal thickening > 1 disc area if located within 1 disc diameter of the center of the macula (Fig. 2c).

Fig. (3). The modified Airlie classification as described by the Diabetic retinopathy study (DRS) [15] and the early treatment diabetic retinopathy study [14] describes the 7 standard fields containing 30° each. Field 1 is centered on the optic disc and field 2 in centered on the fovea. Field 3 is temporal to the fovea. Field 4, 5, 6, and 7 are superotemporal, inferotemporal, superonasal and inferonasal to the optic disc.

fields (7SFs) protocol (The modified Airlie House classification) in which seven 30° photographs of the retina (three horizontally across the macula and four around the optic nerve) were combined to give nearly 75° of visualization

[15]. The ETDRS used the same protocol [14]. Currently non-mydriatic ultrawide field imaging has been shown to have almost similar efficiency in determining the severity of DR and DME when compared to the ETDRS 7SF and clinical examination [16]. Non-mydriatic ultrawide field image acquisition time was noted to be less than half of the time taken for ETDRS 7SF [16]. Reproducibility of fundus color photograph is better than clinical examination, though the latter may be advantageous in picking up mild DME, fine neovascularization elsewhere (NVE), or fine neovascularization of disc (NVD) [17]. Objective monitoring of progression of DR or response of DR to therapy is possible with fundus color photography. The original seven fields have been modified to include center of macula in field 1 and 3 called as 1M, and 3M [18]. Non-mydriatic digital 45 degree fields have been described using a single photograph centering fovea or three such photographs centering fovea, centering nasal margin of the optic disc and centering superiorly and temporally from the fovea respectively [19]. Most retina specialists currently use wide field photography or clinical examination alone in many cases. Fundus Fluorescein Angiography (FFA) FFA is indicated in diabetic retinopathy, • to plan management (focal laser or macular grid) whenever a diagnosis of CSME is made, • to evaluate cause of unexplained vision loss, to rule out macular ischemia and capillary nonperfusion (CNP) areas,

82


Tripathy et al.

Fig. (4). Fundus photograph of right eye shows a ring of hard exudates at the superotemporal macula (Fig. 4a). The corresponding fundus fluorescein angiogram shows multiple microaneurysms, some of which are at the centre of the ring of hard exudate (Focal diabetic macular edema) (Fig. 4b).

Fig. (5). Fundus photograph shows hard exudates, intra retinal hemorrhages and few laser spots of macular grid (Fig. 5a). Fundus fluorescein angiogram demonstrates leaking capillaries at the macula giving rise to diffuse diabetic macular edema (Fig. 5b). There was a neovascularization elsewhere at the field 7.

• to aid differentiation of IRMA (Intraretinal microvascular abnormalities) and neovascularization elsewhere (NVE) when clinical examination is inconclusive, • to confirm diagnosis of clinically suspicious NVE or neovascularization of disc (NVD), • to differentiate non-leaking tractional cystoid macular edema due to VMT from DME in conjunction with OCT [20], and • to monitor the progression and response to treatment in PDR and CSME. According to the clinical picture and FFA, DME is classified into focal (Fig. 4a, 4b), diffuse (Fig. 5a, 5b), ischemic (Fig. 6a, 6b) and mixed varieties. Routine FFA is not indi-

cated for all diabetics [17]. CSME or PDR are clinical diagnoses and FFA is not needed to diagnose these conditions [17]. In patients with diabetic nephropathy, clearance from nephrologist should be taken prior to FFA. FFA is usually a safe investigation, most common adverse reaction being nausea or vomiting. However an emergency management plan should be in place as rarely severe complications like severe allergy and in rare cases even death (1 in 2,00,000) has been reported [21]. Optical Coherence Tomography (OCT) Optical coherence tomography gives an in vivo, noncontact, real time report of vitreoretinal interface, morphology of fovea [spongiform, cystoid, serous detachment (Fig. 7), tractional retinal detachment and taut posterior hyaloid with VMT (Fig. 8), central macular thickness (CMT) and

Advances in DME


83

Fig. (6). The fundus photograph shows few hard exudates, intra retinal hemorrhages and sclerosed arterioles at the posterior pole (Fig. 6a). Corresponding fluorescein angiogram shows few microaneurysms and capillary non-perfusion at macula and temporally suggestive of ischemic maculopathy (Fig. 6b).

Fig. (7). Spectral domain optical coherence tomography shows multiple intraretinal hypo-reflective spaces suggestive of cysts, subretinal fluid and hyper-reflective lesion with shadow (hard exudate).

minute details of posterior pole simulating histopathology. It is based on Michelson low coherence interferometry. Time domain OCT (Stratus OCT, Carl Zeiss Meditec, Dublin, CA, USA) has been superseded by more advanced spectral domain OCT (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA, USA). Newer OCT machines have higher resolution, and increased penetration. OCT gives quantitative measurement of macular edema and is a useful tool to objectively monitor progression or response of DME. However CSMT does not always correlate with visual acuity and OCT cannot give information about the perfusion status of macula [22]. Thus FFA and OCT are complimentary. Ultra Wide Field Imaging (Optos)

plane [23,24]. This leads to peripheral imaging without the need of mydriasis in less than one second [25]. Green (532 nm) or “red-free” laser visualizes the sensory retina to the retinal pigment epithelium (RPE) [25]. Red (635 nm) shows the choroidal features and blue (488 nm) laser is used for ultra-wide field fluorescein angiography [25]. Autofluorescence with green laser light highlights lipofuscin in the RPE. The central pole resolution may be enhanced with proprietary Resmax® (Resolution: 11 μm) [25]. However, images of upper eye lashes often come in view of inferior retina and positioning the patient may be difficult when using this machine. Other drawbacks of the machine are cost, maintenance, unrealistic colors in the image, and distortion of image.

Optos (Optos PLC, Dunfermline, UK) uses scanning laser technology to give single image of up to 82% or 200 degrees of the retina compared to 45-50 degrees achieved with conventional fundus camera [23]. Ellipsoid mirror is used which has 2 focal points, the ray is passed through one focal point and the other focal point is kept behind the pupillary

Photography and fluorescein angiography using the 7SF protocol, even today remains a cumbersome process, requiring a high level of photographic expertise and patient cooperation. However, Optos captures a larger area demonstrating color and angiogram photographs in a non mydriatic eye.

84


Tripathy et al.

Fig. (8). Spectral domain optical coherence tomography shows multiple intraretinal hypo-reflective spaces (cysts), intraretinal hyperreflective dot like structures (hard exudates), hyper-reflective membrane over the retinal surface (epimacular membrane), and traction over the macula by posterior hyaloid membrane (vitreomacular traction, VMT). Table 1. Recommended schedule for dilated eye examination in diabetes mellitus [29]. Diabetes Type

Recommended Time of First Examination

Recommended Follow-up*

Type 1

3-5 years after diagnosis

Yearly

At time of diagnosis

Yearly

Prior to conception and early in the first trimester

No retinopathy to mild or moderate NPDR: every 3–12 months

Type 2 Prior to pregnancy (Type 1 or type 2)

Severe NPDR or worse: every 1–3 months NPDR = nonproliferative diabetic retinopathy. * Abnormal findings may dictate more frequent follow-up examinations.

Wessel et al., compared visualized area of retina, CNP, retinal neovascularization, and panretinal photocoagulation (PRP) of Optos™ angiography to an overly of 7 standard field in 208 eyes with DR [26]. UWFA revealed 3.3 times greater retinal surface area, 3.9 times CNP, 1.9 times greater neovascularization and 3.8 times greater PRP when compared to 7 field imaging [26]. Selective laser of the peripheral capillary nonperfusion and the penumbra (the junction of perfused and nonperfused retina) revealed in Optos FFA, is called targeted retinal photocoagulation (TRP) which may lead to resolution of neovascularization of disc (NVD), or recurrent DME after anti-VEGF injections [27,28]. Treatment of DME Screening According to preferred practice patterns of American Academy of Ophthalmology, the recommended schedule for dilated eye examination by ophthalmologists is given in Table 1 [29]. Correct detection of presence or severity of DR is possible in only half of the diabetics by examining through undilated pupils [30,17].

Systemic Management Systemic control is crucial for management of any complication of DM including DR. Control of Diabetes and Blood Pressure The Wisconsin epidemiologic study of diabetic retinopathy (WESDR) reported prevalence of macular edema and its relationship to a number of risk factors in a population-based study (Table 2) [31,32]. In patients who were diagnosed diabetic before 30 years of age and who were taking insulin; DME was associated with longer duration of diabetes, presence of proteinuria, diuretic use, male gender and higher HbA1c. For those whose age at diagnosis was 30 years or above presence of DME was associated with longer duration of diabetes, higher systolic blood pressure, insulin use, higher HbA1c, and presence of proteinuria. Decrease in macular edema (CSMT) with ranibizumab therapy has been reported to inversely correlate with serum HbA1c [33]. The effect of hyperglycemia control on DR was evaluated by the Diabetes Control and Complications Trial (DCCT) [34], the Epidemiology of Diabetes Intervention and Complications

Advances in DME


85

Table 2A. Prevalence of Diabetic Macular Edema according to severity of diabetic retinopathy in The Wisconsin epidemiologic study of diabetic retinopathy [31,32]. Younger Age Onset (Duration 10 Years or More) Mild NPDR

Moderate/severe

Older Age Onset (Duration 15 Years or More)

PDR

Mild NPDR

Moderate/severe

NPDR 1.7%

20.3%

PDR

NPDR 69.7%

6.3%

63.2%

74.3%

Table 2B. Prevalence of diabetic macular edema according to type of diabetes mellitus (IDDM- Insulin dependent diabetes mellitus, NIDDM- Non insulin dependent diabetes mellitus) [31,32]. Younger Age Onset Diabetes

Older Age Onset Diabetes

Duration less than 5 years

Duration of 20 years

Duration less than 5 years

IDDM

IDDM

NIDDM

IDDM

NIDDM

IDDM

0%

32%

3%

5%-8%

18%

38%

(EDIC) study [35], the United Kingdom Prospective Diabetes Study (UKPDS) [36], the ACCORD (Action to Control Cardiovascular Risk in Diabetes) [37,38], and the ADVANCE (The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) study [39] (Table 3). The effect of antihypertensives in DR has been evaluated by the UKPDS, the ACCORD study [37,38], the EUCLID study [40] (EURODIAB Controlled Trial of Lisinopril in InsulinDependent Diabetes Mellitus), and the DIRECT (DIabetic REtinopathy Candesartan Trials) trial [41,42]. Control of Hyperlipidemia High plasma cholesterol may be associated with more severe hard exudates at macula [8,43,44]. In type 2 diabetics, Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, did not show any significant reduction of non-fatal myocardial infarction (NFMI) or death from coronary heart disease with fenofibrate therapy. However, there were less NFMI and reduced revascularizations leading to reduced total cardiovascular events [45]. Fenofibrate significantly reduced the need for laser in DR [45]. Simvastatin was shown to retard DR progression in diabetics with hypercholesterolemia [46]. Oral atorvastatin reduced lipid migration to subfoveal region and decreased severity of hard exudates in type 2 diabetics with dyslipidemia having CSME in a study by Gupta and colleagues [47,48]. Oral atorvastatin in patients with DM and dyslipidemia resulted in decreased hard exudates and fluorescein leakage [47,49]. Other Systemic Optimization Thiazolidinediones or glitazones cause fluid retention in 5% to 15% patients [50]. In some of these patients, glitazone may cause of fluid retention (macular edema and edema of lower extremity), and stopping the drug may lead to rapid improvement of both peripheral and macular edema [50].

Duration of 20 years

Control of nephropathy, anemia, obesity, and cessation of smoking are other important factors for preventing DR and DME. Ocular Management of Diabetic Macular Edema Laser Laser Photocoagulation The standard treatment for visual impairment due to DME is macular laser photocoagulation [51,52]. Treatment is required for DME when a diagnosis of CSME is made. Laser decreased risk of moderate visual loss {doubling of visual angle, or 15 letter (3 lines) loss in ETDRS chart} in center involving macular edema from 32% in deferral to 15% in laser group at 3 years. Thus ETDRS showed that the chances of moderate vision loss was reduced with laser by 50% [53]. Depending on fluorescein leakage pattern, the laser pattern is determined. Patients with focal leaks from micro aneurysms are lasered directly over these, however, patients demonstrating diffuse capillary leaks are managed using grid laser. Laser of peripheral retinal CNP areas and large ischemic areas in peripheral macula noted with Optos may be considered in non-responding DME [54]. The mechanism of action of laser in DME is unknown. The possible theories are [47,32] • Closure of microaneurysm [55]. • Oxygen supply to the inner retina may be increased by destroying highly oxygen-dependent outer retina (RPE and photoreceptors) with increased temperature. Preretinal oxygen partial pressure may increase in lasered areas [56]. Oxygen supply to inner retina may be increase due to microvascular repair in lasered areas [57]. Autoregulatory vasoconstriction of both arteriole and venule may also results in improvement of oxygenation and thus may reduce the DME [58].

86


Tripathy et al.

Table 3. Trials evaluating role of hyperglycemic control and antihypertensives on diabetic retinopathy Name of Study

Results

Diabetes Control and Complications Trial (DCCT) [34]

Intensive glycemic control (INT) (3 daily insulin injections or a continuous subcutaneous insulin infusion) decreased DR development by 76%, slowed DR progression by 54%; decreased risk of albuminuria by 54% and clinical neuropathy by 60% when compared with conventional (CON) management (1 or 2 daily insulin injections) in type 1 DM.

Epidemiology of Diabetes Intervention and Complications (EDIC) study [35]

Follow up study of DCCT. After additional 8 years, the HbA1C values in groups became similar (INT 7.98%; CON 8.07%), but after 10 years of EDIC study, the benefit of early intensive control persisted with a 53% decrease in risk of further DR progression (metabolic memory).

United Kingdom Prospective Diabetes Study (UKPDS) [8, 36, 153]

In type 2 DM, intensive glycemic control slowed DR progression and decreased risk of other microvascular complications of DM. Sulfonylureas did not increase risk of cardiovascular disease. Intensive BP control slowed DR progression and decreased risk of other microvascular and macrovascular complications of DM [153]. For every 1% decrease in HbA1c diabetic microvascular complications were shown to decrease by 35% [8].

ACCORD (Action to Control Cardiovascular Risk in Diabetes) study [37,38]

In type 2 DM, intensive glycemic control (target HbA1C < 6%) caused increased all-cause mortality (5%) and increased rates of hypoglycemia requiring assistance (10.5%) when compared to standard treatment (target HbA1C 7- 7.9%). For this reason this intensive glycemic control group of the study had to be terminated. Intensive glycemic control decreased the rate of DR progression from 10.4% in standard therapy to 7.3%. Intensive dyslipidemia control with fenofibrate and simvastatin decreased DR progression. However, intensive control of systolic blood-pressure to < 120mm Hg did not reduce DR progression significantly.

ADVANCE (The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) study [39]

Intensive glucose control to reduce HbA1c to 6.5% did not reduce incidence of DR significantly.

The EUCLID study (EURODIAB Controlled Trial of Lisinopril in InsulinDependent Diabetes Mellitus) [40]

Lisinopril may reduce DR progression in non-hypertensive patients who have type 1 DM with little or no nephropathy.

The DIRECT (DIabetic REtinopathy Candesartan Trials) trial [41, 42]

It comprised of 3 randomized trials on the effect of oral candesartan for 4-6 years: DIRECT-Prevent 1, on DR prevention in type 1 DM, DIRECTProtect 1 on protection from DR progression in Type 1 DM and DIRECTProtect 2, on protection from DR progression in Type 2 DM. Though there was a favorable trend with candesartan in decreasing the incidence of DR, no statistically significant advantage was noted for protection against DR or prevention of progression of DR.

• Retinal capillary area is reduced which may decrease leakage.

• Eyes with uncontrolled systemic status especially nephropathy tend to respond very poorly.

• Outer blood–retinal barrier may be restored [57].

Modifications of Conventional Laser

• RPE stimulation by laser produces cytokines (TGF-b) which antagonize vascular permeability caused by VEGF [59].

Modified Grid Laser

The following factors predict response to laser: • Diffuse macular edema caused due to diffuse leakage usually responds poorly and needs multiple retreatments. • Eyes with Diffuse retinal thickening on OCT have better visual improvement and greater reduction of macular thickness with laser than eyes with Cystoid macular edema or vitreomacular adhesion (VMA) [60].

Mild macular grid (MMG) as described by Diabetic retinopathy clinical research network (drcr.net) is ‘potentially more extensive and potentilally milder’ than the conventional modified ETDRS (mETDRS) protocol. The drcr.net Protocol A [61] showed that reduction of CMT was less in MMG than mETDRS, though visual outcomes were almost similar. The study concluded that mETDRS remains the standard treatment for DME. Selective Retina Therapy (SRT) Selective retina therapy (SRT) selectively targets the RPE with less damage to photoreceptors. Q-switched, fre-

Advances in DME

quency doubled Nd:YLF laser (527nm) (neodymium: yttrium lithium fluoride) is used. SRT is intended to stimulate the migration and proliferation of RPE cells, so that metabolism of the diseased retina can be improved [62] and is thought to cause laser-induced biological stimulation and rejuvenation of the chorioretinal junction. Melanosomes of the RPE cells are the most important chromophores in fundus absorbing almost half of incident light in green spectrum [62]. High temperature can be achieved in a small confined target area without collateral damage, when laser duration is shorter than the time required by heat to dissipate [62]. This thermal relaxation time depends on radius of the absorbing spherical particle and the thermal diffusivity (of water). For selectively targeting RPE cell with diameter of 10, the thermal relaxation time is 0.1ms [63]. SRT applies 30 laser pulses (1.7 microseconds, 100 Hz) to edematous retina [62]. Roider J and colleagues showed that SRT did not significantly change leakage in FFA, retinal thickness, and hard exudates. However the best corrected visual acuity (BCVA) was shown to improve at 6 months [64]. Subthreshold Micropulse Diode Laser Photocoagulation (SMDLP) SMDLP applies diode laser (810nm, Argon fluoride) at subthreshold levels, without visible endpoint for laser burns. Laser is delivered in micropulses which are shorter in duration than the thermal relaxation time of the RPE cells. SMDLP increases temperature only during the ‘‘on’’ phase for a very short duration, which selectively damages the RPE cells sparing the adjacent photoreceptors, neural retina or choriocapillaries. The heat dissipates during the ‘‘off’’ phase before the next ‘‘on’’ phase. Visual field changes and scarring may reduce with this method [65]. Diode laser is more compact, cheaper to maintain, does not need a cooling system, and has long operating time [32]. In addition, diode laser may cause less damage to retina than Argon laser, though pain associated with both treatments are comparable [32]. Patterned Scanned Laser (PASCAL) PASCAL (Topcon, Tokyo, Japan) uses frequency-doubled Nd: YAG (532nm, neodymium: yttrium aluminium garnet), optically pumped semiconductor laser (OPSL) [66]. Maximum 56 spots in single predetermined pattern can be given in approximately 0.6 seconds [67]. The available patterns are single spot, arc, triple arc, triple ring, square array, wedge, line, and octant [66,67]. Thus total time required to apply photocoagulation is reduced. Pharmacotherapy Steroids The pathophysiology of DME includes deranged blood retinal barrier, increased vascular permeability due to inflammation, retinal leucostasis, hypoxia induced VEGF expression, complex interaction of other vasoactive factors [including histamine, angiotensin II, platelet derived growth factor (PDGF), endothelin, pigment epithelium derived factor (PEDF), and basic fibroblast growth factor (b-FGF)] and vitreomacular interface abnormalities (Fig. 1) [32]. Glucocorticoids prevent derangement of blood retinal barrier by stabilizing endothelial tight junctions, and inhibiting synthe-


87

sis of VEGF, prostaglandins, and various cytokines [47]. Glucocorticosteroids increase production of annexin-1, inhibit phospholipase A2, and inhibit transcription of genes for cyclooxygenase [68]. This in turn reduces production of proinflammatory cytokines including interleukins and prostaglandins. The results are seen as decreased adhesion, activation and migration of neutrophils; reduced activation and proliferation of T cells; and decreased activation of macrophage as well as fibroblast [68]. They suppress activation of the VEGF gene and down regulate induction of VEGF in a time and dose dependent manner [69]. Steroids and laser still play important roles for management of DME in this era of anti-VEGF. Peribulbar Steroid Peribulbar triamcinolone acetonide injections may be given using posterior sub-tenon (PST), subconjunctival, anterior subtenon (AST) and retrobulbar methods [47]. This approach avoids systemic side effects of steroid, with good local concentration of drug. However, peribulbar steroids can increase intraocular pressures (IOP) and are relatively contraindicated in glaucoma, and in persons with history of increased IOP in response to topical steroids. Penetrating ocular coats is avoided, thereby avoiding associated complications and hence it may be used in eyes with good presenting vision. Some reports suggest the beneficial effects of subtenon or peribulbar steroid injection therapy for resistant DME [70,71]. The drcr.net protocol E study compared AST triamcinolone injection (20mg), PST triamcinolone (40 mg), laser, and combination therapy in mild DME with good BCVA. At 34 weeks there was no significant difference between changes in visual acuity and retinal thickness in various groups. The study concluded that peribulbar triamcinolone is unlikely to be of substantial benefit in mild DME with visual acuity of 20/40 or better [72]. Chances of glaucoma, and IOP rise were shown to increase in the long term with anterior subtenon injections. Posterior subtenon steroid has been noted to cause ptosis. Other rare complications are penetration of ocular coats, subretinal triamcinolone injection with associated retinal detachment, endophthalmitis, and orbital abscess (especially if laser and subtenon injection is given in same sitting). The fungal infections following PST injections have very guarded prognosis, and a case of phthisis has been reported [73]. Pre-injection lens status and IOP must be noted in every case receiving a PST injection. Intravitreal Triamcinolone Acetonide (IVTA) IVTA can be given at a dose of 4mg (0.1ml), 2mg (0.05ml) or 1mg. Protocol B of drcr.net study compared laser photocoagulation versus IVTA 1mg and IVTA 4mg using preservative free triamcinolone [74]. Initially, there was better improvement in BCVA and CMT with steroids compared to laser at 4 months. However, these findings were reversed by 16 months, and laser remained superior to triamcinolone at 3 year. The retinal thickness results paralleled visual acuity results. The inferiority of IVTA was not attributed to cataract as pseudophakes also showed similar results. At 3 years the incidence of cataract surgery and IOP rise of at least 10mm Hg was more with IVTA 4mg than with laser (83% versus 31% and 31% versus 3%). The study concluded laser to be most effective evidence based management in such cases [75]. An exploratory analysis of drcr.net data re-

88


vealed that IVTA 4mg reduced risk of progression of diabetic retinopathy at 3 years. However side effects of IVTA (especially cataract and increased IOP) are too common to warrant the use of IVTA to reduce progression [76,77]. However IVTA may be helpful for DME unresponsive to laser photocoagulation or DME associated with neurosensory detachment. The therapeutic effect of the steroid is typically seen within 1 week, but in many patients re-injections are needed every three to six months as the effect diminishes. There may be rebound increase in CMT after steroid’s effect diminishes. Intravitreal Steroid Implants Retisert (Bausch and Lomb, Rochester, NY, USA) is a sustained release intravitreal non-biodegradable implant of fluocinolone acetonide (FAc) (590g), composed of silicone elastomer cup with polyvinyl alcohol. It is implanted intravitreally through a sclerotomy, anchored to the eye-wall by a suture. Initially FAc is released at a rate of 0.6 g daily. The drug delivery rate then decreases over first month to 0.3 to 0.4g daily with no drug peaks and troughs, and it lasts for approximately 1,000 days (30 months) [78]. It has been FDA-approved in 2005 (Food and Drug Administration, USA) for chronic non-infectious posterior uveitis [79]. MUST trial (the multicenter uveitis steroid treatment trial, clinicaltrials.gov identifier NCT00132691) evaluating its efficacy in uveitis versus systemic anti-inflammatory therapy, showed 4 times increase in glaucoma and 3.3 times increased cataract surgery rate [80]. The device has been shown to reduce retinal thickness in DME, but at 3 years 95% of phakic patients required cataract surgery and 35% patients experienced medically uncontrolled increased IOP that needed either removal of the implant or a glaucomafiltering procedure [81]. Iluvien® (formerly Medidur FA, Alimera Sciences, Alpharetta, GA, USA) is another non-biodegradable implant containing polymer matrix like Retisert. The cylinder (3.50.37 mm) is implanted intravitreally by a 25-gauge needle [82]. It contains 190 micrograms of FAc. This FAc implant has been hypothesized to reduce rates of glaucoma due to reduced delivery rate of FAc (0.2 and 0.5μg daily for at 24-36 months and 18 months respectively) and due to reduced exposure to trabecular meshwork as the reservoir is implanted more posteriorly [47]. 2 years results in persistent DME despite focal laser, showed significant improvement in visual acuity with both 0.2 μg/day and 0.5-μg/day implants with significantly reduced need for glaucoma filtration surgeries in 0.2μg/day group [83]. Three year results of FAME study (Fluocinolone Acetonide Implant Compared to Sham Injection in Patients With Diabetic Macular Edema) included patients with BCVA of 20/400, 67% of leakage originating from leaking microaneurysms (MAs) in the whole edema area or 30%–67% leakage from MAs in the whole edema area, but 67% of the leakage originating from MAs in the central subfield. Diffuse DME was defined when