Dissertation

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

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

Key words:

1Macular edema

2Macular grid laser treatment.

3Intravitreal triamcinolone acetonide.

4 Retinal vein occlusion.

3

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

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

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

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

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

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

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

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

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

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

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

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

• 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Macular edema in branch retinal vein occlusion

Macular grid laser photocoagulation for macular edema

34

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35

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(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

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

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

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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