Romanian Journal of Ophthalmology, Volume 59, Issue 3, July-September 2015. pp:133-136
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`REVIEW
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`DIABETIC MACULAR EDEMA
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`Ovidiu Musat, Corina Cernat, Mahdi Labib, Andreea Gheorghe, Oana Toma,
`Madalina Zamfir, Ana Maria Boureanu
`Central Military Emergency University Hospital „Dr. Carol Davila”,
`Ophthalmology Department, Bucharest, Romania
`
`Correspondence to: Cernat Corina Cristina M.D.
`31 Dinicu Golescu Blvd, Floor 4, District 1, Bucharest, Romania
`Mobile phone: +40721 567 809, E-mail: corina_crisa@yahoo.com
`
`Accepted: July 15, 2015
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`
`
`Abstract
`Diabetic macular edema (DME) remains the most common cause of vision loss among
`diabetic patients. New understanding of the underlying pathophysiology has interest in
`the potential benefits of the specific pharmacologic therapy, such as treatment with
`intraocular steroids, anti-vascular endothelial growth factor (VEGF), and protein kinase
`C-beta (PKCβ) inhibition. At the last time, laser photocoagulation, according to the
`guidelines of the Early Treatment of Diabetic Retinopathy Study (ETDRS), continues to
`be primary standard care treatment in most communities.
`Optical coherence tomography (OCT) is very useful in monitoring macular edema
`progression and response to treatment.
`Key words: diabetic macular edema, risk factors, clinical presentations, physiopathology
`
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`
`
`Definition
`
`is
`(DME)
`Diabetic macular edema
`manifested as retinal thickening caused by the
`accumulation of intraretinal fluid, primarily in
`the inner and outer plexiform layers. It is
`believed to be a result of hyperpermeability of
`the retinal vasculature. DME can be present with
`any level of diabetic retinopathy.
`ETDRS Criteria for Clinically Significant Macular
`Edema (CSME)(1):
`•
` Retinal thickening at the center of the
`macula
` Retinal thickening and/or adjiacent hard
`exudates at or within 500 µ of the center
`of the macula ( Fig. 1 )
` An area of retinal thickening greater
`than or equal to one disc area, any part of
`which is within 1 disc diameter of the
`center of the macula
`
`•
`
`•
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`Romanian Society of Ophthalmology
`© 2015
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`Prevalence and incidence [1] [2]
`
`Fig. 1 CSME
`
`(World Health
`In USA: The WHO
`Organization) estimates 15 million DME half
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`Romanian Journal of Ophthalmology 2015;59(3): 133-136
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`undiagnosed and 50% of 8 million without eye
`care, 25-30% risk of vision loss from CSME.
`International, WHO estimates more than 150
`million patients with diabetes worldwide.
`However, the absolute prevalence of DME might
`be increasing due to the overall increased
`prevalence of diabetes in industrialized nations.
`It is expected that the incidence of DME will
`decrease as excellent metabolic control
`is
`increasingly embraced as a therapeutic goal by
`patients and health care workers.
`
`Clinical associations and risk
`factors
`
`is strongly positively
`Macular edema
`associated with diabetic retinopathy severity.
`Glycemic control is a conclusively identifies risk
`factor for retinopathy progression as well as for
`DME. Duration of diabetes is strongly correlated
`with prevalence and
`incidence of macular
`edema, retinopathy progression, and other
`diabetic complications. The diagnosis of diabetes
`in type 2 subjects occasionally occurs sometime
`after subclinical diabetes has been manifest,
`which yields a small proportion of patients who
`may present with macular edema at the time of
`diagnosis, or even have decreased vision from
`macular edema at the presenting sign. In
`contrast, persons with type 1 diabetes are very
`unlikely to experience advanced retinopathy and
`macular edema before 5 years of duration.
`Clinical Associations with Diabetic Macular
`Edema Severity: [2] [3]
`• Duration of Diabetes – increased risk of
`diabetic retinopathy
`• Glycemic control – The Diabetes Control
`Complication
`Trial
`(DCCT)
`clearly
`and
`demonstrated that tighter control of blood sugar
`is associated with reduced incidence of diabetic
`retinopathy (Glycosylated hemoglobin (HbA1c)
`should be less than 7%)
`• Nephropathy – proteinuria is a good
`marker for development of diabetic retinopathy;
`thus, patients with diabetic with nephropathy
`should be observed more closely
`• Hypertension –
`risk of
`increased
`retinopathy
`(diabetic
`retinopathy with
`superimposed hypertensive retinopathy)
`• Dislipidemia – normalization of
`lipid
`levels reduces retinal leakage and exudates
`deposition
`• Pregnancy – diabetic retinopathy can
`progress rapidly in pregnant women, especially
`those with preexisting diabetic retinopathy
`• Intraocular surgery
`• Uveitis
`• Panretinal Photocoagulation
`
`Pathology and pathophysiology of
`dme
`
`Normal retinal circulation is unique: retinal
`capillaries are non-fenestrated and capillary
`endothelial cells have tight jonctions; normal
`capillaries do not leak fluid, blood. There is no
`lymphatc system in the retina, so in the presence
`of retinal pathology, leaking fluid can accumulate
`and cause edema or swelling. Retina responds to
`ischemia by stimulating growth
`factors to
`produce new vessels (called neovascularization).
`DME is the result of microvascular changes
`in diabetes leading to incompetence of vessels,
`edema. Hypoxic state stimulate VEGF causing
`more edema.
`Thus, 2 key changes occur:
`• Vessel permeability
`- Damaged endothelial wall becomes more
`porous
`- Vessel leaks fluid, lipids, erythrocytes
`- Accumulation of the fluid results
`in
`edema (macular edema if located within the
`central region of the retina)
`• Vessel closure
`- Supply of oxigen and nutrients are
`decreased
`New fragile growth occurs (secondary to
`ischemia)
`
`
`Fig. 2
`Photomicrograp
`h of cystoids
`spaces and
`subretinal fluid
`in the retina of a
`diabetic patient
`with severe DME
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`Clinical presentation of diabetic
`macular edema
`
`Patients with DME present with a range of
`visual symptoms depending on the degree to
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`Romanian Society of Ophthalmology
`© 2015
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`Samsung et al. v. Regeneron IPR2023-00884
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`Romanian Journal of Ophthalmology 2015;59(3): 133-136
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`which the fovea is involved and the chronicity of
`the edema. If the macula center is not involved
`patients are rarely symptomatic; only a few very
`observant
`individuals may notice
`relative
`paracentral scotomas corresponding to focal
`edema and hard exudates. Some patients with
`central macular
`involvement have excellent
`acuity and no visual complains, presumably
`because of only recent involvement of the center.
`Over
`time, patients experience a gradual
`progressive vision loss over weeks to month.
`Patients may complain of loss of color vision,
`poor night vision and washing-out of vision in
`bright sunlight with poor dark-light adaptation.
`Metamorphopsia
`is
`not
`uncommon.
`Frequently, patients with center involved DME
`note fluctuation of vision from day-to-day or
`even over the course of a day. In some cases, the
`patient may relate such changes
`to
`fluid
`retention, hyper or hypoglycemia, or ambient
`lighting.[4][5]
`On fundus examination with slit lamp
`biomicroscopy or contact lens, retinal thickening
`may present
`in some commonly
`identified
`patterns. Focal edema often occurs associated
`with a cluster of microaneurysms, sometimes
`surrounded by an incomplete ring of hard
`exudates. Diffuse DME may be very difficult to
`identify clinically if the retina is of uniform
`thickness, due
`to
`the
`lack of
`reference
`landmarks. Clues include the height of the retinal
`blood vessels over the pigment epithelium, loss
`of the foveal depression or even cystoids spaces.
`Other features sometimes seen with macular
`edema
`include
`variable
`loss of
`retinal
`transparency, a large burden of microaneurysms
`and intraretinal hemorrhages, and dispersed
`flecks of hard exudates.
`
`
`
`
`Fig. 4 Color photograph of a diabetic patient with
`diffuse macular edema
`
`
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`
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`Stereoscopic fundus photographs provide
`an opportunity to evaluate long-term changes in
`the retina.
`in
`is useful
`Fluoresceine angiography
`demonstrating the breakdown of the blood-
`retinal barrier by delineating retinal capillary
`leakage and capillary nonperfusion. Fluorescein
`angiography is not relevant in aiding in the
`diagnosis of CSME but should be performed if
`treatment of CMSE is being considered.
`Optical coherence tomography (OCT) is
`able to demonstrate a moderate correlation
`between retinal thickness and best corrected
`visual acuity, and it is able to demonstrate 3
`basic structural changes of the retina from
`diabetic macular edema, that is, retinal swelling,
`cystoid edema, and serous retinal detachment.
`OCT is not currently required to establish a
`diagnosis and is not prescribed by current
`practice guideline; however, OCT has gained
`widespread acceptance as an additional modality
`to help identify and evaluate macular pathology.
`Quantitative measurement of macular thickness
`and subjective analysis of the foveal architecture
`allow a precise and reproducible way to monitor
`macular edema.
`
`
`
`
`Fig.3 Color photograph of a diabetic patient
`with focal macular edema, with circinate hard
`exudates roughly circumscribing the area of
`retinal thickening
`
`
`
`
`
`
`
`
`
`Fig. 5 OCT scan demonstrates cystoid edema
`
`
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`Romanian Society of Ophthalmology
`© 2015
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`135
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2123 Page 3
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`Romanian Journal of Ophthalmology 2015;59(3): 133-136
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`Treatment
`
`Optimizing diabetic, hypertensive, and lipid
`control has been shown to positively impact
`diabetic retinopathy.
`The ETDRS conclusively demonstrated that
`focal/grid laser photocoagulation was safe and
`effective in reducing vision loss due to DME.
`Significant visual improvement is uncommon;
`the goal of macular laser treatment is to reduce
`progression. [6] Photocoagulation reduced the
`risk of moderate visual
`loss from diabetic
`macular edema by 50%, from 24% to 12%, 3
`years after
`initiation of
`treatment. Laser
`treatment is most effective when initiated before
`visual acuity is
`lost from diabetic macular
`edema; this emphasizes the need for diligent
`monitoring and
`follow-up care. Fluorescein
`angiography and fundus photos are obtained
`prior
`to
`initiation
`of
`laser
`theraphy.
`Ophthalmologist views the FA to guide treatment
`of CSME: for focal leakage, direct laser theraphy
`using green-only Argon laser is applied to all
`leaking microaneurysm between 500 and 3000
`µm from the center of the macula; for diffuse
`leakage of capillary nonperfusion adjiacent to
`the macula, a light-intensity grid pattern using
`green-only Argon laser is applied to all areas of
`diffuse leakage more than 500µm from the
`center of the macula and 500µm from the
`temporal margin of the optic disc. Multiple
`sessions spread out over many months are
`frequently necessary for resolution of DME.
`Given the importance of VEGF in vascular
`permeability and its up regulation in diabetic
`retinopathy, the rationale for use of anti-VEGF
`drugs is clear. Current specific anti-VEGF therapy
`is given intravitreal at frequent intervals, which
`may temporarily blunt the effects of VEGF and
`lessen macular edema.
`Intravitreal triamcinolone acetonide (IVTA)
`has been shown to significantly reduce macular
`edema and to improve visual acuity, particularly
`when macular edema is pronounced. Some
`studies advocate IVTA as primary therapy,
`whereas others label it as adjunctive therapy to
`macular photocoagulation.[7][8]
`A subset of patients with DME has
`coexistent epiretinal membranes and/or partial
`posterior vitreous detachment with retinal
`traction. These patients may benefit from pars
`
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`136
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`plana vitrectomy to address the mechanical
`issues contributing to the retinal edema. Even
`without obvious retinal traction, some clinicians
`believe that many cases of DME respond to
`removal of the vitreous, with or without removal
`of the internal limiting membrane. No large
`randomized trials have evaluated the treatment
`to date.[9]
`The landscape of DME management is
`rapidly changing with the advent of research
`advances leading to better understanding of
`pathophysiologic mechanisms and discovery of
`potential therapeutic compounds. There are
`several challenges that remain in bringing forth
`new treatments with adequate evidence base to
`guide clinicians in timely patient care.
`
`References
`
`1. Albert and Jakobiec’s Principles and Practice of
`Ophthalmology Third edition, second volume2008,
`Editura SAUNDERS ELSEVIER, Canada, page 1793 -
`1996
`2. Pr Gabriel Coscas Oedemes maculaires Aspects
`cliniques et therapeutiques , Editura Springer Science
`& Business Media, 15 sept. 2011, Spain, page 110 - 196
`3. Oct & Retine dr. Marie – Benedicte Rougier, Pr. Marie –
`Noelle Delyfer, Pr. Jean- Francois Korobelnik Centre
`Hospitalier Universitaire de Bordeaux, Editura:
`Laboratoire Thea, 12 Rue Louise Bleriote, France, page
`33- 63
`4. 4.Miron Yanoff ” Ophtalmology” Fourth Edition,
`Editura: Elsevier – 2014, London, page: 600 - 715
`5. Kanski “Clinical Ophtalmology: a systemic approach”
`Autor: Brad Bowling, Editura: Elsevier, 2015, page
`615-668
`6. Abu el Asrar, A. M., & Morse, P. H. (1991). Laser
`photocoagulation control of diabetic macular oedema
`without fluorescein angiography. Br J Ophthalmol,
`75(2), 97-99, ISSN 0007-1161 (Electronic)
`7. Bresnick, G. H. (1983). Diabetic maculopathy. A critical
`review
`highlighting
`diffuse macular
`edema.
`Ophthalmology, 90(11), 1301-1317, ISSN 0161-6420 (
`Electronic )
`8. Klein R, Klein BEK, Moss SE, Cruickshanks K: The
`Wisconsin
`Epidemiologic
`Study
`of Diabetic
`Retinopathy, XVII:
`the 14-year
`incidence and
`progression of diabetic retinopathy and associated risk
`factors in type I diabetes. Ophthalmology105:1801–
`1815, 1998, Editura: Arch Ophthalmology, San
`Francisco, page : 1801–1815
`9. Medical Retina Essentials in Ophthalmology 2007, pp
`131-146 Diabetic Macular
`Edema:
`Current
`Treatments.Florian K. P. Sutter, Mark C. Gillies, Horst
`Helbig Editura: Springer , Berlin Heidelberg NewYork,
`page 131-146
`
`
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`Romanian Society of Ophthalmology
`© 2015
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2123 Page 4
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