Download Diabetic Macular Edema

Ocular Malignancies
Miscellaneous
Diabetic Macular
Edema
B.P. Guliani
MS
B.P. Guliani MS, Rajshekhar Vemparala MS, Sandeep Gupta MS, V.S. Gupta MS
Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi
D
iabetes Mellitus, a multisystem disorder is rising in
epidemic proportions. India has 31.7 million diabetic
subjects at present as per the World Health Organization
(WHO) estimates. The prevalence of (IDDM) is 10-15%
of the diabetic population. By 2030, an estimated 439
million individuals worldwide will have this Most of
them (appox.139 million) will be from ASIA. Diabetic
Retinopathy is a frequent complication of Diabetes
mellitus and is leading cause of blindness among patients
aged 20-74 years. Approximately 25% of patients with
IDDM will have some degree of retinopathy 5 years after
diagnosis NIDDM may go undiagnosed for 4-7 years, with
patients often presenting with some degree of retinopathy
at the time of diagnosis. After 20 yrs of Diabetes almost
all IDDM and more than 80% NIDDM have some degree
of retinopathy. Diabetic Retinopathy progresses from mild
to advanced stage and Diabetic Macular Edema (DME), a
visually threatening complication of Diabetic Retinopathy
can develop at any stage of Diabetic Retinopathy.
What is CSME (Figure 1)
1. Retinal edema and or thickening at or within 500 mm
of centre of fovea.
2. Hard exudates at or within 500 mm of centre of fovea
with adjacent edema which may be outside 500 mm
limit.
3. Retinal edema one disc area or larger, any part of
which is within one disc diameter (1500 mm) of centre
of fovea.
•
The International Clinical Diabetic Retinopathy
and Diabetic Macular Edema Disease Severity
What is DME
Pathologically macular edema is collection of intra-retinal
fluid due to break in blood retinal barrier. Angiographically
it can be focal, diffuse and ischemic. Clinical trials from
time to time have changed the definition of DME and
hence management protocols for Diabetic macular Edema
are also changing.
Early Treatment Diabetic Retinopathy Study (ETDRS)1 1984
defined Diabetic Macular Oedema as CSME and suggested
grid /focal photocoagulation treatment protocols for its
management. ETDRS group provided grading guidelines
that are considered to be the gold standard and have been
used to grade DR in research studies.
Figure 1: Schematic representation of CSME
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Miscellaneous: Diabetic Macular Edema
Diabetic Macular Edema Disease Severity scale (DRS Report 7)2
Proposed Disease Severity Level
Findings observable upon dilated ophthalmoscopy DME
DME apparently absent
DME apparently absent No apparent retinal thickening or hard exudates in
posterior pole
DME apparently present
Some apparent retinal thickening or hard exudates in posterior pole
DME present
Mild DME (some retinal thickening or hard exudates in posterior pole but
distant from the center of the macula) Moderate DME (retinal thickening or
hard exudates approaching the center of the macula but not involving the
center) Severe DME (retinal thickening or hard exudates involving the center
of the macula)
Scales were therefore proposed they are designed
to be more clinically relevant and to facilitate
communication between clinicians.
•
With the advent of OCT concept of Diabetic
Macular Oedema has changed. It is friendlier and
treatment oriented. It is being used in most of the
clinical trials for Macular Oedema (ME) due to
Diabetes and vascular occlusions
Morphological patterns on OCT in DME Brian Y. Kim et
al described different Morphological patterns on OCT in
DME3
1. Diffuse retinal thickening (DRT) appears as increased
retinal thickness with areas of reduced intraretinal
reflectivity (arrow) compared with retina without
thickening.
Flow Chart: Showing pathogenesis of
Diabetic Macular edema
2. Diabetic cystoid macular edema (CME) the large, ovoid
areas of low reflectivity, separated by highly reflective
septae that represent intra-retinal cystoid-like cavities
3. Posterior hyaloidal traction (PHT). Tangential traction
exerted by the PHT is identified on OCT as a highly
reflective band over the retinal surface.
4.Serous retinal detachment (SRD) not associated
with posterior hyaloidal traction (PHT). A dark
accumulation of subretinal fluid in seen beneath the
highly reflective and dome-like elevation of detached
retina (arrowhead). The highly reflective band, which
represents the outer surface of detached retina, helps to
differentiate a SRD from intraretinal fluid.
5. Posterior hyaloidal traction (PHT) and traction retinal
detachment (TRD). PHT is seen as the highly reflective
signal arising from the inner retinal surface. The TRD
is identified as the area of low signal underlying the
highly reflective border of detached retina (asterisks).
TRDs often take on the peaked-shaped configuration as
seen in this OCT scan.
Pathogenesis of DME
The exact pathophysiology of DME is still unclear. Retinal
vascular dysfunction causes hypoxia in diabetic eye disease,
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Figure 2: Diabetic macular edema
which up-regulates the production of VEGF. VEGF induces
vascular permeability due to its pro-permeability factor and
its activity has been shown to be 50,000 times more potent
than that of histamine4. Increased vaso-permeability may
also occur as a result of breakdown of the blood retinal
barrier due to many factors: Flow chart.
Diagnosis of DME: Diagnosis of DME is done by +90D
fundus examination, Fundus Fluorescein Angiography and
Macular OCT.
Ocular Malignancies
Figure 5: Cystoid macular edema
Figure 3: Types of edema on FFA
Figure 6: NSD
2. Cystoid edema (Figure 5).
3. Neurosensory detachment with other features:
This a emergency situation as NSD is there (Figure
6).
4.
VMT: Prognosis for this stage is bad. Surgical
management is the only option (Figure 7).
Figure 4: Spongy edema
•
Fundus examination: accurate assessment of thickening
and edema is done by +90 D slit lamp fundus
examination (Figure 2).
•
Fundus fluorescein angiography: To assess for type of
edema i.e. focal, diffuse, ischemic (Figure 3) which
helps to decide about the type of treatment to be given
to patient.
•
Macular OCT: Following patterns of macular OCT are
seen in our cases of Diabetic macular edema:
1. Spongy edema (Figure 4).
•
Central macular thickness map: Central macular
thickness map is always seen before taking any decision
regarding management. It has nine subfields (Figure 8).
•
Treatment of Diabetic macular edema
Without treatment, 50% of eyes with DME will lose
2 or more lines of vision within two years of diagnosis.
Even though the incidence of DME can be reduced with
systemic control of serum glucose, hypertension, and
hypercholesterolemia, there is need for ocular treatment.
Focal laser, intra-vitreal anti-VEGF agents, corticosteroids
and surgical treatment are different modalities for treatment
of DME.
A. Systemic parameters: Control of modifiable risk factors
like Anaemia, uncontrolled hyperglycaemia, High
level of HbA1c, Dyslipidemia, HT, Protein urea does
help in better prognosis for Diabetic macular edema.
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Miscellaneous: Diabetic Macular Edema
I. Focal vs. grid photocoagulation
Focal
Grid
500-3000 micrometer area Areas of diffuse leakage
away from foveal center
50-100 micrometer
size individual MA
spot 50-200 spot size
0.1 seconds
0.1 seconds
Burnt to whitening
Light intensity burns
Figure 7: VMT
are not treated directly and small mild burns are placed
throughout the macula for DME. At 12 months after
treatment, the mild macular grid technique was less
effective at reducing optical coherence tomographymeasured retinal thickening than the current modified
ETDRS laser photocoagulation approach. It was concluded
that modified ETDRS focal photocoagulation should
continue to be a standard approach for treating DME.
Limitations with laser therapy
Figure 8: Central macular thickness subfields
B. Laser: Laser therapy has been the mainstay of treatment
for CSME since the landmark ETDRS in 1985. ETDRS
is a randomized, prospective study which reported
effect of laser in Diabetic macular edema,evaluation
of photocoagulation and aspirin treatment of diabetic
patients with Clinically Significant Macular Edema
(CSME) and severe NPDR with VA 20/200 or better. It
concluded.
1. Focal/direct and grid photocoagulation decreased
risk of moderate visual loss and reduced retinal
thickening (loss of 15 letters).
2. In all cases of CSME3 years follow up reduced the
risk Of moderate visual loss in Mild and moderate
NPDR BY 50%.
3. Laser scars tend to increase in time hence 17% in
treated group and 5% in non-treated group had
three line improvement at 5 year follow up.
4. Sub retinal fibrosis leading to SRNVM due to laser.
5. No role of aspirin.
6.It suggested parameters of focal and grid
photocoagulation.
A recent, randomized, controlled trial compared modified
ETDRS direct/grid photocoagulation technique with mild
macular grid-laser technique, in which micro aneurysms
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Some eyes with CSME are refractory to treatment with
photocoagulation. A significant proportion of patients
experience progressive worsening of vision despite laser
photocoagulation. Limitations with laser photocoagulation
treatment includes significant risks and adverse effects such
as central and paracentralscotomata, loss of color vision,
progressive enlargement of laser scars (‘‘laser creep’’), and
occasional secondary choroidal neovascularization.
C. Intravitreal anti-VEGFs:
Dual mechanism of Anti-angiogenesis and Antipermeability makesantivegf to be used in treatment of DME.
It reduces the central macular thickness. Ranibizumab is
FDA approved for the treatment of DME.0.05ml/0.5mg in
a prefilled syringe is given monthly for the months with
reviewing central macular thickness map on OCT every
month. There after injection can be given as and when there
is increase in central macular thickness. In our experience
LASER treatment when the thickness is reduced is effective
way of treatment of DME.
D. Intravitreal injection Triamcinolone acetonide (IVTA):
Mechanism of action of IVTA is by inhibition of VEGF,
other cytokines, growth factors and regulating endothelial
cell tight junctions. Its Anti-inflammatory effect contributes
to reduction of edema. Increase diffusion by modulation of
ca channels also account for efficacy of corticosteroid in
decreasing Macular edema. It is given in the dose of 0.1 ml
(4mg). Its main disadvantage is its short duration of action.
Besides complications related to Intravitreal injection, it
has risk of Glaucoma (24%) and Cataract (62%).
Intravitreal implant: Dexamethasone is approved by FDA
in pseudophakia with DME
Ocular Malignancies
II. Mild macular grid vs. modified macular grid5
Burn Characteristic
Direct/Grid Photocoagulation (Modified-ETDRS Mild Macular Grid Photocoagulation
Technique)
Technique
Direct Treatment
Directly treat all leaking microaneurysms in N.A.
areas of retinal thickening between 500 and3000
microns from the center of the macula (but not
within 500 microns of disc)
Change in MA Color with Not required, but at least a mild gray-white burn N.A.
Direct Treatment
should be evident beneath all microaneurysms
Burn
Size
Treatment
for
Direct 50 microns
N.A.
Burn Duration for Direct 0.05-.1 sec
Treatment
N.A.
Grid Treatment
Applied to all areas with diffuse leakage or Applied to entire area described below
non-perfusion within area described below for for treatment (including unthickened
treatment
retina)
Area Considered for Grid 500 to 3000 microns superiorly, nasally and 500 to 3000 microns superiorly, nasally
Treatment
inferiorly from center of macula 500 to 3500 and inferiorly from center of macula
microns temporally from macular center
500 to 3500 microns temporally from
macular center
Burn Size for Grid Treatment No burns are placed within 500 microns of disc No burns are placed within 500
microns of disc
Burn Duration
Treatment
for
Grid 50-200 microns
50 microns
Burn Intensity
Treatment
for
Grid 0.05-.1 sec
0.05-.1 sec
Burn Separation for Grid Barely visible (light gray)
Treatment
2 burn widths apart
Intravitreal implant: Fluocinolone acetonide Approved in
Europe only
The Fluocinolone Acetonide in Diabetic Macular Edema
(FAME) study, a 36-month, phase III study, compared
fluocinolone acetonide with that of sham injection in
patients with persistent or recurrent DME. Treatment
efficacy was similar for low- and high-dose fluocinolone
acetonide but the benefit-to risk profile was more favorable
with the low dose. Fluocinoloneacetonide. Another phase
II/III study showed that there was no significant difference
in the proportion of eyes gaining ≥15 letters between
patients treated with fluocinolone or standards of care
after 3 years post implant. Risks of concerns related to
corticosteroid treatment in DME patients included high
incidence of premature cataract formation and increased
IOP. The risk for interventional procedures, such as cataract
surgery, laser trabeculoplasty, and incisional glaucoma
Barely visible (light gray)
200 to 300 total burns evenly
distributed over the treatment area
outlined above (approx. 2 to 3 burn
widths apart)
surgery, increases treatment morbidity. Cardiovascular
adverse events are commonly reported with fluocinolone
acetonide treatment.
E. Surgery for DME: With the advent of OCT, vitreoretinal
interface disorders as cause of DME surgical treatment
for DME is usually reserved for mechanical causes of the
edema. Surgery includes vitrectomy with detachment
of the posterior hyaloid, if present, and peeling of
any associated epiretinal membranes, with or without
internal limiting membrane removal. Theoretically,
vitrectomy, with or without membrane removal,
may help improve DME via multiple mechanisms.
These mechanisms include the release of abnormal
vitreomacular adhesions, elimination of free and bound
VEGF loads, and improved diffusion of oxygen to the
retina from the vitreous cavity6. AGEs are believed to
promote mechanical changes in the vitreous and at the
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Miscellaneous: Diabetic Macular Edema
vitreous-retinal interface. Vitrectomy may help remove
the AGEs from the vitreoretinal interface or remove
abnormally adherent vitreous that could promote
DME7. Posterior vitreous detachment has been
associated with spontaneous resolution of DME. Eyes
with DME have been shown to have a lower incidence
of PVD compared to eyes without DME.
•
Limitation: Although vitrectomy may clear the
vitreous of its VEGF load, one caveat is that
Intravitreal medications may also be cleared
more quickly once the vitreous is removed. For
example, intravitreal triamcinolone acetonide is
cleared 1.5 times faster in vitrectomized eyes than
nonvitrectomizedeyes.
Future developments in the management
paradigms for diabetic macular edema-(Based on
web search)
Bevacizumab or Laser Therapy (BOLT) study
Bevacizumab or Laser Therapy (BOLT) study was
a phase II RCT comparing the effects of repeated
intravitrealbevacizumab (ivB) and laser therapy. Results at
2 years showed that patients who were treated with ivB had
+8.6 mean letter gain compared with a mean loss of -0.5
letters with laser. The proportion of patients who gained
≥10 letters was significantly greater for ivB than for laser
(49% vs 7%, P=.001). No patient lost ≥15 letters with ivB
but 14% patients in the laser group sustained ≥15 letters
loss (P=.03).
•
Vivid East-DME (NCT01783886),
•
Japanese Safety Study of VEGF Trap-Eye in DME (VividJapan NCT01512966),
•
Study of Intravitreal Administration of VEGF TrapEye (BAY86-5321) in Patients with DME (Vista;
NCT01363440)
Corticosteroids: Currently four corticosteroid-based
intra-vitreal implants are under development
•
The dexamethasone biodegradable implant
•
The helical triamcinolone acetonide implant
•
The fluocinolone acetonide implant
Conclusions
Early diagnosis with timely OCT, Systemic control
of
Hypertension,
Dyslipaedemia,
hypergycaemia,
HbA1C, Correct decision regarding antiVEGF, LASER or
corticosteroids may prevent visual morbidity due to DME.
References
1. Early Treatment Diabetic Retinopathy Study Research Group.
Treatment techniques and clinical guidelines for photocoagulation
of diabetic macular edema. Early Treatment Diabetic Retinopathy
Study Report Number 2. Early Treatment Diabetic Retinopathy
Study Research Group. Ophthalmology. 1987;7:761-74
2.
Wilkinson CP, Ferris FL, Klein RE, Lee PP, et al. Proposed international
clinical diabetic retinopathy and diabetic macular edema disease
severity scales Ophthalmology 2003;9:1677–82.
3.
Brian Y. Kim, Scott D. Smith, Peter K. Kaiser, Optical Coherence
Tomographic Patterns of Diabetic Macular Edema AJO 2006;142:
405-12.
The phase II, double-masked, active-controlled DME
and VEGF Trap-Eye: Investigation of Clinical Impact (DA
VINCI) study, compared the effects of intravitrealaflibercept
compared to those of standard laser treatment. Results at
52 weeks showed greater VA gains for aflibercept (9.712.0 letters) than for laser treatment (-1.3 letters). Patients
who were treated with VEGF Trap-Eye were more likely to
experience gains of ≥10 and ≥15 letters than those who
received laser treatment.
4.
Bhagat N, Grigorian RA, Tutela A, et al. Diabetic macular edema:
Pathogenesis and treatment. SurvOphthamol. 2009;54:1-32.
5.
Fong DS, Strauber SF, Aiello LP et al.; Writing Committee for the
Diabetic Retinopathy Clinical Research Network. Comparison of
the modified Early Treatment Diabetic Retinopathy Study and mild
macular grid laser photocoagulation strategies for diabetic macular
edema. Arch. Ophthalmol. 2007;4:469-80.
6.
Stefansson E. The therapeutic effects of retinal laser treatment and
vitrectomy. A theory based on oxygen and vascular physiology.
ActaOphthalmol Scand. 2001;79:435-40.
Other trials for the use of Aflibrecept
7.
Mitchell P, Wong TY. Diabetic Macular Edema Treatment Guideline
Working Group. Management paradigms for diabetic macular
edema. Am J Ophthalmol. 2014;157:505-13.
(DA VINCI) study
•
VEGF Trap-Eye in Vision Impairment due to DME
(Vivid-DME; NCT01331681),
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