Delhi
Ophthalmological
Society
Contents
5 Editorial Miscellaneous
Experts’ Corner 47 Clinical Trials Related to Age Related Macular
Degeneration
Kirti Singh, Pooja Jain, Nitasha Ahir, Divya Jain
13 Age-related Macular Degeneration 53 Drug Induced Glaucoma – A Review
Theme: Retina Ravi Chandil
17 Evolution
61
Newer Treatments in Wet ARMD Evolution of Vitreo Retinal Surgery
Lalit Verma, Arindam Chakravarti Munish Dhawan, Mayank Dutta,
25 Intravitreal use of IVTA and IVB in DME P.S. Sandhu, S.P. Singh
Meena Chakrabarti, Sonia Rani John,
Arup Chakrabarti PG Corner
Decision Making in Rhegmatogenous Retinal 65 Cotton Wool Spots
Detachment
33 B.P. Guliani, Sandeep Gupta Vinod K. Aggarwal, Bhuvan Chanana
Role of Buckling in the Modern era of
Vitreoretinal Surgeries Monthly Meeting Corner
Sangeeta Roy, Shorya Vardhan Azad, 69
39 Brijesh Takkar, Anil Babanrao Gangwe Secretory Pituitary Tumour Presenting as
Ocular Hypertension
Shikha Gupta, Ramanjit Sihota, Viney Gupta,
Tanuj Dada, Varun Gogia, Ajay Sharma
Diagnostics
71 Choroidal Osteoma with CNVM
43 Spectralis
Ruchir Tewari, Shorya Vardhan Azad Anil B. Gangwe
Sangeeta Roy, Vivek Kumar
Tear Sheet
79 Tamponading Agents in Vitreo-Retinal Surgery
Raji K.
www. dosonline.org l 3
“The future is up for grabs. It belongs to any and all who will take
the risk and accept the responsibility of consciously creating the
future they want.”
-Robert Anton Wilson
Respected seniors & dear friends,
Ophthalmology has undoubtedly evolved to be one of the most developed
specialties in modern medicine. A giant leap in technology over the last few
decades has led many to term the period as “golden age” in ophthalmology.
Significant innovations by great minds have revolutionized the practical
aspects of ophthalmology in all spheres. It surely feels great to be a part of
the present era but what is even more exciting are promises the future holds
for us.
The future belongs to those who believe in the beauty of their dreams. I
feel very thrilled to announce the upcoming DOS Winter Conference on
30 November & 1st December 2013 at Manekshaw center, Delhi Cantt.
There are so many doors to be opened, and I can`t wait to look behind
them. Optimism is a strategy for making a better future. Because, unless you
believe that the future can be better, you are unlikely to step up and take
responsibility for making it so. The past is to be respected and acknowledged,
but not worshipped; it is our future in which we will find our greatness.
The times are promising with nanotechnology trying to change the way
we diagnose and treat eye diseases. Femtosecond laser and newer IOL
technologies are revolutionizing cataract surgery. Considerable progress is
being made in gene replacement therapies for retinal degenerations. Stem
cells are showing promising results in some of the eye diseases with no
effective treatment in the past. Artificial vision with bionic eye, a retinal
prosthesis is also showing positive results.
So it is your choice that will change the future. And the best way to predict
your future is to create it.
Sincerely Yours
Rajesh Sinha
Secretary,
Delhi Ophthalmological Society
www. dosonline.org l 5
Guest Editorial Editorial Board
Evolving Paradigm for DOS EEdditiotroiarl-iBno-carhdief
the Treatment of Diabetic
Macular Edema Rajesh Sinha
Diabetic retinopathy remains the leading cause of Executive Editor
vision loss in working age adults. Diabetic macular
edema (DME) is the leading cause of moderate Sandeep Gupta
vision loss in patients with diabetic retinopathy. The Digvijay Singh
longer patients suffer from diabetic retinopathy, the more likely they are to be
burdened with reduced vision. At 2 years, half of diabetic patients with clinically Editorial Board
significant DME lost more than 10 letters of best corrected visual acuity. By 3
years, similar patients had a 25% rate of severe vision loss (at least three lines, Ritika Sachdev
equal to a doubling of the visual angle). Ramendra Bakshi
Nearly 1 year has passed since the approval of ranibizumab for the treatment Pooja Bandivadekar
of DME via the RISE/RIDE trials, which provided the first FDA-approved
pharmacotherapy for the treatment of DME. The efficacy seen with ranibizumab Sana Tinwala
is without compare. Srilathaa G.
Despite this incredible addition to our management approach of DME, much Dewang Angmo
discussion remains regarding the management of DME. For instance, given Vishnukant Ghonsikar
the availability of ranibizumab, is there a role for focal laser or intravitreal
corticosteroids? Vitrectomy? Dosing ranibizumab in DME is also a topic of Ravi B.
discussion because the monthly dosing used in RISE/RIDE can be challenging in Shorya Vardhan Azad
certain circumstances for clinicians and patients due to the high burden.
The controversies will continue in the coming year as the fluocinolone and Tarun Arora
dexamethasone implants are both slated for FDA consideration for the treatment Anirudh Singh
of DME within the next 10 months. Vinod Agarwal
To conclude, the many recent studies for DME have given retinal specialists new
tools to better treat patients. While focal macular laser can still be effective in Neha Goel
reducing macular thickening, pharmacologic therapy (ie, anti-VEGF and steroid) Parul Jain
has been shown to improve visual outcomes but requires many more treatments. Reetika Sharma
Pars Plana Vitrectomy certainly continues to play a role in treatment for the many
patients with a tractional component of DME. Undoubtedly, in the future we will Rebika
find that patients may need various combinations of these therapies to obtain the
best outcome, and many studies are already beginning to investigate this. DOS Correspondents
Dr. Seenu M. Hariprasad MD
Supriya Arora
Chief, Vitreoretinal Service, Director, Clinical Research, Prateek Kakkar
The University of Chicago Medicine & Biological Sciences, Ruchita Falera
Chicago, Illinois. Ruchir Tewari
Manthan Chaniyara
Cover Designed by: Aman Dua Vineet Sehgal
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Published by Dr. Rajesh Sinha for Delhi Ophthalmological Society Nasreen
Printers: K.D. Printo Graphics, 2/20, 1st Floor, D.D.A. Market Ravish Kinkhabwala
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Email: [email protected] Pulak Agarwal
Akshay Tayade
Advisory Board
R.V. Azad
Y.R. Sharma
J.S. Titiyal
A.K. Grover
Lalit Verma
Rajendra Khanna
Atul Kumar
B.P. Guliani
Harbansh Lal
V.P. Gupta
Ramanjit Sihota
Praveen Malik
Abhishek Dagar
P.K. Sahu
J.K.S. Parihar
B. Ghosh
Tanuj Dada
Amit Khosla
Namrata Sharma
Sanjeev Gupta
Umang Mathur
J.S. Bhalla
Rohit Saxena
Bhavna Chawla
Manisha Agarwal
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Delhi
Ophthalmological
Society
Executive Members
J.S. Titiyal MD Rajendra Khanna DOMS Rajesh Sinha MD, FRCS Neeraj Sanduja MS Sanjeev Gupta MD
President Vice President Secretary Joint Secretary Treasurer
[email protected] [email protected] [email protected] [email protected] [email protected]
M. Vanathi MD Vipul Nayar DOMS, DNB, MNAMS Tinku Bali MS, FRCS Bhavna Chawla MS Rajib Mukherjee DOMS, DNB
Editor Library Officer Executive Member Executive Member Executive Member
[email protected] [email protected] [email protected] [email protected] [email protected]
R.P. Singh MD Neeraj Manchanda DO,DNB Manisha Agarwal MS Deven Tuli MS Arun Baweja MS
Executive Member Executive Member Executive Member Executive Member Executive Member
[email protected] [email protected] [email protected] [email protected] [email protected]
Sanjay Chaudhary MS Rajendra Khanna DOMS Harbansh Lal MS Rohit Saxena MD Ashu Agarwal MS
DOS Representative to AIOS DOS Representative to AIOS Ex-Officio Member Ex-Officio Member Ex-Officio Member
[email protected] [email protected] [email protected] [email protected] [email protected]
Experts’ Corner
Age-related Macular Rajvardhan Azad
Degeneration
Age related macular degeneration(ARMD) has emerged as leading cause of irreversible vision loss Seenu M. Hariprasad
in eldery population in the developed countries. Both with doubling of the eldery population in the Masahito Ohji
next decade and the ever evolving management of ARMD, its imperative for us to keep ourselves
abreast of latest guidlines and treatment followed worldwide. ARMD is a devastating disorder, hence Hyung Woo Kwak
prompt treatment and good follow up is essential for preservation of vision. Here we try to focus on S. Natarajan
management of ARMD and bring together views and guidlines of various national and international
retinal experts across the globe.They share with us their vast experiance on guidlines followed by them
which can provide useful insight towards proper management of ARMD for all retinal experts.
Prof. (Dr.) Rajvardhan Azad (RVA): MD,FRCS,FICS,FAMS Chief and Head Vitreo Retina, Dr.
Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New
Delhi, India.
Dr. Seenu M. Hariprasad (SMH): MD, Associate Professor of Surgery, Section of Ophthalmology
and Visual Science, Chief, Vitreoretinal Service, Director, Clinical Research, The University of
Chicago Medicine & Biological Sciences, Chicago, Illinois.
Dr. Masahito Ohji (MO): Chairman Department of Ophthalmology, Shiga University of
Medical Science Seta Tsukinowacho, Otsu, Japan.
Dr. Hyung Woo Kwak (HWK): Department of Ophthalmology, Kyung Hee University
Medical Center, Seoul, Korea.
Prof. (Dr.) S. Natarajan (SN): DO, MS, FRVS, MABMS, MORCE, FABMS Chairman and
Managing Director, Aditya Jyot Eye Hospital Pvt. Ltd. Mumbai, India.
Shorya Vardhan Azad (SVA): DO, MS, Senior Resident, Vitreo Retina, Dr. Rajendra Prasad
Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.
SVA: What in your opinion is the role of Fundus Fluorescein Angiography (FFA) and
Optical Coherence Tomography (OCT) in AMD?
RVA: Both FFA and OCT have got a definite role in management of AMD and must be
done at baseline to define lesion type, location and leakage. On follow up though, OCT being a
non invasive procedure, is preferred and is sufficient for guiding our treatment. However, FFA can
always be done during follow up in cases which become reactive and/or refractory to treatment.
SMH: In my opinion, although OCT is critical, FFA has a distinct and important role, especially
to tease out other conditions. Fluorescein gives us a unique view of a lesion: its geography and
perfusion characteristics, and its location relative to the fovea. When a patient isn’t responding
well to treatment, fluorescein can help provide answers. I think we can take very good care of
the vast majority of patients with OCT, but I would hate to see the day when FFA isn’t part of the
management of wet AMD.
MO: It is essential for diagnosis and further management during follow ups.
HWK: FFA and Indocyanine green angiography (ICGA) help us identify the CNV and OCT
is performed on the matching lesion. Spetralis Hidelberg retina angiograph (HRA)+OCT allows us
to confirm a lesion by simultaneously performing FFA, ICGA, and OCT. It enables us to check the
sectional view of a lesion along with changes in the microstructure such as subretinal fluid or retinal
pigment epithelium detachment. With the advancement of OCT, we are now able to check the
www. dosonline.org l 13
Experts’ Corner
microstructure such as IS/OS or external limiting membrane if the visual acuity declines or retinal thickness increases, any
(ELM) on macula, which in turn allows us to estimate visual of which indicates a relapse. Once the additional injection is
acuity. given, the patient is followed up every month on a regular
basis and additional injections are consistently given when
SN: Both have an important role for confirmation of the necessary.
diagnosis and for follow up of patients, specially OCT.
SN: Monthly injections for 3 months, protocol varied as
SVA: Would you do ICG to confirm diagnosis of PCV per individual patient response, depending on SRF confirmed
in every case and your protocol to manage them? by OCT.
RVA: It should always be done in cases where we SVA: Which anti VEGF do you prefer and why?
have clinical suspicion of Polypoidal choroidal vasculopathy RVA: I routinely use Lucentis in most of my patients
(PCV) on fundus findings to confirm the lesion. A combination who are insured and affording, although Avastin due to
therapy of PDT and anti-VEGF is the choice of treatment for its comparable results is always an option for those having
PCV. financial short comings. I call Avastin as ‘Poor man’s Lucentis’
due to its non inferiority in terms of outcomes and affordability
SMH: In the United states we see PCV so rarely. in comparison to Lucentis.
Obviously, ICG is very valuable in the diagnosis and SMH: Eylea and Lucentis. The efficacy and dosing strategy
management of PCV. In my opinion, ICG is more valuable in of Eylea is very appealing. However, I have nearly a decade
PCV compared to wet AMD. of experience with Lucenits. Keep in mind that Aflibercept is
the only molecule that inhibits placental growth factor (PlGF),
MO: I always perform ICG when I say “AMD” and a which may be beneficial in cases that are recalcitrant to older-
combination therapy of PDT and anti-VEGF would be the generation anti-VEGF agents. Also, unlike other monoclonal
choice for PCV. antibodies, aflibercept has 1:1 stoichiometric binding to VEGF.
My standard is to offer Eylea to my Naïve patients and switch
HWK: In almost all cases when fundus shows protruding to Eylea in patients recalcitrant to older generation anti-VEGF.
orange-red elevated lesion and PCV is suspected, I use ICGA MO: I use ranibizumab for 50% and aflibercept for the
in order to confirm the diagnosis by checking the polypoidal other 50% because of my study.
lesions. Later on, I perform ICGA again in order to check the HWK: I mainly use ranibizumab or bevacizumab.
change in the lesion, which confirms treatment effect. Although recent reports say that there is no great difference
between the two agents in terms of efficacy, one cannot
I use intravitreal Anti-VEGF injection or photodynamic ignore the possibility that bevacizumab would have systemic
therapy or their combination. I use photodynamic therapy in effect. So I choose one out of bevacizumab or ranibizumab
order to occlude polyps. In addition, I also use an anti-VEGF taking the patient’s conditions into consideration. Since
agent in order to reduce vascular leakage and resolve the ranibizumab is reimbursed up to 10 doses when it is used for
macular edema since VEGF level is elevated in PCV. AMD patients, I tend to use ranibizumab for them. In those
cases with no insurance coverage, I choose bevacizumab or
SN: Yes and the protocol is combination of PDT with ranibizumab taking the economic conditions of the patients
injection lucentis. into consideration.
SN: I prefer giving injection lucentis as it is approved
SVA: Your treatment protocol for Wet AMD other by FDA.
than PCV (PRN/Treat and Extend)? SVA: In which cases do you do Low Fluence PDT?
RVA: I seldom use Low Fluence photodynamic therapy
RVA: Initially I prefer to give three injections upfront (PDT) in my practice but its always an option in case of Chronic
every month, followed by injections as and when required central serous chorio retinopathy (CSCR) and IPCV.
depending on the presence of fluid on OCT further confirmed SMH: I rarely employ PDT. In fact, in the United States,
by leakage on a repeat FFA. During relapse I tend to start all very few specialists utilize PDT for wet AMD. This may be
over again giving an injection every month for three months different for PCV, however, our rates of PCV are incredibly
followed by pro re nata (PRN). low compared to Asia.
MO: Only in CSCR.
SMH: Basically, there are three established dosing HWK: Low Fluence PDT is used in order to reduce RPE
regimens: the on-label, study-related approach, PRN and atrophy, ischemia of the choroidal capillary or secondary CNV
treat-and-extend. For ranibizumab and bevacizumab, on-label which could occur in ordinary PDT cases. I use low fluence
dosing is monthly. For aflibercept, the on-label regimen is PDT for central serous chorioretinopathy. I also try it for AMD
three, monthly loading doses followed by treatment every 2 once the patient is expected to respond to low fluence PDT.
months. SN: In chronic CSCR, IPCV, AMD not responding to
conventional therapy.
In year one, I tend to use Avastin and Lucentis with a
treat and extend regimen. However, I use fixed every other
month dosing with Eylea in year one. In year two, I employ a
treat and extend protocol for all anti-VEGF molecules.
MO: I generally prefer a bimonthly injection of
ranibizumab.
HWK: After confirming CVN through FFA and ICGA,
I give intravitreal anti-VEGF injection three times. During
follow-up, I give additional injections when subretinal fluid
(SRF) or pigment epithelium detachment (PED) is increased or
14 l DOS Times - Vol. 19, No. 3 September, 2013
Experts’ Corner
SVA: Do you still use Laser in cases of Extra Foveal CNVs? SVA: How do you treat large subfoveal bleeds?
RVA: I would apply Laser only in cases of extra foveal RVA: Mostly I use gas and Anti-VEGF.
CNV’s as it has a more definite effect. SMH: If patients present quickly enough, I may consider
SMH: Yes, I do 3-5 MPS laser treatments for extrafoveal subretinal tissue plasminogen activator (tPA) and pneumatic
CNV’s per year. These lesions truly have to be well away from displacement if I believe that the eye has visual potential.
the fovea for me to consider MPS laser. I may also employ MPS However, if patients present too late, or baseline vision is low,
laser after 1 or 2 intravitreal injections. The finite treatment of I may observe or just continue anti-VEGF injections. Fellow
MPS laser in these patients is very appealing. eye status is also an important consideration. Every case is
MO: I still apply laser when it locate far from the fovea. different and requires individualized decision making.
HWK: I rarely use laser these days, since it can lead MO: Pneumatic displacement.
to a permanent scotoma or secondary choroidal neo- HWK: Depending on the patient’s conditions, I
vascaularization. In addition, it can also lead to more relapses use diverse combinations out of intravitreal tPA injection,
on a long-term basis compared to anti-VEGF. intravitreal Gas injection, or intravitreal anti-VEGF injection.
SN: No. A surgical treatment is attempted for massive bleeding but
SVA: When would you consider steroids (Short term/ in case of the non-organized subretinal hemorrhage, which
Implants)? started less than 1 week ago, pneumatic displacement is used
RVA: Generally Anti-VEGFs suffice for the treatment of as a first line. When submacular hemorrhage is displaced, anti-
CNV but I have used Ozuredex in some of my patients having VEGF is given through intravitreal injection and the patient is
persistent leakage or relapse despite best possible treatment. followed-up.
But its not my firstline treatment and should be considered SN: Either tPA + gas + inj Lucentis or gas + inj Lucentis.
only in few selected cases. SVA: What is the role of dietary supplements in AMD?
SMH: Although I believe that there may be an RVA: Both Age related eye disease study (AREDS 1 and
inflammatory component in this disease, there is a paucity of AREDS 2) have shown the efficacy of anti oxidants in delaying
evidence to support the use of steroids to treat wet AMD. I the progression of AMD. More recent AREDS 2, has dismissed
may consider steroids in patients with intraretinal cystic edema the role of omega 3 fatty acids and has replaced beta-carotene
recalcitrant to anti-VEGF therapy. with lutein and zeaxanthine owing to its risk of lung cancer
MO: No. in smokers. I prefer giving anti oxidants to all my patients,
HWK: Some studies suggest that steroid is effective for especially one with dry form of AMD.
all types of CNV; however, other studies also indicate that SMH: AREDS 1 taught us that with use of the
it is less effective than a standard anti-VEGF agent or PDT. recommended dietary supplements, a significant number of
I consider using steroid when the patient does not respond our patients can reduce their risk of converting from dry to
to the standard anti-VEGF treatment or in the case of chronic wet AMD. The impact of this on an individual level can’t be
relapses. I tend to use more of the steroid implant these days underestimated. For an elderly patient, it could mean being
since it has the benefit of releasing steroid in a consistent able to live the rest of his or her life with good vision and the
concentration and remain effective for 3~6 months. accompanying good quality of life. AREDS 2 confirmed this
SN: Recurrent cases not responding to anti VEGF. information and refined our knowledge.
SVA: Is there still a role of Combination Treatment? MO: I explain the efficacy to patients with high risk, but
RVA: Only in case of PCV would I consider combination not strongly suggest.
treatment. HWK: AREDS 1 study was released in 2001 showing
SMH: Absolutely. Not necessarily with PDT, however, that anti-oxidants such as vitamin C or E and zinc delayed
with other molecules like anti-PDGF. the progression of macular degeneration. There was a report
MO: It would be nice for PCV. on the possibility of beta-carotene increasing the risk of lung
HWK: VEGF level is elevated in AMD and VEGF cancer in smokers. AREDS 2 showed that omega 3 fatty acids
increases permeability of vessels and it also gets involved in had no benefit while lutein and zeaxanthine used in place of
the pathogenesis of neo vascularization. Anti-VEGF is expected beta-carotene actually brought down side effect and delayed
to treat AMD; however, it has the drawback of a short duration the progression of macular degeneration. It seems that taking
and repetitive injections required. It is also known to be less nutrient supplements including these components can delay
effective in occluding the CNV. In an attempt to complement the progression of AMD.
this shortcoming, I try to occlude CNV with PDT treatment. SN: They need to be given in dry AMD and specially in
In general, I try Anti-VEGF as a first line and then use the patients with CNVM in one eye.
combination treatment when it fails.
SN: In case evidence of inflammatory component is DOS Correspondent
seen on FFA, combination of anti-VEGF and steroids work Shorya Vardhan Azad DO, MS
well.
www. dosonline.org l 15
Newer Treatments in ReRteitnina
Wet ARMD
Lalit Verma
Lalit Verma MD, Arindam Chakravarti MD MD
Centre For Sight, New Delhi
It is a proven fact that anti- vascular endothelial growth Newer Drugs
factor (VEGF) monotherapy is effective in the treatment VEGF trap-eye
of neovascular age-related macular degeneration (AMD). VEGF Trap-Eye (Aflibercept) is a recombinant fusion
There is equally no doubt that anti-VEGF monotherapy protein consisting of human VEGF receptor extracellular
induces disease resistance in neovascular AMD. domains fused to Fc portion of human IgG1, it is a dimeric
Long-term visual outcomes of anti-VEGF monotherapy glycoprotein. Protein MW- 97 kDa and contains 15%
in the clinical setting, are disappointing. The HORIZON glycosylation to give total MW of 115 kDa. It binds to
extension study1 analyzed patients with choroidal VEGF-A, VEGF-B, and placental growth factors 1 and 2
neovascularization (CNV) secondary to AMD who had with high affinity. This ability to bind other VEGF family
received ranibizumab (Lucentis, Genentech) every 4 weeks members distinguishes VEGF trap from antibodies specific
for 2 years as participants in phase 3 trials of the drug. When for VEGF.
patients who received 2 years of monthly therapy in the Phase 2 experience of VEGF Trap Eye in AMD showed a
original trials were subsequently treated on an as-needed positive functional and anatomical effect in patients with
(prn) basis for an additional 2 years in HORIZON, their Wet AMD. In August 2007, Regeneron and Bayer Health
mean visual acuity returned almost to baseline. Similar Care initiated a Phase 3 trial evaluating VEGF trap-eye
limitations in the long-term outcomes of patients treated in wet AMD. Two similarly designed, phase-3 studies
with anti-VEGF therapies have been observed in other trials of VEGF Trap-Eye: Investigation of Efficacy and Safety in
such as the SECURE and SEVEN-UP studies2,3. Wet AMD [VIEW 1, VIEW 2]5 of neovascular age-related
More recently, in the CATT study4 comparing ranibizumab macular degeneration (AMD) compared monthly and
and bevacizumab (Avastin, Genentech) with monthly and 2 monthly dosing of intravitreal aflibercept injection.
prn dosing schedules, the 2-year results showed similar Patients were randomized to intravitreal aflibercept 0.5
insights. Patients in the crossover arms of this study received mg monthly, 2 mg monthly, 2 mg every 2 months after
monthly anti-VEGF treatment whether ranibizumab or 3 initial monthly doses or ranibizumab 0.5 mg monthly.
bevacizumab and were then switched to prn treatment The primary end point was non-inferiority of the aflibercept
after 1 year. In the second year of the study, the response in regimens to ranibizumab in the proportion of patients
these patients was similar to the response of those who had maintaining vision at 52 weeks. Intravitreal aflibercept
been treated prn from the beginning of the study. dosed monthly or every 2 months after 3 initial monthly
In other words, these studies suggest that anti-VEGF doses produced similar efficacy and safety outcomes as
monotherapy does not result in disease modification; it monthly ranibizumab. These studies demonstrate that
induces no structural advantage in neovascular AMD. It aflibercept is an effective treatment for wet AMD with the
may be that patients with CNVM secondary to AMD would every 2 month regimen offering the potential to reduce the
need anti-VEGF monotherapy indefinitely. What are our risk from monthly intravitreal injections and the burden of
options? monthly monitoring.
www. dosonline.org l 17
Retina
The VIEW trials used a capped 3 month treat-and-observe treatment is followed by a plateau that persists through the
strategy in year 2 but did not test treat-and-extend, thereby study indefinitely. This pattern correlates well with the time
requiring retina surgeons to investigate this strategy course of antipermeability induced by VEGF antagonists.
with post-approval trials. However the popularity of this The pathophysiology of neovascular membrane growth
approach among both patients and physicians suggests that explains the shape of the curve. Anti-VEGF monotherapy
the aflibercept will be used in this manner, with the hope of acts primarily on fenestrated and unprotected endothelial
extending the intervals longer than with either ranibizumab cells in the first few months of treatment, causing a decrease
or bevacizumab. in exudation and initial improvement in visual acuity.
A phase III VEGF Trap Eye trial for central retinal vein Thereafter, however, the rest of the neovascular complex
occlusion has completed enrolment, and similar trials for is protected by the pericyte armor, resulting in the plateau.
diabetic macular edema and branch retinal vein occlusion As soon as anti-VEGF monotherapy is withdrawn, the tip
have begun. cells regrow, the neovascular complex increases in size,
The drug has been approved by FDA and is currently and disease progression with leakage continues.
available in the market for treatment. It may help in larger To summarize, chronic anti-VEGF treatment causes
spacing of treatment intervals leading to fewer injections PDGF upregulation, leading to pericyte recruitment and
and subsequent decrease in financial burden to the patient. neovascular membrane maturation. This concept is well
Role of Platelet-derived growth factor known in the oncology literature, where the role of VEGF
Crucial evidence for anti-VEGF resistance has been identified as a negative regulator of pericyte function and vessel
in the oncology literature for more than a decade. It has to maturation has been well described.
do with pericytes, a type of cell that intimately covers and Pachdakiet al11 recently described submacular surgery
protects the neovascular complex as new vessels develop and excision of neovascular membranes in an eye with
and mature. Pericytes supply VEGF and other cell survival CNV that was unresponsive to bevacizumab treatment.
factors to the proliferating endothelial cells and confer anti- The membrane displayed well-formed neovascular units
VEGF resistance6. consistently exhibiting pericytes, the authors reported.
Platelet-derived growth factor (PDGF) is responsible for Anti-PDGF Therapy
pericyte recruitment, survival and maturation7,8. Studies If pericytes are the source of resistance to anti-VEGF
in the oncology literature have shown that PDGF- therapy in neovascular AMD, then there is a physiologic
deficient mice lack microvascular pericytes, and they form rationale for a combination of anti-PDGF and anti-VEGF
microaneurysms that rupture in late gestation8. Conversely, therapies. The objective would be for the anti-PDGF
PDGF over expression in melanoma cells leads to increased agent to chemically bind to and strip pericytes from the
pericyte proliferation and tumor growth9. neovascular complex, rendering the CNV more vulnerable
These insights from the oncology literature are crucial for to anti-VEGF treatment.
our understanding of neovascularization in AMD. The Ophthotech has developed a PDGF inhibitor (Fovista,
growth of a neovascular complex is not random, but rather formerly E10030), a PEGylated DNA aptamer. Preclinical
specifically directed by a group of specialized cells known work has shown that this agent binds to PDGF and strips
as tip cells10. These tip cells are the only unprotected pericytes from CNV, and that the combination of this
endothelial cells in the neovascular complex; they express agent with an anti-VEGF agent is more effective than
PDGF, which stimulates the maturation and recruitment of anti-VEGF therapy alone in multiple animal models of
pericytes that cover the neovascular complex. neovascularization12.
Anti-VEGF monotherapy is typically effective in obliterating In an uncontrolled dose-ranging phase 1 study with a small
only these unprotected tip cells. The pericytes that have sample size (N=22), the safety profile of this anti-PDGF agent
been recruited form a protective armor around the rest of was excellent, with no dose-limiting toxicities observed13.
the neovascular complex, allowing it to remain in place. Despite the severity of disease in patients recruited for the
When anti-VEGF therapy is stopped, the tip cells become study, a number of patients gained significant vision. A
active and mitotic again, leading to continuation of disease number of patients also showed significant regression of
progression. neovascular complex.
This physiologic process is suggested by the results of Based on these encouraging results, a large phase 2b
clinical studies of anti-VEGF agents in neovascular AMD. study was conducted (clinicaltrials.gov NCT01089517).
The familiar curve showing visual acuity improvement The results of this study were presented at the American
is remarkably consistent among these studies. An initial Academy of Ophthalmology Annual Meeting recently.
improvement in visual acuity in the first 3 or 4 months of The goal of the study was to assess the safety and efficacy
18 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
of a combination of the anti-PDGF agent E10030 plus of SHRM at week 24 showed a clear dose-related response.
ranibizumab compared with ranibizumab monotherapy This clear dose-response effect was also seen in patients
in patients with CNV secondary to AMD. Patients were who gained 3 lines of visual acuity or more. On fluorescein
randomly assigned to 1 of 3 treatment groups: 0.3 mg angiography, there was a clear correlation between lesion
E10030 plus ranibizumab 0.5 mg, 1.5 mg E10030 plus regression and visual acuity gain, whether in patients with
ranibizumab 0.5 mg, or ranibizumab 0.5 mg monotherapy. 3, 4, or 5 lines of visual acuity gain, with superior results
Investigators recruited 449 patients, making this the in the combination arms. In patients who lost vision, there
largest phase 2 superiority study in retina. Unlike other was a clear correlation with growth of the neovascular
recent studies in this area, it was a superiority study, not a membrane, and again the combination regimens were
noninferiority study. protective. Regarding safety, there was no difference in
The primary endpoint was mean change in visual acuity ocular adverse events or systemic serious adverse events
from baseline to week 24. Secondary endpoints included among the 3 treatment groups. There was also, importantly,
mean change in visual acuity at week 12, the proportion of no difference in mean intraocular pressure among the
patients gaining 15 or more letters of visual acuity at week groups, despite requiring 2 injections in the combination
12 and week 24, and mean change in the area of occult arms.
CNV at week 24 as defined by fluorescein angiography. In this large phase 2 clinical trial of E10030 anti- PDGF agent
The baseline demographics of all 3 arms were comparable. in combination with an anti-VEGF agent, both combination
The prespecified superiority primary endpoint of arms met their prespecified primary endpoint of superiority
improvement in visual acuity at week 24 was met by over anti-VEGF monotherapy (P=.019). Results showed
both combination groups. The 1.5 mg combination group a 62% additional benefit of combination therapy over
showed mean improvement of 10.6 letters of vision, the monotherapy.Lessons from the oncology literature suggest
0.3 mg combination group showed improvement of 8.74 that it makes good physiologic sense to combine anti-
letters, and the ranibizumab monotherapy group showed PDGF and anti-VEGF therapies. If the results of this large
improvement of 6.52 letters (P=.019 for ranibizumab only phase 2b trial are confirmed in a planned pivotal phase 3
in comparison with each combination group). trial, this combination therapy modality has the potential to
It is notable that both combination groups met their dramatically and profoundly change our treatment model
prespecified primary endpoint of superiority. In fact, in for patients with neovascular AMD.
the 1.5 mg combination arm there was a 62% additional Rapamycin Therapy
benefit compared with ranibizumab monotherapy. To Broad gaps currently exist in the management of retinal
determine whether any particular subgroup of patients diseases such as neovascular age-related macular
drove these positive study results, numerous prespecified degeneration (wet AMD) and diabetic macular edema
subgroup analyses were conducted. (DME). For instance, fibrosis represents an important
For baseline lesion size, an arbitrary segregation point of component in many retinal diseases, causing irreversible
4 disc areas was chosen. Results in the combination arms photoreceptor death and severe loss of vision. Yet
were superior for lesion sizes both greater than and less fibrosis is not addressed in the current treatment of these
than or equal to 4 disc areas. Additionally, whether the diseases. Rapamycin also known as sirolimus is a highly
median lesion size of 1.21 disc areas or the mean lesion evolutionary nuclear and cytoplasmic protein kinase which
size of 1.78 disc areas was used as the segregation point, acts by inhibiting mTOR. mTOR regulates cell processes in
again the combination arms were superior. response to the environment.
The effect of baseline visual acuity was also examined. For Mammalian target of Rapamycin (mTOR) signals through
relatively good visual acuity of 20/60 to 20/80 or relatively two protein complexes, mTORC1 and mTORC2. It
poor visual acuity of 20/160 or worse, the combination regulates a variety of processes, including angiogenesis
arms were superior. Clinically relevant subgroups were and immune homeostasis. Rapamycin has been found to
also examined. In patients who gained 3, 4, and 5 lines of inhibit VEGF-induced vascular permeability. Sirolimus
visual acuity, the combination arms were always superior (Rapamycin) inhibits the translation and activity of hypoxia-
to the monotherapy arm, with 27%, 71%, and 190% inducible factor-1 alpha (HIF-1a), a stress-activated protein
relative benefits, respectively. In patients who lost 5 letters that activates numerous survival proteins involved in
or more or 10 letters or more, the combination regimens angiogenesis and hyperpermeability14. mTOR inhibitors are
were protective. safe, have broad therapeutic effect, proven clinical utility,
Biomarkers including OCT and fluorescein angiography and down regulates the hypoxic response. Rapamycin also
were also examined. On OCT, of particular interest was inhibits formation of mTORC and reduce VEGF expression
subretinal hyper reflective material (SHRM), the thickness of in RPE cells, inhibits various forms of ocular angiogenesis,
which appears to correlate with visual function. Resolution has potent anti-inflammatory effect, and inhibits fibrotic
www. dosonline.org l 19
Retina
process. In addition, sirolimus has the potential to be an resulted in visual acuity improvement and reduction of
excellent combination agent, improving overall outcomes OCT that lasted at least 90 days.
or prolonging the intervals between anti-VEGF injections. Other agents
Kolosova et al15 investigated the effect of rapamycin on Palomid 529, an inhibitor of both mTORC1 and mTORC2
spontaneous retinopathy in senescence-accelerated OXYS pathway, recently has been shown to possess similar effect
rats, an animal model of age-related macular degeneration. on both ocular neovascularization and on VEGF-induced
Rats were treated with either 0.1 or 0.5 mg/kg rapamycin, vascular permeability. Everolimus, another mTOR inhibitor
which was given orally as a food mixture. In a dose- is also being tried for the treatment of neovascular AMD.
dependent manner, rapamycin decreased the incidence Anti-TNF-a agents can directly neutralize the circulating
and severity of retinopathy. Rapamycin improved some TNF-a and prevent the binding of TNF to its receptors, p55
histological abnormalities associated with retinopathy. and p75. TNF-a antagonists also bind to transmembrane
Thus, in retinal pigment epithelial cell layers, rapamycin TNF-a, thereby inducing complement-dependent
decreased nuclei heterogeneity and normalized intervals cytotoxicity and antibody-dependent cytotoxicity. The
between nuclei. In photoreceptor cells, associated neurons, binding of anti-TNF-a agents with transmembrane TNF-a
and radial glial cells, rapamycin prevented nuclear and initiates outside-to-inside signal transduction, resulting in
cellular pyknosis. More important, rapamycin prevented apoptosis, suppression of cytokine production, and cell
destruction of ganglion neurons in the retina. growth arrest in proinflammatory cells. Consequently, the
Rapamycin (Sirolimus) is locally administered with number of activated cells is significantly reduced at the
minimum systemic effects. A clear, liquid sirolimus product inflamed site16.
(Perceiva) is administered through a subconjunctival Infliximab is a chimeric immunoglobin IgG1 monoclonal
or, alternatively, intravitreal injection using a standard antibody composed of a constant human Fc region and a
30-gauge needle. variable mouse Fab region. It is a TNF-alpha inhibitor that
Sirolimus or rapamycin is being evaluated in three separate has been found to have a role in VEGF inhibition in certain
phase 2 trials, a monotherapy trial by National Eye Institute trials. TNF-alpha is a potent pro-inflammatory cytokine. TNF
for geographic atrophy, a second trial in combination alpha has a role in promoting angiogenesis, at least in part
with ranibizumab (EMERALD trial) for wet ARMD and the through upregulation of molecules, such as VEGF25 and its
DIAMOND trial for diabetic macular edema. In the NEI receptor VEGFR and PDGF-B. Preclinical studies in rodent
study, participants initially received a 20 (micro gm) L440 models have demonstrated the efficacy of agents targeting
intravitreal injection sirolimus in the study eye at baseline TNF-alpha in reducing laser-induced CNV. Two small case
and every two months thereafter unless contraindicated. As series reported that intravenous injection of infliximab, a
of September 2012, sirolimus intravitreal injections were monoclonal antibody directed against TNF-alpha, provided
no longer administered to participants. Both the study and clinical benefit for patients with neovascular AMD and
fellow eyes will be observed every two months until the diabetic macular edema. The intravitreal approach is being
study terminates. The study will not terminate until all examined in a Phase I trial in patients with neovascular
participants have been followed through Month 12. The AMD and diabetic macular edema.
primary outcome is the rate of change in area of geographic Daclizumab is a fully humanized IgG1 monoclonal antibody
atrophy based on masked grading in the study eye and directed against the a-chain (Tac/CD25) of the IL-2 receptor
fellow eye at Month 12 compared to baseline. Secondary (IL-2R). Blockage of IL-2R results in decreased activation
outcomes will include changes in best-corrected visual and proliferation of T-cell clones. Daclizumab also inhibits
acuity (BCVA), changes in drusen area based on masked IFN-a expression in both CD4+ and CD8+ T cells. A pilot
digital grading of fundus photography, absolute and relative prospective study evaluated the use of systemic daclizumab
changes in area of GA measured using fundus photography in four patients with neovascular AMD for 6 months. The
and autofluorescence imaging, and development of results showed that daclizumab appeared to decrease the
exudative AMD measured using optical coherence need for anti-VEGF intravitreal injections by approximately
tomography (OCT). The DIAMOND and EMERALD trial half. The effects of intravenous injection of daclizumab in
have finished enrolment of patients. neovascular AMD are being assessed in a phase II clinical
Two phase 1 studies have been completed: one for diabetic trial. Daclizumab may become a promising adjunctive
macular edema and one for wet AMD. A total of 50 therapy in neovascular AMD, especially for patients who
patients, the majority (82%) of whom had failed previous do not respond to the conventional anti-VEGF agents.
laser photocoagulation, were enrolled into the DME trial. Controlling gene expression via small interfering RNA
Likewise, in the wet AMD study, 30 patients, many with (siRNA) has opened the doors to a plethora of therapeutic
considerable fibrosis, were enrolled. In both dose-escalation possibilities, with many currently in the pipelines of drug
studies, a single subconjunctival or intravitreal injection
20 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
Table 1: Current Investigative Agents in Wet AMD
S.N. Clinical Trial Details of trial and mechanism of action of Trial phase Current Status
trial drug Phase III clinical trial
is now recruiting
1 Bevasiranib Gene silencing Phase I and Phase II Completed. No data
trials of Bevasiranib available yet.
have been completed
Completed. No data
2 TG100801Eye TG100801, a compound is a small Phase 1 available yet
Drops – Targegen molecule, topically applied compound that Completed. No data
acts to inhibit vascular permeability (VEGF available yet
mediated retinal leakage), angiogenesis, Data present in last
and inflammation simultaneously. Clinical AAO Congress
trial involved 44 healthy volunteers without Completed
AMD. It was designed to assess the safety
and tolerance of the eye drop. Recruitment over
for NEI trial on
3 PTK787 Pill For Studied safety and tolerance of a tablet of Phase I/II study geographic atrophy,
AMD – Novartis Vitalanib, taken over three months and the recruitment ongoing
effect on wet macular degeneration. for wet AMD trial
Recruiting
4 Talaporfin Sodium Study was undertaken to determine the Phase I study
PDT – Light safety of photodynamic therapy (PDT), Completed. No data
Sciences LLC using the drug talaporfin sodium (LS11). available yet
Twenty-seven patients were enrolled
5 Ophthotec Compares outcomes between patient Phase 2 b study
(E10030/Fovista) groups receiving standard Lucentis
treatment and those receiving Lucentis and
E10030. E10030 blocks PDGF, that seems
to contribute to wet AMD.
6 REDD14NP– Open-Label, Dose Escalation Trial of PF- Phase 1 study
Quark 04523655 delivered by a single intravitreal
injection to patients with choroidal
neovascularization (CNV) Secondary to
Wet AMD. Drug designed to interfere with
a gene that seems to be active in creating
AMD
7 Sirolimus Sirolimus is designed to stop the growth 3 ongoing phase
(Rapamycin) of blood vessels in the macula. It is an II trials including
antifibrotic agent and acts by inhibiting one for geographic
mTOR. Patients received either one of three atrophy
treatments: sirolimus at a lower dose in
combination with Lucentis, sirolimus at a
higher dose in combination with Lucentis
or placebo in combination with Lucentis.
8 ATG003 Eye Double-masked, randomized, placebo- Phase II study
Drops controlled study of the safety and
effectiveness of ATG003 (topical
mecamylamine) in patients receiving
maintenance injections of either Lucentis or
Avastin.
9 ASap (POT-4) POT-4 affects the complement protein C3 Pilot Phase I study
The objective of this study is to provide
initial safety and tolerability information of
intravitreal POT-4 for treatment of patients
with AMD
www. dosonline.org l 21
Retina
S.N. Clinical Trial Details of trial and mechanism of action of Trial phase Current Status
trial drug Results are now
available. After
10 CABERNET – A tiny source of radiation is placed inside Phase III trial 2 years, the
Strontium-90 Beta the eye near the macula, held there for about study could not
Radiation Implant 4 minutes and then removed. The radiation show epiretinal
Trial destroys the abnormal blood vessels and brachytherapy to
prevents the growth of blood vessels be “non-inferior” to
to stop the progression of wet macular Lucentis.
degeneration vision loss. Enrolled 457 Recruiting
subjects at 45 clinical centers worldwide,
patients received either the standard Ongoing,
injection of Lucentis or the radiation plus recruitment over.
Lucentis.
Recruiting
11 Thera Sight A radioactive button mounted on an Phase I
TM Ocular applicator wand is positioned behind the
Brachytherapy eye and held in place touching the outer
System for Wet surface of the eye for 5 to 20 minutes. The
AMD radioactive button produces low-energy
x-rays that interfere with the abnormal new
blood vessels, potentially reducing further
vision loss.
12 COBALT – Bevasiranib is a small interfering RNA Phase III
Bevasiranib molecule (Cand5) designed to “silence”
& Lucentis the gene that prompts blood vessel growth.
Combination The purpose of the study is to compare
Therapy the safety and effectiveness of Bevasiranib
compared to Lucentis. patients randomized
to receive intravitrealBevasiranib sodium
followed by three Lucentis injections or
Lucentis injections alone for 4 weeks.
13 Pazopanib Eye Pazopanib is a tyrosine kinase inhibitor Phase IIb
Drops Versus of multiple receptors including vascular
Ranibizumab endothelial growth factor receptors and
Intravitreal Injections platelet-derived growth factor receptors.
for the Treatment of
Neovascular Age-
Related Macular
Degeneration
development for various ocular diseases. Despite the in patients with CNVM resulting from neovascular AMD
potential of siRNA technologies, barriers to intracellular that had been refractory to other therapies. Stabilization
delivery significantly limit their clinical efficacy. However, or improvement in visual acuity and foveal thickness was
recent progress in the field of drug delivery strongly suggests observed. No dose-response or dose-limiting effects were
that targeted manipulation of gene expression via siRNA noted.
delivered through nanocarriers can have an enormous Current treatments for wet macular degeneration often
impact on improving therapeutic outcomes for ophthalmic require repeated injections in the eye monthly or less
applications. siRNA-027 is a small interfering RNA targeting often. Epiretinal brachytherapy can reduce the number of
vascular endothelial growth factor receptor-1, in patients injections needed to just two injections over a period of
with choroidal neovascularization (CNV) resulting from 12 months. A tiny source of radiation is placed inside the
neovascular age-related macular degeneration (AMD). It eye near the macula, held there for about 4 minutes and
has been studied in a prospective, open-label, single-dose, then removed. The radiation destroys the abnormal blood
dose-escalation phase 1 trial. A single intravitreal dose of vessels and prevents the growth of blood vessels to stop the
siRNA-027 up to 1600 microgm/eye was well tolerated progression of wet macular degeneration vision loss.In a
22 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
previous study, 34 people with wet macular degeneration 4. Martin DF, Maguire MG, Fine SL, et al. Comparison of Age-related
received a single treatment of NeoVista’s epiretinal Macular Degeneration Treatments Trials (CATT) Research Group.
brachytherapy. Patients received the radiation and two Ranibizumab and bevacizumab for treatment of neovascular age-
injections of Avastin - one dose just before the radiation or related macular degeneration. Ophthalmology 2012;119(7):1388-
at the time of radiation delivery and an additional injection 1398.
of Avastin one month later, depending on which group they
were in. The patients could receive additional injections 5. Heier JS, Brown DM, Chong V. Intravitreal aflibercept (VEGF trap-
of Avastin if the investigator felt it was needed. Seventy eye) in wet age-related macular degeneration. Ophthalmology
six percent of the patients in the study did not require 2012;119(12):2537-48
additional injections of Avastin throughout the year.
After 12 months, 94 percent of patients lost fewer than 6. Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular
15 letters, 39 percent gained 15 or more letters, and 12 cells defines a potential paracrine mechanism for endothelial cell
percent gained 30 or more letters.In contrast to other forms survival. FASEB J. 2001;15(7):1239-1241.
of radiation therapy for wet AMD, NeoVista’s approach
targets the peak dose of energy directly to the lesion without 7. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood
damaging the normal blood vessels or other structures within vessel remodelling is defined by pericyte coverage of the preformed
the eye such as the lens and the optic nerve. No radiation endothelial network and is regulated by PDGF-B and VEGF.
related complications were reported. This was followed Development 1998;125(9):1591- 1598.
by CABERNET, a multicenter, randomized, controlled
Phase III study that enrolled 457 subjects at 45 clinical 8. Lindahl P, Johansson BR, Levéen P, et al. Pericyte loss and
centers worldwide (Table 1). In this research, patients microaneurysm formation in PDGF-B-deficient mice. Science
received standard injection of Lucentis(ranibizumab) or 1997;277(5323):242-245.
the radiation plus Lucentis. After 2 years, the study could
not show epiretinal brachytherapy to be “non-inferior” to 9. Furuhashi M, Sjöblom T, Abramsson A, et al. Platelet-derived growth
Lucentis. Noninferiority was the primary endpoint for the factor production by B16 melanoma cells leads to increased pericyte
clinical trial. Previous research had led to the hope that abundance in tumors and an associated increase in tumor growth
radiation treatment could be used with Lucentis to reduce rate. Cancer Res. 2004;64(8):2725-2733.
the number of injections that were needed.
References 10. Gerhardt H, Golding M, Fruttiger M, et al. VEGF guides angiogenic
sprouting utilizing endothelial tip cell filopodia. J Cell Biol.
1. Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label 2003;161(6):1163-1177.
extension trial of ranibizumab for choroidal neovascularization
secondary to age-related macular degeneration. Ophthalmology 11. Pachydaki SI, Jakobiec FA, Bhat P, et al. Surgical management and
2012;119(6):1175-1183. ultrastructural study of choroidal neovascularization in punctate
inner choroidopathy after bevacizumab. J Ophthalmic Inflamm
2. Silva R, Axer-Siegel R, Eldem B, et al. SECURE Study Group. Infect. 2012;2(1):29-37.
The SECURE Study: Long-Term Safety of Ranibizumab 0.5 mg in
Neovascular Age-related Macular Degeneration. Ophthalmology 12. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor
2013;120(1):130-139. B signaling enhances the efficacy of anti-vascular endothelial growth
factor therapy in multiple models of ocular neovascularization. Am
3. Bhisitkul RB, Rofagha S, Boyer DS, et al. Year 7 outcomes for J Pathol. 2006;168(6):2036-2053.
ranibizumab-treated subjects in ANCHOR/MARINA: a multicenter,
prospective cohort study. Paper presented at: Association for 13. Dugel PU. Anti-Platelet Derived Growth Factor: Where Do We
Research in Vision and Ophthalmology Annual Meeting; May 8, Stand? Paper presented at: American Academy of Ophthalmology
2012; Fort Lauderdale, FL. Annual Meeting; November 10, 2012; Chicago.
14. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-
inducible factor 1alpha expression and function by the mammalian
target of rapamycin. Mol Cell Biol. 2002; 22: 7004-7014.
15. Kolosova NG, Muraleva NA, Zhdankina AA. Prevention of age-
related macular degeneration-like retinopathy by rapamycin in rats.
Am J Pathol. 2012;181(2):472-7
16. Sfikakis PP. The first decade of biologic TNF antagonists in clinical
practice: lessons learned, unresolved issues and future directions.
Curr Dir Autoimmun. 2010;11:180–210.
www. dosonline.org l 23
IntravitrealMonotherapywithBevacizumabandTriamcinoloneVersus ReRteitnina
CombinationTherapyinRecalcitiantDiabeticMacularEdema
Meena Chakrabarti
MS, DO, DNB
Meena Chakrabarti MS, DO, DNB, Sonia Rani John DNB, Arup Chakrabarti MS, DO
Chakrabarti Eye Care Centre, Kochulloor, Trivandrum
Recalcitrant diabetic macular edema (DME) is Focal/Grid laser photocoagulation after IVTA has been
characterized by the accumulation of plaques of hard shown to maintain improved vision and may reduce
exudates in a grossly edematous retina not amenable to recurrent macular edema.
the standard modalities of therapy and showing a very Patients with diabetic macular edema have been found
poor visual potential. These patients usually have a poorly to have increased levels of vascular endothelial growth
controlled glycaemic status of long duration with associated factor (VEGF) in the vitreous. Hence intravitreal injection
co-morbid condition such as systemic hypertension, of anti VEGF may have a role in reducing diabetic macular
dyslipidemia and chronic renal failure. edema5. Their efficacy is similar to IVTA, but they do not
Majority of these eyes would have had several sittings of cause adverse events associated with corticosteroids. On
laser photocoagulation and hence it is necessary to employ the other hand, frequent injection (every 4-6 weeks) for an
alternative treatment modalities. extended period may be required, making injection related
Initial reports on uncontrolled interventional case series complications such as infectious endophthalmitis a major
reported an unprecedented efficacy of intravitreal steroids drawback.
in reducing diabetic macular edema often accompanied There are very few studies on the efficacy of combining
by significant improvement in visual acuity. These triamcinolone acetonide and bevacizumab2,6 (an anti VEGF
uncontrolled series were followed by randomized placebo- antibody). We undertook a pilot study to compare the
controlled trials1,2 demonstrating the efficacy of Intravitreal efficacy of intravitreal monotherapy with Triamcinolone
Triamcinolone Acetonide (IVTA) compared with standard and Bevacizumab versus combination of Bevacizumab and
of care, both short term and long term3. The beneficial triamcinolone in the management of recalcitrant DME not
effect of intravitreal injection of triamcinolone acetonide amenable to laser treatment. We also assessed the Optical
in most cases lasted for 6-9 months. In the Intravitreal cohrerence tomography (OCT) patterns in recalcitrant DME
Triamcinolone acetonide for clinically significant Diabetic which showed a favorable response to intravitreal injection
Macular Edema that persists after laser treatment study of Triamcinolone and Bevacizumab.
(TDMO), the mean number of injections was only 2.4 over We recruited 60 patients who fulfilled all the inclusion
2 years with a total potential for five injections. It has also criteria from March 2006 – March 2008. The inclusion
been reported that repeated intravitreal injection may not criteria for enrolment into the study were:
be as effective as the initial treatment. The high incidence 1. Diabetic age ≥ 10 years
of adverse effects which include cataract (54%), glaucoma 2. Good Glycaemic Control (Hb A1C ≤ 7 gm%)
(20-40%) and need for trabeculectomy (6%) demands 3. Stable Renal Status
caution in its use. 4. Controlled serum lipid level
The introduction of IVTA has been a major advance in the 5. H/o prior Focal/Grid laser Photocoagulation (PHC) (≥
treatment of refractory4 diabetic macular edema. The high
risk of steroid related adverse effects however leaves room
for improvement and innovation in treatment strategies.
www. dosonline.org l 25
Retina
(a)
(b)
Figure 1(a): Pre treatment and (b): post treatment fundus photography, Fluorescein angiographic and OCT appearance showing minimal
regression in a patient who received intravitreal triamcinolone acetonide injection
3 sittings) ≥ 6 months to time of enrolment into the angiographic evaluation and OCT assessment of central
study. retinal thickness and pattern of edema as part of the
baseline evaluation. An informed consent was obtained in
6. Presence of DME clinically and angiographically OCT all the patients. The intervention was performed under strict
showing Central Retinal Thickness (CRT) ≥ 300 μm aseptic precautions in the operation theatre under topical
anesthesia in all the patients. Paracentesis was performed to
7. Absence of significant lens opacity bring the IOP under control and the eye was kept patched
8. Absence of macular ischemia for an hour after the procedure. Postoperatively 3 hours after
9. Absence of Vitreo Macular Traction (VMT) or a taut the procedure applanation tonometry was performed in all
patients using the Keeler Pulsair non contact tonometer.
posterior hyaloid phase in OCT. The patients were instructed to use topical antibiotic drops
Exclusion criteria were poorly controlled diabetes with qid, topical non steroidal anti inflammatory drops qid and
associated nephropathy and dyslipidemia, significant topical dorzolamide drops once at bed time for a period of
cataract precluding fundus evaluation or presence of 7 days postoperatively. Counseling on the appearance of
macular ischemia. The patients were randomized to receive floaters and slight visual blurring were discussed with the
one of the three modes of interventions tested in this study. patients.
Group B: Received 1.25 mg / 0.05 ml Intravitreal injection The patients were followed up on day 7, 30 days and 90
of Bevacizumab (IVB). days after the procedure. At each visit an assessment of the
Group T: Received 4 mg / 0.1 ml Triamcinolone acetonide glycaemic status, control of BP, renal status and serum lipid
injection intravitreally (IVTA). profile was assessed. Fundus fluorescein angiography (FFA)
Group BT: Received both Bevacizumab and Triamcinolone and OCT were performed at 30 days and 90 days after the
acetonide injections administered intravitreally (IVB+ procedure. Refraction, tonometry, slit lamp evaluation for
IVTA). cataract and biomicroscopic macular evaluation for degree
All patients underwent a thorough preoperative evaluation. of macular edema was performed at all visits. Response to
The best corrected visual acuity was determined after therapy was assessed by:
dilated refraction. Slit lamp biomicroscopy of the macula, 1) Improvement in the best corrected visual acuity
applanation tonometry and indirect ophthalmoscopic 2) Slit lamp biomicroscopy and OCT showing reduction
evaluation of the fundus were performed and the
findings noted. The degree of cataract was assessed prior in retinal thickness
to intervention. All patients underwent a fluorescein
26 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
Pre Treatment: (IVB/IVTA) Table 1: Effectiveness of treatment on Vision
Post Treatment: IVB/IVTA (12 months)
Mean SD N Mean P a i r e d P
Figure 2: Pre and posttreatment FFA & OCT showing Diff. ‘t’ test
regression of CSME
IVTA
BT 10.2 2.2 20
AT 11.8 2.6 20 1.6 3.14” 0.005
IVB
BT 10 1.8 20 1.6 4.7” 0.001
AT 11.6 2.0 20
IVB+IVTA
BT 10.6 1.4 20 1.7 5.51” 0.000
AT 12.3 2.1 20
BT: Before Treatment AT: After Treatment
3) FFA showing decrease in fluorescein leakage
4) Progression of lenticular changes 14.0
11.0
5) Presence or absence of post treatment IOP spike and 11.6 12.3
12.0 10.2 10.0 10.0
6) Recurrence 10.0
Follow up data in the IVTA group (Figure 1a & b), IVB Mean Scores 8.0
group and combined group (Figure 2) show regression of 6.0
macular edema. 4.0
2.0
We had recruited 60 patients enrolling 20 patients for each 0.0 IVB IVTA + IVB
mode of intervention. The patients were of the age group post
ranging from 45-70 years (Mean age 58 years). There were IVTA
46 males and 14 females in our study giving a M: F ratio of
2:1. The mean duration of diabetes was 13.5 years (Range: 7 pre
- 20 years) and the mean value of glycosylated hemoglobin
at baseline was 6.7 (Range 5.9 - 7.5). Associated co-morbid
conditions were:
1. Hypertension : 25 (41.67%) Figure 3: Efficacy of intervention with
respect to vision gain
2. Hyperlipidemias : 40 (66.67%)
In the remaining 11 patients the mean reduction in central
3. Chronic Renal failure : 3 (5%) retinal thickness was by 20% of baseline value (from
a mean CRT at baseline of 550 μm ± 26 μm to 350 μm
4. Both HT and HL : 30 (50%) ± 20 μm) at 6 months follow up. Although there was no
improvement in visual acuity, the vision stabilized at the
5. No associated disease : 15 (25%) baseline level. Recurrence of edema was noticed in 9/11
patients (81.81%).
Fifty percent of the patients had proliferative diabetic Progression of cataract was noticed in 6 eyes (30%)
retinopathy associated with maculopathy and 50% had and 2 patients with significant cataract underwent
background diabetic retinopathy with clinically significant phacoemulsification with foldable IOL implantation under
macular edema. topical anesthesia.
Intraocular pressure increased to mid twenties in 3 eyes
Group T (IVTA Group) an improvement in visual acuity (15%) but could be controlled medically with single
was observed in 9/20 eyes (45%) who showed a mean antiglaucoma medication (Dorzolamide).
reduction of central retinal thickness in the OCT scans from There were no cases of endophthalmitis, vitreous
a baseline mean CRT value of 550 μm ± 26 μm to 285 μm hemorrhage or retinal detachment in this group.
± 20 μm. This 45 % reduction in central retinal thickness
persisted up to 6-9 months after which the recurrence of
clinically significant macular edema (CSME) was observed
in 15 of the 20 eyes (75%). These eyes underwent focal/grid
laser photocoagulation / or repeat IVTA in 4 eyes (20%).
www. dosonline.org l 27
Retina
Table 2: Effectiveness of treatment on OCT in one patient (5%) which was amenable to medical
therapy.
Mean SD N M e a n Paired P Group BT (Combined IVTA & IVB): An improvement in
CRT Diff. ‘t’ test visual acuity was observed in 60% (12/20) eyes. The
(mm) reduction in the central retinal thickness was maximum in
this group and was observed in 64% of eyes. The reduction
1 IVTA in retinal thickness peaked at one month post injection and
persisted up to 9 months. Recurrences in 15% of eyes were
BT 511.8 111.5 20 167mm similar to group B showing than an additional injection of
TA did not have any effect in preventing recurrences. A
AT 345.2 87.1 20 higher incidence of elevated intraocular pressure in 22%
of cases questioned the efficacy of adding TA, when IVB
2 IVB+ 20 208 mm 17.02 0.000 alone would have sufficed.
IVTA • All 3 groups were similar with respect to age, sex,
BT 538.1 73.5
diabetic age, HbA1C, pre treatment vision, and
AT 330.3 66.1 20 baseline central retinal thickness on OCT and hence
they are comparable
3 IVB • There was a mean increase of 1.6,1.6 & 1.7 in the pre
treatment and post treatment visual scores in the IVTA,
BT 539.5 65.6 20 201 mm 17.06 0.000 IVB and the combined group which was statistically
significant by the paired “t” test(p=0.005 in IVTA
AT 338.8 67.2 20 group, p=0.001 in the IVB group & p=0.000 in the
combined group) (Table 1, Figure 3)
BT: Before Treatment AT: After Treatment • There was no statistically significant difference between
the increase in visual scores in the 3 groups by ANOVA
Table 3: Comparison of Complications test and hence all three modalities are equally effective
• Cataract: 30% in IVTA group alone developed with respect to visual gain
Effectiveness of Treatment on Central Retinal
cataract Thickness
• Glaucoma: Increase in IOP in 15% IVTA GP, 5% There was a mean decrease in CRT of 167 μm, 201 μm and
208 μm in the IVTA, IVB and the combined group which
IVB GP, & 25% combined GP was not statistically was statistically significant by the paired “t” test (p=0.000)
significant by chi squared test (chi2=3.17, p=0.208) (Table 2)
• Recurrence: In 70% IVTA, 15% IVB, 15% combined • There was no statistically significant difference in the
group was statistically significant by chi squared test decrease of central retinal thickness in the 3 groups by
(chi2=18.15, p=0.000) the ANOVA test (p=0.110) & hence all 3 interventions
were equally effective. Analysis of the complications
Group B (Intravitreal Bevacizumab injection): An showed that the incidence of cataract formation was
improvement in visual acuity was observed in 11/20 eyes highest in the IVTA & Combined Groups (30%).
(55%) in this group. All 20 eyes showed some reduction in Elevated intraocular pressures were observed in 15%
central retinal thickness, however a 25% reduction from of patients in the IVTA Group and in 25% in the
baseline value was obtained in 59% of our patients in this
group. Maximum beneficial effect was observed within 30
days of the injection and with additional laser therapy the
effect persisted up to 9 months. Repeat injection was not
necessary up to 12 months. However some increase in CRT
was noticed in 15% of patients after 9 months for which
additional laser was given. Further follow up alone will
give an idea of the course of disease and the necessity for
reinjections. Elevation in intraocular pressure was noticed
Table 4 Pre injection CRT Post-injection CRT Pre-injection vision Post-injection vision
OCT GRADING (Mean) (Mean) (Mean) (Mean)
500 μm 309 μm 5/60 6/18
Diffuse edema 422 μm 315 μm 3/60 5/60
Cystoid edema 418 μm 256 μm CF 2m 6/36
Subfoveal serous RD 325 μm 250 μm CF 1m CF1m
Plaques of H/E 550 μm 350 μm CF 2m 4/60
Combination
28 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
combination group while only one patient (5%) had optional dosage of IVTA is still somewhat confusing. Audren
elevated intraocular pressure in the IVB group. The F et al13 conducted a randomized prospective trial comparing
correlation was not statistically significant by the chi the efficacy of 2 mg Vs 4 mg of Triamcinolone acetonide
squared test (chi2 = 3.17; p = 0.208). The highest rate in the management of diffuse diabetic macular edema. This
of recurrence of CSME was observed in the IVTA group results showed that there was no dose dependent difference
(70%) and occured within 6 months of the intravitreal in the response to intervention. However Lam DS et al14
pharmacotherapy. Clinically significant macular and Spandau UH et al15 demonstrated close dependency
edema recurred in 15% of the patients randomised in the response to intravitreal injection of triamcinolone
to receive IVB & combined pharmacotherapy. This acetonide.
corelation was statistically significant by chi squared The beneficial effect of an intravitreal injection of
test p=0.000 (Table 3). triamcinolone acetonide in most cases lasts for 6 months–9
• There was no added benefit in adding IVTA to IVB months and repeated injection may not be as efficacious as
We divided the patients in to 4 groups based on the the initial treatment.
preinjection OCT findings: The high incidence of steroid related adverse effects such
1) Diffuse edema (DDME) as
2) Cystoid edema (1) Necessity for cataract extraction in 54% of phakic
3) Sub foveal serous retinal detachment
4) Plaques of hard exudates under fovea. treated eyes
and tried to correlate with the response to therapy as (2) Steroid related evaluation of IOP in 44 % of treated
measured by CRT and improvement in vision.
Our results showed that maximum reduction of central eyes necessitates the use of caution.
retinal thickness and maximum visual gain were observed In order to avoid the adverse effect associated with
in eyes with greater degree of diffuse macular edema and intravitreal therapy, particularly infectious endophthalmitis,
presence of sub foveal serous RD (Table 4). the use of periocular steroids in the management of diabetic
Discussion macular edema has been studied. The results of these trials
The role of steroids is mediated through have been contradictory to each other showing either a
1) Suppression of VEGF beneficial effect or no appreciable effect of the intervention
2) Stabilizing the leakage from retinal vessels on DME.
3) Suppression of the release of endothelial cell activators Investigators continue to report their experience with
and intravitreal injections of Bevacizumab, a humanized
4) Possibly its anti-inflammatory action. monoclonal IgG antibody directed against all five VEGF
Initially uncontrolled interventional case series reported isoforms, in the setting of primary therapy. In a study of 51
an unprecedented efficacy of intravitreal steroids (usually patients, Haritoglou et al5 observed that at 6 weeks after a
triamcinolone acetonide) in reducing diabetic macular single Bevacizumab injection, patients with DME resistant
edema accompanied by significant improvement in visual to other therapies had increased visual acuity as well as
acuity7,8,9,10. These uncontrolled series were followed by decreased central retinal thickness by OCT relative to pre-
randomized placebo controlled trials demonstrating the injection baseline, though the effect on visual acuity was not
efficacy of IVTA compared with standards care both short sustained at 12 weeks. The Pan – American Collaborative
and long term. Retina Study Group studied intravitreal Bevacizumab as a
Several studies in eyes with persistent DME despite focal primary treatment for DME in 78 eyes of 64 patients and
and / or grid laser photocoagulation have demonstrated the found, at six months, over 96 % of eyes had either stable
efficacy of IVTA over laser11,12. However the NEI (National or improved visual acuity or reduction in the mean central
Eye Institute) sponsored trial have conclusively shown that retinal thickness by OCT3. A phase II DCRC.net study of
a focal / grid laser photocoagulation gave longer lasting 109 patients compared two does of Bevacizumab to focal
beneficial effects when compared to the transient effect of laser photocoagulation and demonstrated its efficacy in
intravitreal triamcinolone acetonide injection. decreasing DME in some eyes. To date, no phase III trials
Although most studies have shown a beneficial effect the have been reported that demonstrate a clear benefit for
Bevacizumab in the treatment of DME.
While Ranizumab, an affinity – matured humanized
monoclonal antibody fragment directed against all VEGF
isoforms, is currently in clinical trials for DME, its off
label use in DME patients is limited likely as a result of its
increased cost and less wide spread availability worldwide,
as compared to Bevacizumab. Clinical trials in DME
www. dosonline.org l 29
Retina
Table 5: A comparative analysis of the response to all three decrease in macular thickness and improvement in visual
modalities of treatment acuity at 3 months, but the effect was somewhat blunted,
though still statastically significant at the end of 6 months.
Criteria Group T Group B Group BT The current study compares favorably with these reports,
and confirms their findings with longer follow- up and a
Vision 45% 55% 60% larger no of patients. Furthermore, at the 6 month follow
– up time point we noticed a small worsening of vision
Resolution 45% 59% 69% as described by Kumar and Sinha. When we analyzed our
data comparing eyes that had 1 or 2 injections against those
IOP 17% 5% 22% eyes that had 3 or more injections, there was a significant
drop in BVCA at 6 months in the “1 or 2 injections” group,
Cataract 30% - 30% and not in the “ 3 or more injections” group. This suggests
the need for repeat injection (63.4%) needed at least a
Endophthalmitis - - - second injection at a mean of 15.7 ± 11.9 weeks (range:
4 to 64 weeks).
RD -- - The results of this retrospective study demonstrated the
efficacy of 1.25 mg or 2.5 mg of IVB as primary treatment
Recurrence 75% 15% 15% of DDME, as 49.5% of eyes showed anatomical and
functional improvement. In addition, our results suggest a
patients are limited as a result of its increased cost and reduced risk of visual acuity loss in eyes with DDME treated
less widespread availability worldwide, as compared to with IVB (82.2% of eyes). We found that the anatomical
Bevacizumab. Clinical trials in DME patients are ongoing. and visual benefit of the intravitreal Bevacizumab appears
Two pilot studies of 10 patients each, suggested that it was and reaches its maximum value during the first month and
well tolerated and may have some efficacy in promoting maintains itself over 12 months. Nevertheless, we did not
improvement in visual acuity and reduction in central find statistically significant differences between the 2 doses
retinal thickness by OCT. The READ – 2 (Ranibizumab for of Bevacizumab evaluated.
edema of the macula in diabetics) studies, a phase II trial A phase 1 study (the READ-1 Study, Ranibizumab for
comparing the relative efficacy of Intravitreal Ranibizumab, Edema of the macula in Diabetes, sponsored by the
macular laser photocoagulation, and the combination Juvenile Diabetes Research Foundation) of 20 patients with
of both treatments among patients with DME, who have DME treated with repeated intravitreous injections 0.5 mg
not received prior laser is currently ongoing. Six months of ranibizumab, showed evidence of biological activity
outcomes suggests a greater improvement in visual acuity of ranibizumab in DME as well as safety and tolerability
for patients undergoing intravitreal Ranibizumab alone as (Nguyen, et al. 2006). In the Phase 1 study, patients were
compared to laser or combination treatments. given intravitreal ranibizumab at baseline and at months
A report on 101 consecutive eyes with DDME treated with 1,2,4, and 6. Results showed that at month 7, one month
intravitreal Bevacizumab, resulted in both anatomic and after the final administration of ranibizumab and the
functional improvement. Interestingly, the reduction of primary endpoint of the study, the median reduction of the
retinal thickness and improvement of best corrected visual excess foveal thickness was 97%, and there was a median
acuity (BCVA) were detected within the first 4 weeks after improvement of 10 letters.
the injection in most of the patients. In addition, both doses There have been no adverse events that were believed
(1.25 mg and 2.5 mg) were associated with improvement of to be related to the study drug; in particular, intraocular
BCVA and a greater reduction in central macular thickness, inflammation was not observed.
and no difference between the two were found. Ocular The READ-2 Study is a Phase 2 randomized, multicenter
tolerance of the 2 different doses of IVB was demonstrated, clinical trial sponsored by the Juvenile Diabetes Research
and no serious systemic adverse events were noticed during Foundation. The study enrolled 126 patients from 14
the study. clinical centers throughout the United States.
There are several studies in the literature on the intravitreal Each study subject in the trail was randomized 1:1:1: to 1
administration of antibodies against VEGF for DDME. of 3 treatment groups.
However, none of them deal with anti-VEGF as a primary Group 1 (ranibizumab only)
treatment. Haritoglou et al5 reported that intravitreal Group 2 (laser only)
Ranibizumab has the potential to maintain or improve Group 3 (ranibizumab and laser)
BCVA and reduce retinal thickness in patients with
DDME not responding to previous treatments such as
photocoagulation, intravitreal injection of triamcinolone,
or vitrectomy. Their follow-up period was too short (6
weeks) to provide specific treatment recommendations.
Kumar and Sinha reported results of 20 eyes with DDME
treated with IVB dose of 1.25 mg that had not responded
to previous photocoagulation. Their follow- up period was
6 months. They concluded that IVB resulted in a significant
30 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
Table 6: Comparison with Similar Studies
Author Publication Procedure CRT Vision Comments
Pacola et al4 BJO 2008 IVTA vs. IVB decrease with increase with IVTA superior to IVB on
Shimura M et al1 IVTA IVTA short term
Soheihan et al2 AJO 2008 IVTA vs. IVB decrease with increase with IVTA superior to IVB on
Ahmadieh H6 IVTA IVTA short term
Chakrabarti M Retina 2008 IVB vs. IVB+ decreased increased IVB superior to laser/No
et al IVTA benefit for adding TA
Graefes Arch IVB vs. IVB+ decreased increased No benefit for adding
2008 IVTA TA/á IOP in 8.1%
Present study IVB vs. TA vs. IVB decreased increased No benefit for adding
+IVTA TA/á IOP in 22%
The patients were followed every 12 weeks until month gain (45% Vs 55%) and resolution of CSME (45% Vs
24 (secondary time endpoint). At any study visit, if there 59%). The incidence of elevated IOP in only 5% and
was an increase of a specified amount of retinal thickness recurrence in 15% point to the fact that IVB may be a
on OCT that meet re-treatment criteria, the patients had better option to IVTA
the opportunity to receive a ranibizumab injection of 3. Combining IVB with IVTA, did not have the expected
ranibizumab injection plus laser 7 days later. effect of doubling the resolution and visual recovery.
The re-treatment criteria for patients in all 3 randomized A higher incidence of glaucoma in 22 % makes this
groups are an absolute retinal thickness in OCT central combination unsafe. The incidence of recurrence was
subfield of 250 μm (at time of study visit). same as in IVB group.
Combination Therapy These results comprehensively prove that there is no
As diverse mechanism and patterns of DME are recognized, added benefit of combining IVB and IVTA.
clinicians are using multimodel therapies to approach DME. 4. Greater degree of diffuse edema and presence of sub
In theory, targeting various pathologic mechanisms of DME foveal serous RD are indicators of a favorable response
with combination therapies may have a more lasting effect to IVTA and IVB.
on reversing and maintaining a clinical benefit to patients. 5. The prediction of poor visual prognosis included poor
Focal Laser Photocoagulation is being combined primarily preoperative vision, HbA1C > 7 during the study
with Ocular Steroid therapy (either IVTA or PST-TA) or anti period, plaques of hard exudates under fovea and
VEGF agents. This strategy seeks to take advantage of the presence of large cystoid spaces under fovea.
more immediate effects of pharmacologic agents while Our results compared favourably with those of Soheilian
employing laser therapy for long term stabilization. Anti et al2 and Ahmadieh et al6. who also demonstrated that
VEGF agents have been used to salvage eyes refractory there was no added beneficial effect of combining IVTA &
to steroid therapy, in eyes experiencing steroid related antiVEGF therapy (Table 6).
side effects, and more recently in combination with IVTA Maximum reduction of central retinal thickness and
therapy with positive results. Pharmacological agents also maximum visual gain were obtained in eyes with greater
used at the time of vitrectomy surgery help to prevent degree of diffuse DME and in the presence of subfoveal
recurrent DME. serous RD. These eyes responded best to IVTA or IVB
The present study also has tried to compare the efficacy
of monotherapy with combined modalities of treatment References
(Table 5).
Thus the result of this study show that: 1. Shimura Masahiko, Nakazawa, Tosu, Yasuda Kamako. Comparative
1. IVTA has an excellent transient effect of causing therapy evaluation of intravitreal bevacizumab and triamcinolone
acetonide on persitent diffuse diabetic macular edema. Am J
resolution. Recurrences in 75% elevated IOP in 17% Ophtalmol. 2008;145 (5): 854-61.
of cases point to the fact that IVTA should be advised
with caution and the patients monitored regularly after 2. Masoud Soheilian, Alireza Ramezani, Bijan Bijanzadeh, et al.
intervention. Intravitreal bevacizumab (Avastin) injection alone or combined
2. IVB is as efficacious or more so with respect to visual with triamcinolone versus macular photocoagulation as primary
treatment of diabetic macular edema. Retina 2008 27(9): 1187-1195
3. Kook, Daniel MD, Wolf, et al. Long term effect of intravitreal
bevacizumab (avastin) in patients with chronic diffuse diabetic
macular edema. Retina 2008;28(8) : 1053-60.
www. dosonline.org l 31
Retina
4. L Paccola, R A Costa, M S Fologosa, et al. Intravitreal triamcinolone 10. Gilles MC, Sutter FK, Simpson JM et al. Intravitreal triamicinolone for
versus bevacizumab for treatment of refractory diabetic macular refractory DME: 2 year result of double masked placebo controlled
edema (IBEME study). Br.J Ophthalmol. 2008 Jan;92(1): 76-80. randomized trial. Ophthalmol. 2006; 113(9): 1533-1538.
5. Hartioglou C, Kook D, Neubaucuer A, et al. Intravitreal bevacizumab 11. Sutter FK, Simpson JM et al. Intravitreal triamcinolone for DME that
(Avastin) therapy for persistent diffuse diabetic macular edema. persist after laser treatment: 3 months efficacy and safety results of
Retina 2006;26(9):999-1005. a prospective randomised double masked placebo controlled trial.
Ophthalmology 2004; 111(11): 2044 – 2049.
6. Hamid Ahmadieah, Alireza Ramizani et al.Intravitreal Bevacizumab
with or without triamcinolone acetonide for refractory DME: A 12. Avitabile T, Longo A et al. Intravitreal Triamcinolone compared with
Placebo controlled trial. Graefes Arch Clin Exp Ophthalmol. 2008; macular laser grid photocoagulation for the treatment of cystoid
246:483 - 489 macular edema. Am J.Ophthalmol. 2005; 140(4): 695-702.
7. Jonas JB, SofKer.A et al. Intraocular injection of crystalline cortisone 13. Audren F, Ledeire-Collet A et al. Intravitreal triamcinolone acetonide
as adjunctive treatment of diabetic macular oedema. Am.J. for diffuse DME: phase 2 trial comparing 4 mg Vs 2 mg. Am J.
Ophthalmol. 2001; 132 (3): 425-457. Ophthalmol. 2005; 142(5) :794-799.
8. Jonas JB, Kreissig I, Sofker A, et al. Intravitreal injection of 14. Lam DS, Chan CK, Mohamed S et al. A prospective randomised trial
triamcinolone for diffuse diabetic macular oedema. Arch of different doses intravitreal triamcinolone for diabetic macular
Ophthalmol. 2003; 121(1): 57-61. edema. Br.J Ophthalmol. 2007; 91(2): 199-203.
9. Maritidis A, Duker JS, Greenberg PB et al. Intravitreal triamcinolone 15. Spandau UH, Derse M, et al. Dosage dependency of intravitreal
for refractory diabetic macular oedema. Ophthalmology 2001; triamcinolone acetonide for diabetic macular edema. Br. J.
109(5): 920-927. Ophthalmol. 2005; 89(8): 999-1003.
32 l DOS Times - Vol. 19, No. 3 September, 2013
Decision Making in Rhegmatogenous ReRteitnina
Retinal Detachment
B.P. Guliani
MS
B.P. Guliani MS, Sandeep Gupta MBBS
Vardhman Mahavir Medical College, Safadrjung Hospital New Delhi
As we all know that Retinal detachment is separation 2. Reoperations are unsuccessful in as many as 50% of
of neurosensory retina (NSR) from Retinal Pigment cases.
epithelium (RPE). If it occurs due to one or more full-
thickness retinal breaks it is called Rhegmatogenous retinal 3. Anatomical success is significantly less common
detachment (RRD). in eyes with features suggesting an increased risk of
Important definitions proliferative Vitreoretinopathy (PVR).
1. Retinal break means retinal tear or a retinal hole.
2. Retinal tears are usually associated with well-defined 4. Following anatomically successful surgery, visual
acuity returns to 20/50 or better in only approximately
vitreoretinal traction either on an attached flap or 50% of cases.
operculum.
3. Retinal holes occur more commonly as a result of How one can prevent RD1,2?
localized retinal atrophy and are not associated with By the use of laser photocoagulation (LIO) or cryotherapy
vitreoretinal traction. which create a chorioretinal adhesion around both
4. Symptomatic tear is a tear caused by posterior vitreous visible sites of vitreoretinal adhesion and retinal breaks.
detachment in the eye of a patient complaining of light This is frequently successful in sealing the treated lesion
flashes (photopsias) and/or floaters (entopsias). and preventing it from causing a clinical RD. One must
5. Atrophic round hole in lattice degeneration in a be careful as extensive laser or cryo may cause vitreous
patient with floaters should not be considered to be changes that actually increase the chances of subsequent
symptomatic, since it is unrelated to the posterior vitreoretinal traction and retinal detachment.
vitreous detachment.
6. Fresh tear is either a symptomatic tear or a tear found in What type of tears / flaps should be sealed?
a location where no tear was seen on prior ophthalmic Though there are no clinical trials available for this but
examination. following guidelines may be helpful in deciding whether
7. Giant tear is defined as a tear which is 900 or larger. to treat or not treat.
8. Subclinical (RD) defined as having less than 1–2 disc 1. Symptomatic tears in patients with no history of
diameter (DD) of associated sub retinal fluid (SRF) and
usually do not progress. Retinal Disease
Prevention of RD • Flap (Horseshoe) Tears are associated with
Why is it important to discuss or practice prevention
of RD? symptoms and are dangerous. 25-90 % have been
1. Initial surgical attempts to reattach the retina fail in found to cause retinal detachment. Flap tears
approximately 10–20% of cases. associated with vitreous haemorrhage are more
prone to develop RD. Studies shows only fresh
tears are dangerous. Prophylactic treatment of
symptomatic flap tears has been shown to reduce
the incidence of RD to 0-19%. Such treatment
therefore seems justified.
www. dosonline.org l 33
Retina
• Operculated tears are less likely to cause be 10%. If prophylaxis is effective, this easily
detachment than fresh flap tears. Fresh identifiable high-risk group should benefit from
operculated tears are largely benign, it does not treatment. Clearly then, fellow eyes are at very high
seem reasonable to treat them all. Those that are risk of retinal detachment. The risk is still higher
either large or located superiorly are most likely if there are peripheral vitreoretinal abnormalities.
to cause detachment and should therefore be Several studies have shown that prophylaxis of
treated. Moreover, in evaluating operculated tears such abnormalities is beneficial. Therefore, all
for therapy, it is very important to examine the full-thickness retinal holes, lattice degeneration
vitreous carefully with the Goldmann 3-mirror and vitreoretinal tags with traction in second eyes
lens. If vitreous is adherent to the edge of the round should be treated. Following the introduction of
hole, the hole should be considered the equivalent prophylactic therapy, the incidence of retinal
of a flap tear and should be treated. detachment in fellow eyes decreased from 11% to
3%.
2. Asymptomatic breaks in patients with no history of • Aphakic Fellow Eyes The incidence of retinal
retinal disease detachment in aphakic fellow eyes is 2-3 times
that of phakic fellow eyes (21-36% as compared
• Flap Tears: Eyes with asymptomatic flap tears to 10%) Aphakic fellow eyes with retinal breaks
have been shown to have a very low incidence are thus particularly prone to retinal detachment.
of subsequent retinal detachment. The evidence In such eyes we treat all retinal breaks, as well as
indicates that patients with asymptomatic flap tears lattice degeneration and vitreoretinal tags.
are not highly prone to retinal detachment. Almost 5. Giant Tears
all such tears can be followed without treatment. At Moorfields Eye Hospital, it has been determined that
48% of patients who have a giant tear in one eye, will have
• Asymptomatic Round Holes, with or Without a subsequent retinal detachment in the other eye. Since
Operculum: These holes have been found to be retinal detachments with giant tears are among the most
harmless in several series. There is no evidence difficult detachments to repair, prevention of detachment
that such tears should be treated. in the second eye is very important. At Moorfields, even
if it has no clinically apparent vitreoretinal abnormalities,
• Lattice Degeneration Without Holes Lattice the peripheral retina of the fellow eye is treated with
degeneration is a known precursor of retinal circumferential cryotherapy.
detachment, as vitreous traction on its posterior 6. Breaks in Myopic Eyes
edge may cause a horseshoe tear and are found Because highly myopic eyes are much more likely to
in approximately 30% of patients who undergo develop retinal detachment than non myopic eyes, some
retinal detachment surgery. No treatment is surgeons treat all breaks found, even asymptomatic round
indicated for lattice degeneration without holes. holes. There are 35 myopic eyes with breaks for every
myopic eye which develops a retinal detachment. The
• Lattice Degeneration with Holes Lattice degene- evidence however does not support prophylactic treatment
ration with holes is more likely to lead to of retinal breaks found in asymptomatic myopic eyes.
detachment than is lattice degeneration without 7. Breaks in Senile Retinoschisis
holes, because of the possibility of fluid seepage On routine autopsy examination of eyes with no history
under the retina. Nevertheless, the risk is not of ocular disease, 2.4% were found to have senile
great. 2-3 %population have lattice degeneration retinoschisis. Because of the low incidence of retinal
with holes, but they never develop retinal detachment and because retinal detachments caused by
detachment. Therefore, prophylactic therapy of retinoschisis progress slowly, it is not necessary to treat all
lattice degeneration with holes in low risk is not outer wall holes. Schepens suggests treatment of only large,
indicated. multiple, or posteriorly located outer wall breaks.
Clearly, then, prophylactic therapy applied to patients
3. Breaks in Aphakic Eyes Since approximately 2% of who can be identified as likely to develop detachment
all aphakic eyes develop retinal detachment, 50% of accomplishes far more than less selective treatment. We
which occurs in first years; they should be carefully suggest, therefore, that such treatment, with its attendant
examined for retinal holes and early aphakic retinal hazards [as Central retinal artery occlusion (CRAO)
detachment. Observation is particularly important
during the first year following cataract surgery, when
50% of the detachments occur. Breaks in aphakic eyes
are more common than in phakic eyes.
4. Breaks in Fellow Eyes
• Phakic Fellow Eyes Several studies have shown
the bilateral incidence of retinal detachment to
34 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
Figure 1: Flow chart of proplylactic treatment for prevention of retinal detachment
following block, macular pucker following laser and forces necessary to generate retinal breaks are produced
cryotherapy], is indicated only for eyes with a significant risk upon development of PVD, although not all retinal breaks
of retinal detachment (Figure1), i.e., eyes with symptomatic progress to detachment4. The reported incidence of retinal
flap tears and fellow eyes with vitreoretinal abnormalities. tears in patients with acute symptomatic PVD varies from
Symptomatic operculated tears, asymptomatic breaks in 8–46%5.
aphakic eyes and outer wall holes in retinoschisis might Trends in RRD surgery
occasionally be treated if they are large or posteriorly The fundamental principles involved in reattachment of a
located. Asymptomatic breaks in phakic eyes and lattice retina include identification of all retinal breaks, and relief of
degeneration with and without holes should rarely be the vitreous traction. Traditionally, scleral buckling (SB) was
treated unless the patient is not likely to perceive an early viewed as the gold standard treatment for uncomplicated
retinal detachment or to return for follow up examinations. RRD. Pars plana vitrectomy (PPV) was traditionally
Currently, RRD continues to be an important cause of visual reserved for treatment of eyes with complications (Table
loss. Three factors predispose to development of RRD: 1), such as those showing giant retinal tears or exhibiting
1. Existence of a liquefied vitreous gel significant proliferative Vitreoretinopathy (PVR). As the
2. Tractional forces that precipitate a retinal break view of the retinal periphery is enhanced, identification of
3. Presence of retinal break through which fluid may retinal breaks is rendered easier, achievement of complete
intraoperative retinal attachment is possible, the risks of
access the subretinal space. hemorrhage or retinal incarceration inherent to the external
The vitreous is firmly attached to the vitreous base, an drainage procedure applied during SB is eliminated. PPV
area 3–6 mm in diameter that straddles the ora serrata is less likely to cause a refractive change with the recent
surrounding the retina. The posterior border of the vitreous introduction of small-gauge vitrectomy ie micro incision
base is located both more posteriorly and temporally in vitreous surgery (MIVS), vitrectomy surgery is less invasive,
older individuals. Therefore, retinal tears may occur at a affords fast recovery, and is sutureless. In the 1980s, the
higher frequency at the temporal periphery in such patients, indications for PPV in RRD patients were broadened to
following posterior vitreous detachment (PVD)3. PVD include less complicated instances, and the term “primary
usually presents as an acute event, and is more prevalent vitrectomy” was introduced by Klöti. As the necessary
in patients older than 50 years, with frequencies as high as instrumentation for, and safety of, PPV continue to improve
53%. PVD often precipitates RRD because the tractional with developments in microscope technology, intensified
endoillumination, and wide-angle viewing systems, the
www. dosonline.org l 35
Retina
Table 1: Complications Scleral buckling Primary vitrectomy
Pneunoretinopexy Recurrent retinal detachment Relatively high rates of iatrogenic retinal breakage
Incarceration of vitreous: 1.4% (0.78–24%)
Crystalline lens damage (0.03–9%)
Sub conjuctival gas: 1.1% Epiretinal membrane (ERM) Retinal incarceration at retinotomy sites (0.6–2.9%)
New or missed breaks: 13.3% Extrusion of explants Corneal abrasion (0.6%),
PVR: 4.6% Glaucoma Choroidal effusion (0.5%), as reported in one
Redetachment: 3.0% Infection of explants national audit
Transient or persistent intraocular pressure increases
Mild macular pucvker: 1.8% Band migration have been reported in 15–24% of patients
Phakic patients are at significant risk of developing
Persistent sub retinal fluid: 2.1% Anterior segment ischemia nuclear cataracts; this is especially true of patients
older than 50 years (21–86%).
Minimal ERM: 1.4% Diplopia Retinal redetachment, with or without PVR, usually
by new or missed breaks, or reopening of former
Re-opening of original break: breaks. Recent advances in surgical technology,
1.1% including the development of MIVS and wide-angle
Vitreous haze: 1.1% viewing systems, have reduced the frequency of
anatomic failures
Cystic macular edema, macular pucker, and macular
hole
Although very rare, endophthalmitis has been
reported, as has sympathetic ophthalmia. The
incubation period for the latter condition after
vitrectomy varies from 4 weeks to 2 years
indications for vitrectomy in RRD have been further Decision making in rhegmatogenous retinal detachment is
expanded to include most patients with RRD. Indeed, difficult to answer because there is no large scale clinical
PPV is more useful than SB in eyes requiring simultaneous trial that has shown statistically significant differences
cataract extraction or those of pseudophakic status. among these treatment options. The aim of this paper is to
Whatever method is used one must remember that: teach pros and cons of these retinal re-attachment surgical
1. In “macular on” retinal detachment, urgent surgery techniques. Further recent studies make things more clear.
Ultimately choice depends on socioeconomic status,
should generally be scheduled to prevent detachment availability of instrumentation and type of presentation
of the macula. and surgeons skills. At the time of decision making one
2. Cases with tractional tears tend to progress very rapidly should not forget to assess patient outcomes including
and should be treated urgently. postoperative pain and discomfort, time away from work,
3. Asymptomatic retinal detachments and detachments and quality-of-life to choose what is the best treatment
without tractional breaks e.g., those due to retinal option: pneumatic retinopexy, scleral buckle, vitrectomy
dialyses, atrophic retinal breaks in young myopes or a combination of PPV with buckling. Prospective data
progress more slowly hence some delay, if it allows for a direct comparison of PR to primary vitrectomy are
optimal conditions for surgery, may then be acceptable6. unavailable. Vitrectomy is the procedure of choice in
Techniques used for Rhegmatogenous Retinal reattachment dealing with significant PVR and vitreoretinal traction, and
surgery it may be ideal when vitreous or capsular opacity causes
• Scleral buckling (SB) poor visualization. Vitrectomy tends to induce cataract, it
• Pneumatic retinopexy (PR) is used most commonly in pseudophakic eyes. Tiny breaks,
• Primary Pars plana Vitrectomy (PPV) common in pseudophakic eyes, may be most readily
identified by internal search during vitrectomy. Vitrectomy
yields significantly better single-operation success rates
than SB in pseudophakic eyes. In phakic eyes, vitrectomy
36 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
yielded poorer visual results than SB with no benefit in 6. A meta-analysis of 29 studies on patients with
single-operation success. pseudophakic RD found that both PPV and combined
Comparison of surgical outcome of surgical PPV/SB were associated with a higher SOSR and better
techniques i.e SB, PPV, PR visual acuity outcomes than was SB alone15,16.
SB
The anatomical results following scleral buckling for PR vs SB vs PPV17,18
rhegmatogenous retinal detachments are impressive. An Pneumatic retinopexy (PR) was developed in an attempt
overall reattachment rate of at least 90% is achievable. The to minimize the mentioned problems of SB. This
success rates demonstrated in MUSTARD7 was achieved (in outpatient procedure for retinal reattachment consists of an
patients aged 51 to 60 years) in 86.72%; the outcome was intravitreal gas injection with transconjunctival cryopexy
almost equally positive among very young patients, with or laser photocoagulation, followed by appropriate head
success rates of 85.00% in children up to age 10 years and positioning15. No incisions are required. PR is substantially
86.07% in adolescents aged 11 to 20 years. less expensive than scleral buckling or vitrectomy and
PR vs. SB8,9 has become widely accepted as the treatment of choice
1. The rate of retinal redetachment was found to be 38% for selected retinal detachments, with the vast majority of
vitreoretinal surgeons employing this procedure.
in pneumatic retinopexy when compared to 16% in The multicenter clinical trial conducted as a part of The
scleral buckling Retinal Detachment Study Group with 198 patients in
2. The need for reoperation for retinal detachment was 1989. Scleral buckling was compared with pneumatic
observed to be higher in PR vs SB (38% Vs 14%) retinopexy with regard to single-operation reattachment
3. The incidence of PVR was found to be 12% in PR when (82 versus 73%), reattachment with one operation and
compared to 8% in SB patients. postoperative laser/cryotherapy (84 versus 81%), overall
4. Successful reattachment with one operation was 50% reattachment with reoperations (98 versus 99%), final
in PR compared to 78% in SB patients. visual acuity of 20/50 or better in eye with preoperative
5. Successful reattachment with one operation was 62% detachment of the macula for 2 weeks or less (56 versus
in PR compared to 84% in scleral buckled patients. 80%), PVR (5 versus 3%), and new retinal breaks (13 versus
6. LogMAR visual acuity at final follow-up (mean) was 23%). Excluded were cases with breaks larger than 1 clock-
0.55 (20/70) in PR patients when compared to 0.41 hour or multiple breaks extending over more than 6 clock-
(20/50) in scleral buckled patients. hour of the retina, breaks in the inferior 4 clock-hours of
PPV vs.SB vs. combined PPV /SB the retina, presence of PVR grade C or D (Retina Society
1. The reported primary success rates for RRD repair by Terminology Committee, 1983)13,14 physical disability
PPV range from 64–94%10,11. or mental incompetence precluding maintenance of the
2. Exploiting the recent advances in surgical technology required positioning, severe or uncontrolled glaucoma
including MIVS, several recent case series reported and cloudy media precluding full assessment of the retina.
that the single operation success rate (SOSR) improved Comparing PR with SB, postoperative morbidity was less
to over 90% and that the final average visual acuity and had a shorter duration in the PR group, cataract surgery
was 20/40 or better. was required four times more often after SB. New and
3. Several retrospective series and prospective clinical missed retinal breaks occurred more frequently after PR
trials comparing SB, PPV, and/or combined SB/PPV, but did not usually produce an unfavourable outcome new
found no statistically significant difference in SOSR and missed retinal breaks after SB had the worst prognosis
among the various procedures & postoperative proliferative vitreoretinopathy occurred in
4. However, a few studies reported that PPV was superior 5% in the SB group and 3% in the PR group (not statistically
in terms of either anatomic or visual outcome in significant).
comparison with SB alone12,13,14. Important studies
5. In addition, several reports comparing PPV and 1. One hundred seventy six surgeons from 48 countries
combined PPV/SB also found that the use of a combined
procedure did not significantly influence anatomical or spanning five continents provided information on the
visual outcomes. primary procedures for 7678 cases of RRDs including
4179 patients with uncomplicated RRDs. It states
that it is reasonable to conclude that in phakic eyes,
sclera buckle alone can be considered. However, in
pseudophakic eyes, there is no clear winner and the
surgeon should consider higher risk of level 3 failure
with scleral buckle versus higher risk of level 2 failure
with vitrectomy. Pneumatic retinopexy was found to be
www. dosonline.org l 37
Retina
equivalent to scleral buckle in cases where the retinal 2. Retina 5th edition Stephen J Ryan MD (VOLUME 3)
detachment was induced by atrophic holes. However, 3. Steinberg RH: Research update: report from a workshop on cell
in cases where a flap tear is present, scleral buckle
has a lower failure rate than pneumatic retinopexy. biology of retinal detachment. Exp Eye Res. 1986; 43:695-706
Given this information, pneumatic retinopexy may be 4. Leaver PK, Cleary PE: Macular hole and retinal detachment. Trans
considered in cases of retinal detachment with grade
0 or grade A PVR and atrophic holes7. It studied the Ophthalmol Soc UK. 1975; 95:145-147
outcome of the treatment of complex rhegmatogenous 5. Heimann H, Bartz –Schimidt KU, Bornfeild N, et al. Scleral buckling
retinal detachments The main categories evaluated
in this investigation were: (1) grade B proliferative versus PPV in RRD: a prospective randomized multicentre clinical
vitreoretinopathy (2) grade C-1 PVR, (3) choroidal study. Ophthalmology 2007;114:2142-54
detachment or significant hypotony (4) large or giant 6. Schwartz SG, Flynn HW. Primary retinal detachment: sclera buckle
retinal tears, and (5) macular holes. It showed that or pars plana vitrectomy? Curr Opin Ophthalmol. 2006; 17:245–50.
when grade B PVR is present, performing a vitrectomy, 7. Thelen U, Amler S, Osada N, et al. Outcome of surgery after
with or without a supplemental buckle is better than macula-off retinal detachment - results from MUSTARD, one of the
applying a scleral buckle alone. However, when grade largest databases on buckling surgery in Europe, Acta Ophthalmol.
C-1 PVR is present, no significant difference in the level 2012;90(5):481-6.
1 failure rate is seen when comparing these techniques 8. Heimann H, Bartz-Schmidt KU, Bornfeld N, et al. Scleral Buckling
for repair. There was no statistical difference in the versus Primary Vitrectomy in rhegmatogenous retinal detachment: a
level 1 failure rate between gas and silicone oil when prospective randomized multicenter clinical study. Ophthalmology
vitrectomy was performed in eyes with grade B or C-1 2007; 114:2142-2154.
PVR. When choroidal detachment or hypotony was 9. Brazitikos PD, Androudi S, Christen WG, et al. Primary pars
present, performing a vitrectomy led to a much better plana vitrectomy versus scleral buckle surgery for the treatment
result than not performing one7. of pseudophakic retinal detachment: a randomized clinical trial.
2. A Retrospective, nonrandomized, interventional case Retina 2005; 25:957-964.
series to compare pars plana vitrectomy (PPV) with 10. Sharma YR, Karunanithi S, Azad RV, et al. Functional and
combined PPV and scleral buckle (SB) for the repair anatomic outcome of scleral buckling versus primary vitrectomy in
of noncomplex primary rhegmatogenous retinal pseudophakic retinal detachment. Acta Ophthalmol Scand. 2005;
detachment (RRD) reviewed 181 consecutive cases 83:293-297.
of vitrectomy for primary RRD at 2 major medical 11. Halberstadt M, Chatterjee-Sanz N, Brandenberg L, et al. Primary
centres in Israel. In phakic eyes, SSAS (single surgery retinal reattachment surgery: anatomical and functional outcome in
anatomic success) rates were 92% and 87.5%, phakic and pseudophakic eyes. Eye (Lond) 2005; 19:891-898.
respectively, and in pseudophakic eyes, SSAS rates 12. Azad RV, Chanana B, Sharma YR, et al. Primary vitrectomy versus
were 77.5% and 86.7%, respectively, in the PPV and conventional retinal detachment surgery in phakic rhegmatogenous
PPV plus SB groups. Final VA was 0.41 (20/51) in the retinal detachment. Acta Ophthalmol Scand. 2007; 85:540-545.
PPV group and 0.53 (20/68) in the PPV plus SB group. 13. Arya AV, Emerson JW, Engelbert M, et al. Surgical management of
The reattachment rate and the final VA were similar pseudophakic retinal detachments: a meta-analysis. Ophthalmology
in both groups. The addition of SB did not improve 2006; 113:1724-1733.
the results and was associated with slightly lower VA 14. Hilton GF, Grizzard WS. Pneumatic retinopexy. A two-step
than with PPV alone. Tear location or lens status had outpatient operation without conjunctival incision. Ophthalmology
no significant effect on success rates. It is likely that in 1986; 93:626-641
eyes undergoing PPV for primary RRD, addition of a SB 15. Tornambe PE, Hilton GF. The Retinal Detachment Study Group:
is not warranted19. Pneumatic retinopexy: a multicenter, randomized, controlled
3. MUSTARD: Munster Study on Therapy Achievements clinical trial comparing pneumatic retinopexy with scleral buckling.
in Retinal Detachment20 was conducted to evaluate the Ophthalmology 1989; 96:772-783
anatomic success rates of scleral buckling surgery in 16. Retina Society Terminology Committee: The classification of retinal
the treatment of rhegmatogenous retinal detachment detachment with proliferative vitreoretinopathy. Ophthalmology
with 4325 subjects who underwent surgery between 1983; 90:121-125.
1980 and 2001, established an overall success rate 17. Chen JC, Robertson JE, Coonan P, et al. Results and complications of
of approximately 84% in cases with rhegmatogenous pneumatic retinopexy. Ophthalmology 1988; 95:601-608.
retinal detachment by the first buckling procedure7,11. 18. Kinori M, Moisseiev E, Shoshany N, et al. Comparison of pars
plana vitrectomy with and without scleral buckle for the repair of
References primary rhegmatogenous retinal detachment. Am J Ophthalmol.
2011;152(2):291-297.
1. Benson WE. Prophylactic therapy of retinal breaks. Survey of 19. Grizzard WS, Hilton GF, Hammer ME, et al. A multivariant analysis
Ophthalmology. 1977;22 (1):41–7. of anatomic success of retinal detachments treated with scleral
buckling. Graefes Arch Clin Exp Ophthal. 1994; 232:1-7.
20. Ron A. Adelman, Aaron J. Parnes, Didier Ducournau, Strategy
for the Management of Uncomplicated Retinal Detachments: The
European Vitreo-Retinal Society Retinal Detachment Study Report
1,2. Ophthalmology 2013;120(9):1804-1808.
38 l DOS Times - Vol. 19, No. 3 September, 2013
Role of Buckling in the Modern ReRteitnina
era of Vitreoretinal Surgeries
Sangeeta Roy
MD
Sangeeta Roy MD, Shorya Vardhan Azad DO, MS,
Brijesh Takkar MD, Anil Babanrao Gangwe MD
Rajendra Prasad Centre for Ophthalmic Sciences,
All India Institute of Medical Sciences, New Delhi
Jules Gonin changed the entire concept of pathogenesis Primary repair of fresh and uncomplicated rhegmatogenous
of retinal detachment and identified retinal breaks as the retinal detachment (RRD) has undergone considerable
cause of retinal detachments1. He developed the surgical changes in recent decades. Since the invent of pars plana
technique of drainage of subretinal fluid beneath the retinal vitrectomy (PPV), scleral buckling and PPV have competed
break combined with direct treatment of the break by with each other as methods for the treatment of retinal
transscleral cautery (ignipuncture) with a success rate of detachment. Coventionally, Scleral buckling was the
40%2. The invention of binocular indirect ophthalmoscope method of choice in uncomplicated retinal situations, i.e.,
made the localisation of the breaks easy. Custodis in 1949 single breaks and/or a limited retinal detachment. In contrast,
described non drainage sclera buckling with polyvinyl PPV was indicated in complicated situations, i.e., vitreous
explants with a success rate of 80%. Charles Schepens in hemorrhage/opacity, proliferative vitreoretinopathy (PVR),
1951 described a technique of sclera buckling with the or breaks at the posterior pole. But recently there has been
help of intrascleral silicone implant with diathermy with a a paradigm shift in the management of primary repair of
success rate of 80%. In 1964 Harvey Lincoff used cryopexy fresh RRD from conventional methods of sclera buckling
along with silicone sponges for treatment of retinal to ever evolving and exciting enhancements in vitreous
detachment with a success rate of about 80%. surgery with comparable attachment rates. This has seen
And finally came, the first flirtation with the vitreous when more and more surgeons shifting to par plana vitrectomy
David Kasner in 1969 introduced the concept of planned and a losing the art of traditional buckling surgery.
open sky vitrectomy3. Soon, Robert Machemer developed a This throws up a question that what exactly is the role of
more conservative pars plana vitrectomy in a closed system conventional retinal detachment surgery in comparison to
with controlled intraocular pressure. This served as the recent advances in vitreoretinal surgery. Thus this article
starting of a distinct and separate vitreoretinal speciality4. will try to answer this question, taking into account the pro
Since then there has been significant developments in and cons of both the procedures with a guide to specific
Vitreous surgery with latest cutters, illuminators, endolasers indications for either of the procedures.
and all in one integrated machines making surgery Buckling surgery
minimally invasive and least traumatic for the patients. So, Scleral buckles changes the geometry and physiology
from Machemer’s vitreous infusion suction cutter (VISC) of the eye. It changes the direction of the vector forces
that needed a 17-gauge sclerotomy port we soon shifted so that it overcomes the forces tending to detach the
to a three-port vitrectomy with a 20-gauge system which retina. The principle of buckling surgery is “to seal all
was developed by Conor o Malley5. Recently, 25 and the breaks”. Different methods are used to create these
23-gauge vitrectomy system have been commonly used for chorioretinal adhesions like diathermy, cryopexy or laser
various indications with excellent post operative results. photocoagulation.
Henceforth 27 gauge and 29 gauge instruments have also The advantages of sclera buckling over PPV in RRD are
been developed but there applicability in their present many as enumerated below:
form is still found to be lacking.
www. dosonline.org l 39
Retina
• Excellent attachment rates of 90% in well selected used. The most frequent intra operative complications are
cases. high rates of iatrogenic breaks (0.78 -2%)7,8,9 and lens touch
(0.03%-9%)10,11,12. Rare complications like port site dialysis,
• Essentially extra-ocular, non invasive intra-ocularly haemorrhages at retinotomy site, corneal abrasions can
maintains the internal integrity of the eye and at the also occur.
same time addresses the problem by relieving the Postoperatively the patients may have increased intraocular
dynamic traction. pressure and phakic patients are at significant risk of cataracts.
The major complications include retinal re-detachment
• No intraoperative complication such as iatrogenic with or without PVR usually by new or new breaks or
breaks, lens touch and port site dialysis. reopening of old breaks. Other minor complications
are cystoids macular oedema, macular pucker, macular
• It does not have oil related complications such as hole and silicone oil induced complications. There are
cataract and glaucoma. more concerns for endophthalmitis and hypotony with
microincision vitrectomy systems.
• It is a single procedure as there is no requirement of oil Role of buckling in the era of vitreoretinal surgery
removal later. At last we come to the question, where does conventional
surgery stand up against the ever evolving modern day
• Preferred procedure in young patients. vitreous surgery with vitrectomy machines having better
Intra-operative complications such as scleral perforation fluidics causing less retinal flutter, better endoilluminators,
while passing buckle sutures, retinal incarceration, vitreous bent probe lasers and good microscopes. Possibility exists
incarceration and more disastrous complication as subretinal that the next generation of vitreoretinal surgeons, weaned
bleed reaching till the macula during subretinal fluid on the sutureless incisions, will be slower to acquire the
(SRF) drainage can be expected. Re-detachment following necessary skills in external buckling anyway. So should we
buckling surgery can also be caused by missed break or assume that are we seeing the end of buckling procedures?
new break formation due to PVR. Other complications or does it still have to offer something which PPV can’t?
are glaucoma, epiretinal membranes, buckle extrusion or The answer is YES!
infection, anterior band migration, diplopia, induction of As we have discussed earlier the vitrectomy is not without
refractive error and anterior segment ischemia. complications and it also has as slow learning curve for
Modern era of vitreoretinal surgery the beginners. It is very difficult to achieve a complete
In 1980 Kloti broadened the indications of PPV and coined vitrectomy in a young phakic patient which can predispose
the term “primary vitrectomy in RRD”6. Next three decades to PVR formation leading to redetachments. Increased
saw an immense improvement in instrumentations, IOP, cataract formation in phakic patients and silicone
vitrectomy machines, operating microscope, intensified oil induced corneal de-compensation or band shaped
endoilluminators, endolasers and wide angle viewing keratopathy are the major complications after vitrectomy.
system which further led to the expansion of PPV to all The patients also require a second surgery for silicone oil
kinds of RRD. removal. Thus scleral buckling surgery still has role in this
The advantages of PPV over sclera buckling in RRD are modern era of vitrectomy surgeries in selected cases.
many as enumerated below: In our experience, scleral buckling in young phakic
• It helps in complete reattachment of the retina intra- patients with peripheral breaks, especially posttraumatic
rhegmatogenous retinal detachment with retinal dialysis
operatively. yields excellent results. It can also be done in pseusophakic
• It is less likely to cause refractive error which was very or aphakic patients where we are absolutely sure of the
location and number of breaks and where the configuration
common with sclera buckling of RRD could be explained by the location of the breaks. A
• There is no risk of retinal haemorrhages and retinal segmental buckle can be done in cases of fresh quadrantic
RRD with single break but an encirclage is preferred along
incarceration inherent to external drainage procedure with a buckle in cases with early PVR, multiple breaks in
in sclera buckling. 3 or 4 quadrants and in extensive detachments in which
• Primary PPV - very useful in cases where retinal breaks breaks are difficult to locate like in pseudophakes.
could not be identified preoperatively which is an
essential prerequisite for sclera buckling. On the other hand, PPV is indicated in pseudophakic
• Minimal invasive vitrectomy surgeries help in easy patients with wide and bullous retinal detachment with no
recovery with less pain and more comfort. breaks found, RRD with posterior location of the break, giant
• Preferred in pseudophakic patients. retinal tear induced retinal detachment, multiple breaks in
In addition to all the above mentioned advantages of pars
plana vitrectomy it also has some complications inherent to
the procedure and to the tamponading agent (silicone oil)
40 l DOS Times - Vol. 19, No. 3 September, 2013
Retina
multiple quadrants, RD with proliferative vitreoretinopathy 2. Brown .A.L.: Gonin’s cautery puncture for detached retina. Report of
(more that PVR Grade C1) and macular hole RD. three cases. Trans A.M.A Section Ophthalmol. 1930; 81:236.
Another option is combining the both, encircling band
along with vitrectomy which is also preferred by many 3. Kasner D. Vitrectromy: A new approach to the management of
vitreoretinal surgery. It supports the pre-equatorial vitreous. Highlights Ophthalmol. 1969; 11:304
vitreous preventing recurrent retinal detachment due to
peripheral new breaks or small missed breaks especially 4. Machemer R, Buettner H,Norton EW ,Parel JM.Vitrectomy: a
in pseusophalic or aphakic patients. In phakic patients the pars plana approach Trans Am Acad Ophthalmol Otolaryngol.
complete peripheral vitrectomy is not possible, in these 1971;75(4):813-20
cases an encircling band support the peripheral residual
vitreous. It is also useful in patients with inferior PVR as 5. Charles S, Calzada J. Wood B. Text Book of Vitreous microsurgery
it supports the inferior retina and we can avoid an inferior 2nd edition;1999:45
retinectomy.
Recent studies assessing scleral buckling versus primary 6. DeJuan E Jr,Machemer R,Charles ST et al. Surgery for stage 5
vitrectomy in rhegmatogenous retinal detachment have retinopathy of prematurity. Arch Ophthalmol. 1987;105(1):21.
shown superiority of PPV in pseudophakic and aphakic
eyes in terms of a primary success rate and a rate of 7. Eckardt C. Transconjunctival sutureless 23-gauge vitrectomy. Retina
secondary procedure although no difference was seen in 2005;25(2):208-11.
phakic patients7,8.
In conclusion, scleral buckling surgery still has a very 8. Kloti R. amotio. Chirurgie ohne skleraeindelung. Primare vitrektomie
important and irreplaceable role to play in this modern era Klin monatsbl Augenheikd 1983; 182:474-8
vitrectomy surgery.
References 9. Tewari HK, Kedar S, Kumar A, et al. Comparision of sclera buckling
with combined sclera buckling and pars plana vitrectomy in the
1. Rumpf J. Jules Gonin: Inventor of the surgical treatment for retinal management of rhegmatogenous retinal detachment with unseen
detachment. Surv Ophthalmol. 1976 ;21:276 retinal breaks.Clin Experiment Ophthalmol. 2003;31:403-7
10. Sharma Y R,Karunanidhi S, Azad R V et al.Functional and
anatomical outcome of sclera buckling versus primary vitrectomy
in pseudophakic retinal detachment. Acta Ophthalmol Scand.
2005;83:293-7
11. Azad R V, Chanana B,Sharma Y R et al. Primary vitrectomy versus
conventional retinal detachment surgery in phakic rhegmatogenous
retinal detachment. Acta Ophthalmol Scand. 2007;85:540-5
12. Ahmedieh H,Moradian S,Faghihi H, et al. Anatomic and
visual outcomes of sclera buckling verus primary vitrectomy in
pseudophakic and aphakic retinal detachment of a single operation-
report no.1. Ophthalomology 2005;112:1421-9
www. dosonline.org l 41
DiaDginagonsotsitcicss
Spectralis
Ruchir Tewari
MD
Ruchir Tewari MD, Shorya Vardhan Azad DO, MS,
Sangeeta Roy MD, Vivek Kumar MD
Rajendra Prasad Centre for Ophthalmic Sciences,
All India Institute of Medical Sciences, New Delhi
Recent advances in technology have become a part of our of cSLO based on the pioneering work of Webb et al1,2.
routine clinical imaging for a wide spectrum of ocular Although limited by the optical properties of the human
pathologies. The Optical coherence tomography (OCT) eye, they are able to achieve high-contrast images of the
and confocal scanning laser ophthalmoscopes (cSLO) posterior segment. Today most scanning laser systems
imaging have come up in recent times, as a great diagnostic record their images in real time with a fast frame rate.
and prognostic tool for a myriad of retinal diseases as well OCT was initially reported by Huang3 and coworkers in
as glaucoma. The Spectralis heralds a new era of retinal 1991 and has had a tremendous subsequent impact on
imaging wherein a combination of these imaging modalities in vivo imaging of retinal diseases. It is a noninvasive
into one device aims to provide us with various subsequent technique and allows for visualization of microstructural
advantages, including exact correlation of tomographic alterations of the retinal tomographic architecture. Most
and topographic findings, and to enhance further our ophthalmologists are now using OCT as a standard
understanding of disease pathogenesis, diagnosis, and diagnostic tool for many retinal diseases. Although the
patient management. images it provides are analogous to ultrasonography, it
Background uses light instead of sound to obtain a reflectivity profile
Although the interest in fundus auto-fluorescence (FAF) of the tissue under investigation, measuring the time delay
imaging has been around for nearly forty years, it could and magnitude of backscattered or reflected light by low-
only be incorporated into clinical practice with the advent coherence interferometry.
Figure1: The SDOCT scan of a 50 year old male showing normal foveal architecture. The green lines on the corresponding
IR image map the exact location of the SDOCT scan. The area of the scan can also be varied to include more peripheral regions
www. dosonline.org l 43
Diagnostics
Figure 2: A 68 yr old male with neovascular AMD and a large Pigment Epithelial detachment.
The SDOCT scan clearly visualizes the large PED
The different OCT techniques available in clinical practice of knowing the location, leading to a significantly better
are time-domain OCT and Spectral domain OCT (SDOCT). diagnosis and monitoring of the patient.
In time-domain OCT the depth information of the retina Principle
is acquired as a sequence of samples over time. This is The imaging system cSLO/OCT (Spectralis HRA+OCT)
done either in longitudinal cross sections perpendicular combines high speed, high-resolution SDOCT images with
to or in the coronal plane to the retinal surface. The SD simultaneous recording of fluorescein and indocyanine
OCT marked a significant change in the image resolution, green angiographies, digital infrared and blue reflectance,
notably in the areas of imaging speed, signal to noise ratio or FAF images. On the other hand, the Spectralis OCT
and sensitivity. The time-domain OCT was based on a has only two modes-SDOCT and infrared. Both SDOCT
mechanically moving reference mirror that captured the devices use a new proprietary eye-tracking technology that
reflected light. This limited the speed with which images simultaneously images the eye with two beams of light.
could be captured leading to poor image resolution. The One beam captures an image of the retina and maps over
SDOCT utilizes a stationary reference mirror and the 1,000 points to track eye movement. Using the mapped
OCT signal is acquired either by using a spectrometer as image as a reference, the second beam is directed to the
a detector or by varying the narrowband wavelength of desired location despite blinks or saccadic eye movements.
the light source in time (swept source). Fourier transform4,5 The dual-beam technology mitigates eye motion artifact
of the interference spectrum of the light signal is used to and ensures point-to-point correlations between OCT and
measure echo time delays of light. Increasing imaging fundus images without post-processing of the data.
speed allows for the acquisition of images within a fraction Also, the relocation of the primary site at later exams
of second, thus minimizing motion artifacts. It has also enhances the monitoring of disease progression and
become possible to acquire three dimensional volume treatment decisions. For image clarity, the proprietary
OCT scans that achieve comprehensive retinal coverage6. Heidelberg Noise Reduction feature takes the axial
The Spectralis combines OCT and cSLO and hence offers resolution from 7 microns to 3.5 microns. The SDOCT
a number of subsequent advantages, including an accurate of Spectralis captures 40,000 A-scans per second using
correlation of tomographic with topographic architecture an optical resolution of approximately 7 mm in depth
of the retina, which opens new insights in the pathogenesis (axial resolution) and 14 mm transversally (lateral optical
and morphological alterations of retinal diseases7,8. resolution). The centre wavelength of the OCT light
Additionally a multimodality imaging system provides a source is typically between 870 and 880 nm with the
complete view of the vitreous, retina and choroid, enabling added advantage that the OCT scans can be recorded
clinicians to combine information from six different modes simultaneously with fluorescein angiography, indocyanine-
to assess the eye: fluorescein and indocyanine green green angiography, FAF, infrared, and blue reflectance
angiographies, FAF, infra-red, red-free, and SDOCT. Thus, images. For the A-scans the scan depth is 1.8 mm/512
simultaneous high-resolution fundus imaging and SDOCT pixels, providing a digital axial resolution of 3.5 μm/pixel.
with the Spectralis (Heidelberg Engineering, Heidelberg, B-scans cover a transversal range of 15,20, or 300 field of
Germany) offer high-quality images with the certainty
44 l DOS Times - Vol. 19, No. 3 September, 2013
Diagnostics
Figure 3: A 77 yr old patient with neovascular AMD. The area of leak on the FFA is mapped to the area of
subretinal neovascularization on the SDOCT scan
view. In the high-speed mode scan widths are 384, 512, In large drusen, RPE elevation and derangement can
and 768 A-scans per B-scan with a lateral digital resolution be seen in association with a disrupted photoreceptor
of 11μm/pixel and a scan rate of 89, 69 and 48 B-scans/ band. Additionally, in cases of reticular drusen,
second, respectively. In the high- speed mode, the vertical another example of early AMD, the SDOCT scans
presentation of the OCT scan is magnified twice; therefore shows alterations in the outer retinal and retinal
morphological alterations are presented disproportionately pigment epithelium (RPE) layers. These ultra structural
high in the vertical dimension. The accelerated imaging characteristics may allow distinguishing sub classes
speed allows the acquisition of an image within a fraction of drusen and may allow identifying biomarkers for
of second, thus minimizing motion artifacts. Vertical and disease severity or risk of progression9.
horizontal OCT scans are placed in the area of interest. In advanced cases of dry AMD
The high-resolution modes encompass a scan width of • RPE monolayer loss along with atrophy of the outer
768, 1024, and 1536 A-scans per B-scan with a lateral neurosensory retinal layers can be confirmed. In most
digital resolution of 5μm/pixel at a scan rate of 48,37, and eyes with geographic atrophy the inner retinal layers
25 B-scans/second, respectively. High-resolution fundus are unchanged, whereas the outer retinal layers show
images provide clear cross-sectional scans of the retinal alterations in all eyes. SDOCT provides adequate
anatomical structure, including the retinal surface, intra- resolution for quantifying photoreceptor loss and allows
retinal alterations, as well as sub-retinal morphologic visualization of reactive changes in the RPE cells in the
pathologies. Sequences of B-scans can be acquired to junctional zone of geographic atrophy (GA). In cases of
image a full volume. These volume scans can be obtained GA with foveal sparing it was found that even if some
at 150, 200 and 300 field of view. The number of B-scans per function of the fovea is left, the marked morphologic
volume can be adjusted from 12 to 96 B-scans per 100. In involvement of cell layers might still cause severe
addition, it is also possible to acquire 3D volumetric OCT dysfunction10,11.
scans for comprehensive analysis of the entire retina and, In cases of Wet AMD
therefore, for 3D mapping of pathologic alterations within • Pigment epithelium detachments (PEDs) and choroidal
the retinal layers including the RPE. neovascular membranes can be located and better
Applications visualized.
The new technology of the SDOCT has improved the • It may also enhance the detailed visualization of
visualization of intra-retinal morphologic features allowing activity in new choroidal neovascularization, such as
the evaluation of the integrity of each retinal layer and in presence of sub retinal, intra-retinal, or sub-RPE fluid,
vivo visualization of microstructural morphology of the intra-retinal cysts, or a combination of them12,13. The
retina. high sensitivity on neovascular activity expressed by
1. Age related Macular Degeneration (AMD) the SDOCT features may, in future, obviate the need of
In early stages of AMD angiographies for treatment decisions14.
• Drusen - Small drusen appear as localized detachments 2. Diabetic macular edema (DME)
• SDOCT can better demonstrate conditions such as
of the retinal pigment epithelium (RPE) with intact- cystoid macular edema (CME) and vitreo-macular
layered architecture of the photoreceptor segments.
www. dosonline.org l 45
Diagnostics
traction in cases of DME, along with interface changes Conclusion
such as epiretinal membranes as compared to clinical
bio-microscopy and fundus photography. The OCT-cSLO combination that the Spectralis provides has
• Integrity of the outer retinal layers, which includes heralded a new era in understanding the disease process of
the external limiting membrane, the photoreceptors many a macular pathologies. Its clinical applications have
junction, the RPE, and Bruch’s membrane. One been well recognized as not merely for research but for
first report using the Spectralis SDOCT showed the routine patient care as a tool for diagnosing as managing
importance of the integrity of the external limiting various macular pathologies.
membrane and the photoreceptors junction as
a prognostic feature of visual improvement after Reference
treatment for diabetic macular edema. Also a recent
study also outlined the role of FAF in cystoid macular 1. R.H. Webb, G.W. Hughes, O. Pomerantzeff. Flying spot TV
edema. ophthalmoscope. Applied Optics 1980;19:2991– 2997.
3. Vitreomacular interface and posterior hyaloid
membrane - diagnosis and follow up of patients with 2. R.H. Webb, G.W. Hughes, F.C. Delori. Confocal scanning laser
alterations of the vitreoretinal interface. ophthalmoscope. Applied Optics 1987; 26:1492–1499.
• Epiretinal membranes and macular pucker - vitreoretinal
adhesions at the peak elevation and retinal wrinkling 3. D. Huang, E.A. Swanson, C.P. Lin et al. Optical coherence
can be seen in the cSLO image. In the correspondent tomography Science 1991;254:1178–1181.
SDOCT cross-sectional image the wrinkling of the
inner retinal surface and thickening of the neurosensory 4. A.F. Fercher, C.K. Hitzenberger, G. Kamp, S.Y. El-Zaiat. Measurement
retina, particularly pronounced in the outer nuclear of intraocular distances by backscattering spectral interferometry.
layer and the innermost neurosensory layers, can be Optics Communications 1995;117:43–48.
observed15.
• Macular hole – can demonstrate disruption of 5. G. Hausler and M.W. Lindner. Coherence radar’ spectral radar. New
photoreceptors junction, which is a method of assessing tools for dermatological diagnosis. Journal of Biomedical Optics
structural integrity of the photoreceptors before and 1998;3:21–31.
after macular hole surgery16.
4. Other macular pathologies, such as retinal vascular 6. M. Wojtkowski, V. Srinivasan, J.G. Fujimoto et al. Three- dimensional
occlusive diseases with macular involvement, central retinal imaging with high-speed ultrahigh- resolution optical
serous chorioretinopathy, macular dystrophies and coherence tomography. Ophthalmology 2005; 112:1734–1746.
idiopathic perifoveal telangiectasia still need to be
explored as there are few studies published in the 7. H.M. Helb, P.C. Issa, M. Fleckenstein et al. Clinical evaluation of
literature showing its clinical applications. simultaneous confocal scanning laser ophthalmoscopy imaging
Advantages combined with high-resolution, spectral-domain optical coherence
• Ability to better visualize the vitreoretinal interface tomography. Acta Ophthalmologica 2010; 88:842–849.
and outer retinal layers, especially the photoreceptors
junction, and the possibility to obtain 3-dimensional 8. U.E. Wolf-Schnurrbusch, V. Enzmann, C.K. Brinkmann, S. Wolf.
scans allowing to image structural changes of the Morphologic changes in patients with geographic atrophy assessed
vitreoretinal interface and the retina in large areas. with a novel spectral OCT-SLO combination. Investigative
• Improved visualization of the choroid for measuring Ophthalmology and Visual Science 2008; 49:3095–3099.
choroidal thickness using the enhanced depth imaging
technique. In normal eyes, the subfoveal choroid is 9. A.A. Khanifar, A.F. Koreishi, J.A. Izatt, C.A. Toth. Drusen
thickest and grows thinner at peripheral measurement ultrastructure imaging with spectral domain optical coherence
points. Also choroidal thickness demonstrated a tomography in age-related macular degeneration. Ophthalmology
negative correlation with age. The ability to visualize 2008; 115:1883–1890.
and quantify choroidal thickness is a very interesting
area of research for better understanding of macular 10. S. Bearelly, F.Y. Chau, A. Koreishi, et al. Spectral domain optical
pathologies. coherence tomography imaging of geographic atrophy margins.
Ophthalmology 2009; 116:1762–1769.
11. M. Brar, I. Kozak, L. Cheng et al. Correlation between spectral-
domain optical coherence tomography and fundus autofluorescence
at the margins of geographic atrophy. American Journal of
Ophthalmology 2009; 148:439–444.
12. A. Hassenstein, C.H. Meyer. Clinical use and research applications
of Heidelberg retinal angiography and spectral- domain optical
coherence tomography—a review. Clinical and Experimental
Ophthalmology 2009; 37:130–143.
13. C. Cukras, Y.D. Wang, C.B. Meyerle, et al. Optical coherence
tomography- based decision making in exudative age-related
macular degeneration: comparison of time- vs spectral-domain
devices. Eye 2010; 24:775–783.
14. A. Giani, D.D. Esmaili, C. Luisellietal. Displayed reflectivity of
choroidal neovascular membranes by optical coherence tomography
correlates with presence of leakage by fluorescein angiography.
Retina 2011; 31:942–948.
15. H.M. Helb, P.C. Issa, M. Fleckenstein et al. Clinical evaluation of
simultaneous confocal scanning laser ophthalmoscopy imaging
combined with high-resolution, spectral-domain optical coherence
tomography. Acta Ophthalmologica 2010; 88: 842–849.
16. L.K. Chang, H. Koizumi, R.F. Spaide. Disruption of the photoreceptor
inner segment-outer segment junction in eyes with macular holes.
Retina 2008; 28: 969–975.
46 l DOS Times - Vol. 19, No. 3 September, 2013
MiscMeilslcaelnlaenoeouuss
Clinical Trials Related to Age
Related Macular Degeneration
Kirti Singh
MD, DNB, FRCS
Kirti Singh MD, DNB, FRCS, Pooja Jain MBBS,
Nitasha Ahir MBBS, Divya Jain MD, DNB
Guru Nanak Eye Centre, Maulana Azad Medical College, New Delhi
AREDS (Age Related Eye Disease Study)1 Macular Photocoagulation Study (MPS)2
Purpose: To assess the clinical course, prognosis, and risk Purpose: To evaluate if argon and krypton laser is of
factors of age-related macular degeneration (AMD) and benefit in preventing or delaying loss of central vision in
cataract. patients with Choroidal Neovascular Membrane (CNVM)
Methods: A prospective multicenter randomized clinical due to AMD, presumed ocular histoplasmosis (POH), and
trial involving 3640 participants. idiopathic neovascular membranes (INVM)
Conclusions: People at high risk of developing advanced Method: MPS consisted of 3 sets of Randomized Controlled
stages of AMD lowered their risk by about 25% when Trial (RCTs).
treated with a high-dose combination of vitamin C, vitamin a). Argon Study: Used argon blue-green laser
E, beta-carotene, and zinc. People with intermediate
or advanced AMD in one eye only, the micro nutrients photocoagulation on leaking abnormal blood vessels
reduced risk of vision loss caused by advanced AMD by in CNVM outside the fovea [200 to 2500µ from center
19%. However if only early AMD, the supplements did not of Foveal avascular zone (FAZ)] in the three conditions:
provide any apparent benefit. AMD, POH, and INVM
b). Krypton Study: To assess whether krypton red laser
AREDS 2 (Age Related eye disease study 2) photocoagulation of CNVM lesions with posterior
Purpose: border 1 to 199µ from centre of FAZ is of benefit in
1. Whether oral supplementation with lutien (10mg/ preventing or delaying large losses of vision in patients
with AMD, POH, and INVM.
kg), zeaxanthin (2 mg/d) and /or omega -3 long chain c). Foveal Study: To assess whether laser photocoagulation
polyunsaturated fatty acids (DHA, EFA) (1gm/d) will benefits in preventing or delaying further vision loss in
decrease the risk of progression to advanced AMD, as patients with new or recurrent CNVM under the centre
compared to placebo. of FAZ.
2. Evaluate the effect of eliminating beta carotene and Conclusions:
reduced zinc from the original AREDS formulation on • In all 3 arms, eyes with well-demarcated areas of
the development and progression of AMD. classic CNV, defined by Fluorescein angiography,
Methods: 4000 patients were enrolled for the study from had a better visual prognosis when treated with
September 2006. laser photocoagulation versus observation. However
Conclusion: No over all additional benefit from adding subfoveal CNVM benefited more from laser treatment
omega 3 fatty acids or lutein and zeaxanthin to the vs observation.
formulation. However the study did find benefits in two • Laser treatment for subfoveal CNV caused more visual
sugroups of patients those not given beta carotene and loss in the immediate post laser period vs controls.
those with very little lutein and zeaxanthin in their diets.
www. dosonline.org l 47
Miscellaneous
However, the amount of visual loss in control group at lines), adhering to an intent-to-treat analysis with the last
1yr was same in treatment group. After 1yr, the control observation carried forward to impute for missing data.
group exhibited more visual loss than the treated
group. Conclusions:
TAP(TreatmentofAMDwithPhotodynamictherapy)3 • Visudyne therapy sustained VA, stabilized contrast
Purpose
• To evaluate the efficacy of Visudyne therapy in sensitivity and preserved the quality of vision in
patients with subfoveal CNVM secondary to AMD with patients with occult with no classic CNV.
predominantly classic CNV. • Benefit was most pronounced in smaller lesions (< 4
Methods: MPS DA: macular photocoagulation study disc area) or
609 patients with AMD and subfoveal CNV with a classic lower levels of visual acuity (< 20/50)
component and visual acuity (VA) between 6/12 and 6/60 • Visudyne therapy halted the disease progression and
underwent a 2:1 randomisation between treatment and impeded lesion growth.
control (sham treatment).Retreatment was applied to zones • Fewer patients developed the more aggressive classic
of persistent or new leakage at 3 monthly visits. component of CNV.
Conclusions: VIM trial (Verteporfin in Minimally classic CNVM)5
• Visudyne therapy sustained VA, stabilized contrast Purpose: To evaluate the potential benefits of reducing the
sensitivity and preserved the quality of vision in light fluence in eyes with minimally classic CNVM.
patients with predominantly classic CNV (irrespective Methods: 117 patients were randomly assigned (1:1:1) to
of lesion size) a) verteporfin infusion (6 mg/m²) and light application with
• Twice as many patients treated with Visudyne an reduced fluence (RF) rate (300 mW/cm²) for 83 seconds
therapy retained vision (loss of less than 3 lines of (light dose of 25 J/cm²) or b) an standard fluence (SF) rate
VA) compared with placebo.Visudyne therapy halted (600 mW/cm²) for 83 seconds (light dose of 50 J/cm²) or c)
disease progression and impeded growth of CNVM. to placebo infusion with RF or SF.
Treatment offers no advantage in minimally classic Conclusions: Patients with Visudyne therapy with either a
subgroup. reduced or standard light fluence had significantly better
VIP (Verteporfin in photodynamic therapy)4 vision outcomes and lesser conversion to predominantly
Purpose: classic CNVM.
To evaluate the efficacy of Visudyne therapy in occult with VISION trial (VEGF Inhibition Study In Ocular
no classic CNVM or presumed early onset CNVM and Neovascularisation)6
good visual acuity. Vision-Year 1
Methods: Purpose: To evaluate the usefulness of Pegaptanib in
Patients of AMD, with subfoveal CNV lesions measuring treating neovascular AMD. Entire spectrum of AMD, as
no greater than 5400 µ in greatest linear dimension with encountered in clinical practice was included.
either Methods: Prospective, double-masked study, Phase 3,
a) Occult with no classic choroidal neovascularization, placebo-controlled trial. 1186 patients randomized to
BCVA score of at least 50 (Snellen equivalent sham (0 mg), 0.3 mg, 1.0 mg, or 3.0 mg of drug. Intravitreal
approximately 20/100), and evidence of haemorrhage injections were given every 6 weeks.
or recent disease progression; or The Primary endpoint was proportion of patients avoiding
b) Evidence of classic CNVM with a BCVA score of at least 3 lines / 15 letters (EDTRS) of vision loss at one year.
70 (better than a Snellen equivalent of approximately Secondary endpoints were visual gain (>15 letters of
20/40); were assigned randomly (2:1) to verteporfin vision) and/or mean change from baseline visual acuity.
therapy or placebo therapy. At follow-up examinations Results:
every 3 months, retreatment with the same regimen was • Primary endpoint: achieved by 70% of treated (0.3mg)
applied if angiography showed fluorescein leakage. vs. 55% of controls (p<0.001) representing a 27%
The main outcome measure was at least moderate vision increase in responders over controls.
loss, that is, a loss of at least 15 letters (approximately 3 • Secondary endpoints: Risk of severe loss of vision
(>30 letters ETDRS) was seen in10% of treated cases
vs. 22% in control eyes. Visual gain (>15 letters) was
better in treated eyes at 6% (in 0.3mg), 7% (in 1.0 mg),
4% (in 3.0mg) vs. 2% of controls.
48 l DOS Times - Vol. 19, No. 3 September, 2013
Miscellaneous
• Change in visual acuity defined as any gain in vision Methods:
(>0 letters) was seen in 33% of treated vs 10% of Phase III, multi-centre, randomised, double masked, sham
control eyes. injection-controlled trial, involving 716 patients, who were
randomised to intravitreal Ranibizumab 0.3 or 0.5mg or
Conclusions: sham treatment once a month for 24 months
• Combined analysis for the Primary endpoint showed Results:
• Maintaining vision: Patients losing < 15 letters
that Pegaptanib appeared to be efficacious at all doses
tested (0.3mg, 1.0mg and 3.0mg). The FDA reviewed vision was seen in 95% (452/478) of treated vs. 62 %
this data and approved the lowest dose of Pegaptanib, (148/238) of control group (p<.0001)
0.3mg, for a broad label (all subtypes). • Improving vision: Gain of ≥ 15 letters was seen in 25%
(59/238) of 0.3 mg Ranibizumab vs. 34% (81/240) of
Vision - Year 2 0.5 mg of Ranibizumab versus 5% (11/238) of controls.
Purpose: The difference between treated (both doses) and control in
• To evaluate the efficacy of one year of pegaptanib mean change in visual acuity from baseline was 17 letters.
Visual acuity of > 6/12 at 12 months was seen in 40 %
therapy vs. two years of pegaptanib therapy. (188/478) of treated vs. 11% (26/238) of control patients.
Methods: At 12 months on an average 7 letters gained in treated
• 1053 patients (out of 1186) continued in the VISION group vs. 10.5 letters lost by control group.
Conclusions:
study for a second year. Intravitreal Ranibizumab 0.3 or 0.5mg was beneficial in
• Patients in treatment arms were re-randomized to arresting visual loss due to minimally classic or occult
CNVM.
observation (i.e. treated for year one, observed for year Anti-VEGF antibody for the treatment of pre-
two) OR continue Pegaptanib injections in the same dominantly classic choroidal neovascularisation in
dose group. AMD (ANCHOR)8
• Patients in the sham arm were re-randomized to receive Comparing two different doses of Ranibizumab to
Pegaptanib or continue to receive sham. verteporfin photodynamic therapy (PDT) in treating
Primary endpoint was: Time until > 3 lines or 15 letters of subfoveal neovascular macular degeneration.
vision was lost. Secondary end points were: Mean change Methods:
in VA at week 102, proportion of eyes becoming legally A Phase III, randomised, multi-centre double-masked
blind (<6/60) and proportion of patients losing >15 letters active treatment-controlled trial. It enrolled 423 patients
at week 102. and randomised 1:1:1 to either PDT plus sham injection
Conclusions: or to placebo PDT plus Ranibizumab (0.3 mg or 0.5 mg)
• Intravitreal injections of 0.3mg Pegaptanib are effective monthly for 24 months. Fluorescein angiography was done
in treating exudative AMD. every 3 months to determine the need for additional PDT
• The therapeutic benefit is maintained regardless of or placebo PDT.
lesion composition or size. Inclusion criteria were patients with predominantly classic
• Treatment benefit is greater for two years of sustained CNV and VA of 6/12 – 6/96. Primary endpoint was
treatment rather than one year. proportion of subjects losing <15 ETDRS letters at 1 year
• Pegaptanib did not show statistically significant benefit and secondary endpoint was change in VA from baseline.
among patients with occult disease or in lesions greater Results:
than 4 disc areas regardless of composition. • Maintaining vision: Patients losing <15 letters at 1
• Continuing visual benefit was observed in patients who year was 94% in 0.3 mg Ranibizumab group vs. 96%
were randomized to receive therapy with Pegaptanib in 0.5mg Ranibizumab vs. 64% in PDT group (p <
in year 2 of the VISION. trials when compared with 2 0.0001).
years usual care or cessation of therapy at year 1. • Improving vision: Patients gaining ≥ 15 letters
Minimally Classic/Occult Trial of the Anti-VEGF was 36% in 0.3 mg Ranibizumab, 40% in 0.5 mg
Antibody Ranibizumab in the Treatment of Ranibizumab and 6% in PDT (p < 0.0001).
Neovascular AMD (MARINA)7
Purpose:
• To evaluate the efficacy of Ranibizumab in CNVM
www. dosonline.org l 49
Miscellaneous
• On average, 9 and 11 letters were gained with 0.3 mg Comparison of ARMD treatment trials (CATT)10
and 0.5 mg Ranibizumab respectively vs. 10 letters Purpose
lost in PDT group (p<0.0001). Severe visual loss was • To evaluate effects of Ranibizumab (Lucentis) and
seen in 13% of PDT group versus none occurred in
Ranibizumab groups. Bevacizumab (Avastin) when administered monthly or
as needed for 2 years
• Leakage on FFA decreased by 2 disc areas (DA) in • To describe the impact of switching to as needed
Ranibizumab group and increased by 1/3 DA in PDT treatment after 1 year of monthly treatment.
group (p<0.0001). Methods:
CATT enrolled 1200 participants aged 50 and older with
Conclusions: subfoveal CNV secondary to AMD in at least one eye and
Ranibizumab provided greater clinical benefit than visual acuity between 20/40 and 20/320, inclusive. CATT
verteporfin PDT in patients with ARMD with new-onset, participants completed a total of 24 monthly study visits for
predominantly classic CNVM. Rates of serious adverse 2 years.
events were low. All participants were assigned randomly to one of 4
ProNTO (Prospective OCT Imaging of Patients treatment groups.
with Neovascular AMD Treated with Intra-Ocular 1) Lucentis on a fixed schedule of every 4 weeks for 1
Ranibizumab)9 year; at 1 year, re-randomization to Lucentis every 4
Purpose: Whether dosing on the basis of fluid in the macula weeks or to variable dosing.
results in fewer injections but has similar visual acuity 2) Avastin on a fixed schedule of every 4 weeks for 1 year;
outcomes to a monthly dosing regimen. at 1 year, re-randomization to Avastin every 4 weeks or
Methods: 3 consecutive monthly injections of 0.5 mg to variable dosing.
Ranibizumab were given. Monitoring for anatomical and 3) Lucentis on variable dosing for 2 years; i.e., after initial
functional effects was done by OCT and FFA respectively. treatment, monthly evaluation for treatment based on
Injections were repeated only if required. signs of lesion activity.
Results: After 1 year, the mean improvement in VA from 4) Avastin on variable dosing for 2 years; i.e., after initial
baseline was 9.3 letters (p<0.001), and at 2 years it was treatment, monthly evaluation for treatment based on
11.1 letters (p<0.001). Around35% eyes gained at least 15 signs of lesion activity.
letters of VA at 1 year and 43% gained at least 15 letters at Those who were assigned to fixed monthly dosing groups
2 years. would receive treatment at every visit. Those assigned
Conclusions: VA outcomes comparable with the outcomes to variable dosing groups were evaluated for treatment
from the phase III clinical studies, but fewer intravitreal at every visit. If lesion activity was seen, the participant
injections were required. received a study treatment.
Ongoing studies with Ranibizumab: FOCUS, PIER, Results:
HORIZON, PROTECT etc. • In same regimen for 2 years, mean gain VA was similar
SANA trial- Systemic Avastin for neovascular AMD for both groups (bevacizumab and Ranibizumab). The
Purpose: To evaluate the short-term safety of systemic difference in gain of VA was 1.4 letters (p= 0.21, not
bevacizumab and its effects on vision and subfoveal CNV significant.)
in patients with neovascular AMD • Mean gain was greater for monthly than for as needed
Methods: single-center, uncontrolled clinical study. AMD treatment (difference 2.4 letters, p=0.046)
patients with subfoveal CNV (N = 9) and best-corrected VA • The proportion of patients with 1 or more systemic
letter scores of 70 to 20 (approximate Snellen equivalent, serious adverse events was higher with bevacizumab
20/40-20/400). Patients were treated at baseline with than Ranibizumab.
an infusion of bevacizumab (5 mg/kg), followed by 1 Conclusion:
or 2 additional doses given at 2-week intervals. Safety Ranibizumab and bevacizumab had similar effects on
assessments were performed at all visits. VA over 2 year period. Treatment as needed resulted in
Conclusion: Significant improvement in VA and decreased less gain in VA, whether instituted at enrollment or after
retinal thickness (OCT) were seen. The systemic side 1 year of monthly treatment. No differences between the
effects led to the exploratory use of intravitreal injection of
bevacizumab to treat CNV in AMD patients.
50 l DOS Times - Vol. 19, No. 3 September, 2013
Miscellaneous
two drugs in rates of death or arterio-thrombotic events was Therapy (TAP) Study Group. Photodynamic therapy of subfoveal
noted. choroidal neovascularisation in age related macular degeneration
VEGF Trap –Eye in Phase 3 trial with Verteprofin: one-year results of 2 randomized clinical trials:
Purpose: TAP report 1. Arch Ophthalmol. 1999;117:1329-45.
Investigate efficacy and safety of Aflibercept in wet AMD. 4. VIP Study Group. Verteprofin therapy of subfoveal choroidal
Results: neovascularisation in age-related macular degeneration: two-
year results of a randomized clinical trial including lesions with
• Phase 1 and 2 trials showed that monthly or bimonthly occult with no classic choroidal neovascularisation: Verteprofin
Aflibercept was not inferior to monthly Ranibizumab in in Photodynamic Therapy (VIP) report 2. Am J Ophthalmol. 2001;
preventing vision loss (< 15 letter loss). The visual gain 131:541-60.
and safety was comparable with the two treatments. 5. Treatment of Age-Related Macular Degeneration with Photodynamic
Therapy (TAP) Study Group. Photodynamic therapy of subfoveal
• Year 2 treatment involved monthly pro re nata ( as choroidal neovascularisation in age-related macular degeneration
needed) with required injections every 3 months with verteprofin: one-year results of 2 randomized clinical trials-TAP
and maintained vision gains from the first year, with report1. Arch Ophthalmol. 1999; 117:1329-1345.
an average of 4.2 injections of Aflibercept and 4.7 6. VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.)
injections of Ranibizumab. Clinical Trial Group. Year 2 efficacy results of 2 randomized
controlled clinical trials of Pegaptanib for Neovascular Age-Related
References Macular Degeneration. Ophthalmology 2006 Sep; 113(9):1508.
7. Rosenfeld PJ, Brown DM, Heier JS, et al. MARINA Study Group.
1. AREDS Study Group. A randomized, placebo-controlled, clinical Ranibizumab for neovascular age-related macular degeneration. N
trial of high-dose supplementation with vitamins C and E, beta Engl J Med. 2006 Oct 5;355(14):1419-31.
carotene, and zinc for age related macular degeneration and vision 8. Brown DM, Kaiser PK, Michels M, Soubrane G, et al. ANCHOR
loss: AREDS report no. 8. Arch Ophthalmol. 2001; 119:1417-36. Study Group. Ranibizumab versus verteporfin for neovascular age-
related macular degeneration. N Engl J Med. 2006;355:1432-1444.
2. Macular Photocoagulation Study Group. Subfoveal neovascular 9. Lalwani GA, Fung AE, Michels S, et al. An OCT-guided variable-
lesions in age-related macular degeneration. Guidelines for dosing regimen with Ranibizumab (Lucentis) in neovascular
evaluation and treatment in the macular photocoagulation study. AMD: two year results of the PrONTO study. Poster presented
Arch Ophthalmol. 1991 ; 109:1242-57. at: Annual Meeting of the Association for Research in Vision and
Ophthalmology; May 7, 2007; Fort Lauderdale, Fla.
3. Treatment of Age-related Macular Degeneration with Photodynamic 10. The CATT Research Group. Ranibizumab and bevacizumab for
treatment of neovascular age-related macular degeneration: 2-year
results. Ophthalmology. Epub 2012 May 1.
www. dosonline.org l 51
MiscMeilslcaelnlaenoeouuss
Drug Induced Glaucoma –A
Review
Ravi Chandil
Ravi Chandil DOMS
Consultant Glaucoma, Ratan Jyoti Netralaya, Gwalior, M.P
Glaucoma is an optic neuropathy with characteristic closure mechanism. These are topical anticholinergic
structural damage to the optic nerve and visual field or sympathomimetic pupil dilating drops, tricyclic anti-
loss. It is usually associated with raised Intra ocular pressure depressants, monoamine oxidase inhibitors, antihistamines,
(IOP). anti-Parkinson drugs, antipsychotic medications and
The glaucoma has traditionally been divided on the basis antispasmolytic agents. These drugs will incite an attack
of primary and secondary forms. Drug-induced glaucoma in individuals with very narrow anterior chamber angles
is a form of secondary glaucoma induced by topical and that are prone to occlusion, especially when the pupils are
systemic medications. Although most common one is dilated.
glucocorticoid1, but it is not the only one. Drug induced Idiosyncratic reaction
glaucoma is not synonymous to steroid induced glaucoma. Sulfonamide-containing medications may induce an
There are many other non-steroidal systemic medicines angle closure glaucoma (ACG) by a different mechanism,
(Table 1) as well as ophthalmic medicines which involving the anterior rotation of the cilliary-body5,6,7,8,9,10.
(Table 2) have the potential to raise IOP, even anti glaucoma Typically, the angle-closure is bilateral and occurs within
drugs…. YES antiglaucoma drugs. the first few doses. Patients with narrow or wide open
angles are susceptible to this rare idiosyncratic reaction.
Mechanisms of IOP elevation in drug-induced Pathophysiology of Drug-induced Glaucoma
glaucoma (Figure 1)
IOP elevation can occur via an open-angle or angle-closure Open-angle
mechanism (Table 1 and 2). The exact pathophysiology of steroid-induced glaucoma is
Open-angle unknown. It is known that steroid-induced IOP elevation is
Corticosteroid is a group of drugs that may produce IOP
elevation by open-angle mechanism. Not all the patients Figure 1: Mechanism of Drug Induced Glaucoma
taking steroid will develop IOP elevation. The risk factors
include preexisting primary open-angle glaucoma (OAG), a
family history of glaucoma, high myopia, diabetes mellitus
and young age and rheumatoid arthritis2,3,4.
It has been shown that 18-36% of the general population
respond to topical ocular administration of corticosteroids
with an elevation of IOP. IOP rises usually within 2-4
weeks after therapy has been instituted. Topically applied
eye drops and creams to the periorbital area and intravitreal
injections are more likely to cause IOP elevation than
intravenous, parenteral and inhaled forms.
Closed-angle
Some drugs may produce IOP elevation acutely by angle-
www. dosonline.org l 53
Miscellaneous
54 l DOS Times - Vol. 19, No. 3 September, 2013
Miscellaneous
secondary to increased resistance to aqueous outflow11,12. rotation of the ciliary body with or without choroidal
But the following observations and theories have been effusions, resulting in a shallow anterior chamber and
reported. blockage of the trabecular meshwork by the iris. The
1. Some evidence shows that there could be increased exact reason causing ciliary body swelling is unknown in
susceptible individuals.
accumulation of glycosaminoglycans producing Clinical Assessment for Drug-induced Glaucoma
biological oedema13,14 or increased production History
of trabecular meshwork-inducible glucocorticoid The patient’s detailed history regarding systemic illness
response (TIGR) protein, which could mechanically which could require chronic corticosteroid use like uveitis,
obstruct the aqueous outflow. collagen vascular disease, asthma, dermatitis should be
2. Other evidence suggests that the corticosteroid- asked. History of neurological disease and medications
induced cytoskeletal changes could inhibit pinocytosis should be carefully elicited.
of aqueous humour or inhibit the clearing of Patient’s risk factor to be steroid responders like preexisting
glycosaminoglycans, resulting in the accumulation of primary open-angle glaucoma, a family history of primary
this substance and blockage of the aqueous outflow15. open-angle glaucoma, diabetes mellitus, high myopia, or
3. Direct physical obstruction of the trabecular meshwork connective tissue diseases should be elicited.
with crystalline steroid particles16,17.
Pathophysiology of Non Steroidal drugs e.g dicyclomine Symptoms
causing open-angle glaucoma are much more varied In drug induced open angle glaucoma, the pressure elevation
including the release of pigment during the pupillary dilation is gradual. Therefore, there are very few symptoms during
with subsequent obstruction of the trabecular meshwork, the early stage of disease. Some time patient may complain
and a possible increase of inflow during pupillary dilation. of coloured haloes. At a later stage, patients may complain
Closed-angle of loss of the peripheral visual field. At the more advanced
The pathophysiology of angle-closure glaucoma is stage, when the central vision is also affected, patients may
usually due to pupillary blockage, i.e. iris-lens contact complain of blurring of vision.
at the pupillary border resulting from pupillary dilation. In drug-induced acute angle-closure glaucoma, the
Medications have a direct or secondary effect, either in symptoms are the same as in primary acute angle-closure
stimulating sympathetic or inhibiting parasympathetic glaucoma. These include sudden eye pain, headache
activation causing pupillary dilation, which can precipitate associated with nausea and/ or vomiting, blurring of vision
acute angle-closures in patients with occludable anterior and halos around bright objects.
chamber angles.
Sulfa-containing medications result in acute angle-closures Physical Examination
in a different mechanism18,19. This involves the anterior A complete ophthalmic examination should be performed
including:
www. dosonline.org l 55
Miscellaneous
Figure 2: Optic disc changes in steroid induced glaucoma case Figure 3: Humphery visual field changes
in steroid induced glaucoma case
Visual acuity, pupil reaction, intraocular pressure
measurement, anterior chamber examination for assessment resolution. This technique is used to evaluate the anterior
of anterior chamber depth. Signs of other secondary chamber angle configuration i.e. open or closed and the
glaucoma such as uveitic, pigment dispersion and position of the cilliary body e.g. anterior rotation (Figure 5)
pseudoexfoliation glaucoma should looked for. Posterior Anterior Segment OCT (ASOCT)
subcapsular cataract may present in chronic steroid users. It applies the same principle as OCT but it provides images
Gonioscopic examination of the anterior chamber including the angle and the lens.
Gonioscopy for evaluation of angle anatomy i.e. open or Treatment of Drug-induced Glaucoma
narrow and to determine whether the angle is occludable If the patient’s underlying medical condition can tolerate
during pupil dilation. discontinuation of drugs, then cessation of the medication
Optic disc evaluation will usually result in normalization of IOP.
Stereoscopic examination of the optic disc (Figure 2) is Medical management for Open-angle drug induced
necessary to document glaucomatous damage. This can be glaucoma
done by slit lamp biomicroscopy (78D & 90D). In the case of topical corticosteroid drops, using a lower
Investigations potency steroid medication, such as the phosphate
Perimetry forms of prednisolone, loteprednol or fluorometholone
Visual Field testing such as Humphrey (Figure 3) is used should be considered. These drugs have a lesser chance
to evaluate the severity of optic neuropathy. Even when of IOP rise20,21,22, but they are usually not as effective as
optic nerve damage not present, baseline documentation an anti-inflammatory drug. Topical NSAID medications
of visual field is essential. can be considered, but they may not have enough anti-
Optical Coherence Tomography (OCT) inflammatory activity to treat the patient’s underlying
OCT is an optical signal acquisition and processing method. condition23,24.
It is used to evaluate the retinal nerve fibre thickness around
the optic disc (Figure 4) in glaucoma patients. Serial scans
can be used to demonstrate any progression of disease.
Ultrasound Biomicroscopy (UBM)
UBM is an imaging technique that uses high frequency
ultrasound to produce images of the eye at near microscopic
56 l DOS Times - Vol. 19, No. 3 September, 2013
Miscellaneous
In cases in which the patient’s IOP does not normalize Figure 4: OCT RNFL changes in steroid
upon cessation of the steroid or in those patients who induced glaucoma case
must continue to be on corticosteroid medications, topical
antiglaucoma medications are considered. Figure 5: Anterior rotation of the ciliary body
with choroidal effusion
Medical management for Closed-angle drug induced
glaucoma IOP rise can be asymptomatic initially especially in open-
If the aetiology is because of sulfa-containing medications, angle type. General practitioners should be aware of
the increase in IOP generally will resolve upon stopping the the risk factors for glaucoma before prescribing a drug
medication. However, severe cases of sulfonamide-induced that has the potential to cause, precipitate or exacerbate
angle-closure may not respond to simply discontinuing glaucoma whenever in doubt, an ophthalmologist should
the offending medication. These cases may respond to be consulted. When prescribing such medicines for long
intravenous mannitol. term, regular and complete eye checkup should be done.
For other aetiologies of drug-induced angle-closure, they References
are treated similar to primary acute angle-closure glaucoma
by using antiglaucoma medications including topical beta 1. Tripathi RC, Parapuram SK, Tripathi BJ, et al. Corticosteroids and
blockers, prostaglandin analogues, cholinergic agonists glaucoma risk. Drugs Aging 1999;15:439-450.
and often oral acetazolamide.
2. Podos SM, Becker B, Morton WR. High myopia and primary open-
Laser treatment angle glaucoma. Am J Ophthalmol. 1966; 62(6):1038-1043.
For open-angle glaucoma, Argon laser trabeculoplasty
or selective laser trabeculoplasty can be applied in the 3. Becker B. Diabetes mellitus and primary open-angle glaucoma. Am
absence of ocular inflammation if the IOP is suboptimal J. Ophthalmol. 1971; 1-16.
with medication25,26.
In closed-angle glaucoma, argon laser peripheral iridoplasty 4. Gaston H, Absolon MJ, Thurtle OA, et al. Steroid responsiveness in
(ALPI) may be applied to deepen the anterior chamber and connective tissue diseases. Br J Ophthalmol. 1983; 67(7):487-490.
widen the angle. Laser iridotomy (LI) can be performed
to reverse pupillary block or to prevent further pupillary 5. Kakaria V, Chalam, Tillis T, Farhana S, Brar SA. Acute bilateral
block. simultaneous angle closure glaucoma Topiramate administration: a
Laser iridotomy is not effective in cases of acute ACG case report. J Med Case Reports 2008;2:1.
caused by sulfa drug like topiramate because secondary
angle closure glaucoma occurs without pupillary block.
Surgical treatment for Open-angle and Closed
angle cases
Indication
1. Medical therapy is ineffective in lowering the IOP to
target pressure or
2. The patient is intolerant of medical therapy or
3. In patients whom both medical and laser therapy have
failed to lower the IOP adequately.
Usually, trabeculectomy, a guarded filtration procedure,
with or without intraoperative antimetabolites, is the
primary procedure.
In case of posterior subtenon steroid and in intravitreal
steroid, vitrectomy is helpful to lower the load of steroid
and IOP.
Conclusion
Uncontrolled increase in IOP can lead to permanent optic
nerve damage and permanent blindness. Drug-induced
www. dosonline.org l 57
Miscellaneous
6. GuMHP, Thiagalingam S, Ong P, Goldberg I. Bilateral acute angle intraocular pressure changes after a single intravitreal triamcinolone
closure caused by supraciliary effusion associated with Velafaxine injection. J Glaucoma 2008;17(2):128-132.
intake. MJA 2005; 182:121- 123. 18. Tripathi RC, Triathi BJ, Haggerty C. Drug-induced glaucomas:
mechanism and management. Drug 2003; 26:749–767.
7. Nemet A, Nesher R, Almog Y, Assia E. Bilateral acute angle closure 19. Geanon JD, Perkins TW. Bilateral acute angle-closure glaucoma
glaucoma following Topiramate treatment. Harefuah 2002; 141:597- associated with drug sensitivity to hydrochlorothiazide. Arch
9. Ophthalmol. 1995; 113:1231–1232.
20. Leibowitz HM, Ryan WJ Jr, Kupferman A. Comparative anti-
8. Singh SK, Thapa SS, Badhu BP. Topiramate induced bilateral angle- inflammatory efficacy of topical corticosteroids with low glaucoma-
closure glaucoma. Kathmandu University Medical Journal 2007; inducing potential. Arch Ophthalmol. 1992;110(1):118-120.
5:234. 21. Mindel JS, Tavitian HO, Smith H Jr, et al. Comparative ocular pressure
elevation by medrysone, fluorometholone, and dexamethasone
9. Chan KCY, Sachdev N, Wells AP. Bilateral acute angle closure phosphate. Arch Ophthalmol. 1980;98(9):1577-1578.
secondary to uveal effusions associated with Flucloxacillin and 22. Morrison E, Archer DB. Effect of fluorometholone (FML) on the
Carbamazepine. Br J. Ophthalmol. 2008; 92:428-430. intraocular pressure of corticosteroid responders. Br J Ophthalmol.
1984;68(8):581-584.
10. Levy J, Yagev R, Petrova A, Lifshitz T. Topiramate – induced bilateral 23. Gieser DK, Hodapp E, Goldberg I, et al. Flurbiprofen and intraocular
angle-closure glaucoma. Can J Ophthalmol. 2006; 41:221-5. pressure. Ann Ophthalmol. 1981;13(7):831-833.
24. Strelow SA, Sherwood MB, Broncato LJ, et al. The effect of diclofenac
11. Jones R III, Rhee DJ. Corticosteroid-induced ocular hypertension and sodium ophthalmic solution on intraocular pressure following
glaucoma: a brief review and update of the literature. Curr Opin cataract extraction. Ophthalmic Surg 1992;23(3):170-175.
Ophthalmol. 2006; 17(2):163-167. 25. Ricci F, Missiroli F, Parravano M. Argon laser trabeculoplasty in
triamcinolone acetonide induced ocular hypertension refractory
12. Kersey JP, Broadway DC. Corticosteroid-induced glaucoma: a to maximal medical treatment. Eur J Ophthalmol. 2006;16(5):756-
review of the literature. Eye 2006; 20(4):407-416. 757.
26. Rubin B, Taglienti A, Rothman RF, et al. The effect of selective laser
13. François J. The importance of the mucopolysaccharides in intraocular trabeculoplasty on intraocular pressure in patients with intravitreal
pressure regulation. Invest Ophthalmol. 1975; 14(3):173-176. steroid induced elevated intraocular pressure. J Glaucoma
2008;17(4):287-292.
14. François J, Victoria-Troncoso V. Mucopolysaccharides and
pathogenesis of cortisone glaucoma [in German]. Klin Monatsbl
Augenheilkd. 1974; 165(1):5-10.
15. Bill A. The drainage of aqueous humor [editorial]. Invest Ophthalmol.
1975;14(1):1-3
16. Singh I P, Ahmad SI, Yeh D, et al. Early rapid rise in intraocular
pressure after intravitreal triamcinolone acetonide injection. Am J
Ophthalmol. 2004;138(2):286-287.
17. Im L, Allingham RR, Singh I, et al. A prospective study of early
58 l DOS Times - Vol. 19, No. 3 September, 2013
Miscellaneous
Book Review
It is my pleasure to review the book entitled: Handbook of Clinical
Trials in Ophthalmology.
It is written by two young bright Ophthalmologists – Dr. Vinod K
Aggarwal and Dr. Neha Goel - guided by a very senior teacher
in the profession – Prof. A.K. Gupta (who happened to be my
teacher as well). The book summarises various clinical trials in
Ophthalmology in different diseases affecting the eye. The book
has 314 pages covering 19 chapters, published by Jaypee Brothers
Medical publishers in 2013.
It is a very well written handbook and is a good compilation of
multicentre clinical trials undertaken in the World. In our day to day
practice we often need to know the latest trends in management of
a particular disease, as determined by evidence based clinical trials.
It is not always easy to immediately access the literature/ evidence
available on internet. With vast coverage of topics this book will be
an excellent handy reference book for researchers, students, teachers
as well as practitioners.
The book has extensively and exhaustively covered important
subspecialty topics like Diabetic Retinopathy, Vascular occlusions,
ARMD, ROP etc. These are hot topics in today’s era and everyone;
especially posterior segment surgeons require knowledge of latest
trends and better options of treatment available. For the anterior
segment surgeons the book has incorporated clinical trials in Cornea
and Glaucoma, which are very informative.
In this book consolidated and readily available information will be
very useful in improving management of patient care. The hand book has summarised the data of clinical trials without
distorting the facts or giving their own opinions. The results and conclusions at the end give a useful summary of each trial.
For more information on a particular subject, references have been provided at the end of the chapters.
I understand that it is impossible to include all topics but a good effort has been made to include as many trials as possible.
Although “The endophthalmitis vitrectomy study” has been reviewed, it would have been beneficial to include some
studies on prophylaxis of postoperative endophthalmitis after intraocular surgery, which is very important for a general
Ophthalmologist. It would also have been good to include studies on trial of various treatment options available for
managing a case of endophthalmitis; as also on Bacterial and Fungal corneal infections.
In the end I would like to congratulate the authors for an excellent ready reference handbook, which should be kept in
one’s place of practice.
Dr. R.B. JAIN
RBM Eye Institute, Delhi
E-mail: [email protected]; [email protected]
Former President:
Delhi Ophthalmological Society
All India Ophthalmological Society
Life Time Achievement Award - Conferred By:
All India Ophthalmological Society
Delhi Ophthalmological Society
www. dosonline.org l 59
Evolution of Vitreo Evolution
Retinal Surgery
Munish Dhawan
MD
Munish Dhawan1 MD, Mayank Dutta2 MD, P.S. Sandhu1 MS, S.P. Singh1 MS
1. Baba Farid University of Health Sciences, Faridkot, Punjab
2. Mahajan Eye Hospital Jalandhar, Punjab
Although ophthalmology traces its origins as a surgical step, for it proved that vitreous was expendable. Another
specialty to 2000 BC with the first description of quantum jump was soon made and this was by a colleague
cataract couching, retinal surgery is still in its infancy of Kasner, Robert Machemer.
by comparison. Retinal diseases remained a mystery Robert Machemer’s Early Vitrectomy with Vitreous
until doctors had a method of actually looking into the Infusion Suction Cutter (VISC) 1972
living human eye. With Helmholtz’s development of the Robert Machemer, MD (1933-2009) is rightfully regarded
ophthalmoscope in 1850, retinal surgery as a specialty was as the “Father of Vitreous Surgery” for his introduction of
born. Being able to fix retinal detachments and cure retinal pars plana vitrectomy in 1972. He continued to pioneer
disease still took time however. Successful retinal surgery not only instrumentation for vitrectomy but our knowledge
was basically non-existent until Jules Gonin introduced his of the procedure itself. While a faculty member at Bascom
procedure called “Ignipuncture” in 1919. This marks the Palmer Eye Institute in Miami in the 1970’s, he developed
true birth of retinal surgery. Custodis introduced scleral the VISC - one of the first commercially available instruments
buckling in 1949, another important milestone. The birth to remove vitreous. Machemer had great insight to realize
of Vitreous Surgery is largely credited to Robert Machemer that best area to approach vitreous for removal was pars
in 1972; however it really was the Japanese who really plana, for here RPE and anterior continuation of retina that
introduced vitreous surgery years before. Tsugio Dodo is, ciliary epithelium are so firmly adherent that an opening
published his technique of “Open Sky” vitrectomy in 1955, could be made here without causing retinal detachment.
and C. Haruta published his closed vitrectomy technique To achieve this end he succeeded in devising a motorised
in 1959. instrument with about 18 gauge tip size and working in his
Birth of Vitreo Retinal surgery garage could remove egg albumin through a small opening
Although the success rates of retinal detachment surgery in the egg shell. Soon the instrument was used in vitreous
went to an unthought figure of 80-90%, thanks to the untiring related blindness clinically. He called this instrument VISC.
efforts of Gonin, Custodis, Schepens, Harvey Lincoff and Machemer’s technique of Trans Pars plana Vitrectomy
many others, proliferative vitreoretinopahy (PVR) remained (TPPV) included a single 18 gauge port in Pars Plana and
the most common cause of failure of retinal detachment introduction of the instrument probe through this opening
(RD) surgery. It was deemed to be untouchable and the into the vitreous cavity. This probe would infuse fluid into
eye doomed to blindness. Such was the vitreous sanctity the eye, cut the vitreous and aspirate it thus removing the
that controversy raged in late 1960s and early 1970s that vitreous, opaque or otherwise and leave the vitreous cavity
“can we touch the vitreous and go unpunished”. In 1969, filled with balanced salt solution (BSS) or ringer lactate. In
the bubble of “inviolability” of vitreous was finally burst many cases of untreatable ocular blindness accompanied
by Kasner, who through cornea, after removing lens, cut by vitreous opacities (haemorrhage etc.) fairly good results
and removed opaque vitreous in two patients with primary were obtained but his reported first 28 cases of (PVR), all
amyloidosis. These patients regained vision. This was a big failed.
www. dosonline.org l 61
Evolution
Later Machemer added fiber optic light to the probe Table 1: Milestones of Pars Plana Vitrectomy
to be able to see through microscope and corneal lens
system right upto the macula clearly by enhancing the Early 1970s Machemer and Kloti both have the idea of
illumination. The 16G instrument was a unimanual, full shifting the site of vitrectomy access to the
function probe. Initially, the VISC utilized slit illumination pars plana area in an effort to preserve the
from the microscope, but soon this was replaced by a lens “Birth of Pars Plana Vitrectomy”
coaxial illumination sleeve. In addition to the light and
aspiration channels, a third channel brought in gravity-fed 1974 O’Mally and Heintz introduced the 20
fluid infusion. This system had a very slow cutting rate at guage vitrectomy system, today’s “gold
about 1 cut per second. Aspiration was applied manually. standard”
Connor O’Malley in 1974 proposed three port vitrectomy
- all sized 20 gauge. Infusion cannula was in the lower 1974 Kloti recommends the use of guiding
temporal quadrant to continuously infuse the vitreous cannulas – the precursors of microcannulas
cavity with balanced salt solution during surgery and two – for ease of and added eye protection
ports were made close to recti muscles in superotemporal during instrument change
and superonasal quadrants. These two ports being equal
sized, opening were interchangeable. Through one port 1990 Dejuan and Hickingbotham present first 25
endoilluminator was introduced and through the second port 1995 guage vitrectomy set and recommends its
vitrectomy probe was introduced. This probe would cut the use in pediatric interventions in particular
vitreous and aspirate it. Thus VISC of Machemer which was At the ARVO meeting, Singh et al, present
18 gauge or of larger size and limited the maneuverability a 23 guage vitrectomy system whose use
inside the vitreous cavity was replaced by 20 gauge sized however clearly is restricted to specific
instruments which enhanced maneuverability and also office based intervention
permitted use of any instrument which was of 20 gauge size
to be introduced into the vitreous cavity. This could be a 2002 Fujji et al present first fully integrated 25
scissors, foreign body forceps, epiretinal membrane removal guage vitrectomy system consisting of
instruments like Pics, scratchers. Thus multifunctional VISC microtrocar cannulas, vitrectome and
was replaced by O’Malley’s 3 port vitrectomy systems infusion and demonstrated its safety and
which continues to be used. Initial vitreous suction system efficiency especially in simple vitrectomies
in 1970s was primitive - assistant hand controlled, surgeons
hand controlled, solenoid peristaltic foot control system. 2004/2005 Eckardt introduces first fully integrated 23
In 1976, Steve Charles introduced linear and delta suction Upto 2010 guage vitrectomy system and demonstrates
controlled system. By foot pressure, suction pressure could its safety and efficiency
be set to a present level from 0-400 mm Hg. This was a Ongoing enhancement of instrumentation
tremendous advance which permitted surgeons to work and ranges of application of 25 guage and
very close to the retina without fear of causing iatrogenic 23 guage system
unintentional retinal tear. Charles also introduced flute
needle for internal drainage of sub retinal fluid (SRF). Flute These flatten the retina by their heavier specific gravity
needle now has been replaced by silicone tipped extrusion and have proved extremely valuable in the most feared
needle and suction can be controlled from same foot switch condition of giant retinal tear
which operates the vitrectomy probe. The First 25G Transconjunctival Vitrectomy Probe
Endolasers and vitreous sustitutes The last decade has seen a general trend toward efficient,
In eighties, endolasers became available and better bipolar minimal invasive interventions in several areas of medicine.
diathermy systems were introduced. Prolonged intraocular Ever since the introduction of pars plana vitrectomy over 30
tamponade long acting gas (SF6) was introduced in 1975 years ago, the instrumentation of posterior segment surgery
by Norton. Longer acting gas (C3F8) is in greater use now. too has been subject to incessant change. In this, two
Gases gives temporary tamponade varying from 1 to 4 objectives have been in the foreground: one is reducing
weeks. For permanent tamponade, silicone oils introduced surgery times, and the other speeding the recovery of the
by Cibis et. al. are available in varying range of viscosity eye. The primary means of reaching these targets lies in
from 1000 Cs to 13000Cs. Silicone oil is lighter than water. instruments that are smaller – and thus induce less surgical
Heavier than water silicone oil which flatten the inferior trauma – and at the same time more efficient, while
retina is also available (flurosilicone). Perfluorcarbon affording improved visualization and illumination of the
liquids which are heavier than water have proven valuable operating field. While the 20-gauge vitrectomy system was
intraoperative tools in various vitreo-retinal conditions. considered the “gold standard” of pars plana vitrectomy, the
last 5 years, in particular, have seen fast-paced innovation
in the field of the posterior segment instrumentation toward
smaller, more efficient 25-gauge and 23-gauge vitrectomy
62 l DOS Times - Vol. 19, No. 3 September, 2013
Evolution
Table 2: Cannula guage number and corresponding outer in cooperation with DORC (The Netherlands) eventually
diameter introduced a complete 23-gauge instrumentarium and
demonstrated its safety and efficiency in a first evaluation
Gauge Outer Diameter (mm) study. 23-gauge instruments combine considerably higher
stiffness and stability than 25-gauge instruments, with a
17 G 2.3 diameter that is smaller than that of 20-gauge instruments;
this permits them to be introduced into the eye through
19 G 1.1 transconjunctival sutureless sclerotomies. Unlike the
25-gauge trocars, 23-gauge trocars are not introduced
20 G 0.9 perpendicular to the scleral surface, but at an angle,
and instrumentation is brought to a vertical position in
23 G 0.6 subsequent steps. This type of two-step access is designed
to facilitate postoperative closure of the sclerotomies by
25 G 0.5 intraocular pressure, ensuring higher integrity of wound
closure than with 25-gauge sclerotomies. As early as
systems, which nowadays are routinely used in everyday 2005, Eckardt was able to demonstrate that all 23-gauge
clinical practice. sclerotomies were selfsealing and tight. Another very
De Juan and Hickingbotham developed a 25-gauge interesting method under anatomical physiological
instrument set for pediatric use in 1990, since the aspects was recently proposed by Rizzo et al., who
“conventional” 20-gauge vitreous cutters had proven to suggested turning the blade by 30° or a little more. This
be big and lacking in precision, especially in children. wound configuration considers the course of the collagen
This first 25-gauge instrument set, which consisted of just fibers, which ensures even better wound closure. Since
a pneumatic vitrectome, scissors, and a manipulator for 23-gauge instruments can be said to be similar to 20-gauge
membrane removal, at first was used mainly in pediatric instruments for stiffness and stability, the training period for
surgery. It was 12 years later, when eventually a complete a surgeon when switching to 23-gauge is much shorter than
25-gauge vitrectomy system was introduced by Fuji et al, with 25-gauge instruments. In addition, distinctly higher
which consisted of microtrocar cannulas, affording ease infusion and aspiration rates could safely be expected with
and safety of instrument introduction and withdrawal, as the 23- gauge system than are obtained with the 25-gauge
well as an array of integrated 25-gauge instruments. system, so that careful and extensive vitreous removal,
Due to their small diameter (0.5 mm), 25-gauge cannulas which should continue to be the standard routine, would
allow transconjunctival introduction, thus avoiding the time pose no problem when using the 23-gauge system. Thanks
consuming preparation of the conjunctiva that is required to higher flow rates plus increased instrument stability, the
in conventional 20-gauge sclerotomies. Using a trocar with 23-gauge system may be employed in simple as well as in
forceps, the conjunctiva, in this procedure, is pulled back complicated vitrectomies, and thus is suitable for a wider
a little prior to inserting the cannula, and this displacement application range than the 25-gauge systems.
provides a slight staggering of the wounds in the sclera The application range of 23-gauge vitrectomy is almost
and conjunctiva in relation to each other. In 25-gauge identical to that of the 20-gauge system, while surgery
vitrectomy, the trocar is introduced perpendicularly to the times are shortened and interventions are less invasive; it
sclera, i.e., it is directed to the center of the eye. This does follows, therefore, that it does combine the benefits of the
not, in fact, create a two-step self-sealing wound. But since 25-gauge and 20-gauge systems.
the conjunctiva will slip back to its more anterior position, Improvement in speed- Not only did the diameter of the
where it is bound to cover the sclerotomy and probably vitrector decrease but the cut rate improved significantly
provides a temporary tamponade to the opening – and also which contributed to lesser time taken per procedure.
in view of the small sclerotomy diameter – no suturing is Compared to the cut rate of one/sec in the original VISC
required. system, the modern machines have a cut rate of as high
The accelerated efforts seen over the last 5 years in the as 5000 cpm and the all new Alcon Constellation® Vision
development of a 23-gauge system designed to unite the System promises to bring 7500 cpm by the year end.
benefits of the 20-gauge and the 25-gauge system were The ‘duty cycle control’- Until now, retinal surgeons could
mainly driven by the limitations described for the 25- gauge manage flow through a vitrectomy system by controlling 3
system. Singh et al. had, in fact, introduced a first electronic surgical parameters: infusion pressure, cutting speed, and
23-gauge vitrectome as early as 1995, which they later aspiration. For the most part, a surgeon could increase flow
complemented by a 23-gauge infusion system. This, by decreasing cut rates or increasing aspiration rates. This
however, was not a complete 23-gauge system providing has changed with the new machines offering substantial
a wide array of instruments, but just a portable system improvements in these areas, but also offers control over
whose use was meant exclusively for vitreous biopsies and
minor officebased interventions. Almost 10 years passed
before a fully integrated 23-gauge vitrectomy system for
routine clinical use had been designed. In 2005 Eckardt
www. dosonline.org l 63
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