research work on branch and central retinal vein occlusion patients

1. ABSTRACT
Introduction
Macular edema is the most frequent complication of retinal vein occlusion.
The patients with poor visual acuity due to macular edema get benefit from
macular grid laser or intravitreal triamcinolone acetonide. In this study both
modalities of treatment were combined together to see if combination
therapy is better than monotherapy.
Objective:
To evaluate the efficacy of combination therapy (IVTA with MGLT) vs.
monotherapy (MGLT) on macular edema of branch and central retinal vein
occlusion patients
Study Design:
Randomized control trial
Setting and Duration of study:
Study was conducted in P.O.F’s Hospital (Wah Cantt.) ophthalmology department,
from 01-06-2009 to 30-11-2009 (6 months).
1

2. Sample size:
A total of 68 patients sample was calculated by W.H.O sample size
calculator. 34 patients were taken in each group.
Methods:
MGLT-IVTA group was treated by intravitreal triamcinolone acetonide injection
followed by macular grid laser. MGLT Group was treated by macular grid laser
alone. Improvement in BCVA and change in macular edema was noted and data
was analyzed by spss.
Results:
It was found two modalities of treatment are different in their final outcome. There
was significant decrease in macular edema (p=0.002) and the improvement in
BCVA was also significant (p=0.007), the mean improvement of visual acuity in
MGLT-IVTA group is 0.39512 SD 0.17243 whereas mean improvement in
MGLT group is 0.28782 SD 0.14792 which indicates mean increase in BCVA is
more in MGLT-IVTA group.
Conclusion:
The combination therapy is much more effective than monotherapy in decreasing
macular edema in branch and central retinal vein patients.
2

3. Key words:
1Macular edema
2Macular grid laser treatment.
3Intravitreal triamcinolone acetonide.
4 Retinal vein occlusion.
3

4. INTRODUCTION
Macular edema is the most frequent complication of branch retinal vein
occlusion (BRVO) 60% and central retinal vein occlusion (CRVO) 50%.Patients in
this disorder ultimately develop severe visual impairment and need visual
rehabilitation with low vision aids. 1-3
The branch retinal vein occlusion study group demonstrated that macular
grid laser treatment (MGLT) is effective in reducing visual acuity loss due to
macular edema. The mean visual out come in this group was gain of 1.33
lines (Snellen’s acuity) 2, 3
Unfortunately conventional grid laser treatment leads to a very limited
improvement of visual acuity and may be associated with several
complications like enlargement of laser scars, choroidal neovascularisation,
sub retinal fibrosis and visual field sensitivity deterioration.3, 4
A few studies on patients with branch retinal vein occlusion (BRVO) have
suggested that intravitreal corticosteroid can reduce macular edema and
increase visual acuity .Intravitreal triamcinolone acetonide shows its
improvement in very short period of time but after sometime there is drop in
post injection visual acuity .Intravitreal triamcinolone is also very useful in
macular edema which is involving fovea area and macular edema which is
4

5. refractory to conventional therapy. Macular edema may persist or recur after
the conventional macular grid laser treatment or intravitreal triamcinolone
when given independently.5, 6
The conventional treatment requires repeated laser treatment or injection in
most of patients and visual out come is usually not very satisfactory to
patient. This means we should look for a better treatment which will satisfy
both patients and ophthalmologists.4-6
The rationale of this study is to compare conventional MGLT vs. IVTA
combined with MGLT in order to evolve better treatment of macular edema
in retinal vein occlusion patients which will preserve and improve visual
acuity.
The latest study has shown 91% patients have shown a mean improvement
of best corrected visual acuity (BCVA) of 3.4 lines in group treated with
MGLT and IVTA as compared to mean improvement of 1.3 lines of BCVA
in 62% of patients in MGLT group.7
In a country like Pakistan with high percentage of poor patients, we need to
5

6. develop treatments which are not only effective but also cost effective so
that patients can afford treatment which improves if not cures the disease
6

7. REVIEW OF LITERATURE
Venous obstructive disease of retina is a relatively common retinal vascular
disorder, second only to diabetic retinopathy in incidence. It typically affects the
patients who are 50 years of age or older. Retinal vein obstructions are classified
according to whether the central vein or one of its branches is affected8-11. Central
retinal vein obstruction and branch retinal vein obstruction differ with respect to
pathophysiology, underlying systemic associations, and average age of onset,
clinical course and therapy. The clinical course of central retinal vein occlusion
(CRVO) and branch retinal vein occlusion (BRVO) may differ but a major cause
of visual loss is macular edema in both the diseases. Other causes of visual loss are
ischemia and the presence of central hemorrhage. 12-23
Therapies in RVO have two aims. One is to reduce macular edema and the other is
to prevent neovascularisation caused by retinal ischemia. Many therapies such as
laser photocoagulation, anticoagulation, hemodilution, laser-induced chorioretinal
anastemosis, anti-VEGF treatment, and vitrectomy, sheathotomy, and intravitreal
steroids have been used to treat this complication. 24-57
Among these treatments, only anti-VEGF medications, laser photocoagulation, and
intravitreal steroids address the pathophysiological mechanisms responsible for
vein occlusion. Anti-VEGF medications (Ranibizumab and Bevacizumab) have
excellent effects except in cases of severely ischemic retina. Laser
7

8. photocoagulation improves visual acuity (VA) in patients with BRVO associated
macular edema but is ineffective in improving VA in patients with macular edema
associated with CRVO. Overall, laser treatment of perfused macular edema only
minimally improves vision and offers little hope for patients with poor
pretreatment visual acuity. The benefits for ischemic macular edemas are still not
known. 58-67
Reports have suggested a role for surgical interventions in the treatment of retinal
vein occlusion but results of randomized clinical trials are not favorable. . 68
Being a less traumatic option of treatment, intravitreal steroids are gaining
popularity. At this time intravitreal triamcinolone (IVTA) is the most frequently
used steroid. Small case series confirmed the visual benefit of IVTA in both
perfused and ischemic macular edema. Studies have revealed that it reduces
macular edema in both CRVO and BRVO. Greater effects were observed on non
ischemic CRVO than ischemic CRVO. 69-70
8

9. CENTRAL VEIN OCCLUSION
Central retinal vein obstructions can be divided further into ischemic and non
ischemic varieties. This distinction among central retinal vein obstructions,
although somewhat arbitrary up to two thirds of the patients who have the ischemic
variety develop iris neovascularisation and neovascular glaucoma. 71-94
Central retinal vein occlusion has strong association with diabetes mellitus,
systemic arterial hypertension and arteriosclerosis cardiovascular disease. Direct
relationship to pathogenesis remains unclear. A significant inverse relationship is
present with physical activity, education and in women with estrogen use. 12-14
Open angle glaucoma is a relatively common finding in patients with retinal vein
obstruction. the patient having history of glaucoma are 5 times more at risk of
developing glaucoma than those who don’t, presumably because of structural
alteration at level of lamina cribrosa induced by elevated intraocular pressure. 10, 11,
93, 94
The precise pathogenesis of central retinal vein obstruction remains unclear. The
obstruction is believed to be the result of thrombus formation in central retinal
vein, at, or posterior to lamina cribrosa. Arteriosclerosis of neibouring central
retinal artery that causes turbulent flow and endothelial damage is often implicated.
An alternative theory is that thrombus formation in central retinal vein is end stage
9

10. phenomenon, induced by variety of primary lesions. 12
0ccular manifestations
Both types of obstructions share similar findings10-12, 93, and 94
•dilated and tortuous retinal veins
•Retinal hemorrhages in all four quadrants.
•Cotton wool spots
•Macular edema
•Optic disc edema
The distinction between two types is some what arbitrary and is based on the total
area of non perfusion on fluorescien angiography. The ischemic variety is
associated with severe retinal disease while non ischemic variety runs a milder
course. The distinction between the two is the presence of more than ten disc
diameters of ischemia on fluorescien angiogram.
10

11. NON-ISCHEMIC CENTRAL VEIN OCCLUSION
Alternative names include partial, incomplete, imminent, and incipient or
impending vein obstruction as well as venous stasis retinopathy.75-80% can be
classified as having this form of disease. Patients usually have mild to moderate
loss of visual acuity. Intermittent blurring or transient visual obscurations may also
be present. Pain is rare. A very slight afferent papillary defect may be present.
Ophthalmoscopy reveals variable number of dot and blot hemorrhages are present
in all the four quadrants. Optic nerve head swelling is quiet common and
engorgement and tourtuoisity of retinal veins is characteristic. Cotton wool spot if
present are few in numbers and located posteriorly. Decrease vision is usually the
result of macular hemorrhage or edema or both. 12, 14, 93, 94
There is less than 2% evidence of neovascularisation. Central vein occlusion study
group noted 34% incidence of conversion of non-ischemic variety into ischemic
occlusion within 3 years
Macular edema may resolve completely to leave a normal appearance .However
persistent cystoid macular edema can linger, can result in permanent visual loss
often leading to pigmentary changes, Epiretinal membrane formation or sub retinal
fibrosis. 94
11

12. ISCHEMIC CENTRAL RETINAL VEIN OCCLUSION
Ischemic central retinal vein obstruction referred as severe, complete, or total
venous obstruction and hemorrhagic retinopathy. They account for 20-25% of total
cases. Acute markedly decreased visual acuity is usually the initial complaint.
Vision usually ranges from 6/60 to hand movements. A prominent afferent
papillary defect is the hallmark. It is characterized by extensive retinal
hemorrhages in all the four quadrants, most notably centered in the posterior pole.
The optic disc is usually edematous and the retinal veins are markedly engorged
and tortuous. Cotton wool spots are more than 6 in numbers. Macular edema is
usually very severe but may be obscured by retinal hemorrhages. Massive lipid
exudation in macular region can occur. 10, 68
The incidence of anterior segment neovascularisation ischemic central retinal vein
occlusion is 60% or higher. Neovascularisation of angle and the glaucoma may
occur within 3 months of the disease (90 day glaucoma) and it can result in
intractably elevated pressure. Neovascularisation of optic disc and retina may be
seen as well. The findings may decrease or resolve within 6-12 months. Permanent
macular changes may develop that include pigmentary changes, Epiretinal
membrane formation and sub retinal fibrosis that resembles disciform scarring.
Macular ischemia may be present as well. 1, 10, 94
12

13. HEMI CENTRAL RETINAL VEIN
In about 20% population there is dual trunk of central retinal vein which merge
behind lamina cribrosa. In these eyes obstruction of one trunk can lead to hemi
central retinal vein occlusion although only one half of the retina is involved but
these obstructions act like central retinal vein obstruction in terms of visual
outcome and response to treatment. 10
13

14. Diagnosis and ancillary testing of central retinal vein occlusion
• Characteristic fundus findings as already explained.
• Fluorescien angiography may show marked hypofluroscence which may be
secondary to blockage from extensive hemorrhages or cotton wool spots.
• Macular edema is the most common cause of visual loss in CRVO. It may
manifest as large cystoid spaces or diffuse leakage on fluorescien
angiogram. macular edema may be obscured by hemorrhages but as
hemorrhage clear and edema resolve, macular ischemia may become
apparent
• Fluorescien angiography also reveals optic nerve head leakage and
perivenous staining in later stags of disease, generalized extensive capillary
non-perfusion, arteriovenous collateral vessels, and microaneurysyms are
seen. The macular region shows persistent edema or pigmentary
degeneration.
• The central vein occlusion study demonstrated 37% of ischemic central
retinal vein occlusion has anterior segment neovascularisation at or before
4months follow up.
• Visual acuity alone is a powerful, less expensive and non invasive
14

15. measurement to determine the prognosis and follow up in such cases.
• Laboratory evaluation may include a complete blood count, glucose
tolerance test, lipid profile, serum protein electrophoresis, and syphilis
serology.
• If there is positive history than further hematological tests such as lupus
anticoagulant level, anticardiolipin antibody, protein s and protein c levels
should also be considered.
Systemic association
Central retinal vein obstruction has been associated with following systemic
diseases. 1,11,14,94
• Hypertension
• Diabetes mellitus
• Cardiovascular disease
• Primary open angle glaucoma.
• Blood dyscrasias
• Dysprotinemias
• Paraprotinemias
• Viscidities of syphilis and sarcoidosis.
15

16. • Autoimmune diseases.
• Oral contraceptives.
Pathology
Alteration in blood flow, viscosity, and vessel wall abnormality may
produce central retinal vein obstruction by enabling a thrombus of central
retinal vein to form. Local factors can predispose to retinal vein obstruction.
Glaucoma has been associated with retinal vein obstruction. It has been
hypothesized that glaucoma causes stretching and compression of lamina
cribrosa leading to vessel wall abnormality, increased resistance to flow and
ultimately formation of a thrombus. 10
16

17. Treatment
No treatment has been shown to reverse the pathology in retinal vein
obstruction. Aspirin , systemic treatment with couamarin, heparin and
antiplase, local anticoagulant with antiplase, corticosteroids , anti-
inflammatory agents , isovolemic hemodilution, plasmapheresis, optic nerve
sheath decompression all have been advocated but without definitive proof
of efficacy. Certain complications of CRVO may be preventable. 23-67, 69-90
17

18. Complications of CRVO
Neovascular glaucoma
Neovascular glaucoma is devastating complication of CRVO. Intractable
glaucoma, blindness, and pain culminates in to enucleation can occur. Some
studies advocate prophylactic PRP for anterior segment neovascularisation
while other in favor of PRP after development of complication. 9, 12,14,16,94
Macular edema
Macular edema and permanent macular dysfunction occur in virtually all the
patients with ischemic central retinal vein obstruction, and in many of
patients with non ischemic central retinal vein obstruction the central rental
vein study group evaluated the efficacy of macular grid laser in patients with
macular edema in central retinal vein obstruction group. Patients with both
ischemic and non-ischemic groups were studied although macular grid laser
conclusively reduced the angiographic evidence of macular edema. 10, 94
The study did not find a difference pretreatment and post treatment level
visual acuity. 94
18

19. Course and outcome
The prognosis for visual recovery is highly dependant on subtype of retinal
vein occlusion. In general it can be predicted from the visual acuity. Patients
who have non-ischemic central retinal vein occlusion may experience
complete recovery of the vision but most of them deteriorate to the level of
6/60 or worse. More than 90% of patients with ischemic central retinal vein
occlusion have visual acuity less than 6/60.
Almost 7% of the patients develop retinal vein obstruction in fellow eye. 10,
14
19

20. BRANCH RETINAL VEIN OCCLUSION
BRVO is venous occlusive disease o elderly. Visual loss from branch retinal vein
occlusion is mainly because of macular edema, macular ischemia, or vitreous
hemorrhages. 93
Epidemiology and pathogenesis
BRVO occur 3times more commonly than central retinal vein obstruction. Men
and women are affected equally with usual age of onset between 60 and 70 years.
Most of the evidence implicates arteriolar disease as underlying pathogenesis.
BRVO mostly occurs at arteriovenous crossings, where artery and vein share a
common adventitial sheath. The artery is almost always anterior to vein in sheath.
It is postulated a rigid atherosclerotic artery compresses the retinal vein, which
results in the turbulent blood flow and endothelial damage, followed by thrombosis
and obstruction of the vein. Most other branch retinal vein obstruction occurs.
superotemporally, probably because this is where the highest concentration of
arteriovenous crossings lies.
Rarely local ocular disease, especially of inflammatory nature, can result in
secondary branch retinal obstruction. This has been reported in diseases like
toxoplasmosis, Eales disease, Bechet’s syndrome, and ocular sarcoidosis. Also
macroaneurysyms, coats disease, retinal capillary hemangioma, and optic disc
drusens have been implicated in development of branch retinal occlusion.
20

21. Glaucoma is also the risk factor for development of branch retinal vein occlusion.
It is usually unilateral with 9% of the patients having bilateral involvement. 11, 13
21

22. Ocular manifestations
Patients with branch retinal vein occlusion usually complain of sudden onset of
blurred vision or a visual field defect. Retinal hemorrhages confined to the
distribution of vein are characteristic of branch retinal vein occlusion. As result of
distribution hemorrhage usually takes the triangular configuration with the apex
towards the side of blockage. Flame shaped hemorrhages predominate .mild
obstructions are associated with relatively small amount of hemorrhage. Complete
obstruction usually results in the form of extensive hemorrhage, cotton wool spots,
and widespread capillary non perfusion. If the macular region is involved, macular
edema or hemorrhage can occur, which causes the decreased visual acuity. Visual
acuity may range from 6/6to counting fingers. 1-14, 93
If the macula is spared, a branch retinal obstruction may be asymptomatic which is
than found only on routine examination. Occasionally a partial branch retinal vein
occlusion with little hemorrhage and edema may progress to completely occluded
vein, with an increase in hemorrhage and edema and corresponding decrease in
visual acuity. 13
Retinal neovascularisation occurs in about 20% of the cases. It typically develops
within first 6-12 months of occlusion. Anterior segment neovascularisation is
rarely seen in branch retinal vein occlusion, unless other ischemic conditions co
exists. With time, the dramatic picture of an acute branch retinal vein occlusion
22

23. can become more subtle. Hemorrhages fade with time so that the fundus can look
almost normal. Collateral vessels and micro vascular abnormalities can develop to
drain the effected area. The collateral vessels often cross the horizontal raphae. The
corresponding retinal artery is narrowed and sheathed.microaneurysm formation
and lipid exudation may be there. Capillary non perfusion is seen in later stages
when hemorrhages have cleared. Epiretinal membrane formation and maculae
pigment epithelial change may occur as a result of chronic cystoid macular edema.
Exudative retinal detachment in the local area may also be seen. 14
23

24. Diagnosis and ancillary testing
Characteristic retinal findings as described above 93.
• Fluorescien angiography is helpful adjunct for both establishment of
diagnosis and guidance for branch retinal vein occlusion treatment.
Arteriolar filling is usually normal, but the venous filling in the affected
vessel is usually delayed in the acute phase. Hypofluorescence caused by
hemorrhages and capillary non perfusion are common findings.
• Collateral vessels may cross the horizontal raphae. The retinal vessels
particularly veins wall stain with fluorescien, especially at the site of
obstruction.
• Macular edema which is noted clinically more than angiographically may
indicate ischemia. Classic pateloid cystoid macular edema may involve the
entire fovea, depending upon the level of obstruction.
24

25. Systemic associations
• Hypertension
• History of cardiovascular disease
• Primary open angle glaucoma
• Higher serum levels of alpha-2 globulin
• Reduced risk with moderate alcohol consumption and increased levels
of high density lipoproteins
Pathology
A histopathological study showed a fresh or reacnalised thrombus at site of
vein occlusion in all eyes and varied degree of atherosclerosis and 50% of
eyes have cystoid macular edema 14, 93, 94
Pathogenesis of Macular Edema in BRVO
The development of macular edema (ME) followed by BRVO has been
hypothesized to be caused by fluid flux from vessels to tissue according to
Starling's law, which is based on the breakdown of the blood-retinal barrier
(BRB) as a result of damage to the tight junctions of capillary endothelial
cells, vitreoretinal adhesion, and secretion into the vitreous of
vasopermeability factors produced in the retina. Observations by Noma
25

26. suggest that in patients with BRVO, vascular occlusion induces the
expression of vascular endothelial growth factor (VEGF) and Interleukin-6
(IL-6), resulting in BRB breakdown and increased vascular permeability.
Thus, VEGF and IL-6 may contribute to the development and progression of
vasogenic ME in BRVO. Macular edema is closely associated with retinal
hypoxia, and the degree of hypoxia in the center of the macula corresponds
to the decrease in visual acuity (VA). If marked hypoxia persists, irreversible
structural changes in the macula occur, and the disturbed VA is almost
always lasting. It is generally known that Macular edema and intraretinal
hemorrhage occurring in BRVO usually disappear within 6 to 12 months. In
these cases, collateral systems often develop. The main purpose of the
treatment is to decrease the duration of edema to prevent photoreceptor
damage, if no spontaneous improvement occurs. 5-9, 11, 14-67
26

27. Treatment
The treatment is for the two distinct complications of branch retinal occlusion,
namely macular edema and neovascularisation. 14-67, 69-90
Treatment guidelines for macular edema in BRVO
• Wait for the clearance of retinal hemorrhages to allow for adequate
fluorescien angiography visualization.
• For macular edema with visual acuity better than 6/12, no treatment is
usually required.
• For macular edema with visual acuity worse than 6/12, determine if
decreased visual acuity is mainly because of macular edema or ischemia
• If macular edema explains the visual loss and no spontaneous improvement
have occurred by 3 months, grid macular photocoagulation is recommended.
• If capillary non perfusion explains the visual loss than no treatment is
required.
27

28. Treatment guidelines for neovascularisation in branch retinal vein occlusion
• Good quality fluorescien angiogram is obtained after retinal hemorrhages
have sufficiently cleared.
• If more than 5 disc diameters of non perfusion is seen on angiogram, the
patient should be followed at 4 months interval to look for development of
neovascularisation.
• If neovascularisation develop, pan retinal photocoagulation should be done.
28

29. Course and outcome
Without treatment about one third of patients have visual acuity better than 6/12;
however two thirds have decreased visual acuity secondary to macular edema,
macular ischemia, macular hemorrhage or vitreous hemorrhage. Laser treatment
for macular edema significantly improves the chance that the patient’s visual
acuity will improve by two lines. Poor visual prognostic factors include advancing
age, male sex, and fewer risk factors. Patients should be followed after every three
to four months.
Approximately 20% of patients with branch retinal vein occlusion will develop
neovascularisation. Of these patients about 60% will have episodic vitreous
hemorrhage. Fortunately laser treatment can reduce this by one half to thirty
percents. Newer modalities of treatment are still in experimental and
investigational phase. 1-9, 14-67, 69-80
29

30. LASERS FOR MACULAR TREATMENT
The use of ophthalmic lasers is becoming increasingly widespread, with most eye
departments now having at least one type of laser. Many patients are treated with
lasers and many more request such treatment, even when it is not indicated. The
indications for ophthalmic lasers are constantly changing as experience with
established treatments increases and new equipment is developed: 4, 4, 73, and 75
Principle of laser:
Laser is an acronym for light amplification by the stimulated emission of radiation.
Emission of radiation is stimulated by elevating electrons in a suitable gas or solid
material into "high energy states" with an electric current or light of an appropriate
wavelength. When a high energy electron is struck by a photon of the correct
wavelength it emits two photons. These two photons (the stimulated emission) are
of identical phase, direction, and wavelength. The laser energy is amplified and
focused into a delivery system that incorporates devices to protect the user and
others present in the laser suite. The interaction between the laser beam and tissues
consists of four components. These are in sequence, laser transmission, absorption,
degradation, and the tissue reaction. 83
The transparency of the ocular media lends itself to the transmission of laser light
30

31. in the visible and near infrared spectrum. Ocular absorption is related to the laser
wavelength and the type of pigment in the target tissue. The main absorbing ocular
pigment is melanin, which is present mainly in the retinal pigment epithelium, iris
pigment epithelium, and the trabecular meshwork. Argon, krypton, dye, and diode
laser 5
Wavelengths are all absorbed by melanin. Other absorptive pigments found in the
eye include xanthophyll, which is found in the retina at the macula, and the light
absorbing pigments found in the rod and cone photoreceptor cells. Argon blue is
absorbed by macular xanthophyll and may cause damage to the inner retina. Green,
red, and infrared wavelengths are used for treating macular lesions as they do not
damage macular xanthophyll. 15, 74, 75
Diode and neodymium YAG (yttrium-aluminum-garnet) lasers produce invisible
infrared wavelengths which readily pass through the sclera was well as the cornea,
aqueous, lens and vitreous. These lasers can therefore be used to treat intraocular
structures by using a beam which passes through either the cornea or the sclera. 15
Laser energy can cause several types of degradation in targeted tissue. These
include photocoagulation, photo disruption, and photo ablation.
31

32. Photocoagulation
Photocoagulation is a thermal process in which laser radiation is absorbed by the
target tissue and converted into heat, resulting in thermal denaturation ofproteins.
Argon, krypton, and tune able dye lasers all work on this principle, as do the more
recently introduced continuous wave YAG and diode lasers. Photocoagulation is
used for treating proliferative retinopathy, diabetic maculopathy, macular edema,
macular degeneration, retinal holes, and chronic open angle glaucoma. 85, 88, 89, 91
Photocoagulation in macular edema
Dysfunction of the macular capillary endothelium secondary to diabetes allows
fluid and lipid to leave the capillaries and enter the inner retina and impair central
vision. Treatment with laser burns to the leaking areas or in a grid over the macula
can be successful in "drying" the retina.
Current laser treatments are quick, relatively painless, and well tolerated. Some
ophthalmic techniques can be performed only by laser while others have a lower
morbidity than alternative treatments. 15, 65-91
32

33. The hazard of macular photocoagulation
When using the argon blue laser’ wavelength is not confined to the patient.
Ophthalmologists performing argon blue green laser pan retinal photocoagulation
stare for a long time at the reflection of a weak blue-green laser aiming beam, as
they guide the laser across the retina. And it has now been shown that frequent and
prolonged use of lasers can damage ophthalmologist’s color vision. A protective
filter should be placed in the ophthalmologist's viewing pathway to remove the
damaging blue argon wavelength. 67, 71, 75, 81, 85, 87, 90-92
33

34. Macular edema in branch retinal vein occlusion
Macular grid laser photocoagulation for macular edema
34

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35

36. INTRAVITREAL TRIAMCINOLONE ACETONIDE INJECTION
The natural outcome of RVO is very poor. Macular edema associated RVO has
always been a difficult condition to treat. Until recently there has been no proven
treatment of this pathology.
The rationale for the use of corticosteroids to treat macular edema secondary to
CRVO [central retinal vein occlusion] follows the observation that the increase in
retinal capillary permeability that results in macular edema may be caused by a
breakdown of the blood retina barrier mediated in part by VEGF [vascular
endothelial growth factor], a 45-kDa glycoprotein," "Therefore, attenuation of the
effects of VEGF, noted to be up regulated in eyes with CRVO, may reduce
macular edema associated with CRVO. Corticosteroids have been demonstrated to
inhibit the expression of VEGF and therefore may be an effective therapy for
macular edema." 8, 16, 17, 24
There are several case reports showing short-term reduction in macular edema due
36

37. to CRVO and BRVO as measured by OCT following IVTA. Significant
improvement in VA is reported in both eyes after injection with 25 mg of IVTA in
a patient with macular edema due to CRVO. They found decreased fluorescien
leakage and did not find any significant complications except mild cataract
progression and transient increase in IOP. There is also anatomical and functional
improvement in eyes with macular edema due to non ischemic CRVO. In a study
of 4mg IVTA injections and an average follow up of 4.8 months, they found that
60% of the eyes gained ≥2 lines of VA. 14-67
IVTA is frequently used for the treatment of various intraocular neovascular and
edematous conditions such as RVO and diabetic retinopathy. Typically, steroids
are administered intravitreal because steroids given as drops, systemically, or
injected into the sub conjunctival and sub-Tenon’s space do not reach high enough
concentrations to be effective. Additionally, corticosteroids used systemically for
prolonged periods of time increased the risk for systemic side effects. 63
Although the mode of action by which triamcinolone induces resolution of macular
edema remains poorly understood, in vitro studies and clinical observations
indicate that triamcinolone has the capacity to reduce the permeability of the outer
blood-retinal barrier. 16
Intravitreal triamcinolone has been shown to be safe and effective when used for
37

38. the treatment of cystoid macular edema caused by uveitis, diabetic maculopathy,
central retinal vein occlusion, and post-cataract surgery. IOP elevation may occur
in up to 50% of eyes after triamcinolone injection. Other potential risks include
cataract development, retinal detachment, and endophthalmitis. Despite good
initial anatomical and visual response to intravitreal triamcinolone when used in
these conditions, macular edema has been reported to recur following treatment,
often necessitating repeated injections. Further follow up is required to determine
if macular edema recurs following treatment in branch retinal vein occlusions. 2, 3,
14-67
38

39. Method of IVTA injection
Topical xylocaine was used for anesthesia. Povidone-iodine 5% was then applied
to the conjunctiva. An intravitreal injection of triamcinolone acetonide (4 mg in 0.1
ml) (Kenalog, Bristol-Myers Squibb, Middlesex, UK) is administered through the
pars plana with a 30 gauge needle using a sterile technique. 14-60
39

40. PROCEDURE-RELATED ADVERSE EVENTS
Procedure-related adverse events include hemorrhage, vitreous loss or
incarceration, retinal perforation, retinal detachment, introduction of needle in
anterior chamber, angle or intra ocular lens, rupture of zonules or incomplete entry
in choroids with expulsive choroidal hemorrhage or detachment. Mild symptoms
associated with the injection, such as transient discomfort or blurring. 6, 16, 17
40

41. Post injection adverse effects
ELEVATED IOP
Corticosteroid-related adverse events in treated eyes had a significantly increased
risk of developing mild or moderate elevation of the IOP.
Elevated IOP can be adequately treated with topical medication in all eyes, without
recourse to laser or surgical treatment. In particular, all eyes with IOP’s greater
than 25 to 40 mm Hg during treatment can benefit from only 1 medication. The
pressure is quickly normalized (<25 mm Hg in eyes without cupped discs and <18
mm Hg in eyes with preexisting glaucoma) in all eyes by the addition of further
medications, as appropriate. The decision to treat elevated IOP is based on
conventional considerations in each patient, including the degree of elevation, the
extent of cupping of the optic nerve head, and whether there was a history or
family history of glaucoma. 8, 24, 25, 34, 65
41

42. CATARACT
Treated eyes had a significantly increased risk of moderate progression of cataract.
It could be nuclear, cortical, and posterior sub capsular lens opacities with
intravitreal triamcinolone injection. There was significant progression of cataract in
the triamcinolone-treated eyes. Cataract surgery can be performed after intravitreal
triamcinolone injection treatment. The decision to recommend cataract surgery is
based on conventional considerations, including the density of the opacification,
the level of visual acuity in the fellow eye, and the patient's willingness to undergo
surgery. 24, 25, 39, 62
42

43. STERILE ENDOPHTHALMITIS (PSEUDOHYPOPYON)
The pseudohypopyon, vitreous haze, and CMO (as demonstrated on optical
coherence tomography) develop after IVTA with worsening of visual acuity.
The triamcinolone is dispersed throughout the vitreous rather than forming a
discrete mass as is usually observed after injection. This dispersion is due to partial
“jamming” of crystalline triamcinolone in the barrel of the 30 gauge needle during
injection, resulting in spraying of the drug into the vitreous at high velocity, and
leading to formation of a diffuse vitreous suspension. It is possible that this
tendency to dispersion may be reduced by using a 27 gauge needle.
Hypopyon associated with non-infectious endophthalmitis following intravitreal
triamcinolone injection has been described; however, the “pseudo” hypopyon is a
unique feature is due to the presence of a posterior capsule defect enabling the
passage of triamcinolone from the vitreous cavity into the anterior chamber.
Presumably, the triamcinolone crystals are carried into the anterior chamber by
currents generated by saccadic eye movements in the partially vitrectomised
vitreous cavity.
43

44. The absence of ocular pain, photophobia, ciliary’s injection, or iris vessel dilation
suggests a non-inflammatory response and perhaps it would be appropriate to
monitor such patients closely rather than administering intravitreal antibiotics. 24, 25,
56, 57, 62
44

45. INFECTIOUS ENDOPHTHALMITIS
In a study, calculated risk of endophthalmitis was 0.87% in the first 6 weeks
following IVTA injection. This is considerably higher than the prevalence noted
after other intravitreal drug injections. For example, Engstrom and Holland
reviewed the literature and reported that the corresponding rate of endophthalmitis
following intravitreal ganciclovir injection for cytomegalic viral retinitis was
0.29%. This susceptibility may increase the risk of endophthalmitis in diabetic
patients, especially following a local corticosteroid injection. Blepharitis is a
reported risk factor for endophthalmitis and the risk may be increased during an
office-based procedure where the sterile technique may not be as rigorous as in the
operating room setting. Despite disinfection of the lids and conjunctival surface
with povidine iodine, the lashes may serve as a nidus of infection if they abut the
needle before its entry into the eye. The treatment of infectious endophthalmitis is
in similar way as any other case of infected endophthalmitis but its more refractory
to treatment. 36, 39 and 50
45

46. OBJECTIVES
The objectives of the study were to:
To evaluate the efficacy of combination therapy (IVTA with MGLT) vs.
monotherapy (MGLT) on macular edema of branch and central retinal vein
occlusion patients.
OPERATIONAL DEFINITION
Macular edema in CRVO/BRVO:
Hard exudates on macula or in an area of one disc diameter around macula in
patients of BRVO and CRVO.
The patient will be seen by researcher with direct ophthalmoscope.
Efficacy:
It will be measured on basis of following two criteria.
Best corrected visual acuity (BCVA):
It will be measured before treatment and after treatment at intervals one month,
three months and six months on basis of standard Snellen’s charts in terms of gain
of numbers of lines on chart by researcher herself.3
46

47. Macular edema on intravenous fluorescien angiography
(IVFA):
IVFA will be performed before treatment and four months after treatment and it
will be seen whether there is decrease of macular edema or not on IVFA by
comparing pre treatment and post treatment IVFA.1, 3
47

48. HYPOTHESIS
There is difference between efficacy of combination therapy (MGLT -IVTA) and
monotherapy (MGLT) in treatment of macular edema of branch and central retinal
vein occlusion patients.
48

49. Study design:
Randomized control trial (RCT)
MATERIAL AND METHODS
SETTINGS
The study will be carried out in ophthalmology department of P.O.F’s hospital
Wah cantt on OPD basis, a teaching hospital affiliated with Wah Medical College.
It is 50-beded unit with an average daily turnover of 130 patients in outpatient
department.
DURATION OF STUDY
Six months, from 01-06-2009 to 30-11-2009
SAMPLE SIZE
A total of 68 patients sample was calculated .2
sample size was calculated by using values from latest study , mean BCVA
improvement of 3.4 with S.D of 2 in SGLT-IVTA group and mean BCVA
improvement of 1.3 with S.D of 4 by using WHO sample size calculator taking
49

50. CI=95%,power of test 80% and ratio of sample size (group2/group1) =1.2
• 34 patients were taken in first group labeled as MGLT-IVTA group
• 34 patients were taken in second group labeled as MGLT group.
SAMPLING TECHNIQUE
Non probability consecutive sampling
Specific number of patients was taken in the time interval specified which met all
the selection criteria
SAMPLE SELECTION
Inclusion criteria:
Patients with following characteristics would be included in the study.
1Well perfused macular edema involving fovea.
2Sufficient clearing of retinal hemorrhages.
3BCVA of 6/12 or poor
4patients of both gender
50

51. 5age Macular edema in BRVO/CRVO occurring 3-18 months earlier.2-4
6above 50 years
Exclusion criteria:
1Detection of capillary non-perfusion more than 5 disc diameter on IVFA 3-7
2Coexistence of any chorio-retinal disease.
3Age related macular degeneration
4Presence of mature cataract.
5Previous laser treatment.
6Diabetes
51

52. DATA COLLECTION PROCEDURE
Each patient under went complete ophthalmologic examination including best
corrected visual acuity with refraction using Snellen’s chart, slit lamp
biomicroscopic examination, and fluorescien angiography before treatment and
after treatment and at interval of three months.
Slit lamp biomicroscopic examination was carried out using Topcon
SL-30(Japanese made), anterior and posterior segment of every patient was
examined. .Intravenous fluorescien angiography was carried out using Heidelberg
retina angiograph system.
The patient randomization to either monotherapy or combination therapy was done
by lottery method. All the pre-treatment examination was done by a single person
(third year trainee). Treatment was given by the researcher herself. Post-treatment
evaluation was done by a third person (consultant) to rule out the biases of study.
IVTA was in Operation Theater under sterile conditions. 4mg of decanted
triamcinolone acetonide (0.1 ml) was injected 3.5-4mm posterior to limbus of eye2
The macular grid laser was performed by ARGON LASER A.R.C laser GmbH
classic G (German made). The laser treatment was given two weeks after IVTA.
The laser parameters were 50-200µm spot diameter, 0.10 sec exposure with
52

53. enough power to produce gentle white burn of retina. 2-4
The confounders like diabetic disease of eye, retinal and choroidal diseases, and
age related macular degeneration were excluded from the study. The other
confounders like age, glaucoma, smoking and hypertension were dealt at analysis
stage by frequency presentation and chi square testing and were found to be non
significant.
53

54. STUDY DESIGN
Randomized control trial (RCT)
DATA ANALYSIS PROCEDURE
All data was entered and analyzed using SPSS version 10.
For continuous variables (BCVA and age) mean +SD was calculated. For
categorical variables (decrease in macular edema on IVFA, smoking, HTN and
glaucoma) frequency was calculated.
For comparison of two means (BCVA) independent sample t-test was used. For
comparison of two proportions (decrease in macular edema on IVFA, smoking,
hypertension and glaucoma) chi-square test was used. P value of ‹ 0.05 was
considered significant.
.
54

55. RESULTS
During the study period 68 patients were enrolled in the study; 34 were included in
the first group called the MGLT group and 34 were included in second group
called the MGLT group.
Table no.1
The age distribution between two groups
Age in years
Std.
treatment group Mean n
Deviation
combination therapy
65.18 33 6.67
(IVTA and MGLT)
monotherapy( MGLT) 66.24 33 6.81
Total 65.71 66 6.71
55

56. Demographic data of two groups is listed in table 1.The age distribution between
the two groups was found to be similar. In MGLT-IVTA group most of the patients
were in the age group 58-69 years, whereas in MGLT group patients were present
in same age group. The mean age of the patients included in MGLT-IVTA group is
65.18 and while in MGLT it is 66.24
56

57. Comparison between ages in two groups (graph no. 1)
6
5
4
3
2
treatment group
combination therapy
1
(IVTA and MGLT)
Count
0 monotherapy( MGLT)
56 58 61 63 66 68 70 72 74 76 80
age in years
The graph clearly indicates the age trend is similar in both group.
57

58. Pie graph of gender distribution (graph no. 2)
Regarding gender distribution 57.4 % patients are male and 41.2 % are female,
with more male patients in MGLT-IVTA group as compared to MGLT group.
58

59. Smoking status of the patients (graph no.3)
28.4% of the patients are smokers while 71.6 % of patients are non smokers with
almost equal number of smokers in both groups. The p value is much above
acceptance level (p=.728) clearly indicating that treatment outcome is not
significantly effected by smoking status.
59

60. The frequency of POAG in patients (graph no. 4)
46.3 % patients have open angle glaucoma while 53.7% of patients have no
glaucoma, with almost equal distribution in both treatment groups and it also does
not significantly effect the final treatment outcome in both groups (p=.720)
60

61. The frequency distribution of hypertension in patients
(Graph no. 5)
no
yes
Most of patients (58.8 %) are having hypertension as compared to 41.2 % which
are non hypertensive. MGLT-IVTA group has more (22) patients as compared to
MGLT group (18). The presence of hypertension similarly does not significantly
alter final out come.
61

62. Table No. 2
Frequency distribution of decrease in macular edema on IVFA
Decrease
in macular Frequency Percent
edema
Valid yes 49 72.1
no 19 27.9
Total 68 100.0
62

63. Table No.3
Decrease in macular edema on IVFA in both treatment groups.
P- value
(chi-
treatment group Total
square
test)
combination
Monotherapy
therapy (IVTA 0.002
( MGLT)
and MGLT)
decrease
in
macular yes 30 19 49
edema
on IVFA
no 4 15 19
Total 34 34 68
63

64. There is significant decrease in macular edema (72.1%) in patients in both groups
as compared to 27.9 % patients have no decrease in macular edema as shown in
table no. 2.
30 patients have shown decrease in macular edema and 4 patients have no change
or decrease in macular edema as shown by table no.3 in MGLT-IVTA group.
Whereas in MGLT group only 19 patients have shown improvement and 15
patients have no improvement in macular edema as shown in table no. 3.
Decrease in macular edema is one of important outcome variable of this study,
there is decrease in macular edema in both groups but there is significant decrease
in one group as indicated by p value ( p=0.002 ) as shown n table no. 3 which
indicates the two modalities of treatment are different from each other ( accepting
alternate hypothesis ) . MGLT-IVTA group has much more significant
improvement in maculae edema in 30 patients as compared to 19 patients in
MGLT group (table no. 3) which proves macular grid laser combined with
intravitreal triamcinolone is much better treatment option than macular grid laser
alone.
64

65. Table No. 4
Mean of BCVA before and after treatment
n Minimum Maximum Mean Std. Deviation
best corrected
visual acuity 68 .100 .250 .14449 5.1855E-02
before treatment
best corrected
visual acuity 68 .100 .667 .34147 .16537
after treatment
65

66. BCVA is one of important outcome variable in this study. The mean of BCVA in
both groups before treatment is .14449 (table no. 4) as compared to mean of
BCVA after treatment which is .34147 (table no.4) which shows both treatment
modalities have significantly improved the BCVA.
Cross tabulation of BCVA before treatment shows that Combination therapy group
has more number of patients in lower range of BCVA i.e. .100 and .167 as
compared to Monotherapy group. Where as higher number of patients with high
baseline BCVA i.e. .250 fall into Monotherapy group.
It has been clearly shown in table no.5 the mean improvement in BCVA
Monotherapy group is .287 (table No.5) which is lower than the mean
improvement in best corrected visual acuity in Combination therapy group which
is .395 (table No. 5). The highest improved level of BCVA is .667 which
corresponds to 6/9 on Snellen’s visual acuity chart, 6 patients have improvement
up to that level in Combination therapy group as compared to only 1 patient who
this much improved visual acuity in Monotherapy group.
66

67. In order to check our hypothesis the independent sample T test was applied to the
quantitative variable BCVA, its results were highly significant (.007) as shown in
table no. 5. It clearly accepts the hypothesis of study i.e. the treatment modalities in
treatment of macular edema are significantly different in terms of their out com
(BCVA). This clearly rejects the null hypothesis.
67

68. Table No. 5
Comparison of mean improvement of BCVA in both treatment groups after
treatment.
Group Statistics
P-value
(independent
treatment group n Mean Std. Deviation
sample T
test)
best
corrected combination
.
visual acuity therapy (IVTA and 34 .17243 0.007
39512
after MGLT)
treatment
Monotherapy .
34 .14092
( MGLT) 28782
68

69. As hypothesis of study has already been accepted, in order to know which of
treatment modality is better than the other, the mean improvement of BCVA with
its S.D is an excellent variable. The mean improvement of BCVA with its S.D in
Combination therapy group is .39512 which is equaling to more than 6/18 on
Snellen’s visual acuity chart as compared to base line BCVA (.1449) table no. 4
which is equaling to less than 6/36 on Snellen’s visual acuity chart thus showing an
improvement of more than three lines .
The mean improvement in Monotherapy group is .28782 with S.D of .14092 (table
no.5) which is equaling to 6/24 on Snellen’s visual acuity chart from base line of
6/36 (mean .1449) table no.4 which means an improvement of more than one line
on Snellen’s visual acuity chart. These results clearly indicate the combination
therapy (MGLT-IVTA) group produces an improvement of three lines from
baseline (Snellen’s visual acuity chart) as compared to Monotherapy group
(MGLT) group which produces an improvement of one and half line (Snellen’s
visual acuity chart ) from baseline .
69

70. Summary
The above analysis clearly indicates both treatment modalities are different from
each other on the basis of results of out come variable, decrease in macular edema
on IVFA and improvement of BCVA (p<0.05) and mean values of both variables
with their S.D. indicate the Combination therapy group (MGLT-IVTA) is a good
treatment option for macular edema of central and branch retinal vein occlusion
patients regarding its efficacy.
70

71. Discussion
On reviewing the national as well as international literature many studies were
found in which the two modalities of treatment i.e. macular grid laser treatment
and intravitreal triamcinolone acetonide were studied separately but in only few of
international studies in which they were compared with each other in terms of
efficacy and safety. 1-12
In my study the two modalities of treatment are compared with each other to find
out an effective treatment for macular edema of central and branch retinal vein
occlusion patients, which not only decreases macular edema but also produce
improvement in final visual out come and is also cost effective for patients. The
study was designed to estimate the improvement in terms of decrease in macular
edema and improvement in final best corrected visual acuity of retinal vein
occlusion patients with macular edema.
In the 1984 most instrumental studies carried out 93 were branch and central vein 94
occlusion study group in 1995 which formed the basis for further studies regarding
treatment modalities of this condition and its complications like macular edema
and neovascularisation. Much improvement has been observed both in safety as
well as efficacy of treatment but still the improvement is either short lived or there
71

72. is not much pronounced improvement in final best corrected visual acuity. 11-15
After 2000 so many modalities of treatment has been studied like macular grid
laser, intravitreal steroid injections and anti vascular endothelial growth factor
substances. But they have been investigated and studied separately and further
more the latest treatment option the anti vascular endothelial growth factor
substances are very expensive out of reach of even middle class. 1-9
Although macular grid laser alone produces improvement of 1.33 lines at 3years
but it can bring about potential complications including enlargement of scar,
choroidal neovascularisation, sub retinal fibrosis, and visual field sensitivity
deterioration 69 -92.
The intravitreal triamcinolone acetonide has recently shown to stabilize the inner
blood-retinal barrier and reduce the macular edema and thus improve the visual
acuity in several disorders including retinal vein occlusion. But this treatment
alone has certain limitations like temporary effect in macular edema reduction and
vision improvement, high incidence of secondary intra ocular hypertension and
cataract progression. Most of all even performing repeated injections are
troublesome both for patients and ophthalmologist. 15-67
Further more after injection alone the improved visual acuity is not maintained
72

73. over long period of time. 62.
The purpose of present study was to verify that macular grid laser combined with
single dose of intravitreal triamcinolone acetonide injection could increase the
visual functions in the eyes with macular edema associated with central or branch
retinal vein occlusion over a period of six months.
The rationale of study is based on the hypothesis that a significant advantage can
be obtained by combining the treatment SGLT which acts slowly and prolong the
positive effects of injection with IVTA which causes rapid resolution of macular
edema. More specifically the study aims to assess whether the effects of MGLT
could be enhanced by exploiting the positive effect of IVTA thus improving the
final visual outcome.
The results of my study confirm the hypothesis (P=.007) table no.5 in particular the
final BCVA in MGLT-IVTA group is 0.395 as compared to 0.287 in MGLT group
(Table No. 5)
With regard to decrease in macular edema the there was more rapid reduction in
greater number of patients in MGLT-IVTA group as compared to MGLT group
73

74. (table no. 3)
In essence , the combined MGLT-IVTA treatment of macular edema secondary to
retinal vein occlusion allow a significant visual acuity improvement and decrease
in macular edema when compared to single treatment SGLT alone or both
treatment modalities are different in terms of their final visual outcomes.
74

75. LIMITATIONS IN MY STUDY:
There are few limitations which merit mentioning.
The principle limitation was time factor. As this study was being conducted as a
fulfillment of training requirement of the examination of FCPS in ophthalmology,
its duration had to be contained to the training period. This leads to emergence of
few stats of affairs, which produced bias.
First of all was inability to match the two groups for different confounding factors
like expertise of operator, Age, glaucoma, smoking and hypertension.
Each of these could have a bearing on the ultimate outcome of the point under
consideration. Therefore, any of these could have affected our results in any
direction unknowingly. But application of chi square showed them to be of not
much significance but still they need to be evaluated in greater detail by another
research study.
Secondly to carry out study in time, only the efficacy of treatment was studied but
not its safety which has major role in deciding a treatment for a patient. Therefore
safety of both treatments should be evaluated before putting them into practice.
Further more the latest equipment optical coherence tomography could have
75

76. increased the credibility of results many folds by measuring foveal thickness
before and after treatment.
Keeping in view the foregoing discussion, we think it would have been prudent if
we could have been able to include these factors in our framework before talking
about our results/their generalizability.
76

77. Conclusion:
Although, results cannot be generalized because of the factors listed above but it
can be concluded that MGLT-IVTA group is much more effective than MGLT
group in terms of decreasing macular edema(p=0.002) and improving best
corrected visual acuity,(p=0.007) in patients of macular edema of branch and
central retinal vein occlusion patients.
77

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