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Diabetic macular odema update 2016

This document discusses diabetic macular edema (DME), including its prevalence, evaluation, treatment options, and intravitreal injection technique. DME is a leading cause of vision loss in diabetic retinopathy. Evaluation involves visual acuity testing, slit lamp examination, and imaging like OCT and FA. Treatment includes tight blood sugar and blood pressure control, as well as therapies like anti-VEGF agents, corticosteroids, and laser photocoagulation. Intravitreal injections are a common method to deliver these medications, with 30-gauge needles typically used for anti-VEGF drugs and 27-gauge for corticosteroids like triamcinolone.

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DIABETIC MACULAR ODEMA 2016 ANTI VEGF ,STEROIDS,LASER Indoredrishti.wordpress.com
DR DINESH MITTAL DR SONALEE MITTAL DRISHTI EYE HOSP VIJAYNAGAR INDORE
Diabetic Macular Odema the leading cause of decrease in vision in Diabetic Retinopathy
•In western countries, the expected prevalence of diabetic retinopathy is close to 35 % in the diabetic population, while DME may be present in 7–10 % of patients . After 2 years, over half of patients with DME will lose two or more lines of visual acuity (VA) . Worldwide, it has been estimated that 21 million people have DME
Treatment of DME • Treatment for DME includes treatment of the systemic disease by maintaining tight blood sugar and blood pressure control, weight loss, and the lowering of circulating triglycerides and cholesterol. •However, once there is progression to DME,therapy is indicated to slow the rate of vision loss and to attempt to improve the long- term prognosis.
retinal thickening of the posterior pole and detected by slit lamp biomicroscopy or optical coherence tomography (OCT ) DIABETIC MACULAR ODEMA ( DME )
Evaluation • Previous history of diagnosis or treatment if any should be taken thoroughly. • Comprehensive eye examination including VISUAL ACUITY , IOP measurement , • slit lamp examination of anterior segment and dilated funduscopic examination
Evaluation • ophthalmoscopy in a dilated pupil is helpful. • posterior pole examination is best done with slit lamp biomicroscopy with accessory lenses . • imaging modalities commonly used in the management are fundus photography , FA & OCT
OCT and FA are the most useful investigations in DME • Confirm presence macular edema • Know type of macular edema • Assess macular thickness • Know response to intravitreal pharmacotherapy • For follow up and documentation OCT role in DME
FA role • Type of leak focal or diffuse • Rule out macular ischaemia Increasingly OCT is being used for evaluation of macular edema . Spectral domain ( SD OCT ) has replaced time domain OCT ( TD OCT ) .
Diabetic macular odema • Slit lamp biomicroscopy , color fundus photography or ophthalmoscopy may not be able to detect mild DME . Here OCT is very helpful in measuring central foveal thikness. • OCT has become gold standard in monitoring the progression and treatment response in DME • give micrometer sensitive measurements in central retinal thickness.
DME • One in every 25 diabetic patients of age 40 or older experiences diabetic macular edema (DME). Although there has been a paradigm shift in their management with the advent of anti-VEGF agents, a sizeable number of patients with DME are resistant to these agents despite frequent (monthly) intravitreal injections. Several recent studies have shown incomplete response to such agents despite rigorous study protocols, illustrating the problem of persistent DME. The management of these patients is challenging and frustrating
1. nerve fiber layer ( hyper reflective ) 2. ganglion cell layer ( hypo reflective ) 3. internal limiting membrane ( hyper reflective ) 4. inner plexiform layer ( hyper reflective ) 5. inner nuclear layer ( hypo reflective ) 6. outer plexiform layer ( hyper reflective ) 7. outer nuclear layer ( hypo reflective ) 8. external limiting membrane ( hyper reflective ) 9. photoreceptors ( hyper reflective ) 10.pigment epithelium ( hyper reflective ) Normal retina layers
MACULA layers
vitreous internal limiting membranenerve fiber layer ganglion cell layer & inner plexiform layer inner nuclear layer & outer plexiform layer photoreceptors pigment epithelium bruch’s membrane & choriocapilaris outer nuclear layer & external limiting memmbrane sclera TEN RETINAL LAYERS
LAYERS OF RETINA ON OCT
OCT can also produce a retinal thickness map. The OCT software automatically de- termines the inner and outer retinal boundaries and produces a false- color topographic map showing areas of increased thickening in brighter colors and areas of lesser thickening in darker colors
An assessment of macular volume can also be obtained from the retinal thickness map. By evaluating differences in retinal volume over time, the clinician can judge the efficacy of therapy RETINAL THICKNESS MAP
OCT gold standard in monitoring the progression and treatment response in DME patients . Retinal thickness is the most commonly used quantitative parameter. CIRRHUS measures the retinal thickness between ILM & anterior edge of RPE layer . Normal subjects central retinal thickness is 265 µm with CIRRHUS OCT .
Why macula only & not other parts of retina become odematous •Anatomically, the macula ( area centralis ) is defined as the central retinal region containing more than one layer of ganglion cells and presenting xanthophyll pigment, which is located mainly in the layer of the fibers of Henle and in the inner nuclear layer . At its center lies the fovea, a 1.5 mm depression that is devoid of ganglion cells and thinnest at its central area, the umbo.
Why macula only & not other parts of retina become odematous . The macula has several anatomical features that diverge from remaining retina; these include a high cell density with almost no extracellular space , loose arrangement of thick fibers in Henle’s layer, & avascularity of its central zone, which is a watershed zone between choroidal and retinal circulations primarily supplied by choriocapillaris.
Why macula only & not other parts of retina become odematous . These unique anatomical characteristics of macula, combined with its high metabolic demand, make it a preferential site for fluid accumulation and edema
Definition of Macular Edema • Macular edema is defined as accumulation of fluid in macula. Histologically, fluid accumulation may occur in intercellular space or may be intracellular, causing cellular swelling. Clinically, ME can be classified as diffuse, with generalized leakage throughout the posterior pole, or focal, if discrete areas of retinal thickening are present (usually caused by leakage from microaneurysms or dilated capillaries).
Definition of Macular Edema •In cystoid ME, clear fluid-filled cystoid spaces are present in the retina, most commonly in the outer plexiform and inner nuclear layers, and they are visible by ophthalmoscopy, OCT, and/or FA , which shows a typical petaloid pattern on FA
Pathophysiology of Macular Edema •Macular edema (ME) is final common pathway of numerous retinal diseases, and a major cause of blindness . In a physiological setting, the blood-retinal barrier (BRB), is largely formed by retinal pigment epithelium and retinal capillary endothelial cells. When this barrier is broken, water and proteins can enter the retinal extra- and intracellular space, with fluid accumulation leading to edema and vision loss.
AETIOLOGY MACULAR ODEMA
INNER BRB
OUTER BRB
Mechanisms in DR Leading to DME •For decades DR has been mainly considered simply a microvascular disorder, caused by endothelial cell damage, pericyte loss, and secondary breakdown of the inner blood- retinal barrier (BRB), leading to DME formation. Other factors such as hypoxia, altered blood flow, retinal ischemia, and inflammation are also associated with the progression of DR and DME
Mediators in DME (VEGF) • Vascular Endothelial Growth Factor (VEGF) is increased in human ocular fluids and plays a crucial role in ischemic retinal diseases, such as DR and retinal vein occlusions . The VEGF family includes different isoforms: VEGF-A has been shown to be upregulated in hypoxic tissues. In DR, the loss of retinal capillaries is believed to lead to hypoxia, which is the main stimulus for increased retinal expression of VEGF-A, mediated through hypoxia-inducible factors. VEGF-A has an angiogenic role that is responsible for the progression of DR to the proliferative stage. Apart from its angiogenic role, VEGF-A increases vascular permeability . Thus, the role of VEGF-A may be central to DME pathogenesis. Moreover, several studies have demonstrated the efficacy of anti-VEGF treatment of DME, thus supporting the role of VEGF.
Mediators in DME The Inflammatory Cascade • Efficacy of anti-VEGF treatment of DME support role of VEGF. Funk demonstrated that while anti- VEGF treatment decreases aqueous VEGF to sub-physiologic levels, this effect does not induce a complete resolution of DME. This study also demonstrated correlation between high intraocular cytokine levels and presence of DME. These data suggest that VEGF alone cannot be unique driving factor for development of DME
•DME is a result of endothelial dysfunction, increased vascular permeability, and release of several cytokines. Currently, anti-VEGF agents are the first-line therapy—and the gold standard—for managing DME. Although these agents are effective in several cases, some patients can be resistant to treatment. It is thought that inhibition of VEGF alone is insufficient, and that other proinflammatory cytokines and pathways may play more important roles in such resistant cases.
•Corticosteroids have multiple mechanisms of action, including inhibition of VEGF synthesis and leukocyte migration, down-regulation of intercellular adhesion molecule-1 expression, antagonism of prostaglandins and other cytokines, and an antipermeability effect, thereby enhancing the barrier function of vascular tight junctions. •The superiority of the dexamethasone implant over bevacizumab in macular edema control in some cases is thought to be related to its myriad mechanisms of action, as opposed to the sole action of VEGF
•Ranibizumab in 2012 & Aflibercept in 2014 were approved for treatment of DME by the FDA .chronic use of the anti-VEGF agents in this patient population warrants close monitoring by FA and OCT . •In the phase 3 RISE and RIDE studies that compared ranibizumab 0.3 and 0.5 mg, the higher dose was associated with more deaths without providing any efficacy advantage compared to the lower dose. As a result of these studies, Ranibizumab 0.3 mg is the approved dose for treating DME.
•when an eye fails to respond to anti- VEGF agents as expected (within the first 3-6 months), then we have a low threshold to switch to corticosteroids, with the goal of achieving macular deturgence at the earliest point in time. This threshold is even lower for pseudophakic eyes. An additional advantage is the need for fewer injections, and therefore fewer patient visits.
•As we know, corticosteroid agents are not without attendant risks. IOP elevation and cataract formation are most notable side effects, for which we regularly monitor our patients started on steroids . In our experience, these side effects, although common, are effectively managed with topical glaucoma medications and cataract surgery, respectively .
DEXAMETHASONE AND FLUCINOLONE IMPLANT • The dexamethasone intravitreal implant 0.7 mg was approved in 2014 for the treatment of DME, but was initially granted approval only in select patient groups (pseudophakes and phakic patients scheduled to undergo cataract surgery). Approval had been limited because of the increased number of adverse events— namely, cataract formation and iop spikes. The FDA removed restrictions on lens status in October 2014. • Fluocinolone acetonide 0.19 mg has been approved for the treatment of DME. As with the other steroids, however, this implant is associated with increased cataract formation, increased IOP, and the necessity for surgical treatment of elevated IOP. As a result, its approval has been limited to patients who have previously shown no significant rise in IOP.
Do use fluorescein angiography (FA) at baseline in your patients? •Yes For most patients, particularly those with macular edema, I will use FA look for areas of retinal neovascularization that cannot be detected clinically and areas of nonperfusion.
Do you do laser •Although laser usage has decreased, it has not been totally eliminated. I still use the laser for high-risk, extra-foveal areas with circinate exudates. Since the introduction of anti-VEGF, my laser use has significantly decreased. LASER is also used after anti vegf and steroid therapy to supplement there effect and to reduce the number of injections . If DME is not invoving centre and pt is asymptomatic then also we may apply laser .
INTRAVITREAL INJECTION
INTRAVITREAL INJECTIONS •Intravitreal injections and implants, most often an office procedure, are a safe, effective and common method of delivering medication to the eye. •Topical anesthesia usually sufficient • Sterile technique with eyelid speculum used • Small gauge needles 30-gauge can be used for intravitreal injections
INTRAVITREAL INJECTIONS •Effective method to deliver anti-vascular endothelial growth factor (VEGF) medications, corticosteroids, anti- bacterials, anti-viral agents, air and gas . For Anti VEGF 30 g needle and for triamcinolone 27 g needle is used . For dexamethasone implant 22 g inserter is used .
Intravitreal Injections Introduction •The office delivery of medication directly into the vitreous cavity via injection or implant has become commonplace in ophthalmology. This method allows for higher concentrations in the eye with less systemic absorption compared to other methods of medication administration. •In 1911, the injection of air into the vitreous cavity for retinal detachment (RD) repair was initially reported.
INTRAVITREAL INJECTION TECHNIQUE RECOMMENDA TIONS
Intra vitreal injection site
PRE-INJECTION PREPARATION •Treatment of overt, active blepharitis should be done prior to injection to attempt to decrease bacterial load, which may increase risk of infection. Patients with bacterial or viral conjunctivitis should be treated to manage infection and have their injection rescheduled. As with any surgical procedure all patients should sign an informed consent after being explained the risks, benefits, and alternatives to injection
INJECTION •The needle used for injection should be 30 g for a routine injection of medication or gas. A smaller needle gauge may result in less procedure discomfort for patients. The force required to penetrate the sclera is almost twice as much using a 27-gauge needle compared to 30- or 31-gauge needles. Needle length should be 1/2 to 5/8 inches to prevent globe trauma.
INJECTION which gauge of needle •The majority of retinal specialists surveyed in 2010 used a 30-gauge needle for BEVACIZUMAB and RANIBIZUMAB, and a 27-gauge needle for TRIAMCINOLONE. Triamcinolone can precipitate within the syringe and clog a needle smaller than 27-gauge.
INJECTION dose of drug for dme Intravitreal drug avastin lucentis triamcinolone Intravitreal dose 1.25 mg .3 mg 2 mg strength in vial 25 mg / ml 10 mg / ml 40 mg / ml Amt in cc injected .05 ml .03 ml .05 ml Needle gauge used 30 g 30 g 27 gauge To be repeated after 1 month 1 month 3 to 4 months Cost per inj 5 thousand rs 25 thousand rs 100 rs
INJECTION • Separate needles should be used to remove medication from vial & to perform the actual injection. This helps prevent both contamination & dulling of the needle. The injection is through pars plana and should be performed approximately 3.5 mm from the limbus in pseudophakic patients and 4.0 mm from the limbus in phakic patients. Injections are commonly performed in inferotemporal and superotemporal quadrants.
INJECTION The quadrant of injection may be influenced by indication for injection or other factors. For example, injecting an opaque steroid superiorly may obscure the visual axis more initially than injecting inferiorly. Similarly, a patient with a large inferotemporal retinoschisis cavity may benefit from having their injection in another quadrant
INJECTION •The traditional injection method involves inserting needle perpendicular to the ocular scleral surface in a single plane to penetrate globe. Another tunneling method has been described which involves needle insertion at a 30 degree angle initially with repositioning of the needle to perpendicular and towards the center of the globe. Final needle direction should always be towards the center of the eye to prevent damage to other intraocular contents.
INJECTION •Inserting needle perpendicular to eye is preferred over other techniques . •The injection should be done in a slow, steady maneuver to prevent a sudden flux through the vitreous cavity, as this may disrupt vitreoretinal adhesions. •A sterile cotton tip applicator may be used to prevent reflux for injections
Injection Technique • Confirm informed consent obtained • Surgical time-out to confirm correct medication and correct eye •Place patient in near supine position; make sure the headrest of the chair is stable • Topical proparacaine (wait 10-15 seconds before placing Betadine) • 10% Betadine swab to inferior cul-de-sac, to allow Betadine to start working; ask patient to blink multiple times to spread Betadine .
Injection Technique •Place 2% lidocaine jelly on the eye, focusing on inferotemporal quadrant. • (Note: Betadine placed prior to lidocaine jelly to sterilize the globe prior to placing the jelly so as not to have bacteria trapped in the jelly and possibly increase risk of endophthalmitis). • Ask patient to close their eyes, and return in 2-5 minutes.
Injection Technique •Apply Betadine swab again to inferotemporal quadrant and inferior cul-de-sac, as well as to eyelashes (do not manipulate much so as not to liberate bacteria from the lashes) • Place sterile closed-blade eyelid speculum (careful not to cause corneal abrasion and save yourself a phone call from the patient with a painful corneal abrasion). • Clean again with Betadine
Injection Technique • Mark location of injection: 3-3.5mm for pseudophakes, 3.5-4.0 mm for phakic patients. Tip: Can use the end of a TB syringe (without needle attached) to mark 3.5-4.0 mm. After marking and causing an indentation with the TB syringe, you can place Betadine again - Betadine will sit in indentation ring and nicely highlight the injection site. Careful with subconj anesthesia so as not to cause too much chemosis or subconj hemorrhage as this case
Injection Technique •Have the patient look 180 degrees away from the injection site. For example, if injecting the right eye in the inferotemporal quadrant, ask the patient to look up and to the left. •Hold syringe in dominant hand, and a cotton tip in the non-dominant hand •Do not talk and ask patient not to talk during the injection. Make sure the needle tip (which is usually short 30g) is always kept absolutely sterile •Using your dominant hand, rest your wrist on the patient's cheek for hand stabilization
Injection Technique •Insert the needle at marked site in a smooth and single motion, aiming for mid-vitreous cavity •Insert the short 30g needle about 1/2 length in (to make sure you are in the vitreous cavity and not in subretinal space) •Swing over with your non-dominant hand to push down on the plunger in a smooth fashion. (Note: some surgeons prefer to inject with one-hand; the author feels that using two hands is more stable).
Injection Technique • Do not move the needle while inside the eye so as to not cause traction on the vitreous and potentially cause a retinal tear / detachment. •As you remove the needle out, cover the injection site with a cotton tip that is in your non-dominant hand •Rinse the Betadine off of the patients eye
Injection Technique •Ensure optic nerve perfusion (patient should be at least light perception). Paracentesis is usually not required, unless a large volume of medication is injected. Some Retina Specialists prefer to check and document the IOP and not let the patient leave until the IOP has reduced to an acceptable level.
BEVACIZUMAB • Recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting VEGF-A • It received its first approval in 2004, for combination use with standard chemotherapy for metastatic colon cancer • It has since been approved for use in • Certain lung cancers, • Renal cancers, • Ovarian cancers • Glioblastoma multiforme of the brain
ADMINISTRATION AND DOSING •In ophthalmology, Bevacizumab is typically given by transconjunctival intravitreal injections into the posterior segment • Intravitreal injections for retinal pathologies are typically administered at 4-6 week intervals, although this varies widely based on disease and response. •DOSE: The typical dose is 1.25mg in 0.05ml in adults,and half that dose in babies.
PHARMACOKINETICS •Time to reach steady state is predicted to be 100 days. •Estimated half-life is approximately 20 days
RANIBIZUMAB • Available as Injection, intravitreal 10 mg/mL • Binds to and inhibits the biologic activity of VEGF-A Pharmacokinetics: • Absorption: • C max is below the concentration thought necessary to inhibit biological activity of VEGF-A by 50% (0.3 to 2.36 ng/mL). • T max is 24 h. • Elimination: Vitreous elimination half-life is approximately 9 days.
AFLIBERCEPT • Recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin
Based on recent clinical trial data, which anti-VEGF do you use first? • I start almost every patient on bevacizumab because of affordability . Patients with relatively good vision and not a great deal of edema would probably do well on any of the anti-VEGF drugs. (DRCR protocol T data) . Overall, aflibercept (Eylea, Regeneron) has proved best for patients with diabetic retinopathy and vision less than 20/40 or with >400 μm of edema.
Based on recent clinical trial data, which anti-VEGF do you use first? • I would, however, switch any nonresponders with severe edema to another anti-VEGF because they have different mechanism of action . I might also switch a patient with poor vision (20/200) to aflibercept if they had more than 400 μm of edema, based on Protocol T findings ( )
threshold for starting anti- VEGF injections in a patient? •If my patient is symptomatic, I begin treatment. But DME differs from AMD in several ways. For one, you do not have to treat a patient with DME immediately. If a patient is 20/20 or 20/25 and asymptomatic, even with 350 to 400 μm of edema, I watch and wait.
threshold for starting anti- VEGF injections in a patient? •Improving this patient’s condition may require seven to eight ocular injections during the first year, and outcomes might not be discernable to the patient. •If a patient’s vision worsens within 2 or 3 months, I begin injections
NON RESPONDER •For me, a nonresponder is someone who has had less than a 10% or 20% improvement on their OCT within the first month of treatment. Even though anti-VEGF might have had a minimal effect on the macular edema in 4 or 5 months, you might see a profound effect on the patient’s level of retinopathy, making the case for continuing the anti-VEGF or combining it with a steroid where required for edema.
Switching or combine steroid • Switching is not the issue. I think it is more a question of continuing the anti-VEGF and then adding a drug. Some patients are pure anti-VEGF responders, while others do extremely well on steroids alone. Some do well on both. In some cases after steroid injections, patients re-accumulate fluid quickly (within 8 weeks) and require anti- VEGF therapy again. Instead of switching, it might be more a question of continuing the anti-VEGF and then periodically giving patients a bolus dose of a steroid.
If you choose to include steroids in your treatment regimens, which one do you use first •I use triamcinolone suspension, 1 mg to 2 mg as recommended by the Protocol B and the SCORE studies. I used to use a 4-mg dose, but now we know that the same biologic effect occurs with 1 mg, and that greatly reduces the complication rate.
Chronicity of macular odema • Does length of time a patient has had macular edema & their history of treatment make you move to steroids faster than you would for a patient with recent-onset macular edema? • I am certainly more likely to require something additional for long-standing edema, as borne out in the FAME study. Any patient with chronic edema has a problem, whether it is denial or lack of follow-up. Thus, it is important to consider using something that will be less of a burden on these patients .
Chronicity of macular odema •The FAME study showed a significant improvement using the fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien, Alimera Sciences) in patients with long-standing macular edema, but very often as clinicians, we do not know how long a patient has had their macular edema. I would begin treatment with anti-VEGF followed by IV TA 2 mg if the patient does not respond promptly.
Use of flucinolone •It is important to provide a steroid challenge before resorting to fluocinolone. You have to know if a patient will respond to a steroid. Bear in mind that patients would need multiple injections with an intravitreal before we should start fluocinolone, since a significant number of patients will not get any steroid rise, even after their first, second, or sometimes after their third injection.
STEROID IN DME •For younger patients who do not have cataracts, clinicians must explain that using a steroid will hasten the formation of a cataract. As we dry out their retina, their vision may worsen, necessitating cataract surgery. However, the 20-year insulin- dependent diabetic might not respond to anti-VEGF until you add the steroid. At the same time, you will be putting them on a road you do not want them to travel.
STEROID IN DME • True, but I assure my patients that cataracts will not make them go blind, and they can be fixed; however, if their macular edema persists, it will cause substantial vision loss . • In Protocol I, pseudophakic patients do as well with steroids as they do with the anti- VEGF and require only three injections in the first year. So, I think there is a place for steroids
IST YEAR ANTI DME TREATMENT • The great outcomes in RISE/RIDE, VIVID/VISTA and Protocol I require a very heavy burden, especially in that first year. That is one of the real key points, as there is a fair amount of undertreatment in the community in the first year. In AMD, the initiation phase/loading dose has usually involved three injections; and people have been applying this concept to DME. However, in DME, there is a much heavier injection burden in the first year. The visual acuity curves in RISE/RIDE show an improvement after the first three injections, but the curve continues to gradually go up over the first 18 months. It is a very steady, gradual improvement in both visual acuity and OCT outcomes
DRCR.net Protocol I • DRCR.net Protocol I, patients were started off with a loading dose of four injections, but if patients did not have 20/20 vision and no edema, they were given an additional two injections. So in reality, it was a six-dose loading phase. Comparatively speaking, in AMD it is traditionally a three-dose loading phase.
DRCR.net Protocol I •Most of the AMD studies that utilized a p.r.n. dosing strategy required six to seven injections in the first year in comparison to Protocol I and T, where the average was higher with nine to 10 injections . Protocol I was instrumental in showing us that monthly treatment is not necessary to achieve vision stabilization and letter gain comparable with the more continuous treatment regimens in RISE/RIDE .
DRCR .net protocol I intravitreal anti vegf agents with early or deferred laser Superior Over laser alone laser with steroids steroids alone or or
DRCR .net protocol T • All Three Anti Vegf Agents RANIBIZUMAB , BEVACIMIZUMAB & AFLIBERCEPT Are Effective In Management Of DME . •RANIBIZUMAB And AFLIBERCEPT Are Slightly Better Than BEVACIMIZUMAB if vision is less But Latter Is More Economical .
TREATMENT OF DME VS ARMD • It is important to distinguish wet AMD from DME—these are, indeed, two very different diseases. For patients with wet AMD, we are treating choroidal neovascularization with exudation. For patients with DME, we are only treating edema, the source of which is retinovascular incompetence. While we are trying to get that macula to a satisfactory dry status, the burden over time tends to fall off in DME.
TREATMENT OF DME VS ARMD •In wet AMD, there is more of a continuous burden year after year for an indefinite time frame in most patients. In DME, studies with discontinuous or P.R.N. style therapy such as Protocol I and Protocol T, many patients were eventually able to cease therapy .
TREATMENT OF DME VS ARMD •With wet AMD, whether it is P.R.N. or TREAT- AND-EXTEND (TAE), the mean number of treatments will typically reach a plateau after the first year. It does not tend to decrease much thereafter. But with DME, P.R.N. studies that we have seen, Protocol I in particular, started with a mean of eight to nine injections in year 1, then three to four in year 2, two to three in year 3 and by years 4 and 5, many had no further treatment .
How to reduce numer of injections •Steroids can be used for reduced burden of treatment as a combination therapy, but probably not as a low-burden monotherapy for most diabetic patients. There may be special cases where steroids are best choice as a monotherapy, such as in a newly pseudophakic patient who develops macular edema post-operatively, but results are simply not as robust as with anti VEGF therapy.
DME BUT STILL NO TREATMENT • Protocol I allowed for patients to have DME if it was stable without a decrease in vision. It was possible to have patients with persistent DME, as long as vision did not drop and there was not an increase in the OCT thickness. In DME, we now know that persistent DME does not translate into lost vision. With results reported out to 5 years, Protocol I showed those great visual improvements at year 1 could be maintained with an injection burden that dramatically decreased in years 2 through 5.
Type of response to anti VEGF •My patients typically fall into one of three categories. The first is what we all want—a patient who is exquisitely sensitive to anti- VEGF therapy and needs only one injection to have a very dramatic improvement. The second group is what we dread—no measurable response with anti-VEGFs after three or four injections. The third group, however, is what most of us see—people who have some response to the anti-VEGF therapy.
COMBINATION THERAPY IN DME • Monotherapy with anti-VEGF agents or sequential monotherapy, anti-VEGF followed by steroids, gives us a good result. There is a role for laser at some point in the process in selected case such as when there is persistent or refractory edema and you see an obvious source of leakage on fluorescein angiography (FA) with large, leaking microaneurysms. Targeted focal laser can provide adequate drying and stabilization, so I do consider it. I almost never use it for center-involving DME, but there is a role for laser as second-line treatment .
final • After all the studies, I think it is safe to say anti-VEGF is our first-line defense. We have long-term outcomes from the studies, and those results are extremely efficacious. But it is a complex disease. Even when you look at the results from Protocol T, the agent that worked the best (aflibercept) still left one-third of the patients with more than 250 microns of edema at 1 year. And that range was as high as 60% with bevacizumab. Most of us are using bevacizumab, and 60% of our patients are going to have persistent fluid after 10 treatments in the first year. That means there’s a role for other treatments. We don’t have large studies to dictate whether or not the intravitreal triamcinolone should be our preferred second-line agent. There are some new studies being undertaken by the DRCR.net on the combination of anti-VEGF and steroid
ROLE OF LASER • Laser may be appropriate in patients with focal extrafoveal macular edema secondary to focal microaneurysms. If one laser treatment could spare them the burden of a series of multiple injections, it may be worthwhile to consider. • The gold standard based on evidence accumulated over the past few years is that for center-involving, symptomatic DME, pharmacotherapy is the gold standard. Laser has a role for the center-involving patient as a deferred therapy, and is still a primary therapy for non-center-involving.
How to tell pt requirement of so many injections . • I discuss that anti-VEGF treatment is an ongoing process and in some ways analagous to chemotherapy. I emphasize that regular injections often keep the disease process under control, may be able to improve the vision. While the initial injections occur monthly, it may be possible to reduce the number of visits or injections over time
How to tell pt requirement of so many injections • There is a different conversation for the AMD patient and the DME patient. I tell the wet AMD patient that these injections serve as disease control and there is a good chance for good outcomes, but it is going to be an indefinite, ongoing treatment process. I do let them know that, while rare, some patients do improve to the point where we can stop treatment altogether. • With DME, I tell patients there will be a lot of treatment up front, a lot of visits initially, as the disease is usually slow to respond. But I also tell them that compared with AMD, there is a better chance of coming off therapy
How to tell pt requirement of so many injections • For DME, I explain to patients that we will require monthly injections for a prolonged period of time, and that as the disease stabilizes, there may be an opportunity for us to increase the interval between injections. I do alert them that there will be multiple injections during that first year but that too will vary from one patient to the next. Once I have a patient’s visual acuity and edema within a normal range, I begin a TAE regimen. I inform him or her that we may need to cut back interval between injections if there is a recurrence. If they have stable vision but thick edema, I will discuss need to introduce combination therapy
COMBINATION THERAPY IN DME • We begin with an anti-VEGF and are guided by Protocol T. If the patient cannot demonstrate improvement after three intravitreal injections, we consider adding a steroid. We are constantly walking the line between pushing the VEGF or inflammatory component. So we continue with the anti-VEGF in those that do respond until we hit the maximum effect & Once the patient has stable vision .
COMBINATION THERAPY IN DME • If there is continued macular thickening, we consider introducing either a steroid or laser therapy. FAME did show one subgroup with chronic DME for more than 3 years did a lot better on steroids, so that may be a key differentiating point. It is a nice option to have steroids for people who don’t respond to our previous treatments.
SWITCHING •I switch between anti-VEGF agents first because ranibizumab and aflibercept have different mechanisms of effect. If that does not work, I might switch to a steroid, combine medications, or consider a laser, either extrafoveal focal or micropulse
STEROIDS •Steroids also can be considered for patients who have an increased risk of thromboembolic events and want to avoid the theoretical risk with Anti-VEGF agents, for treating pregnant women with DME rather than potentially exposing the fetus to an anti-VEGF agent, and finally for people who are not willing to tolerate the high injection burden (nine to 10 treatments in the first year) with anti-angiogenic therapy
STEROIDS •I like adding steroids in pseudophakic patients. I am more apt to try another anti- angiogenic agent in a phakic patient before going straight to a steroid. I like steroids for DME, but it is not without a cost. I will probably do at least one antiangiogenic switch between agents after Protocol T before going to steroid in phakic patients. But it will not be a rapid switch
Intravitreal Steroids
Intravitreal Steroids •Corticosteroids are well known for their antiangiogenic, antiedematous, and anti-infl ammatory properties. Consequently, these have been widely used in treatment of many retinal diseases since the early 1950s. Later, intravitreal steroids emerged as an essential tool, allowing for optimal drug efficacy when given locally. The topical or local route offers the great advantage that there is no significant systemic side effect
Intravitreal Steroids • Randomized studies have properly shown that steroids are very effective in the treatment of posterior segment diseases such as retinal vascular occlusion, diabetic macular edema, and uveitis. This is true for both, disease activity and visual outcome. Today because of the anti-infl ammatory, antiangiogenic, and antipermeability properties, steroids are an attractive therapeutic option for vascular and inflammatory retinal diseases
Intravitreal Steroids •Recent advances in ocular drug delivery methods led to the development of intraocular implants, which help to provide prolonged treatment with a continuous drug release. An increasing number of ophthalmologists use intravitreal steroids for the treatment of various posterior segment disorders, not only when traditional therapeutic methods have failed, but more and more as a first-line therapy .
Relative anti-inflammatory strength of various corticosteroids
Treatment of DME with Triamcinolone •Triamcinolone has been shown to reduce VEGF production, decrease prostaglandin production, and stabilize the blood–retinal barrier . This action of decreasing vascular permeability has led investigators to try triamcinolone in the treatment of DME .
Treatment of DME with Triamcinolone •studies have shown the efficacy of IVTA to temporarily reduce DME and increase visual acuity . The mean reduction in macular thickening reaches 85 % 3 months after injection with a mean two-line improvement of visual acuity . However, recurrence of DME occurs between 3 and 6 months after injection.
Treatment of DME with Triamcinolone •Recurrence of DME occurs between 3 and 6 months after injection. Due to the high rate of complications and the absence of evidence of its superiority over laser photocoagulation, IVTA is generally reserved for patients refractory to focal/grid laser therapy and anti-VEGF agents .
Treatment of DME with Dexamethasone • The dexamethasone 700 μg posterior segment drug delivery system (Ozurdex®) is a bioerodible Implant delivered intravitreally using a 22-gauge injector . • Considering the higher cost but similar efficacy , side effect profile and frequency of administration we generally prefer 2mg dose of Triamcinolone over Dexamethasone implant (Ozurdex) .
Treatment of DME with Dexamethasone • treatment was well tolerated and had an acceptable safety profile. Similar to IVTA, DEX-DDS has the advantage of repeatability, as long as the IOP and cataract effects are mitigated. The advantages of DEXDDS over intravitreal triamcinolone include a possible longer duration of action, absence of postinjection “visual clouding” or floater-like symptoms, and a lower rate of IOP increase. month 12.
Treatment of DME with Fluocinolone Acetonide FAc Insert • Two fluocinolone acetonide (FAc) intravitreal devices have been studied for the treatment of DME: a FAc implant (Retisert) and a FAc insert (ILUVIEN®). • ILUVIEN is a non-bioerodible insert implanted in the eye via injection through the pars plana using a 25-gauge needle. ILUVIEN contains 0.19 mg of Flucinolone acetonide .
Treatment of DME with Fluocinolone Acetonide FAc Insert FAME •The Fluocinolone Acetonide for Macular Edema (FAME) studies were two large prospective, randomized, controlled studies that followed 956 eyes randomized to receive 0.2-μg/day (lowdose) or 0.50-μg/day (high- dose) inserts or sham. The most common adverse event was cataract, and almost all phakic patients in the FAc insert groups developed cataract
Treatment of DME with Fluocinolone Acetonide FAc Insert FAME •The incidence of increased IOP (37.1 and 45.5 %, in the low-dose and high- dose insert groups, respectively), need for IOP-lowering medication (38.4 and 47.3 %, respectively), incisional glaucoma surgery (4.8 and 8.1 %, respectively), and trabeculoplasty (1.3 and 2.5 %, respectively)
Treatment of DME with steroids. adverse events different steroids
Conclusions •Interestingly, reductions in OCT central subfield thickness in ptotocol I were similar between ranibizumab and triamcinolone groups, suggesting the visual benefits of intravitreal corticosteroids may be tempered by their side-effects of cataract and elevated IOP . • Many randomized clinical studies have shown the clinical efficacy of steroid injections to treat DME, but their use is limited by their adverse events, including cataract progression and intraocular pressure (IOP) increase .
Role For Surgery In Patients With DME • Vitreomacular traction (VMT) is something we watch very carefully; however, we have been surprised to see some patients with epiretinal membrane (ERM) dry out that we suspected would need vitrectomy surgery. In the patients with ERMs, edema tends to recur quickly, but we do much less vitrectomy surgery in these patients now because the anti-VEGFs actually improve the anatomic configuration of the retina, even in presence of an ERM. Some patients have taught hyaloids or ERM that refuse to dry out despite intravitreal anti-VEGF and/or steroid injections you may consider surgery.
Trials of different anti VEGF
Trials of different steroids
Advantages of steroid
Disadvantages of steroid
Treatment details avastin •The 1.25 mg dosage is administered monthly . "Another consideration with bevacizumab is the preparation of doses for intravitreal injection. A common approach used in the clinical studies is for a pharmacy department to aseptically prepare a batch of syringes for use in a later clinic with one study reporting storage of such syringes for up to 14 days in a refrigerator.
Treatment details avastin • Each vial of Avastin® contains 100 mg of bevacizumab, sufficient for 80 doses however it would be difficult to extract this exact quantity. • One method employed is to fill syringes with between 2.0 and 2.5 mg of bevacizumab (0.08 to 0.10 millilitre) resulting in up to 50 doses per vial of Avastin®."
Treatment details avastin • "An alternative is for the clinical team to prepare doses in the treatment room immediately prior to administration using aseptic technique but this option may present greater risk of cross contamination. The number of doses extracted per vial could be reduced to a minimum of one, which will reduce the risk of cross contamination but will also eliminate some of the cost benefits presented by use of bevacizumab."
Treatment details avastin • "Pre-packaged syringes of bevacizumab for intravitreal use are available to purchase from special manufacturing units. Moorfields Pharmaceuticals, of Moorfields NHS hospital, can supply syringes of 1.25 mg in 0.05 ml at £85 per syringe, excluding VAT and delivery charges. The syringes must be stored in a refrigerator and have an expiry date of six weeks from the date of manufacture, which would mean an effective expiry of about two to four weeks from receipt of delivery."
Treatment details avastin •"Any compounding of a single vial of drug into multiple dose units will carry some risk of microbial and particulate cross contamination beyond that associated with preparation of a single dose. This risk can be minimised by performing the procedure in an aseptic clean room using trained staff and storing the finished product in a refrigerator."
Safety Of Bevacizumab For The Treatment Of AMD • The systematic review concluded that adverse events were rare amongst 1,400 patients who had received a total of several thousand intravitreal injections of bevacizumab. In the former report, with a mean follow-up of 3.5 months, the maximum incidence of any single event was 0.21% . In the latter report, that included a majority proportion of non-AMD patients, the total incidence of systemic adverse events was 1.5% (18 patients) and included hypertension, stroke, myocardial infarction, aneurysm, digit amputation, and fatalities, although none were conclusively and causally linked to bevacizumab. • The review authors state that the type and incidence of effects ‘does not seem to be very different from … two large RCTs of ranibizumab
DME RECOMMENDATIONS
summary •For patients in whom macular edema has been confirmed clinically, we usually order OCT to get a baseline retinal thickness & volume. • If there are moderate to severe diabetic changes in the periphery, we do a FA to establish degree of nonperfusion and to rule out neovascularization elsewhere. If we were considering any form of focal laser therapy for extra foveal leakage, we would also do an angiogram. we also check HbA1c hemoglobin levels to determine if the patient’s diabetes is under control .
summary • For symptomatic patients or patients with some vision loss and central retinal thickening on OCT, our first-line treatment regimen is therapy. For asymptomatic patients who have good vision, we , as outer-retinal disease affords you the luxury of time. If a patient’s condition worsens over a period of time, particularly if they have 350 μm or more of fluid, we start treatment—usually with bevacizumab (Avastin)—even if they have good vision. we also try to get all patients to improve their control of their blood pressure, blood sugar, and lipids.
DME • Our strategy in management of DME is as follows – for cases of centre involving DME with diffuse leak or leak close to the fovea, intravitreal anti-VEGF followed by laser is used. . . In cases of DME where the leak is away from macular centre without significant thickening of fovea laser alone is preferred .
•The major problems with anti-VEGF therapy are cost and frequency of administration. At present, ranibizumab at a dose of 0.3 mg has undergone the most rigorous testing, but due to cost issues, worldwide, BEVACIZUMAB 1.25 mg is the drug of choice for DME . . • Triamcinolone 2 mg is used to enhance the effect or to decrease number of required injections of anti vegf drugs keeping in mind its complications of cataract and glaucoma . • Focal and grid laser should be used where indicated .
THANK YOU DR DINESH DR SONALEE
Diabetic macular odema update 2016

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Diabetic macular odema update 2016

  • 1.
    DIABETIC MACULAR ODEMA 2016 ANTIVEGF ,STEROIDS,LASER Indoredrishti.wordpress.com
  • 2.
    DR DINESH MITTALDR SONALEE MITTAL DRISHTI EYE HOSP VIJAYNAGAR INDORE
  • 3.
    Diabetic Macular Odema theleading cause of decrease in vision in Diabetic Retinopathy
  • 4.
    •In western countries,the expected prevalence of diabetic retinopathy is close to 35 % in the diabetic population, while DME may be present in 7–10 % of patients . After 2 years, over half of patients with DME will lose two or more lines of visual acuity (VA) . Worldwide, it has been estimated that 21 million people have DME
  • 5.
    Treatment of DME •Treatment for DME includes treatment of the systemic disease by maintaining tight blood sugar and blood pressure control, weight loss, and the lowering of circulating triglycerides and cholesterol. •However, once there is progression to DME,therapy is indicated to slow the rate of vision loss and to attempt to improve the long- term prognosis.
  • 6.
    retinal thickening of theposterior pole and detected by slit lamp biomicroscopy or optical coherence tomography (OCT ) DIABETIC MACULAR ODEMA ( DME )
  • 7.
    Evaluation • Previous historyof diagnosis or treatment if any should be taken thoroughly. • Comprehensive eye examination including VISUAL ACUITY , IOP measurement , • slit lamp examination of anterior segment and dilated funduscopic examination
  • 8.
    Evaluation • ophthalmoscopy ina dilated pupil is helpful. • posterior pole examination is best done with slit lamp biomicroscopy with accessory lenses . • imaging modalities commonly used in the management are fundus photography , FA & OCT
  • 9.
    OCT and FA arethe most useful investigations in DME • Confirm presence macular edema • Know type of macular edema • Assess macular thickness • Know response to intravitreal pharmacotherapy • For follow up and documentation OCT role in DME
  • 10.
    FA role • Typeof leak focal or diffuse • Rule out macular ischaemia Increasingly OCT is being used for evaluation of macular edema . Spectral domain ( SD OCT ) has replaced time domain OCT ( TD OCT ) .
  • 11.
    Diabetic macular odema •Slit lamp biomicroscopy , color fundus photography or ophthalmoscopy may not be able to detect mild DME . Here OCT is very helpful in measuring central foveal thikness. • OCT has become gold standard in monitoring the progression and treatment response in DME • give micrometer sensitive measurements in central retinal thickness.
  • 12.
    DME • One inevery 25 diabetic patients of age 40 or older experiences diabetic macular edema (DME). Although there has been a paradigm shift in their management with the advent of anti-VEGF agents, a sizeable number of patients with DME are resistant to these agents despite frequent (monthly) intravitreal injections. Several recent studies have shown incomplete response to such agents despite rigorous study protocols, illustrating the problem of persistent DME. The management of these patients is challenging and frustrating
  • 13.
    1. nerve fiberlayer ( hyper reflective ) 2. ganglion cell layer ( hypo reflective ) 3. internal limiting membrane ( hyper reflective ) 4. inner plexiform layer ( hyper reflective ) 5. inner nuclear layer ( hypo reflective ) 6. outer plexiform layer ( hyper reflective ) 7. outer nuclear layer ( hypo reflective ) 8. external limiting membrane ( hyper reflective ) 9. photoreceptors ( hyper reflective ) 10.pigment epithelium ( hyper reflective ) Normal retina layers
  • 14.
  • 15.
    vitreous internal limiting membranenervefiber layer ganglion cell layer & inner plexiform layer inner nuclear layer & outer plexiform layer photoreceptors pigment epithelium bruch’s membrane & choriocapilaris outer nuclear layer & external limiting memmbrane sclera TEN RETINAL LAYERS
  • 16.
  • 17.
    OCT can alsoproduce a retinal thickness map. The OCT software automatically de- termines the inner and outer retinal boundaries and produces a false- color topographic map showing areas of increased thickening in brighter colors and areas of lesser thickening in darker colors
  • 18.
    An assessment ofmacular volume can also be obtained from the retinal thickness map. By evaluating differences in retinal volume over time, the clinician can judge the efficacy of therapy RETINAL THICKNESS MAP
  • 21.
    OCT gold standardin monitoring the progression and treatment response in DME patients . Retinal thickness is the most commonly used quantitative parameter. CIRRHUS measures the retinal thickness between ILM & anterior edge of RPE layer . Normal subjects central retinal thickness is 265 µm with CIRRHUS OCT .
  • 22.
    Why macula only& not other parts of retina become odematous •Anatomically, the macula ( area centralis ) is defined as the central retinal region containing more than one layer of ganglion cells and presenting xanthophyll pigment, which is located mainly in the layer of the fibers of Henle and in the inner nuclear layer . At its center lies the fovea, a 1.5 mm depression that is devoid of ganglion cells and thinnest at its central area, the umbo.
  • 23.
    Why macula only& not other parts of retina become odematous . The macula has several anatomical features that diverge from remaining retina; these include a high cell density with almost no extracellular space , loose arrangement of thick fibers in Henle’s layer, & avascularity of its central zone, which is a watershed zone between choroidal and retinal circulations primarily supplied by choriocapillaris.
  • 24.
    Why macula only& not other parts of retina become odematous . These unique anatomical characteristics of macula, combined with its high metabolic demand, make it a preferential site for fluid accumulation and edema
  • 25.
    Definition of MacularEdema • Macular edema is defined as accumulation of fluid in macula. Histologically, fluid accumulation may occur in intercellular space or may be intracellular, causing cellular swelling. Clinically, ME can be classified as diffuse, with generalized leakage throughout the posterior pole, or focal, if discrete areas of retinal thickening are present (usually caused by leakage from microaneurysms or dilated capillaries).
  • 26.
    Definition of MacularEdema •In cystoid ME, clear fluid-filled cystoid spaces are present in the retina, most commonly in the outer plexiform and inner nuclear layers, and they are visible by ophthalmoscopy, OCT, and/or FA , which shows a typical petaloid pattern on FA
  • 27.
    Pathophysiology of Macular Edema •Macularedema (ME) is final common pathway of numerous retinal diseases, and a major cause of blindness . In a physiological setting, the blood-retinal barrier (BRB), is largely formed by retinal pigment epithelium and retinal capillary endothelial cells. When this barrier is broken, water and proteins can enter the retinal extra- and intracellular space, with fluid accumulation leading to edema and vision loss.
  • 28.
  • 29.
  • 30.
  • 31.
    Mechanisms in DR Leadingto DME •For decades DR has been mainly considered simply a microvascular disorder, caused by endothelial cell damage, pericyte loss, and secondary breakdown of the inner blood- retinal barrier (BRB), leading to DME formation. Other factors such as hypoxia, altered blood flow, retinal ischemia, and inflammation are also associated with the progression of DR and DME
  • 32.
    Mediators in DME(VEGF) • Vascular Endothelial Growth Factor (VEGF) is increased in human ocular fluids and plays a crucial role in ischemic retinal diseases, such as DR and retinal vein occlusions . The VEGF family includes different isoforms: VEGF-A has been shown to be upregulated in hypoxic tissues. In DR, the loss of retinal capillaries is believed to lead to hypoxia, which is the main stimulus for increased retinal expression of VEGF-A, mediated through hypoxia-inducible factors. VEGF-A has an angiogenic role that is responsible for the progression of DR to the proliferative stage. Apart from its angiogenic role, VEGF-A increases vascular permeability . Thus, the role of VEGF-A may be central to DME pathogenesis. Moreover, several studies have demonstrated the efficacy of anti-VEGF treatment of DME, thus supporting the role of VEGF.
  • 33.
    Mediators in DME TheInflammatory Cascade • Efficacy of anti-VEGF treatment of DME support role of VEGF. Funk demonstrated that while anti- VEGF treatment decreases aqueous VEGF to sub-physiologic levels, this effect does not induce a complete resolution of DME. This study also demonstrated correlation between high intraocular cytokine levels and presence of DME. These data suggest that VEGF alone cannot be unique driving factor for development of DME
  • 34.
    •DME is aresult of endothelial dysfunction, increased vascular permeability, and release of several cytokines. Currently, anti-VEGF agents are the first-line therapy—and the gold standard—for managing DME. Although these agents are effective in several cases, some patients can be resistant to treatment. It is thought that inhibition of VEGF alone is insufficient, and that other proinflammatory cytokines and pathways may play more important roles in such resistant cases.
  • 35.
    •Corticosteroids have multiplemechanisms of action, including inhibition of VEGF synthesis and leukocyte migration, down-regulation of intercellular adhesion molecule-1 expression, antagonism of prostaglandins and other cytokines, and an antipermeability effect, thereby enhancing the barrier function of vascular tight junctions. •The superiority of the dexamethasone implant over bevacizumab in macular edema control in some cases is thought to be related to its myriad mechanisms of action, as opposed to the sole action of VEGF
  • 36.
    •Ranibizumab in 2012& Aflibercept in 2014 were approved for treatment of DME by the FDA .chronic use of the anti-VEGF agents in this patient population warrants close monitoring by FA and OCT . •In the phase 3 RISE and RIDE studies that compared ranibizumab 0.3 and 0.5 mg, the higher dose was associated with more deaths without providing any efficacy advantage compared to the lower dose. As a result of these studies, Ranibizumab 0.3 mg is the approved dose for treating DME.
  • 37.
    •when an eyefails to respond to anti- VEGF agents as expected (within the first 3-6 months), then we have a low threshold to switch to corticosteroids, with the goal of achieving macular deturgence at the earliest point in time. This threshold is even lower for pseudophakic eyes. An additional advantage is the need for fewer injections, and therefore fewer patient visits.
  • 38.
    •As we know,corticosteroid agents are not without attendant risks. IOP elevation and cataract formation are most notable side effects, for which we regularly monitor our patients started on steroids . In our experience, these side effects, although common, are effectively managed with topical glaucoma medications and cataract surgery, respectively .
  • 39.
    DEXAMETHASONE AND FLUCINOLONE IMPLANT •The dexamethasone intravitreal implant 0.7 mg was approved in 2014 for the treatment of DME, but was initially granted approval only in select patient groups (pseudophakes and phakic patients scheduled to undergo cataract surgery). Approval had been limited because of the increased number of adverse events— namely, cataract formation and iop spikes. The FDA removed restrictions on lens status in October 2014. • Fluocinolone acetonide 0.19 mg has been approved for the treatment of DME. As with the other steroids, however, this implant is associated with increased cataract formation, increased IOP, and the necessity for surgical treatment of elevated IOP. As a result, its approval has been limited to patients who have previously shown no significant rise in IOP.
  • 40.
    Do use fluoresceinangiography (FA) at baseline in your patients? •Yes For most patients, particularly those with macular edema, I will use FA look for areas of retinal neovascularization that cannot be detected clinically and areas of nonperfusion.
  • 41.
    Do you dolaser •Although laser usage has decreased, it has not been totally eliminated. I still use the laser for high-risk, extra-foveal areas with circinate exudates. Since the introduction of anti-VEGF, my laser use has significantly decreased. LASER is also used after anti vegf and steroid therapy to supplement there effect and to reduce the number of injections . If DME is not invoving centre and pt is asymptomatic then also we may apply laser .
  • 42.
  • 43.
    INTRAVITREAL INJECTIONS •Intravitreal injectionsand implants, most often an office procedure, are a safe, effective and common method of delivering medication to the eye. •Topical anesthesia usually sufficient • Sterile technique with eyelid speculum used • Small gauge needles 30-gauge can be used for intravitreal injections
  • 44.
    INTRAVITREAL INJECTIONS •Effective methodto deliver anti-vascular endothelial growth factor (VEGF) medications, corticosteroids, anti- bacterials, anti-viral agents, air and gas . For Anti VEGF 30 g needle and for triamcinolone 27 g needle is used . For dexamethasone implant 22 g inserter is used .
  • 45.
    Intravitreal Injections Introduction •Theoffice delivery of medication directly into the vitreous cavity via injection or implant has become commonplace in ophthalmology. This method allows for higher concentrations in the eye with less systemic absorption compared to other methods of medication administration. •In 1911, the injection of air into the vitreous cavity for retinal detachment (RD) repair was initially reported.
  • 46.
  • 47.
  • 48.
    PRE-INJECTION PREPARATION •Treatment ofovert, active blepharitis should be done prior to injection to attempt to decrease bacterial load, which may increase risk of infection. Patients with bacterial or viral conjunctivitis should be treated to manage infection and have their injection rescheduled. As with any surgical procedure all patients should sign an informed consent after being explained the risks, benefits, and alternatives to injection
  • 49.
    INJECTION •The needle usedfor injection should be 30 g for a routine injection of medication or gas. A smaller needle gauge may result in less procedure discomfort for patients. The force required to penetrate the sclera is almost twice as much using a 27-gauge needle compared to 30- or 31-gauge needles. Needle length should be 1/2 to 5/8 inches to prevent globe trauma.
  • 50.
    INJECTION which gaugeof needle •The majority of retinal specialists surveyed in 2010 used a 30-gauge needle for BEVACIZUMAB and RANIBIZUMAB, and a 27-gauge needle for TRIAMCINOLONE. Triamcinolone can precipitate within the syringe and clog a needle smaller than 27-gauge.
  • 51.
    INJECTION dose ofdrug for dme Intravitreal drug avastin lucentis triamcinolone Intravitreal dose 1.25 mg .3 mg 2 mg strength in vial 25 mg / ml 10 mg / ml 40 mg / ml Amt in cc injected .05 ml .03 ml .05 ml Needle gauge used 30 g 30 g 27 gauge To be repeated after 1 month 1 month 3 to 4 months Cost per inj 5 thousand rs 25 thousand rs 100 rs
  • 52.
    INJECTION • Separate needlesshould be used to remove medication from vial & to perform the actual injection. This helps prevent both contamination & dulling of the needle. The injection is through pars plana and should be performed approximately 3.5 mm from the limbus in pseudophakic patients and 4.0 mm from the limbus in phakic patients. Injections are commonly performed in inferotemporal and superotemporal quadrants.
  • 53.
    INJECTION The quadrant ofinjection may be influenced by indication for injection or other factors. For example, injecting an opaque steroid superiorly may obscure the visual axis more initially than injecting inferiorly. Similarly, a patient with a large inferotemporal retinoschisis cavity may benefit from having their injection in another quadrant
  • 54.
    INJECTION •The traditional injectionmethod involves inserting needle perpendicular to the ocular scleral surface in a single plane to penetrate globe. Another tunneling method has been described which involves needle insertion at a 30 degree angle initially with repositioning of the needle to perpendicular and towards the center of the globe. Final needle direction should always be towards the center of the eye to prevent damage to other intraocular contents.
  • 55.
    INJECTION •Inserting needle perpendicularto eye is preferred over other techniques . •The injection should be done in a slow, steady maneuver to prevent a sudden flux through the vitreous cavity, as this may disrupt vitreoretinal adhesions. •A sterile cotton tip applicator may be used to prevent reflux for injections
  • 56.
    Injection Technique • Confirminformed consent obtained • Surgical time-out to confirm correct medication and correct eye •Place patient in near supine position; make sure the headrest of the chair is stable • Topical proparacaine (wait 10-15 seconds before placing Betadine) • 10% Betadine swab to inferior cul-de-sac, to allow Betadine to start working; ask patient to blink multiple times to spread Betadine .
  • 57.
    Injection Technique •Place 2%lidocaine jelly on the eye, focusing on inferotemporal quadrant. • (Note: Betadine placed prior to lidocaine jelly to sterilize the globe prior to placing the jelly so as not to have bacteria trapped in the jelly and possibly increase risk of endophthalmitis). • Ask patient to close their eyes, and return in 2-5 minutes.
  • 58.
    Injection Technique •Apply Betadineswab again to inferotemporal quadrant and inferior cul-de-sac, as well as to eyelashes (do not manipulate much so as not to liberate bacteria from the lashes) • Place sterile closed-blade eyelid speculum (careful not to cause corneal abrasion and save yourself a phone call from the patient with a painful corneal abrasion). • Clean again with Betadine
  • 59.
    Injection Technique • Marklocation of injection: 3-3.5mm for pseudophakes, 3.5-4.0 mm for phakic patients. Tip: Can use the end of a TB syringe (without needle attached) to mark 3.5-4.0 mm. After marking and causing an indentation with the TB syringe, you can place Betadine again - Betadine will sit in indentation ring and nicely highlight the injection site. Careful with subconj anesthesia so as not to cause too much chemosis or subconj hemorrhage as this case
  • 60.
    Injection Technique •Have thepatient look 180 degrees away from the injection site. For example, if injecting the right eye in the inferotemporal quadrant, ask the patient to look up and to the left. •Hold syringe in dominant hand, and a cotton tip in the non-dominant hand •Do not talk and ask patient not to talk during the injection. Make sure the needle tip (which is usually short 30g) is always kept absolutely sterile •Using your dominant hand, rest your wrist on the patient's cheek for hand stabilization
  • 61.
    Injection Technique •Insert theneedle at marked site in a smooth and single motion, aiming for mid-vitreous cavity •Insert the short 30g needle about 1/2 length in (to make sure you are in the vitreous cavity and not in subretinal space) •Swing over with your non-dominant hand to push down on the plunger in a smooth fashion. (Note: some surgeons prefer to inject with one-hand; the author feels that using two hands is more stable).
  • 62.
    Injection Technique • Donot move the needle while inside the eye so as to not cause traction on the vitreous and potentially cause a retinal tear / detachment. •As you remove the needle out, cover the injection site with a cotton tip that is in your non-dominant hand •Rinse the Betadine off of the patients eye
  • 63.
    Injection Technique •Ensure opticnerve perfusion (patient should be at least light perception). Paracentesis is usually not required, unless a large volume of medication is injected. Some Retina Specialists prefer to check and document the IOP and not let the patient leave until the IOP has reduced to an acceptable level.
  • 64.
    BEVACIZUMAB • Recombinant humanizedmonoclonal antibody that blocks angiogenesis by inhibiting VEGF-A • It received its first approval in 2004, for combination use with standard chemotherapy for metastatic colon cancer • It has since been approved for use in • Certain lung cancers, • Renal cancers, • Ovarian cancers • Glioblastoma multiforme of the brain
  • 65.
    ADMINISTRATION AND DOSING •Inophthalmology, Bevacizumab is typically given by transconjunctival intravitreal injections into the posterior segment • Intravitreal injections for retinal pathologies are typically administered at 4-6 week intervals, although this varies widely based on disease and response. •DOSE: The typical dose is 1.25mg in 0.05ml in adults,and half that dose in babies.
  • 66.
    PHARMACOKINETICS •Time to reachsteady state is predicted to be 100 days. •Estimated half-life is approximately 20 days
  • 67.
    RANIBIZUMAB • Available asInjection, intravitreal 10 mg/mL • Binds to and inhibits the biologic activity of VEGF-A Pharmacokinetics: • Absorption: • C max is below the concentration thought necessary to inhibit biological activity of VEGF-A by 50% (0.3 to 2.36 ng/mL). • T max is 24 h. • Elimination: Vitreous elimination half-life is approximately 9 days.
  • 69.
    AFLIBERCEPT • Recombinant fusionprotein consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin
  • 70.
    Based on recentclinical trial data, which anti-VEGF do you use first? • I start almost every patient on bevacizumab because of affordability . Patients with relatively good vision and not a great deal of edema would probably do well on any of the anti-VEGF drugs. (DRCR protocol T data) . Overall, aflibercept (Eylea, Regeneron) has proved best for patients with diabetic retinopathy and vision less than 20/40 or with >400 μm of edema.
  • 71.
    Based on recentclinical trial data, which anti-VEGF do you use first? • I would, however, switch any nonresponders with severe edema to another anti-VEGF because they have different mechanism of action . I might also switch a patient with poor vision (20/200) to aflibercept if they had more than 400 μm of edema, based on Protocol T findings ( )
  • 72.
    threshold for startinganti- VEGF injections in a patient? •If my patient is symptomatic, I begin treatment. But DME differs from AMD in several ways. For one, you do not have to treat a patient with DME immediately. If a patient is 20/20 or 20/25 and asymptomatic, even with 350 to 400 μm of edema, I watch and wait.
  • 73.
    threshold for startinganti- VEGF injections in a patient? •Improving this patient’s condition may require seven to eight ocular injections during the first year, and outcomes might not be discernable to the patient. •If a patient’s vision worsens within 2 or 3 months, I begin injections
  • 74.
    NON RESPONDER •For me,a nonresponder is someone who has had less than a 10% or 20% improvement on their OCT within the first month of treatment. Even though anti-VEGF might have had a minimal effect on the macular edema in 4 or 5 months, you might see a profound effect on the patient’s level of retinopathy, making the case for continuing the anti-VEGF or combining it with a steroid where required for edema.
  • 75.
    Switching or combinesteroid • Switching is not the issue. I think it is more a question of continuing the anti-VEGF and then adding a drug. Some patients are pure anti-VEGF responders, while others do extremely well on steroids alone. Some do well on both. In some cases after steroid injections, patients re-accumulate fluid quickly (within 8 weeks) and require anti- VEGF therapy again. Instead of switching, it might be more a question of continuing the anti-VEGF and then periodically giving patients a bolus dose of a steroid.
  • 76.
    If you chooseto include steroids in your treatment regimens, which one do you use first •I use triamcinolone suspension, 1 mg to 2 mg as recommended by the Protocol B and the SCORE studies. I used to use a 4-mg dose, but now we know that the same biologic effect occurs with 1 mg, and that greatly reduces the complication rate.
  • 77.
    Chronicity of macularodema • Does length of time a patient has had macular edema & their history of treatment make you move to steroids faster than you would for a patient with recent-onset macular edema? • I am certainly more likely to require something additional for long-standing edema, as borne out in the FAME study. Any patient with chronic edema has a problem, whether it is denial or lack of follow-up. Thus, it is important to consider using something that will be less of a burden on these patients .
  • 78.
    Chronicity of macularodema •The FAME study showed a significant improvement using the fluocinolone acetonide intravitreal implant 0.19 mg (Iluvien, Alimera Sciences) in patients with long-standing macular edema, but very often as clinicians, we do not know how long a patient has had their macular edema. I would begin treatment with anti-VEGF followed by IV TA 2 mg if the patient does not respond promptly.
  • 79.
    Use of flucinolone •Itis important to provide a steroid challenge before resorting to fluocinolone. You have to know if a patient will respond to a steroid. Bear in mind that patients would need multiple injections with an intravitreal before we should start fluocinolone, since a significant number of patients will not get any steroid rise, even after their first, second, or sometimes after their third injection.
  • 80.
    STEROID IN DME •Foryounger patients who do not have cataracts, clinicians must explain that using a steroid will hasten the formation of a cataract. As we dry out their retina, their vision may worsen, necessitating cataract surgery. However, the 20-year insulin- dependent diabetic might not respond to anti-VEGF until you add the steroid. At the same time, you will be putting them on a road you do not want them to travel.
  • 81.
    STEROID IN DME •True, but I assure my patients that cataracts will not make them go blind, and they can be fixed; however, if their macular edema persists, it will cause substantial vision loss . • In Protocol I, pseudophakic patients do as well with steroids as they do with the anti- VEGF and require only three injections in the first year. So, I think there is a place for steroids
  • 82.
    IST YEAR ANTIDME TREATMENT • The great outcomes in RISE/RIDE, VIVID/VISTA and Protocol I require a very heavy burden, especially in that first year. That is one of the real key points, as there is a fair amount of undertreatment in the community in the first year. In AMD, the initiation phase/loading dose has usually involved three injections; and people have been applying this concept to DME. However, in DME, there is a much heavier injection burden in the first year. The visual acuity curves in RISE/RIDE show an improvement after the first three injections, but the curve continues to gradually go up over the first 18 months. It is a very steady, gradual improvement in both visual acuity and OCT outcomes
  • 83.
    DRCR.net Protocol I •DRCR.net Protocol I, patients were started off with a loading dose of four injections, but if patients did not have 20/20 vision and no edema, they were given an additional two injections. So in reality, it was a six-dose loading phase. Comparatively speaking, in AMD it is traditionally a three-dose loading phase.
  • 84.
    DRCR.net Protocol I •Mostof the AMD studies that utilized a p.r.n. dosing strategy required six to seven injections in the first year in comparison to Protocol I and T, where the average was higher with nine to 10 injections . Protocol I was instrumental in showing us that monthly treatment is not necessary to achieve vision stabilization and letter gain comparable with the more continuous treatment regimens in RISE/RIDE .
  • 85.
    DRCR .net protocolI intravitreal anti vegf agents with early or deferred laser Superior Over laser alone laser with steroids steroids alone or or
  • 86.
    DRCR .net protocolT • All Three Anti Vegf Agents RANIBIZUMAB , BEVACIMIZUMAB & AFLIBERCEPT Are Effective In Management Of DME . •RANIBIZUMAB And AFLIBERCEPT Are Slightly Better Than BEVACIMIZUMAB if vision is less But Latter Is More Economical .
  • 87.
    TREATMENT OF DMEVS ARMD • It is important to distinguish wet AMD from DME—these are, indeed, two very different diseases. For patients with wet AMD, we are treating choroidal neovascularization with exudation. For patients with DME, we are only treating edema, the source of which is retinovascular incompetence. While we are trying to get that macula to a satisfactory dry status, the burden over time tends to fall off in DME.
  • 88.
    TREATMENT OF DMEVS ARMD •In wet AMD, there is more of a continuous burden year after year for an indefinite time frame in most patients. In DME, studies with discontinuous or P.R.N. style therapy such as Protocol I and Protocol T, many patients were eventually able to cease therapy .
  • 89.
    TREATMENT OF DMEVS ARMD •With wet AMD, whether it is P.R.N. or TREAT- AND-EXTEND (TAE), the mean number of treatments will typically reach a plateau after the first year. It does not tend to decrease much thereafter. But with DME, P.R.N. studies that we have seen, Protocol I in particular, started with a mean of eight to nine injections in year 1, then three to four in year 2, two to three in year 3 and by years 4 and 5, many had no further treatment .
  • 90.
    How to reducenumer of injections •Steroids can be used for reduced burden of treatment as a combination therapy, but probably not as a low-burden monotherapy for most diabetic patients. There may be special cases where steroids are best choice as a monotherapy, such as in a newly pseudophakic patient who develops macular edema post-operatively, but results are simply not as robust as with anti VEGF therapy.
  • 91.
    DME BUT STILLNO TREATMENT • Protocol I allowed for patients to have DME if it was stable without a decrease in vision. It was possible to have patients with persistent DME, as long as vision did not drop and there was not an increase in the OCT thickness. In DME, we now know that persistent DME does not translate into lost vision. With results reported out to 5 years, Protocol I showed those great visual improvements at year 1 could be maintained with an injection burden that dramatically decreased in years 2 through 5.
  • 92.
    Type of responseto anti VEGF •My patients typically fall into one of three categories. The first is what we all want—a patient who is exquisitely sensitive to anti- VEGF therapy and needs only one injection to have a very dramatic improvement. The second group is what we dread—no measurable response with anti-VEGFs after three or four injections. The third group, however, is what most of us see—people who have some response to the anti-VEGF therapy.
  • 93.
    COMBINATION THERAPY INDME • Monotherapy with anti-VEGF agents or sequential monotherapy, anti-VEGF followed by steroids, gives us a good result. There is a role for laser at some point in the process in selected case such as when there is persistent or refractory edema and you see an obvious source of leakage on fluorescein angiography (FA) with large, leaking microaneurysms. Targeted focal laser can provide adequate drying and stabilization, so I do consider it. I almost never use it for center-involving DME, but there is a role for laser as second-line treatment .
  • 94.
    final • After allthe studies, I think it is safe to say anti-VEGF is our first-line defense. We have long-term outcomes from the studies, and those results are extremely efficacious. But it is a complex disease. Even when you look at the results from Protocol T, the agent that worked the best (aflibercept) still left one-third of the patients with more than 250 microns of edema at 1 year. And that range was as high as 60% with bevacizumab. Most of us are using bevacizumab, and 60% of our patients are going to have persistent fluid after 10 treatments in the first year. That means there’s a role for other treatments. We don’t have large studies to dictate whether or not the intravitreal triamcinolone should be our preferred second-line agent. There are some new studies being undertaken by the DRCR.net on the combination of anti-VEGF and steroid
  • 95.
    ROLE OF LASER •Laser may be appropriate in patients with focal extrafoveal macular edema secondary to focal microaneurysms. If one laser treatment could spare them the burden of a series of multiple injections, it may be worthwhile to consider. • The gold standard based on evidence accumulated over the past few years is that for center-involving, symptomatic DME, pharmacotherapy is the gold standard. Laser has a role for the center-involving patient as a deferred therapy, and is still a primary therapy for non-center-involving.
  • 96.
    How to tellpt requirement of so many injections . • I discuss that anti-VEGF treatment is an ongoing process and in some ways analagous to chemotherapy. I emphasize that regular injections often keep the disease process under control, may be able to improve the vision. While the initial injections occur monthly, it may be possible to reduce the number of visits or injections over time
  • 97.
    How to tellpt requirement of so many injections • There is a different conversation for the AMD patient and the DME patient. I tell the wet AMD patient that these injections serve as disease control and there is a good chance for good outcomes, but it is going to be an indefinite, ongoing treatment process. I do let them know that, while rare, some patients do improve to the point where we can stop treatment altogether. • With DME, I tell patients there will be a lot of treatment up front, a lot of visits initially, as the disease is usually slow to respond. But I also tell them that compared with AMD, there is a better chance of coming off therapy
  • 98.
    How to tellpt requirement of so many injections • For DME, I explain to patients that we will require monthly injections for a prolonged period of time, and that as the disease stabilizes, there may be an opportunity for us to increase the interval between injections. I do alert them that there will be multiple injections during that first year but that too will vary from one patient to the next. Once I have a patient’s visual acuity and edema within a normal range, I begin a TAE regimen. I inform him or her that we may need to cut back interval between injections if there is a recurrence. If they have stable vision but thick edema, I will discuss need to introduce combination therapy
  • 99.
    COMBINATION THERAPY INDME • We begin with an anti-VEGF and are guided by Protocol T. If the patient cannot demonstrate improvement after three intravitreal injections, we consider adding a steroid. We are constantly walking the line between pushing the VEGF or inflammatory component. So we continue with the anti-VEGF in those that do respond until we hit the maximum effect & Once the patient has stable vision .
  • 100.
    COMBINATION THERAPY INDME • If there is continued macular thickening, we consider introducing either a steroid or laser therapy. FAME did show one subgroup with chronic DME for more than 3 years did a lot better on steroids, so that may be a key differentiating point. It is a nice option to have steroids for people who don’t respond to our previous treatments.
  • 101.
    SWITCHING •I switch betweenanti-VEGF agents first because ranibizumab and aflibercept have different mechanisms of effect. If that does not work, I might switch to a steroid, combine medications, or consider a laser, either extrafoveal focal or micropulse
  • 102.
    STEROIDS •Steroids also canbe considered for patients who have an increased risk of thromboembolic events and want to avoid the theoretical risk with Anti-VEGF agents, for treating pregnant women with DME rather than potentially exposing the fetus to an anti-VEGF agent, and finally for people who are not willing to tolerate the high injection burden (nine to 10 treatments in the first year) with anti-angiogenic therapy
  • 103.
    STEROIDS •I like addingsteroids in pseudophakic patients. I am more apt to try another anti- angiogenic agent in a phakic patient before going straight to a steroid. I like steroids for DME, but it is not without a cost. I will probably do at least one antiangiogenic switch between agents after Protocol T before going to steroid in phakic patients. But it will not be a rapid switch
  • 104.
  • 105.
    Intravitreal Steroids •Corticosteroids arewell known for their antiangiogenic, antiedematous, and anti-infl ammatory properties. Consequently, these have been widely used in treatment of many retinal diseases since the early 1950s. Later, intravitreal steroids emerged as an essential tool, allowing for optimal drug efficacy when given locally. The topical or local route offers the great advantage that there is no significant systemic side effect
  • 106.
    Intravitreal Steroids • Randomizedstudies have properly shown that steroids are very effective in the treatment of posterior segment diseases such as retinal vascular occlusion, diabetic macular edema, and uveitis. This is true for both, disease activity and visual outcome. Today because of the anti-infl ammatory, antiangiogenic, and antipermeability properties, steroids are an attractive therapeutic option for vascular and inflammatory retinal diseases
  • 107.
    Intravitreal Steroids •Recent advancesin ocular drug delivery methods led to the development of intraocular implants, which help to provide prolonged treatment with a continuous drug release. An increasing number of ophthalmologists use intravitreal steroids for the treatment of various posterior segment disorders, not only when traditional therapeutic methods have failed, but more and more as a first-line therapy .
  • 108.
  • 109.
    Treatment of DMEwith Triamcinolone •Triamcinolone has been shown to reduce VEGF production, decrease prostaglandin production, and stabilize the blood–retinal barrier . This action of decreasing vascular permeability has led investigators to try triamcinolone in the treatment of DME .
  • 110.
    Treatment of DMEwith Triamcinolone •studies have shown the efficacy of IVTA to temporarily reduce DME and increase visual acuity . The mean reduction in macular thickening reaches 85 % 3 months after injection with a mean two-line improvement of visual acuity . However, recurrence of DME occurs between 3 and 6 months after injection.
  • 111.
    Treatment of DMEwith Triamcinolone •Recurrence of DME occurs between 3 and 6 months after injection. Due to the high rate of complications and the absence of evidence of its superiority over laser photocoagulation, IVTA is generally reserved for patients refractory to focal/grid laser therapy and anti-VEGF agents .
  • 112.
    Treatment of DMEwith Dexamethasone • The dexamethasone 700 μg posterior segment drug delivery system (Ozurdex®) is a bioerodible Implant delivered intravitreally using a 22-gauge injector . • Considering the higher cost but similar efficacy , side effect profile and frequency of administration we generally prefer 2mg dose of Triamcinolone over Dexamethasone implant (Ozurdex) .
  • 113.
    Treatment of DMEwith Dexamethasone • treatment was well tolerated and had an acceptable safety profile. Similar to IVTA, DEX-DDS has the advantage of repeatability, as long as the IOP and cataract effects are mitigated. The advantages of DEXDDS over intravitreal triamcinolone include a possible longer duration of action, absence of postinjection “visual clouding” or floater-like symptoms, and a lower rate of IOP increase. month 12.
  • 114.
    Treatment of DMEwith Fluocinolone Acetonide FAc Insert • Two fluocinolone acetonide (FAc) intravitreal devices have been studied for the treatment of DME: a FAc implant (Retisert) and a FAc insert (ILUVIEN®). • ILUVIEN is a non-bioerodible insert implanted in the eye via injection through the pars plana using a 25-gauge needle. ILUVIEN contains 0.19 mg of Flucinolone acetonide .
  • 115.
    Treatment of DMEwith Fluocinolone Acetonide FAc Insert FAME •The Fluocinolone Acetonide for Macular Edema (FAME) studies were two large prospective, randomized, controlled studies that followed 956 eyes randomized to receive 0.2-μg/day (lowdose) or 0.50-μg/day (high- dose) inserts or sham. The most common adverse event was cataract, and almost all phakic patients in the FAc insert groups developed cataract
  • 116.
    Treatment of DMEwith Fluocinolone Acetonide FAc Insert FAME •The incidence of increased IOP (37.1 and 45.5 %, in the low-dose and high- dose insert groups, respectively), need for IOP-lowering medication (38.4 and 47.3 %, respectively), incisional glaucoma surgery (4.8 and 8.1 %, respectively), and trabeculoplasty (1.3 and 2.5 %, respectively)
  • 117.
    Treatment of DMEwith steroids. adverse events different steroids
  • 120.
    Conclusions •Interestingly, reductions inOCT central subfield thickness in ptotocol I were similar between ranibizumab and triamcinolone groups, suggesting the visual benefits of intravitreal corticosteroids may be tempered by their side-effects of cataract and elevated IOP . • Many randomized clinical studies have shown the clinical efficacy of steroid injections to treat DME, but their use is limited by their adverse events, including cataract progression and intraocular pressure (IOP) increase .
  • 121.
    Role For SurgeryIn Patients With DME • Vitreomacular traction (VMT) is something we watch very carefully; however, we have been surprised to see some patients with epiretinal membrane (ERM) dry out that we suspected would need vitrectomy surgery. In the patients with ERMs, edema tends to recur quickly, but we do much less vitrectomy surgery in these patients now because the anti-VEGFs actually improve the anatomic configuration of the retina, even in presence of an ERM. Some patients have taught hyaloids or ERM that refuse to dry out despite intravitreal anti-VEGF and/or steroid injections you may consider surgery.
  • 122.
  • 123.
  • 126.
  • 127.
  • 128.
    Treatment details avastin •The1.25 mg dosage is administered monthly . "Another consideration with bevacizumab is the preparation of doses for intravitreal injection. A common approach used in the clinical studies is for a pharmacy department to aseptically prepare a batch of syringes for use in a later clinic with one study reporting storage of such syringes for up to 14 days in a refrigerator.
  • 129.
    Treatment details avastin •Each vial of Avastin® contains 100 mg of bevacizumab, sufficient for 80 doses however it would be difficult to extract this exact quantity. • One method employed is to fill syringes with between 2.0 and 2.5 mg of bevacizumab (0.08 to 0.10 millilitre) resulting in up to 50 doses per vial of Avastin®."
  • 130.
    Treatment details avastin •"An alternative is for the clinical team to prepare doses in the treatment room immediately prior to administration using aseptic technique but this option may present greater risk of cross contamination. The number of doses extracted per vial could be reduced to a minimum of one, which will reduce the risk of cross contamination but will also eliminate some of the cost benefits presented by use of bevacizumab."
  • 131.
    Treatment details avastin •"Pre-packaged syringes of bevacizumab for intravitreal use are available to purchase from special manufacturing units. Moorfields Pharmaceuticals, of Moorfields NHS hospital, can supply syringes of 1.25 mg in 0.05 ml at £85 per syringe, excluding VAT and delivery charges. The syringes must be stored in a refrigerator and have an expiry date of six weeks from the date of manufacture, which would mean an effective expiry of about two to four weeks from receipt of delivery."
  • 132.
    Treatment details avastin •"Anycompounding of a single vial of drug into multiple dose units will carry some risk of microbial and particulate cross contamination beyond that associated with preparation of a single dose. This risk can be minimised by performing the procedure in an aseptic clean room using trained staff and storing the finished product in a refrigerator."
  • 133.
    Safety Of BevacizumabFor The Treatment Of AMD • The systematic review concluded that adverse events were rare amongst 1,400 patients who had received a total of several thousand intravitreal injections of bevacizumab. In the former report, with a mean follow-up of 3.5 months, the maximum incidence of any single event was 0.21% . In the latter report, that included a majority proportion of non-AMD patients, the total incidence of systemic adverse events was 1.5% (18 patients) and included hypertension, stroke, myocardial infarction, aneurysm, digit amputation, and fatalities, although none were conclusively and causally linked to bevacizumab. • The review authors state that the type and incidence of effects ‘does not seem to be very different from … two large RCTs of ranibizumab
  • 135.
  • 136.
    summary •For patients inwhom macular edema has been confirmed clinically, we usually order OCT to get a baseline retinal thickness & volume. • If there are moderate to severe diabetic changes in the periphery, we do a FA to establish degree of nonperfusion and to rule out neovascularization elsewhere. If we were considering any form of focal laser therapy for extra foveal leakage, we would also do an angiogram. we also check HbA1c hemoglobin levels to determine if the patient’s diabetes is under control .
  • 137.
    summary • For symptomaticpatients or patients with some vision loss and central retinal thickening on OCT, our first-line treatment regimen is therapy. For asymptomatic patients who have good vision, we , as outer-retinal disease affords you the luxury of time. If a patient’s condition worsens over a period of time, particularly if they have 350 μm or more of fluid, we start treatment—usually with bevacizumab (Avastin)—even if they have good vision. we also try to get all patients to improve their control of their blood pressure, blood sugar, and lipids.
  • 138.
    DME • Our strategyin management of DME is as follows – for cases of centre involving DME with diffuse leak or leak close to the fovea, intravitreal anti-VEGF followed by laser is used. . . In cases of DME where the leak is away from macular centre without significant thickening of fovea laser alone is preferred .
  • 139.
    •The major problemswith anti-VEGF therapy are cost and frequency of administration. At present, ranibizumab at a dose of 0.3 mg has undergone the most rigorous testing, but due to cost issues, worldwide, BEVACIZUMAB 1.25 mg is the drug of choice for DME . . • Triamcinolone 2 mg is used to enhance the effect or to decrease number of required injections of anti vegf drugs keeping in mind its complications of cataract and glaucoma . • Focal and grid laser should be used where indicated .
  • 140.