KOLEGIUM ILMU KESEHATAN

MATA INDONESIA

MANAGEMENT
OF DIABETIC
RETINOPATHY

Abdul Karim Ansyori

 .

References
References
 PENDAHULUAN

Prevalensi diabetes mellitus (DM) di dunia

meningkat secara dramatis dari 30 juta kasus
di 1985 menjadi 285 juta di 2010 dan
Indonesia merupakan termasuk dalam
peringkat 10 besar negara dengan
penderita DM terbanyak

Diabetes Mellitus adalah suatu penyakit kronik yang membutuhkan pelayanan kesehatan berkelanjutan, dukungan, dan
edukasi pasien mengenai penyakit maupun pengobatan yang harus dilaksanakan untuk mencegah komplikasi-komplikasi
akut, antara lain ketoasidosis diabetikum (KAD), status hiperosmolar hiperglikemik (SHH), asidosis laktat dan hipoglikemi,
dan menurunkan resiko terjadinya komplikasi jangka panjang, yaitu komplikasi makrovaskular yaitu coronary artery
disease (CAD), peripheral vascular disease (PAD), dan cerebrovascular disease (stroke), dan komplikasi mikrovaskular
yaitu diabetik nefropati, neuropati, dan retinopati.
 PENDAHULUAN
Diabetic Retinopaty merupakan penyebab penting
terjadinya kerusakan penglihatan dan kebutaan.
Kondiri ini disebabkan oleh diabetes yang
mempengaruhi kerusakan pada pembuluh darah di
retina. (WHO)

Suatu penyakit kronis progresif yang

DIABETIC berpotensi mengancam penglihatan,
mempengaruhi mikro vaskular retina akibat
RETINOPATHY hiperglikemia lama dan kondisi lain yang
berhubungan dengan diabetes mellitus
seperti hipertensi
(The Royal College of Ophthalmologist)

sight-threatening diabetic retinopathy atau STDR merupakan akibat dari beberapa mekanisme,
diantaranya: edema makula, iskemia makula, perdarahan pembuluh darah baru, dan kontraksi dari
jaringan fibrosa yang menyertai, yang mengakibatkan ablasio retina traksional
 PENDAHULUAN

Retinopati diabetika dapat terjadi dalam berbagai tingkatan sehingga menimbulkan gangguan penglihatan mulai
dari yang ringan sampai berat bahkan sampai menjadi kebutaan permanen

Risiko mengalami retinopati meningkat sejalan dengan lamanya menderita diabetes sehingga hiperglikemia yang
berlangsung lama diduga sebagai faktor risiko utama.
 FAKTOR RISIKO DAPAT DI MODIFIKASI
DAN TIDAK DAPAT DI MODIFIKASI
Non-modifiable Modifiable-proven Modifiable-variable
evidence
Duration of diabetes Hyperglycaemia Dyslipidaemia
Diabetes type Hypertension Diabetic kidney disease
Pregnancy - Anaemia
Puberty (Type 1 diabetes) - Smoking
Age - High salt intake
Genetic factors - Glitazone drugs
Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
 FAKTOR RISIKO DAPAT DI MODIFIKASI
Hiperglikemia
Pada pasien diabetes dengan retinopati memiliki kadar gula darah yang lebih tinggi dibandingkan dengan yang tidak terdiagnosis
retinopati. Sehingga kadar gula darah yang tinggi berpengaruh terhadap kejadian retinopati diabetika.

Hipertensi
Hipertensi merupakan komorbid tersering pasien retinopati dengan diabetes, 17% pasien retinopati diabetika tipe 1 memiliki
hipertensi dan 25% pasien menjadi memiliki hipertensi setelah 10 tahun terdiagnosis retinopati diabetika. Hipertensi berperan dalam
kegagalan autoregulasi vaskularisasi retina yang akan memperparah patofisiologi terjadinya retinopati diabetikum.

Hiperlipidemia
Dislipedemia mempunyai peranan penting pada retinopati proliferatif dan makula. Dislipidemia
berhubungan dengan tebentuknya hard exudate pada penderita retinopati.

Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
 MAJOR DIABETES COMPLICATIONS
Common micro- and macro-vascular comorbidities in diabetes patients

Source:
1. Centers for Disease Control and Prevention. National diabetes fact sheet 2011.
2. Centers for Disease Control and Prevention. Diabetes data & trends.
3. United States Renal Data System. Atlas of chronic kidney disease in the United States: United States Renal Data System 2011 annual report. Volume 1.
4. Ferris FL, Patz A. Surv Ophthalmol 1984:28;452–61.
 KOMPLIKASI DIABETES
Durasi terjadinya retinopati diabetikum pada pasien diabetes :
Durasi diabetes mungkin merupakan prediktor terkuat untuk perkembangan dan perkembangan retinopati.
Di antara pasien diabetes dengan onset lebih muda di WESDR, prevalensi retinopati adalah :
- 8% pada 3 tahun
- 25% pada 5 tahun
- 60% pada 10 tahun
- 80% pada 15 tahun.
Prevalensi PDR adalah
- 0% pada 3 tahun dan meningkat menjadi 25% pada 15 tahun.
Insiden retinopati juga meningkat seiring dengan peningkatan durasi. Insiden 4 tahun berkembangnya
retinopati proliferatif pada kelompok awitan WESDR meningkat dari 0% selama 5 tahun pertama menjadi
27,9% selama tahun 13-14 dari diabetes. Setelah 15 tahun, kejadian PDR tetap stabil.

Source: ADA. Diabetic Cara https://care.diabetesjournals.org/content/27/suppl_1/s84

 KOMPLIKASI RETINOPATI DIABETIKUM
Retinopati Diabetikum telah dilaporkan melibatkan pertumbuhan abnormal pembuluh darah di retina, komplikasinya
dapat menyebabkan masalah penglihatan yang serius. Komplikasi pertama yang terkait adalah perdarahan vitreous di
mana pembuluh darah baru mengeluarkan darah menjadi zat bening seperti agar-agar yang mengisi di tengah mata. Selain
itu, darah memenuhi rongga vitreous dan sepenuhnya menghalangi penglihatan pada kasus yang parah. Pendarahan tidak
menyebabkan kehilangan penglihatan permanen dan sering hilang setelah beberapa minggu atau bulan.

Komplikasi kedua yang terkait dengan Retinopati Diabetikum disebut sebagai retinal detachment di mana pembuluh darah
abnormal yang terkait dengan DR merangsang pertumbuhan jaringan parut, yang menarik retina menjauh dari bagian
belakang mata, pada akhirnya menyebabkan bintik-bintik mengambang di penglihatan, berkedip. kehilangan penglihatan
ringan atau bahkan parah.

Komplikasi lain yang diinduksi DR adalah glaukoma neovaskular di mana kebocoran pembuluh darah dan pertumbuhan
abnormal pembuluh baru di retina menyebabkan pertumbuhan pembuluh darah abnormal di iris, yang dapat mengganggu
aliran normal cairan di mata yang menyebabkan tekanan meningkat. Akhirnya menyebabkan kerusakan pada saraf optik
dan dalam kasus yang parah, menyebabkan kerusakan permanen pada penglihatan.

Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
INTERNATIONAL CLASSIFICATION OF DIABETIC
RETINOPATHY & DISEASE SEVERITY
Disease severity Findings observable upon dilated ophthalmoscopy

Diabetic retinopathy (DR)

No Apparent DR No abnormalities
Mild NPDR Microaneurysms only
More than just microaneursyms, but less than severe NPDR,
Moderate NPDR (microaneurysms with other signs like intraretinal hemorrhages, hard
exudates, cotton wool spots)

Any of the following (4:2:1)

1. More than 20 intraretinal hemorrhages in each 4 quadrants
Severe NPDR 2. Definite venous beading in 2+ quadrants
3. Prominent intraretinal microvascular abnormalities IRMA in 1+
quadrant (and no signs of PDR)

One or more of the following:

PDR 1. Neovascularization
2. Vitreous/preretinal hemorrhage
Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
INTERNATIONAL CLASSIFICATION OF DIABETIC
RETINOPATHY & DISEASE SEVERITY
Menurut skalaini, DR diklasifikasikan kedalam lima tahap, berdasarkan temuan yang dapat diamati pada fundus
oftalmosokopi dilatasi: tidak ada DR yang jelas, NPDR ringan, NPDR sedang, dan NPDR berat dan PDR. Dengan demikian,
secara klinis NPDR hanya terdiri dari tiga sublevel gravitasi (ringan, sedang, dan berat)
 
NPDR ringan ditentukan oleh keberadaan mikroaneurisma saja.
Tahap sedang dimaksudkan sebagai tahap perantara antara bentuk ringan dan berat.
Bentuk NPDR yang parah ditentukan, dengan tidak adanya tanda PDR, dengan salah satu temuan berikut: adanya
perdarahan intraretinal berat dan mikroaneurisma di empat kuadran, venous beading di dua kuadran atau lebih, dan IRMA di
setidaknya satu kuadran
 
PDR dengan karakteristik risiko tinggi didefinisikan sebagai memiliki salah satu temuan berikut:
NVD apapun dengan perdarahan vitreous atau preretinal, luasnya NVD lebih besar atau sama dengan seperempat luas disc,
dengan atau tanpa perdarahan vitreous atau preretinal, luasnya NVE lebih besar dari atau sama dengan satu-setengah luas
disc, dengan perdarahan vitreous atau preretinal

Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
INTERNATIONAL CLASSIFICATION OF DME
Diabetic macular edema (DME) by clinical appearance
No apparent DME No retinal thickening or hard exudates at the macula
Mild DME Some retinal thickening or hard exudates in posterior pole but
distant from the centre of the macula
Moderate DME Retinal thickening or hard exudates approaching the centre of
the macula but not involving the centre
Severe DME Retinal thickening or hard exudates involving the centre of the
macula
DME classification by centre of macula involvement using OCT
Non-central involving DME Retinal thickening in the macula that does not involve central
sub-field zone in OCT (1 mm diameter)
Centre involving DME Retinal thickening in the macula that involves the central
subfield zone in OCT (1 mm diameter)
Source: International Council of Ophthalmology. Updated 2017 ICO Guidelines for Diabetic Eye Care. ICO Guideline Diabetic Eye Care 2017.
 Anti diabetic agent

Antibodi AntiRAGE,
TNF-alfa, flavonoid,
decursin
Neuroprotective Oxidative stress
agent

Anti VEGF

Anti VEGF, Steroid,

Laser and Vitrectomy
Source: Judith L, et al. The pathology associated with diabetic retinopathy.
Elsevier 2017. PDR DME
 DIABETIC MACULAR EDEMA
Swelling of the retina due to leaking of fluid from blood vessels within the macula

Retinal edema

Hard
exudates

Thickening of the basement membrane and a reduction in the number of

pericytes lead to increase permeability and leakage of plasma constituents in
the surrounding retina.
 Current
Diabetic
Retinopathy
Treatment

Systemic
Ocular therapy
therapy

Systemic therapy
To prevent retinopathy and its
development
Blood sugar, blood pressure, lipid
profile control
Multi-modality treatment : lifestyle,
nutrition, geriatry, psychology
From the pathophysiology of DR, it is but natural
to reach the conclusion that reducing the
number of people with DM, would lead to a
reduction in the number of people with DR.
Thus, the foremost strategy to reduce DR would
be to reduce the prevalence and severity of DM
in the population, and effective control of
plasma glucose levels in individuals with DM.
This would necessarily entail the control of DM
and many associated co-morbidities. There are
both modifiable and non-modifiable risk factors,
that need focus and management. Modifiable
risk factors are those amenable to
interventions. Proven factors are those that
carry level 1 evidence (obtained from a
systematic review of all relevant randomized
controlled trials), and variable evidence from
large observational studies (level 3 evidence).

Ocular therapy
Preventing vision loss by improving VA,
reducing DR grading, screening DR,
neuroprotective agent, antibody anti-RAGE
Anti VEGF and steroid injection
Laser treatment
Surgery (Vitrectomy)
While diabetic retinopathy has been commonly
considered as a disease of the microvasculature,
there is robust evidence showing that
dysfunctional neurovascular crosstalk plays a
critical role in this complication.
Type 1 diabetes patients experience a diminution
of their inner retinal layer thicknesses over time,
supporting the hypothesis of retinal
neurodegeneration.
60-70% Diabetic Neuropathy in diabetes patient.
Neuroprotective agent such as : citicoline.
 RECENT STUDY ABOUT
TREATMENT TO INHIBIT DR
Antibodi Anti RAGE

TNF-∝ INHIBITOR Inhibition of transcription gene cytokine

proinflammation (IL-1a, IL-6, TNF-A, and
Expression of molecular adhesive (ICAM-1,
FLAVONOID V-CAM-1, thrombomodulin, endhotelin-1.

DECURSIN

Source:
1. Mathebula, Solani D. Biochemical changes in diabetic retinopathy triggered by hyperglycaemia: A review. Afr Vision Eye Health 2018.
2. Investigative Ophthalmology & Visual Science 2011;52(3):1336-44.
3. Journal of Cerebral Blood Flow & Metabolism 2009:29, 1559–1567
4. Nutrients 2020;12:3169
 MANAGEMENT OF
DIABETIC RETINOPATHY
DR status Observe PRP Macula Anti VR surgery
laser laser VEGF
Mild NPDR X - - -
NPDR-DME, centre not
involved - - X - -

NPDR-DME, centre involved - - - X -

Severe NPDR-large areas of
CNP - X - X -

PDR- flat NVE - X - X -

PDR- NVD - X - - -
PDR- elevated NVE - X - - -
PDR with DME X X
Vitreomacular traction - - - - X
Traction retinal detachment - - - - X
Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
TREATMENT RECOMMENDATION FOR DME

Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
THE RECOMMENDED TIMING OF THE FIRST OPHTHALMIC
(AND RETINAL) EXAMINATION & SUBSEQUENT FOLLOW-
UP EXAMINATIONS FOR PEOPLE WITH DIABETES
Type of diabetes Recommended initial Recommended follow-
retinal assessment up
Within 5 years of diagnosis
Type 1 DM Anually
of diabetes

Type 2 DM At the time of diagnosis of Anually

diabetes
1. No DR to mild NPD:
Pregnancy (T1DM/T2DM) Prior to conception and every 3-6 months;
early in the first trimester 2. Severe NPDR or worse:
every 1-3 months

Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
 VEGF AS A THERAPEUTIC TARGET
Anti-VEGF Antibodies

Inhibitors of Intracellular Transcription

Inhibitors of Extracellular VEGF

Inhibitors of VEGF Receptor Expression

Inhibitors of Intracellular Signaling Cascade Activating VEGF

Protein Kinase C (PKC) Beta Inhibitor

Source: Gupta N, Mansoor S, Sharma A, et al. Diabetic retinopathy and VEGF. Open Ophthalmol J. 2013;7:4-10. Doi:10.2174/1874364101307010004
 ANTI VEGF

Ocular therapy The expanding indications for anti-VEGF

therapy as intravitreal injections now include
Preventing vision loss by improving VA, DME and PDR. Clinical trials have shown that
reducing DR grading, screening DR, anti-VEGF treatment is better than laser
neuroprotective agent, antibody anti-RAGE
regarding the preservation and improvement
of vision in DME patients. When compared with
Anti VEGF and steroid injection laser therapy alone, ranibizumab was more
effective in monotherapy or combined with
Laser treatment laser. From those that used ranibizumab
injections, 46% of the patients improved vision
versus 18% with laser only.
Surgery (Vitrectomy)

Source: Stefan C, et al. Anti-vascular endothelial growth factor indications in ocular disease. Rom J Ophthalmol. 2015 Oct-Dec; 59(4): 235–242.
ANTI-VEGF
DRUGS
Monoclonal
antibody
Bevacizumab (Avastin®)

Antibody Ranibizumab (Lucentis®)

derivative
Aptamer Pegaptanib (Macugen®)

Oral small Lapatinib

molecules Sunitinib
(Inhibit tyrosine Sorafenib
kinases)

Fusion proteins VEGF trap-eye

(Aflibercept)
Miscellaneous siRNA
Bevasiranib
adPEDF
Source: Alexa Klettner and Johann Roider, 2012
ANTI VEGF CONTRAINDICATIONS

Ocular /
periocular Hypersensitivity
infection

Active intraocular
inflammation
 ANTI VEGF
Bevacizumab Pegabtanib Aflibercept

Binds to VEGFR 1 and 2 that

Specifically binds to
Binds directly to VEGF are fused to the Fc portion
VEGF165 isomer of the human IgG G1

Protein that plays a critical

Forms protein complex Forms protein complex
role in angiogenesis

Incapable of further binding Incapable of further binding

to VEGF receptor sites which Increased permeability to VEGF receptor sites which
would initiate vessel growth would initiate vessel growth

Source: Osaadon P, Fagan XJ, Levy J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye (2014) 28, 510–520.
 BROLUCIZUMAB
01 Humanized single-chain antibody fragment

Inhibitor of all isoforms of VEGF-A

02
03 Has the smallest molecular weight (26 kDa)

Stable and soluble, allows to achieve high doses

in a single 50 microliter intravitreal injection 04
Source: Yannuzzi NA, Freund KB. Brolucizumab: evidence to date in the treatment of
neovascular age-related macular degeneration. Clinical Ophthalmology 2019:13 1323–1329.
 STRUCTURAL, PHARMACODYNAMICS, AND
PHARMAKOKINETICS
Pegaptanib Ranibizumab Bevacizumab Aflibercept

Structure RNA aptamer Humanized Fab Humanized IgG1 r-fusion protein

Target VEGF165 All VEGF-A All VEGF-A VEGF-A/B, PlGF

MW (kDa) 40 48 148 115

Fc portion No No Yes Yes

Affinity (Kd, pM) 200 9.2-179 58-4456 0.49-9263

Potency (IC50, pM) 750–1400 88-1140 500-1476 16-90

t1/2 (vitreous, days) 10.4 7.2-9 6.7 NA

t1/2 (plasma, days) 7-8 0.083 (9)a 19 5-6

Systemic route No No Yes Yes

Source: Fogli S, Re MD, Rofi E, Posarelli C, Figus M, Danesi R. Clinical pharmacology of intravitreal anti-VEGF drugs. Eye (2018) 32:1010–1020.

30
TREATMENT RESPONSE AFTER INJECTION

Source: Cho YJ, Lee DH, Kim M. Optical coherence tomography findings predictive of response to treatment in diabetic macular edema. Journal of International Medical
Research 2018, Vol. 46(11) 4455–4464.
 WHEN TO STOP ANTI-VEGF?

Society Conclusion
AMD8 • If the macula remained “dry”, treatment was extended by 1- to 2-week
intervals until the injections were 12 weeks apart.
• Treatment was stopped if there were no signs of disease activity, and
reinitiated if there was new or recurrent CNV.
Horner F et al., 2019 • Half of the patients needed yearly injections, and a quarter of the patients
were able to stop injections for a year or more due to achieving stability.

Source: Horner F et al. Real-World Visual And Clinical Outcomes For Patients With Neovascular Age-Related Macular Degeneration Treated With Intravitreal Ranibizumab: An 8-Year
Observational Cohort (AMD8). Clin Ophthalmol 2019;13:2461-2467.
Julia A et al., 3 Experts on Anti-VEGF Tx for AMD: Starting, Switching, and Stopping. AAO Articles. October 2016
 WHEN TO SWITCH FROM ANTI-VEGF TO LASER?
Failure Futility
Criteria Criteria
Growth of NV after at
least 4 consecutive
injections NV persisted or Permit
NV is greater in recurred such that it Panretinal
extent than when was equal to or
treatment was greater than when
Photocoagulation
initiated treatment was
Definite NV initiated
worsening, following
an injection

Source: Sun JK, Glassman AR, Beaulieu WT, Stockdale CR, Bressler NM, et al. Rationale and Application of the Protocol S Anti-VEGF Algorithm for Proliferative Diabetic Retinopathy.
Ophthalmology. 2019 Jan; 126(1): 87–95.

33
 COMBINING LASER WITH ANTI VEGF

Five-Year Outcomes of Ranibizumab With Prompt or Deferred Laser Versus

Laser or Triamcinolone Plus Deferred Ranibizumab for Diabetic Macular Edema

Conclusions
Recognizing limitations of follow-up available at 5 years, eyes receiving initial
ranibizumab therapy for center-involving DME were likely have better long-
term vision improvements than eyes managed with laser or triamcinolone +
laser followed by very deferred ranibizumab for persistent thickening and
vision impairment.

Susan B, et al. five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. HHS Public Access.
2016 Apr; 164: 57–68.
COMPARISON OF LASER AND ANTI VEGF THERAPY
IN TREATMENT OF DIABETIC MACULAR EDEMA
Study from August 2018 to
May 2019 at Madinah Avastin therapy was found
Teaching Hospital, more effective in diabetic
Faisalabad. Eyes were macular edema
randomized to grid laser management than the
photocoagulation (N=15) Laser therapy in follow-ups
and Anti-VEGF (N=15)

Intravitreal Avastin improved BCVA most significantly (OR: +7.01 95%CI (2.56 to 11.39)) in 1 month
follow-up and Laser less significantly (+8.19 (5.07 to 11.96)) in one month follow up. Intravitreal
Avastin decreased retinal thickness most significantly (-111.34 (-254.61 to 37.93)) in one months
and Laser decreased less significantly

Source: Hira A, et al. Comparison of laser and anti VEGF therapy in treatment of diabetic macular edema. Med Crave 2020:Volume 10 Issue 1.
 Ranibizumab monotherapy and combined with laser provided superior visual acuity
gain over standard laser in patients with visual impairment due to DME. Visual acuity
gains were associated with significant gains in VFQ-25 scores. At 1 year, no
differences were detected between the ranibizumab and ranibizumab + laser arms.
Ranibizumab monotherapy and combined with laser had a safety profile in DME
similar to that in age-related macular degeneration

RESTORE STUDY (Ranibizumab Monotherapy or Combined with Laser versus Laser

Monotherapy for Diabetic Macular Edema)
BOLT STUDY (Bevacizumab or
Laser Therapy)
Comparison of laser and anti
VEGF therapy in treatment of
diabetic macular edema
VIVID STUDY (Intravitreal
Aflibercept versus Laser
Photocoagulation)
Intravitreal corticosteroid implant
vs intravitreal ranibizumab for the
treatment of macular edema: a
meta-analysis of randomized
controlled trials
This study provides evidence supporting longer-term use of
intravitreous bevacizumab for persistent center-involving CSME
Avastin therapy was found more effective in diabetic macular
edema management than the Laser therapy in follow-ups
VT-AFL treatment resulted in significant visual and anatomic
improvements in Asian patients with DME
Compared with ranibizumab, corticosteroid implant did not
have greater improved BCVA, but corticosteroid implant had
less CST reduction. The advantages of corticosteroids are fewer
injections, while the advantages of ranibizumab include fewer
side effects.
TAILORING TREATMENT TO PATIENTS BASED ON
NON-OCULAR FACTORS
Compliance to follow
Age Systemic disease
up

For healthy patients, Easy to follow up,

consider anti-VEGF consider anti-VEGF
In younger patients
with a clear lens,
consider anti-VEGFs Severe or recent MI,
as first-line therapy stroke or other In cases where there is a
thromboembolic events risk of non-compliance,
and/ or high risk for an consider Dex Implant to
event, consider intravitreal lessen follow up burden
corticosteroids
TAILORING TREATMENT TO PATIENTS BASED ON
OCULAR FACTORS
Presence of
glaucoma or high Lens status Vitrectomized
IOP
In patients with a
If uncontrolled, use
clear lens, consider
anti-VEGFs as first- In patients with
anti-VEGFs as first-
line therapy
line prior vitrectomy
consider Dex
If controlled, may If pseudophakic, Implant® as
consider Dex consider first-line therapy
Implant® as second- corticosteroid
line therapy implant
 RESTORE STUDY: Mean change in BCVA from baseline over time

Slow VA improvement in laser group

within 12 month

Safety set (last observation carried forward)

BCVA: best-corrected visual acuity; ETDRS: early treatment diabetic retinopathy study; SE: standard error
 PHOTOCOAGULATION LASER

Ocular therapy
Preventing vision loss by improving VA,
reducing DR grading, screening DR,
neuroprotective agent, antibody anti-RAGE

Anti VEGF and steroid injection

Laser treatment

Surgery (Vitrectomy)
PHOTOCOAGULATION MECHANISMS OF ACTION

Formation of scars
and burns on RPE • Photocoagulation-
Light energy is and photoreceptors induced injury →
Direct action to blood
converted into heat → decreased cytokine production
vessels → closure
energy at the retinal → reduces VEGF load
of leaky blood oxygen demand
level → protein and subsequently
vessels and increased reduces edema →
denaturation
inner retinal activation of RPE
oxygenation

Source: Jhingan M et al. Laser in Current Retina Practice. Retina Today January/Febryary 2017.

47
 LASER TREATMENT MECHANISM AT
Visible
Choroidal
Decreased
Light
RPE
consumption
of
sc RPE
ars and
(laser) light
retina
oxygen
absorption
diffuses
oxygen
through
and thermal
in melanin in
laser
coagulation
of outer
cells reaches
and adjacent
in laser scars
photoreceptors
retina
inner
RETINAL LEVEL
Increas
ed
oxygen
tensio
n of
inner
retina
D
e
cr
e
a
s
e
d
V
E
G
F
pr
o
d
u
ct
io
n
A
ut
or
e
g
ul
at
or
y
ar
te
ri
ol
ar
v
a
s
o
c
o
nt
ri
ct
io
n

Source: Stefansson Einar. The Mechanism of Retinal Photocoagulation-How Does The Laser Work?. Touch Briefings 2008.

48
LASER TREATMENT MECHANISM AT RETINAL LEVEL

Decreased VEGF production Autoregulatory arteriolar vasoconstriction

Decreased endothelial proliferation

Decreased hydrostatic pressure in capillaries and venules

Decreased permeability of
vessels
Decreased neovascularization

Decreased water flux from vascular to tissue compartment

Decreased edema formation

Source: Stefansson Einar. The Mechanism of Retinal Photocoagulation-How Does The Laser Work?. Touch Briefings 2008.
 Treatment
Diabetic retinopathy and diabetic macular edema treatment
are using laser photocoagulation.

Diabetic Retinopathy Study

“Panretinal photocoagulation (PRP) reduced the risk of severe vision
loss in patients with PDR or severe NPDR by at least 50% compared
with untreated eye.”

Early Treatment of Diabetic Retinopathy Study

“The risk of visual loss in patients with clinically significant
DMO was substantially reduce by focal photocoagulation.”

Source: J H Lock, MBBS, K C S Fong, FRCOphth. Retinal Laser Photocoagulation. Med J Malaysia Vol 65 No 1 March 2010.

50
 LASER CONTRAINDICATIONS
Panretinal photocoagulation
If macular edema is present and the proliferative retinopathy is less than
“high-risk,” panretinal photocoagulation often may be delayed (though only for
a few weeks or months) until after macular edema has been treated, since the
panretinal treatment could worsen the macular edema.

Focal laser
Ischaemic maculopathy, diffuse DME and patients who fail to appreciate the
risk-benefit profile of the treatment

Grid Laser
Visual acuity < 20/200 (0.1) is a contraindication for grid laser treatment. The
results of such treatment are contradictory and not of high evidence
Source:
1. Graham McMahon. Panretinal Photocoagulation. 2011
2. Diabetic Retinopathy: There is still a role for laser and surgery in the anti-VEGF era. 2017
3. Aljoscha S. Neubauer, Michael W. Ulbig. Laser Treatment in Diabetic Retinopathy. 2007
 DME TREATMENT WITH LASER AND ANTI-VEGF

Non centre-involved diabetic macular oedema left eye (left) resolved after laser
treatment (right) Centre-involved diabetic macular oedema left eye (left upper and lower),
resolved after three intravitreal, anti-vascular endothelial growth factor
(VEGF) injections. (right upper and lower)

Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
LASER-TREATED PDR
 LASER TREATMENT: ETDRS LANDMARK TRIAL

• Focal macular laser reduced risk of moderate vision loss (doubling of visual
angle) by up to 50% in eyes with clinically significant macular edema
• Set treatment criteria for clinically significant macular edema
 CLINICALLY SIGNIFICANT MACULAR
EDEMA: ETDRS CRITERIA

Retinal thickening within

500um or 1/3 disc
diameter of macular
Hard exudates within
center
500um of macular center
with adjacent retinal Thickening > than 1 disc
thickening. diameter (DD) in size
within 1 DD of macular
center
 LASER TREATMENT

Source: J H Lock, MBBS, K C S Fong, FRCOphth. Retinal Laser Photocoagulation. Med J Malaysia Vol 65 No 1 March 2010.

56
FOCAL AND GRID TREATMENT
 WHICH ONE IS BETTER, IVTA OR LASER?
• 840 eyes of 693 subjects
• Focal/grid laser vs IVTA 1mg or 4mg
• 3 year follow up
• Laser = + 5 letter score
• IVTA = no change in mean letter score

Three-year follow-up of a randomized trial comparing

focal/grid photocoagulation and intravitreal
triamcinolone for diabetic macular edema
INDICATIONS FOR FOCAL LASER TREATMENT
TREATMENT
RESPONSE
AFTER
LASER
 WHEN SHOULD THE PATIENT
VITRECTOMY HAVE A VITRECTOMY?
Severe vitreous hemorrhage of 1–3
1 months duration or longer that does
not clear spontaneously.
Premacular subhyaloid hemorrhage.

2 Advanced active proliferative DR that

persists or recurrent despite extensive
PRP

Traction macular detachment of recent

3
onset or Tractional macular edema or
epiretinal membrane involving the
macula.

4 Combined traction-rhegmatogenous
retinal detachment.

67
 PURPOSE OF SURGERY/VITRECTOMY
• Remove traction of mechanical factor: scaffold
of posterior cortical vitreous + fibrovascular
stumps, vitreomacular traction (such as DME)
• Clears visual axis (remove blood, PVR)
• Allows PRP
• ? removes angiogenic factors
• ? Improves oxygenation to ischaemic retina
 DIABETIC VITRECTOMY
• DRVS- 1972- vitrectomy at its infancy
• Advances in instrumentations- microscissors,
heavy liquid, xenon endoillumination
• Advances in surgical techniques
 ROLE OF VITREOUS IN DR
• Scaffold for NVD/E to grow
• Fibrovascular stump
• High level of vascular growth factors
• Persistent vitreoretinal traction
 OBJECTIVES OF DIABETIC VITRECTOMY
• Removes of mechanical factor: scaffold of posterior cortical vitreous +
fibrovascular stumps
• Removal of vitreomacular traction
• Clears visual axis
• Removes angiogenic factors
• Improves oxygenation to ischaemic retina
 SURGICAL TECHNIQUE
• Pars plana vitrectomy, 3 ports
• Removal 0f vitreous body, hemorrhage
• Removal of posterior cortical vitreous + relieve traction by fibrovascular stumps
• +/- laser Rx
• +/- tamponade
• +/- encirclement for adherent posterior cortical vitreous
• High level of technical skill + surgical judgement required
 SURGICAL TECHNIQUE

Entry for infusion

line to maintain IOP

Entry for vitreous

cutter, endolaser
probe, etc.

Entry for fibreoptic

light source to
illuminate the
inside of eye
 COMPLETE VITRECTOMY
• Vitreoschisis
• Split in posterior cortical vitreous
• Failure to recognize this may result in persistent vitreoretina
traction / macular oedema/ recurrent VH
• Through vitreous base trimming in VH to avoid ghost cell glaucoma,
recurrent VH
 ENDOLASER PHOTOCOAGULATION
• Endolaser performed when necessary
• Peripheral retina can be lasered with scleral depression
 COMPLICATIONS OF VITRECTOMY
• Vitreous haemorrhage 10-50%
• Retinal tears
• Severe fibrinous reaction
• Corneal epithelial defect
• Neovascular glaucoma
• Ghost cell glaucoma
• Aggravation of macula/ optic nerve head ischaemia
• Cataract
• Endophthalmitis
• Balance risk-benefit
• Timing of surgery- ocular and systemic considerations
• Surgeon-dependant
 MINIMIZE RISKS OF VITRECTOMY

• Quick and adequate dissection

• Avoid prolonged raised IOP intra-op to minimize macula/ optic nerve
head ischaemia, corneal oedema
• Meticulous cleaning/ draping of eye to prevent endophthalmitis
• Combined phaco/ vitrectomy
DRVS: early vitrectomy was beneficial for patients with
VA > 20/400 (3/60) plus one of the following:
• Severe neovasc. And fibrous proliferation
• Fibrous proliferation and moderate VH
• Moderate neovasc, severe fibrous proliferation and moderate VH.
--------------------------------------------------------------------------
early vitrectomy observation group
--------------------------------------------------------------------------
VA > 20/40 44% 28%
(4years follow up)
--------------------------------------------------------------------------
 VITRECTOMY-TREATED PDR

Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
VITRECTOMY FOR DME
COMPARISON OF TREATMENTS
DIABETIC RETINOPATHY SCREENING

Is it important ?
 SCREENING, FOLLOW-UP IN PEOPLE WITH
DM WITH AND WITHOUT DR

Source: Strengthening diagnosis and treatment of diabetic retinopathy in the South-East Asia Region. WHO 2020.
 SUMMARY
• Several treatment options are now available for diabetic macular edema
• An understanding the risks and benefits of each modality can help customize
each patient’s treatment
• Individualized treatment can optimize outcomes while providing safety and
.
lessening treatment burden
 TAKE HOME MESSAGES
• Treatment of diabetic retinopathy include systemic and ocular treatment
• There is strong evidence that good control of DM and associated systemic conditions reduces the
incidence of sight-threating retinopathy, and/or improves prognosis after standard treatment of
DR
• Treatment of diabetic retinopathy can reduce the risk of blindness, but can not restore vision loss
• The objective of DR and DME treatment is to delay disease progression by optimum glucose
control, reducing or normalizing the thickness of central retinal, and improving or maintaining the
visual acuity
• New pharmacological treatment base on understanding of the causaline mechanism of DR will be
development and address the need for both vascular and neuroprotector therapy
• To achieve an optimum treatment outcome, there is an emerging need:
to establish an appropriate referral flow or collaborative work between endocrinologist/diabetic
treating doctors and ophthalmologist/retina specialist to ensure appropriate timing and
intervention of glucose control, initiating/re-initiating DR and DME treatment
• Intravitreal anti-VEGF treatment is effective in the prevention of the visual acuity drop, and also in
the promotion of a visual regain
THANK
YOU