Branch

Retinal

Vein

Occlusion

Pathogenesis

Visual

Prognosis

and

Treatment

Modalities

In

branch

retinal

vein

occlusion

-LRB-

BRVO

-RRB-

abnormal

arteriovenous

crossing

with

vein

compression

degenerative

changes

of

the

vessel

wall

and

abnormal

hematological

factors

constitute

the

primary

mechanism

of

vessel

occlusion

In

general

BRVO

has

a

good

prognosis

of

eyes

are

reported

to

have

a

final

visual

acuity

-LRB-

VA

-RRB-

of

or

better

even

without

treatment

One

important

prognostic

factor

for

final

VA

appears

to

be

the

initial

VA.

Grid

laser

photocoagulation

is

an

established

treatment

for

macular

edema

in

a

particular

group

of

patients

with

BRVO

while

promising

results

for

this

condition

are

shown

by

intravitreal

application

of

steroids

or

new

vascular

endothelial

growth

factor

inhibitors

Vitrectomy

with

or

without

arteriovenous

sheathotomy

combined

with

removal

of

the

internal

limiting

membrane

may

improve

vision

in

eyes

with

macular

edema

which

are

unresponsive

to

or

ineligible

for

laser

treatment

BACKGROUND

Method

of

Literature

Search

Eligible

studies

were

identified

through

a

comprehensive

literature

search

of

electronic

databases

-LRB-

Medline

September

and

Science

Direct

all

years

-RRB-

Additional

articles

were

selected

from

review

of

the

reference

lists

of

the

articles

generated

from

the

above

search

The

following

keywords

and

combinations

of

these

words

were

used

in

compiling

the

search

branch

retinal

vein

occlusion

retinal

circulatory

disorders

pathogenesis

hematological

disorders

risk

factors

therapy

methods

visual

prognosis

In

total

of

these

were

used

for

this

mini-review

Epidemiology

Classification

Retinal

vein

occlusion

-LRB-

RVO

-RRB-

is

the

second

most

common

retinal

vascular

disorder

after

diabetic

retinopathy

and

is

a

significant

cause

of

visual

handicap

Its

prevalence

has

been

shown

to

vary

from

to

In

a

population-based

study

an

overall

incidence

of

symptomatic

RVO

was

found

in

of

patients

aged

or

older

Hayreh

et

al.

investigated

the

demographic

characteristics

of

various

types

of

RVO

in

patients

-LRB-

eyes

-RRB-

In

this

study

a

male

female

ratio

of

was

noted

in

a

group

of

patients

with

RVO

Of

the

two

main

types

of

RVO

central

retinal

vein

occlusion

-LRB-

CRVO

-RRB-

and

branch

retinal

vein

occlusion

-LRB-

BRVO

-RRB-

the

latter

is

more

common

A

further

group

is

hemi-vein

occlusion

a

distinct

clinical

entity

presenting

as

occlusion

of

only

one

trunk

of

the

central

retinal

vein

in

the

area

of

the

anterior

part

of

the

optic

nerve

Hayreh

et

al.

postulated

that

its

pathogenesis

is

closely

related

to

CRVO

The

first

case

of

BRVO

was

reported

by

Leber

in

Some

studies

showed

a

higher

proportion

of

BRVO

patients

older

than

at

the

onset

of

the

disease

compared

to

CRVO

but

others

found

no

significance

of

age

in

the

distribution

of

CRVO

and

BRVO

BRVO

is

divided

into

two

distinct

entities

major

BRVO

when

one

of

the

major

branch

retinal

veins

is

occluded

and

macular

BRVO

when

one

of

the

macular

venules

is

occluded

In

of

eyes

with

BRVO

there

is

occlusion

of

the

major

branch

in

the

superotemporal

quadrant

followed

by

of

eyes

with

occlusion

of

the

major

branch

in

the

inferotemporal

quadrant

Owing

to

absent

subjective

BRVO

symptoms

in

nasal

quadrants

the

diagnosis

of

occlusion

in

this

localization

is

mostly

accidental

and

therefore

rare

Very

often

BRVO

in

nasal

quadrants

is

diagnosed

only

when

its

complication

as

bleeding

from

neovascularizations

into

the

vitreous

cavity

occurs

The

cumulative

probability

of

developing

a

second

episode

of

occlusion

in

the

other

eye

within

years

is

about

in

patients

with

BRVO

Pathogenesis

The

pathogenesis

of

RVO

is

multifactorial

while

BRVO

may

be

due

to

a

combination

of

three

primary

mechanisms

compression

of

the

vein

at

the

arteriovenous

-LRB-

A/V

-RRB-

crossing

degenerative

changes

of

the

vessel

wall

and

abnormal

hematological

factors

In

the

following

sections

these

factors

are

discussed

Arteriovenous

Crossing

Koyanagi

in

first

reported

the

association

between

BRVO

and

A/V

crossing

and

now

it

is

established

that

mechanical

narrowing

of

the

venous

lumen

at

these

intersections

plays

a

role

in

the

pathogenesis

of

BRVO

Anatomic

features

of

A/V

crossings

and

secondary

effects

of

arteriolar

sclerosis

may

explain

the

apparent

vulnerability

of

the

crossing

site

to

venous

occlusion

In

the

majority

of

A/V

crossings

the

thin-walled

vein

lies

between

the

more

rigid

thick-walled

artery

and

the

highly

cellular

retina

The

sharing

by

artery

and

vein

of

the

common

adventitial

sheath

and

the

narrowing

of

the

venous

lumen

that

normally

occurs

at

the

A/V

crossing

provide

the

setting

for

BRVO

The

risk

of

occlusion

may

be

accentuated

when

arteriolar

sclerosis

results

in

increased

rigidity

of

the

crossing

artery

Duker

and

provided

further

support

for

a

mechanical

basis

of

BRVO

development

when

they

examined

the

relative

anatomic

position

of

the

crossing

artery

and

vein

at

the

site

of

occlusion

in

eyes

with

BRVO

They

found

in

all

eyes

the

artery

anterior

to

the

vein

-LRB-

towards

the

vitreous

cavity

-RRB-

Zhao

et

al.

evaluated

the

anatomic

position

of

the

crossing

vessels

in

eyes

with

BRVO

and

found

the

artery

anterior

to

the

vein

at

the

obstructed

site

in

of

affected

eyes

However

other

mentioned

risk

factors

must

play

a

role

too

because

in

approximately

of

normal

A/V

crossings

without

BRVO

the

artery

lies

anterior

to

vein

Degenerative

Changes

of

Vessel

Wall

A

number

of

studies

have

investigated

the

histological

changes

of

vessel

wall

at

the

A/V

crossing

An

investigation

by

Jefferies

et

al.

showed

that

the

expected

venous

compression

at

the

crossing

in

histological

view

does

not

exist

He

described

the

bending

of

the

vein

into

the

nerve

fiber

layer

at

this

point

without

its

compression

Histological

investigation

of

the

venous

lumen

at

the

A/V

crossing

in

patients

with

a

number

of

months

to

several

years

duration

of

BRVO

showed

organized

thrombus

with

varied

extent

of

recanalization

in

this

part

described

the

clinical

histological

correlation

in

one

eye

with

BRVO

of

a

few

hours

after

onset

There

was

no

blood

thrombus

obliterating

the

venous

lumen

at

the

A/V

crossing

and

even

the

fundoscopic

examination

showed

strong

dilated

and

tortuous

vein

distal

to

the

crossing

In

the

area

of

the

A/V

crossing

alteration

of

the

endothelium

and

intima

media

was

present

Seitz

suggests

that

the

trophic

changes

of

venous

endothelium

and

intima

media

as

they

follow

the

compression

from

overlaying

artery

is

the

root

of

the

pathogenesis

of

BRVO

The

formation

of

the

thrombus

follows

as

a

secondary

process

The

findings

of

Frangieh

et

al.

support

this

hypothesis

of

the

patients

in

their

study

had

evidence

of

intima

media

layer

hypertrophy

and

all

had

evidence

of

intravenous

thrombosis

Systemic

hypertension

diabetes

mellitus

atherosclerosis

and

smoking

are

reported

to

be

more

common

in

patients

with

RVO

Sclerosis

of

the

retinal

artery

which

is

associated

with

these

systemic

disorders

may

result

in

further

compression

of

the

vein

when

the

increased

rigidity

of

arterial

wall

and

contraction

of

the

adventitial

sheath

shared

by

artery

and

vein

occur

Mechanical

obstruction

of

the

vein

through

the

rigid

artery

in

the

A/V

crossing

may

result

in

turbulent

blood

flow

producing

damage

to

venous

endothelium

and

intima

media

and

the

sequence

of

events

leading

to

occlusion

of

the

vein

The

turbulent

blood

flow

was

confirmed

by

Christoffersen

and

Larsen

in

an

investigation

which

analyzed

the

fluorescein

angiograms

of

patients

with

BRVO

Hematological

Disorders

Some

studies

have

revealed

an

association

between

BRVO

and

hyperviscosity

due

to

high

hemotocrit

Higher

blood

viscosity

increases

under

conditions

of

low

blood

flow

and

erythrocyte

aggregation

Viscosity

is

mainly

dependent

upon

the

hematocrit

-LRB-

the

greater

the

number

of

erythrocytes

the

larger

they

aggregate

-RRB-

and

plasma

fibrinogen

-LRB-

required

for

aggregation

to

occur

-RRB-

Another

discussed

hematological

disorder

in

the

pathogenesis

of

BRVO

is

dysregulation

of

the

thrombosis-fibrinolysis

balance

The

coagulation

cascade

including

different

blood

factors

results

in

the

production

of

thrombin

which

converts

circulating

fibrinogen

to

fibrin

The

coagulation

sequence

is

held

in

check

and

inhibited

by

specific

anticoagulants

including

protein

C

protein

S

and

antithrombin

Table

shows

the

major

disorders

studied

in

patients

with

RVO

The

results

of

published

studies

however

are

inconsistent

and

the

role

of

coagulation

factors

in

the

development

of

RVO

remains

unclear

TABLE

Most

discussed

coagulation

and

anticoagulation

disorders

in

the

etiology

of

BRVO

Resistance

to

activated

protein

C

-LRB-

especially

factor

V

Leiden

mutation

-RRB-

Protein

C

or

protein

S

deficiency

Deficiency

of

antithrombin

III

Genetic

mutation

in

the

prothrombin

-LRB-

factor

II

-RRB-

gene

Anti-phospholipid

antibodies

Hyperhomocysteinemia

Resistance

to

Activated

Protein

C

and

Deficiency

of

Protein

C

or

Protein

S

Protein

C

is

serine

proteinase

whose

activated

form

is

a

potent

inhibitor

of

coagulation

factors

V

and

VIII

Factors

V

and

VIII

are

a

part

of

the

coagulation

cascade

leading

to

conversion

of

fibrinogen

to

fibrin

Patients

with

protein

C

deficiency

frequently

manifest

superficial

and

deep

venous

thrombosis

and

pulmonary

embolism

Protein

S

and

phospholipids

are

co-factors

in

the

inactivation

of

factors

V

and

VIII

by

activated

protein

C.

An

absolute

deficiency

of

protein

C

or

S

is

relatively

rare

and

several

other

authors

have

reported

normal

levels

in

patients

with

RVO

The

concept

of

resistance

to

activated

protein

C

-LRB-

so-called

APC

resistance

-RRB-

was

first

introduced

by

Dahlbäck

et

al.

in

APC

resistance

was

subsequently

shown

to

be

a

risk

factor

for

venous

thrombosis

More

than

of

patients

with

APC

resistance

have

been

shown

to

have

a

single

point

mutation

in

factor

V

gene

This

mutation

hinders

the

degradation

of

factor

V

normally

occurring

through

protein

C.

Several

investigators

have

reported

an

increased

frequency

of

APC

resistance

in

a

cohort

of

patients

with

RVO

but

this

association

has

not

been

confirmed

in

other

studies

Moreover

some

results

are

inconclusive

due

to

small

patient

samples

or

the

lack

of

control

groups

The

meta-analysis

of

Janssen

et

al.

showed

the

odds

ratios

for

factor

V

Leiden

mutation

in

patients

with

RVO

-LRB-

CI

-RRB-

Despite

the

evidence

of

the

significance

of

Leiden

mutation

the

effect

of

this

hematological

disorder

in

the

etiology

of

RVO

is

only

marginal

Deficiency

of

Antithrombin

and

Mutation

in

the

Prothrombin

Gene

In

recent

studies

of

patients

with

RVO

no

significant

association

with

a

deficiency

of

antithrombin

or

with

prothrombin

mutation

was

found

Anti-Phospholipid

Antibodies

and

Hyperhomocysteinemia

Antiphospholipid

antibodies

-LRB-

APA

-RRB-

consist

of

a

heterogeneous

group

of

immunoglobulins

mainly

anti-cardiolipin

antibodies

-LRB-

ACA

-RRB-

and

lupus

anticoagulants

-LRB-

LA

-RRB-

Circulating

APA

leads

to

a

hypercoagulable

state

and

recurrent

thrombosis

through

thrombocyte

activation

and

inhibition

of

the

natural

anticoagulant

pathways

by

binding

of

membrane

phospholipids

Both

the

presence

of

LA

and

increased

level

of

ACA

are

associated

with

a

to

increased

risk

of

venous

thrombosis

An

elevated

level

of

the

amino

acid

homocysteine

is

now

generally

accepted

to

be

a

risk

factor

for

systemic

vascular

disease

Homocysteine

appears

to

have

a

deleterious

effect

on

vascular

endothelium

and

may

induce

increased

platelet

aggregation

and

thrombosis

Levels

of

homocysteine

may

be

increased

by

dietary

habits

prescription

medicines

or

enzymatic

mutations

affecting

homocysteine

metabolism

The

results

of

meta-analyses

confirm

total

homocysteine

to

be

an

independent

risk

factor

for

RVO

Loewenstein

et

al.

investigated

the

prevalence

of

genetic

mutation

in

the

enzyme

methylentetrahydrofolate

reductase

-LRB-

MTHFR

-RRB-

whose

impaired

activity

may

lead

to

hyperhomocysteinemia

The

prevalence

of

this

mutation

was

significantly

higher

in

patients

with

RVO

compared

with

the

incidence

of

MTHFR

in

a

control

population

However

these

results

were

not

confirmed

in

other

studies

The

meta-analysis

of

Cahill

et

al.

showed

an

association

between

retinal

vascular

occlusion

and

hyperhomocysteinemia

but

not

with

the

mutation

in

the

gene

for

MTHFR

Pathogenesis

of

Macular

Edema

in

BRVO

The

development

of

macular

edema

-LRB-

ME

-RRB-

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

-LRB-

BRB

-RRB-

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

et

al.

suggest

that

in

patients

with

BRVO

vascular

occlusion

induces

the

expression

of

vascular

endothelial

growth

factor

-LRB-

VEGF

-RRB-

and

-LRB-

-RRB-

resulting

in

BRB

breakdown

and

increased

vascular

permeability

Thus

VEGF

and

may

contribute

to

the

development

and

progression

of

vasogenic

ME

in

BRVO

ME

is

closely

associated

with

retinal

hypoxia

and

the

degree

of

hypoxia

in

the

center

of

the

macula

corresponds

to

the

decrease

in

visual

acuity

-LRB-

VA

-RRB-

If

marked

hypoxia

persists

irreversible

structural

changes

in

the

macula

occur

and

the

disturbed

VA

is

almost

always

lasting

It

is

generally

known

that

ME

and

intraretinal

hemorrhage

occurring

in

BRVO

usually

disappear

within

to

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

Clinical

Signs

and

Diagnosis

In

general

diagnosis

of

BRVO

is

not

a

problem

owing

to

its

classical

features

Major

BRVO

can

be

asymptomatic

or

with

visual

blurring

usually

involving

the

sector

of

visual

field

corresponding

to

the

area

of

the

retina

involved

In

macular

BRVO

there

is

always

a

central

visual

disturbance

with

normal

peripheral

vision

Acute

BRVO

presents

characteristic

clinical

features

with

flame-shaped

dot

and

blot

hemorrhage

soft

and

hard

exudates

retinal

edema

and

dilated

tortuous

vein

in

a

segmental

distribution

Signs

of

old

occlusion

are

vascular

sheathing

and

venous

collaterals

The

diagnosis

is

based

on

clinical

examination

under

slit

lamp

and

fundoscopy

in

artificial

mydriasis

VA

is

of

great

importance

for

future

visual

prognosis

BRVO

often

leads

to

retinal

non-perfusion

zones

in

the

occlusion

area

Fluorescein

angiography

is

particularly

useful

in

determining

the

extent

of

ME

and

ischemia

although

the

ischemic

areas

are

often

obscured

by

the

presence

of

intraretinal

hemorrhage

Retinal

neovascularization

occurs

in

of

eyes

with

an

area

of

non-perfusion

greater

than

disc

diameter

RVO

is

associated

with

an

increase

in

vascular

causes

of

death

-LRB-

both

cerebral

and

cardiac

-RRB-

in

large

prospective

follow-up

studies

In

all

patients

with

RVO

the

systemic

risk

factors

-LRB-

hypertension

diabetes

mellitus

blood

lipid

disorders

-RRB-

should

be

investigated

and

managed

by

appropriate

specialists

Natural

Course

and

Visual

Prognosis

The

visual

outcome

following

the

natural

course

of

BRVO

is

well

documented

In

general

BRVO

has

a

good

prognosis

of

eyes

have

been

reported

to

have

a

final

VA

of

or

better

even

without

any

treatment

The

natural

course

of

BRVO

is

determined

by

the

site

and

degree

of

occlusion

the

integrity

of

arterial

perfusion

to

the

affected

sector

and

the

efficiency

of

the

developing

collateral

circulation

Chronic

ME

and

bleeding

into

the

vitreous

from

neovascularizations

account

most

frequently

for

a

poor

final

VA.

Retinal

neovascularization

and

persistent

ME

develop

in

and

of

eyes

respectively

Gutman

et

al.

found

that

in

the

natural

course

of

BRVO

only

of

eyes

with

chronic

ME

retained

a

VA

of

or

better

while

had

a

final

VA

of

or

worse

He

concluded

that

chronic

ME

has

a

poor

prognosis

in

terms

of

final

VA.

Schilling

et

al.

observed

a

worse

visual

prognosis

in

cases

of

ischemic

ME

compared

to

perfused

ME

However

findings

by

showed

that

of

eyes

with

macular

ischemia

recovered

vision

within

one

year

with

a

VA

of

or

better

The

conflicting

reports

and

small

number

of

studied

eyes

make

it

difficult

to

reach

definitive

conclusions

on

visual

prognosis

in

patients

with

BRVO

VA

is

a

very

sensitive

indicator

of

the

oxygen

situation

in

the

macula

For

this

reason

pre-treatment

VA

may

be

an

important

prognostic

factor

Six

studies

analyzing

the

relation

between

initial

and

final

VA

were

found

Five

were

used

in

an

analysis

of

the

data

of

eyes

with

unsatisfactory

final

VA

-LRB-

or

worse

-RRB-

in

relation

to

initial

VA

-LRB-

Table

-RRB-

There

were

groups

the

first

consisted

of

eyes

with

an

initial

VA

of

or

better

and

the

second

group

of

eyes

with

an

initial

VA

of

or

worse

In

the

second

group

were

found

a

considerably

higher

percentage

of

eyes

with

a

final

VA

of

or

worse

regardless

whether

the

eyes

had

undergone

laser

treatment

or

not

Since

there

were

differently

divided

subgroups

for

final

VA

the

study

of

Subramanian

et

al.

was

not

included

in

our

analysis

Magargal

et

al.

investigated

the

visual

prognosis

in

eyes

with

BRVO

divided

into

two

groups

with

and

without

laser

treatment

The

obtained

analysis

illustrates

that

in

the

group

of

eyes

with

an

initial

VA

or

better

no

eye

-LRB-

not

receiving

laser

treatment

-RRB-

and

only

eyes

-LRB-

had

undergone

laser

treatment

-RRB-

had

a

final

VA

of

or

worse

whereas

in

the

group

of

eyes

with

an

initial

VA

or

worse

of

eyes

-LRB-

not

receiving

laser

treatment

-RRB-

and

of

eyes

-LRB-

had

undergone

laser

treatment

-RRB-

had

this

unsatisfactory

final

VA.

In

an

analogous

way

the

data

for

the

final

VA

or

better

in

relation

to

the

initial

VA

were

analyzed

-LRB-

Table

-RRB-

We

can

see

that

in

the

group

of

eyes

with

an

initial

VA

or

better

of

eyes

-LRB-

not

receiving

laser

treatment

-RRB-

and

of

eyes

-LRB-

had

undergone

laser

treatment

-RRB-

retained

this

good

VA

whereas

in

the

group

of

eyes

with

an

initial

VA

or

worse

only

of

eyes

-LRB-

not

receiving

laser

treatment

-RRB-

and

only

of

eyes

-LRB-

had

undergone

laser

treatment

-RRB-

had

a

final

VA

or

better

Similar

data

are

reported

in

the

other

studies

-LRB-

Tables

and

-RRB-

A

chi-squared

test

with

Yates

correction

was

used

to

analyze

the

data

In

cases

in

Table

and

in

cases

in

Table

respectively

the

results

were

statistically

significant

-LRB-

p

-RRB-

Our

analysis

shows

that

in

eyes

with

an

initial

VA

or

better

the

visual

prognosis

is

good

even

without

treatment

It

could

also

be

concluded

that

the

cases

of

BRVO

with

an

initial

VA

of

or

worse

have

a

statistically

significantly

poorer

visual

prognosis

than

those

with

an

initial

VA

of

or

better

Subramanian

et

al.

showed

that

in

patients

with

BRVO

who

underwent

laser

treatment

of

ME

the

level

of

preoperative

VA

can

be

a

useful

predictor

of

visual

outcome

TABLE

Final

visual

acuity

of

or

worse

in

relation

to

initial

visual

acuity

Chi-squared

test

with

Yates

correction

-LRB-

p

-RRB-

Initial

visual

acuity

or

better

Initial

visual

acuity

or

worse

Chi-squared

test

p

Natural

course

without

laser

treatment

-LRB-

-RRB-

-LRB-

-RRB-

Significant

-LRB-

-RRB-

-LRB-

-RRB-

Significant

Had

undergone

laser

treatment

-LRB-

-RRB-

-LRB-

-RRB-

No

-LRB-

-RRB-

-LRB-

-RRB-

No

-LRB-

-RRB-

-LRB-

-RRB-

Significant

-LRB-

-RRB-

-LRB-

-RRB-

Significant

TABLE

Final

visual

acuity

or

better

in

relation

to

initial

visual

acuity

Chi-squared

test

with

Yates

correction

-LRB-

p

-RRB-

Initial

visual

acuity

or

better

Initial

visual

acuity

or

worse

Chi-squared

test

p

Natural

course

without

laser

treatment

-LRB-

-RRB-

-LRB-

-RRB-

Significant

-LRB-

-RRB-

-LRB-

-RRB-

Significant

Had

undergone

laser

treatment

-LRB-

-RRB-

-LRB-

-RRB-

No

-LRB-

-RRB-

-LRB-

-RRB-

Significant

-LRB-

-RRB-

-LRB-

-RRB-

Significant

-LRB-

-RRB-

-LRB-

-RRB-

Significant

Treatment

Current

treatment

options

focus

on

the

sequelae

of

the

occluded

venous

branch

such

as

ME

retinal

neovascularization

vitreous

hemorrhage

and

traction

retinal

detachment

There

have

been

a

number

of

treatment

modalities

advocated

for

the

management

of

BRVO

-LRB-

Table

-RRB-

Many

studies

that

examine

interventions

for

BRVO

suffer

from

methodological

limitations

including

insufficient

power

resulting

from

small

sample

sizes

short

follow-up

periods

absence

of

a

control

group

or

inappropriate

control

group

-LRB-

absence

of

placebo

or

best

practice

intervention

as

control

groups

-RRB-

and

lack

of

distinction

between

clinical

entities

A

number

of

such

investigations

have

therefore

produced

conflicting

data

Hence

the

results

of

randomized

clinical

trials

are

the

most

important

The

complex

pathogenesis

of

this

disease

requires

investigation

and

treatment

of

all

risk

factors

-LRB-

hypertension

diabetes

mellitus

blood

lipid

disorders

hematological

disorders

-RRB-

TABLE

Treatment

modalities

for

BRVO

Anti-aggregative

therapy

and

firbrinolysis

Isovolemic

hemodilution

Laser

treatment

Intravitreal

and

periocular

application

of

steroids

Intravitreal

injection

of

VEGF

inhibitors

Sheathotomy

and

vitrectomy

Anti-Aggregative

Therapy

and

Fibrinolysis

Systemic

treatment

with

oral

acetylsalicylic

acid

subcutaneous

heparin

or

intravenous

thrombolysis

have

not

been

shown

to

be

effective

treatments

for

CRVO

while

for

BRVO

no

randomized

clinical

trials

have

been

published

as

of

the

date

of

this

review

Thrombolysis

using

administration

of

tissue

plasminogen

activator

intravitreally

or

directly

into

the

retinal

vein

-LRB-

mostly

upper

temporal

branch

close

to

the

optic

disc

-RRB-

has

been

demonstrated

to

improve

VA

in

patients

with

CRVO

but

the

results

were

based

only

on

noncomparative

interventional

series

There

is

no

general

current

acceptance

of

this

treatment

Houtsmuller

et

al.

in

a

double-blind

study

examined

the

platelet

aggregation

inhibiting

effect

of

ticlopidine

in

patients

with

BRVO

less

than

weeks

from

the

onset

of

symptoms

Compared

with

placebo

therapy

a

significant

improvement

in

VA

was

observed

with

ticlopidine

therapy

for

six

months

In

the

treated

group

of

patients

experienced

an

improvement

in

VA

whereas

of

placebo

group

reported

improvement

Troxerutin

has

been

suggested

to

inhibit

erythrocyte

and

platelet

aggregation

and

to

improve

erythrocyte

deformability

thus

reducing

blood

viscosity

and

the

retinal

microcirculation

A

double-blind

randomized

study

of

patients

with

BRVO

compared

troxerutin

with

placebo

At

months

follow-up

more

of

the

patients

receiving

troxerutin

treatment

had

a

mean

VA

of

or

better

than

the

control

group

although

this

difference

was

not

found

to

be

statistically

significant

After

months

all

patients

were

treated

with

troxerutin

for

years

At

the

completion

of

this

follow-up

period

for

those

patients

initially

treated

with

troxerutin

a

significant

improvement

in

VA

and

improvement

of

ME

was

demonstrated

The

limitation

of

this

study

is

that

there

is

no

separation

in

the

analysis

of

results

for

patients

with

BRVO

and

CRVO

who

were

included

in

the

study

too

Both

studies

mentioned

that

investigated

the

medical

treatment

of

BRVO

are

limited

by

a

small

sample

size

and

short

follow-up

period

-LRB-

and

months

-RRB-

Isovolaemic

Hemodilution

Chen

et

al.

demonstrated

positive

results

for

isovolemic

hemodilution

given

up

to

months

after

the

on-set

of

the

symptoms

of

BRVO

in

patients

with

a

hematocrit

of

or

more

In

this

randomized

controlled

study

patients

were

treated

for

weeks

with

venesection

and

volume

replacement

using

hydroxyethylstarch

and

compared

to

untreated

control

patients

After

a

one

year

follow-up

the

final

VAs

were

and

for

treated

and

untreated

patients

respectively

-LRB-

p

-RRB-

Patients

with

ME

and

a

VA

or

worse

underwent

months

after

including

into

the

study

macular

grid

laser

photocoagulation

-LRB-

MLG

-RRB-

Sector

photocoagulation

was

applied

if

ocular

neovascularization

developed

or

if

at

months

the

fluorescein

angiogram

showed

an

area

of

capillary

non-perfusion

greater

than

disc

areas

of

the

hemodiluted

patients

required

MLG

compared

to

of

the

control

group

this

difference

was

not

statistically

significant

-LRB-

p

-RRB-

Sector

photocoagulation

was

required

by

of

both

groups

of

patients

Hydroxyethylstarch

has

a

capacity

to

expand

the

plasma

volume

by

up

to

of

the

volume

infused

and

has

a

duration

of

action

of

approximately

hours

It

is

non-antigenic

and

has

a

low

incidence

of

allergic

reactions

Poupard

et

al.

randomized

patients

to

either

hemodilution

with

dextran

for

days

-LRB-

n

-RRB-

hemodilution

combined

with

heparin

for

days

-LRB-

n

-RRB-

or

heparin

treatment

for

days

followed

by

anti-vitamin

K

drugs

for

a

further

days

-LRB-

n

-RRB-

The

study

showed

that

for

those

receiving

heparin

followed

by

anti-vitamin

K

drugs

mean

VA

remained

unchanged

to

baseline

values

by

days

For

those

treated

with

hemodilution

and

heparin

a

statistically

significant

increase

in

VA

was

found

by

days

For

those

treated

with

hemodilution

alone

a

significant

improvement

in

VA

was

found

by

day

In

a

randomized

study

by

Hansen

et

al.

of

patients

with

BRVO

patients

were

treated

by

hemodilution

for

a

period

of

to

weeks

-LRB-

targeted

hematocrit

-RRB-

A

control

group

of

patients

were

only

observed

At

follow-up

months

later

patients

had

completed

the

therapy

Seven

of

the

who

received

hemodilution

demonstrated

a

VA

increase

of

lines

or

more

compared

with

of

the

patients

who

did

not

receive

hemodilution

-LRB-

p

-RRB-

Reported

complications

of

hemodilution

include

headache

exertional

dyspnea

tiredness

deep

vein

thrombosis

and

hypotension

The

treatment

was

noted

to

be

generally

well-tolerated

even

in

elderly

patients

The

use

of

hemodilution

to

treat

BRVO

is

currently

not

generally

accepted

Interpretation

of

the

above-mentioned

studies

is

difficult

because

most

of

them

incorporated

other

treatments

in

combination

with

the

hemodilution

Further

prospective

randomized

trials

with

adequate

controls

and

sufficient

follow-up

are

required

for

any

definitive

conclusions

and

recommendations

Arteriovenous

Crossing

Sheathotomy

and

Vitrectomy

Osterloh

and

first

reported

improvement

in

VA

in

patients

with

BRVO

after

treatment

using

the

technique

of

surgical

sheathotomy

The

principle

steps

of

this

procedure

are

a

pars

plana

vitrectomy

followed

by

separation

of

the

retinal

artery

from

the

vein

by

creating

an

incision

in

the

adventitial

sheath

adjacent

to

the

A/V

crossing

and

then

separation

of

the

adhesions

Several

studies

have

shown

significantly

better

functional

outcomes

in

patients

treated

by

sheathotomy

compared

to

controls

-LRB-

Table

-RRB-

Reported

complications

are

few

but

include

cataract

hemorrhage

retinal

tears

postoperative

gliosis

and

retinal

detachment

described

a

combination

of

A/V

sheathotomy

and

injection

of

thrombolytic

into

the

occluded

vein

which

resulted

in

thrombus

release

in

cases

and

significant

correlation

with

early

surgery

and

better

final

VA.

The

role

of

the

sheathotomy

alone

in

visual

improvement

is

insufficiently

clear

Some

authors

suggest

that

vitrectomy

is

the

most

important

part

of

the

sheathotomy

surgery

leading

to

reduction

of

ME

Yamamoto

et

al.

compared

the

effect

of

sheathotomy

combined

with

vitrectomy

to

the

effect

of

vitrectomy

alone

and

found

no

advantage

of

sheathotomy

Eyes

with

pre-existing

posterior

vitreous

detachment

were

not

studied

For

this

reason

the

benefit

of

vitrectomy

of

these

eyes

is

unknown

Surgical

detachment

of

posterior

hyaloid

could

be

more

important

than

the

sheathotomy

itself

The

vitreous

is

postulated

to

have

a

role

in

the

pathogenesis

of

neovascularization

and

ME

which

may

complicate

BRVO

and

its

removal

may

help

in

the

management

of

these

sight

threatening

complications

Vitrectomy

and

removal

of

the

posterior

hyaloid

with

peeling

of

the

internal

limiting

membrane

-LRB-

ILM

-RRB-

appears

to

improve

oxygenation

of

the

retina

which

may

lead

to

visual

improvement

Peeling

of

the

ILM

improves

the

surgical

outcome

during

A/V

adventitial

sheathotomy

too

To

date

no

randomized

clinical

trials

on

the

surgical

treatment

of

BRVO

have

been

published

Any

evidence

supporting

these

procedures

is

based

on

non-ramdomized

case

series

only

TABLE

Summary

of

studies

evaluating

the

treatment

of

macular

edema

in

BRVO

by

sheathotomy

-LRB-

VA

visual

acuity

ME

macular

edema

ILM

internal

limiting

membrane

-RRB-

Author

Study

type

Patients

Follow-up

-LRB-

mean

-RRB-

Outcomes

Comments

Osterloh

and

Case

report

eye

months

VA

improved

from

to

First

report

of

sheathotomy

Garcia-Arumi

et

al.

Prospective

interventional

nonrandomized

study

eyes

all

underwent

vitrectomy

sheathotomy

and

injection

of

mg

of

tissue

plasminogen

activator

into

occluded

vein

months

Thrombus

release

in

eyes

-LRB-

-RRB-

correlated

with

early

surgery

VA

increased

from

to

-LRB-

p

-RRB-

Yamamoto

et

al.

Retrospective

interventional

comparative

case

series

eyes

sheathotomy

control

eyes

-LRB-

posterior

vitreous

detachment

via

vitrectomy

-RRB-

months

VA

significantly

better

in

both

groups

-LRB-

p

and

p

respectively

-RRB-

VA

and

foveal

thickness

were

not

significantly

different

between

the

groups

Charbonnel

et

al.

Prospective

nonrandomized

interventional

case

series

eyes

sheathotomy

months

Improvement

in

VA

ETDRS

lines

in

eyes

-LRB-

-RRB-

Absence

of

previous

posterior

vitreous

detachment

correlated

with

improvement

in

VA.

Sohn

et

al.

Retrospective

interventional

case

series

eyes

sheathotomy

ILM

peeling

in

all

eyes

months

Improvement

in

VA

-LRB-

log

MAR

-RRB-

from

to

-LRB-

p

-RRB-

All

eyes

pretreated

with

grid

laser

or

triamcinolone

Kumagai

et

al.

Prospective

randomized

comparative

interventional

study

Group

eyes

sheathotomy

Group

controls

-LRB-

vitrectomy

without

sheathotomy

-RRB-

months

VA

-LRB-

log

MAR

-RRB-

in

group

In

group

Differences

between

group

and

was

not

significant

Avci

et

al.

Retrospective

interventional

comparative

case

series

eyes

sheathotomy

control

eyes

grid

laser

photocoagulation

months

VA

-LRB-

log

MAR

-RRB-

sheathotomy

Grid

laser

Difference

was

significant

Horio

et

al.

Interventional

case

series

eyes

months

Significant

improvement

in

retinal

blood

flow

-LRB-

p

-RRB-

and

reduced

macular

thickness

-LRB-

p

-RRB-

Lakhanpal

et

al.

Retrospective

interventional

case

series

eyes

weeks

VA

-LRB-

logMAR

-RRB-

improved

from

to

-LRB-

p

-RRB-

transvitreal

limited

arteriovenous

crossing

manipulation

without

vitrectomy

Mester

et

al.

Prospective

interventional

nonrandomized

case-control

study

eyes

sheathotomy

eyes

additionally

ILM

peeling

control

eyes

weeks

patients

-LRB-

-RRB-

gained

lines

of

VA.

Better

result

in

patients

with

ILM

peeling

ME

and

intraretinal

hemorrhage

resorbed

in

all

patients

All

patients

had

isovolaemic

hemodilution

for

days

Opremcak

et

al.

Prospective

interventional

case

series

eyes

years

Snellen

VA

improved

in

patients

-LRB-

-RRB-

by

an

average

of

lines

vision

-LRB-

range

lines

-RRB-

In

patients

resolution

of

ME

but

no

improvement

of

VA.

Retinal

vascular

bleeding

in

patients

Asensio

Sanchez

et

al.

Prospective

interventional

nonrandomized

study

eyes

sheathotomy

eyes

underwent

additionally

ILM

peeling

months

VA

improved

in

patients

-LRB-

-RRB-

Better

results

in

patients

with

ILM

peeling

Lerche

et

al.

Prospective

nonrandomized

intervention

case

series

eyes

sheathotomy

months

VA

-LRB-

logMAR

-RRB-

improved

from

to

Mason

et

al.

Prospective

nonrandomized

comparative

interventional

study

with

concurrent

control

group

eyes

sheathotomy

control

eyes

-LRB-

of

them

without

intervention

and

another

underwent

grid

laser

-RRB-

months

-LRB-

sheathotomy

-RRB-

months

-LRB-

controls

-RRB-

VA

improvement

Sheathotomy

from

to

Controls

from

to

-LRB-

p

-RRB-

of

the

surgical

group

had

final

VA

compared

with

of

the

controls

Data

only

for

whole

control

group

together

Cahil

et

al.

Retrospective

non-controlled

case

series

eyes

sheathotomy

months

Resolution

of

ME

in

-LRB-

-RRB-

patients

reduction

in

-LRB-

-RRB-

and

persistence

in

-LRB-

-RRB-

Becquet

et

al.

Prospective

nonrandomized

interventional

case

series

eyes

-LRB-

sheathotomy

ILM

peeling

controls

-LRB-

ILM

peeling

only

-RRB-

months

Significant

improvement

of

VA

in

both

groups

No

difference

in

VA

or

foveolar

thickness

between

the

groups

-LRB-

p

p

respectively

-RRB-

Martinez-Soroa

et

al.

Retrospective

interventional

case

series

eyes

sheathotomy

months

Improvement

in

VA

from

to

patients

improved

lines

-LRB-

Snellen

-RRB-

Le

Retrospective

interventional

case

series

eyes

sheathotomy

months

No

improvement

in

VA

observed

All

patients

with

initial

VA

Dotrelova

et

al.

Retrospective

interventional

case

series

eyes

sheathotomy

months

VA

improved

in

patients

to

in

patient

stabilized

-LRB-

-RRB-

Shah

et

al.

Retrospective

interventional

case

series

eyes

sheathotomy

years

VA

preoperative

in

all

patients

Improved

in

eyes

from

to

eye

with

counting

fingers

remained

unchanged

Crafoord

et

al.

Retrospective

interventional

case

series

eyes

sheathotomy

months

VA

improved

in

eyes

-LRB-

-RRB-

in

eye

-LRB-

-RRB-

remained

unchanged

and

deteriored

in

eyes

-LRB-

-RRB-

patients

received

additionally

mg

triamcinolone

acetonide

at

the

end

of

the

surgery

Han

et

al.

Retrospective

interventional

case

series

eyes

pars

plana

vitrectomy

and

dissection

of

the

arteriovenous

crossing

without

separation

of

the

vessels

months

In

eyes

-LRB-

-RRB-

improved

VA

lines

Mean

improvement

of

VA

-LRB-

logMAR

-RRB-

was

-LRB-

p

-RRB-

Steroids

Intravitreal

Corticosteroids

In

several

nonrandomized

comparative

studies

intravitreal

corticosteroids

were

successfully

used

for

the

treatment

of

BRVO

Currently

published

randomized

studies

are

very

rare

and

limited

by

virtue

of

evaluating

patients

with

ME

of

different

etiology

making

comparisons

difficult

In

various

studied

doses

from

to

mg

triamcinolone

acetonide

-LRB-

TA

-RRB-

has

been

reported

to

be

-LRB-

Table

-RRB-

In

a

randomized

interventional

three-arm

clinical

trial

Avitable

et

al.

compared

the

results

of

treating

diabetic

patients

and

a

small

group

of

BVRO

patients

with

cystoid

ME

by

TA

and

MLG

From

a

total

of

patients

were

treated

by

TA

-LRB-

mg

-RRB-

underwent

MLG

and

in

patients

these

methods

were

combined

-LRB-

TA

MLG

-RRB-

The

greatest

improvement

in

VA

was

found

in

patients

treated

by

TA

combined

with

MLG

VA

-LRB-

log

MAR

-RRB-

in

this

group

increased

significantly

from

at

baseline

to

at

the

end

of

follow-up

months

later

-LRB-

p

-RRB-

In

patients

treated

by

TA

VA

improved

significantly

from

at

baseline

to

at

months

after

injection

-LRB-

p

-RRB-

VA

in

the

group

of

patients

treated

by

MLG

remained

the

same

The

results

of

this

study

are

limited

however

owing

to

the

different

ME

etiologies

in

evaluated

patients

only

patients

had

ME

secondary

to

BRVO

Oh

et

al.

used

a

retrospective

interventional

case

series

to

compare

VA

after

single

TA

injection

-LRB-

mg

-RRB-

in

patients

with

mean

duration

of

ME

months

after

onset

of

BRVO

versus

patients

with

ME

months

after

onset

In

patients

with

a

disease

duration

months

VA

significantly

improved

from

baseline

over

months

of

follow-up

However

in

those

with

a

duration

of

months

improved

VA

though

apparent

at

one

month

was

not

maintained

at

or

months

after

TA

injection

This

study

is

limited

by

its

retrospective

design

and

short

follow-up

period

Ozkiris

et

al.

evaluated

the

effect

of

TA

injection

on

persistent

ME

in

BRVO

that

failed

to

respond

to

previous

laser

photocoagulation

During

a

mean

follow-up

time

of

months

best

corrected

VA

-LRB-

log

MAR

-RRB-

improved

significantly

-LRB-

p

-RRB-

from

at

baseline

to

at

one

month

after

the

injection

VA

after

months

was

and

at

the

end

of

follow-up

was

The

authors

concluded

that

intravitreal

application

of

TA

may

be

helpful

in

patients

who

do

not

respond

to

laser

photocoagulation

However

in

published

studies

the

resulting

reduced

macular

thickness

and

improved

VA

is

only

temporary

and

requires

repeated

treatment

One

to

four

times

re-application

has

been

reported

Cekic

et

al.

performed

a

retrospective

chart

review

of

patients

who

underwent

intravitreal

injections

with

mg

TA

Six

eyes

received

a

single

injection

Repeated

injections

were

performed

in

eye

twice

eyes

three

times

and

eyes

four

times

During

a

mean

follow-up

of

months

central

foveal

thickness

decreased

by

more

than

Final

VA

improved

in

eyes

-LRB-

range

Snellen

lines

-RRB-

remained

the

same

in

eyes

-LRB-

range

Snellen

lines

-RRB-

and

worsened

in

eyes

-LRB-

range

Snellen

lines

-RRB-

compared

to

baseline

Retinal

thickness

decreased

in

all

cases

while

vision

improved

in

most

cases

One

of

the

most

common

side

effects

of

TA

was

steroid-induced

elevation

of

intraocular

pressure

Other

complications

were

infectious

endophthalmitis

post-injection

steroid-induced

cataract

and

retinal

detachment

Reported

risk

of

infectious

endophthalmitis

per

injection

range

was

from

to

The

most

recent

report

by

Bhavsar

et

al.

found

in

two

large

studies-Diabetic

Retinopathy

Clinical

Research

Network

-LRB-

DRCR.net

-RRB-

and

SCORE

-LRB-

Standard

Care

versus

Corticosteroid

for

Retinal

Vein

Occlusion

-RRB-

an

endophthalmitis

prevalence

of

-LRB-

one

case

in

the

injections

-RRB-

TABLE

Summary

of

studies

evaluating

the

treatment

of

macular

edema

in

BRVO

by

intravitreal

application

of

triamcinolone

acetonide

-LRB-

TA

triamcinolone

acetonide

VA

visual

acuity

ME

macular

edema

MLG

macular

laser

grid

photocoagulation

-RRB-

Author

Study

type

Patients

Follow-up

-LRB-

mean

-RRB-

Outcomes

Comments

Avitabile

et

al.

Randomized

interventional

parallel

three-arm

clinical

trial

Intravitreal

TA

-LRB-

mg

-RRB-

eyes

MLG

eyes

TA+MLG

eyes

months

TA

group

VA

improved

from

to

log

MAR

-LRB-

p

-RRB-

MLG-group

VA

unchanged

TA+MLG

group

VA

improved

from

to

logMAR

-LRB-

p

-RRB-

Different

etiology

of

ME

only

eyes

with

BRVO

Oh

et

al.

Retrospective

interventional

comparative

case

series

eyes

with

ME

-LRB-

mg

TA

-RRB-

Disease

duration

eyes

months

eyes

months

months

Group

months

VA

-LRB-

logMAR

-RRB-

improved

from

to

in

month

-LRB-

p

-RRB-

and

to

in

months

-LRB-

p

-RRB-

Ozkiris

et

al.

Retrospective

non-controlled

case

series

treated

eyes

-LRB-

mg

TA

-RRB-

months

VA

-LRB-

logMAR

-RRB-

improved

from

to

VA

improved

in

eyes

and

remained

unchanged

in

eyes

Jonas

et

al.

Prospective

nonrandomized

comparative

study

treated

eyes

-LRB-

mg

TA

-RRB-

untreated

controls

TA

patients

months

Controls

months

TA

patients

VA

increased

from

to

-LRB-

p

-RRB-

Controls

VA

decreased

significantly

-LRB-

p

-RRB-

VA

increased

higher

in

non-ischemic

group

Significant

increase

of

intraocular

pressure

in

treated

group

Cekic

et

al.

Retrospective

non-controlled

case

series

eyes

-LRB-

mg

TA

-RRB-

months

VA

improved

in

eyes

remained

the

same

in

eyes

worsened

in

eyes

Foveolar

thickness

decreased

in

of

patients

-LRB-

p

-RRB-

VA

improvement

significantly

correlated

with

patient

age

-LRB-

p

-RRB-

Lee

et

al.

Retrospective

non-controlled

case

series

eyes

-LRB-

mg

TA

-RRB-

days

Improvement

in

VA

lines

in

eyes

-LRB-

-RRB-

VA

from

to

final

eyes

treated

with

re-application

of

TA

Ozkiris

et

al.

Retrospective

interventional

comparative

case

series

eyes

-LRB-

mg

TA

-RRB-

eyes

MLG

months

VA

-LRB-

logMAR

-RRB-

improved

in

TA

group

from

to

and

in

MLG

group

from

to

-LRB-

in

both

groups

p

-RRB-

Improvement

in

TA

group

was

significantly

higher

than

in

MLG

-LRB-

p

-RRB-

Yepremyan

et

al.

Retrospective

non-controlled

case

series

eyes

-LRB-

mg

TA

-RRB-

months

VA

improved

lines

in

of

eyes

after

month

and

in

of

eyes

at

last

follow

up

eyes

developed

recurrent

ME

at

an

average

of

months

after

initial

TA

injection

Cheng

et

al.

Prospective

nonrandomized

interventional

comparative

study

eyes

-LRB-

mg

TA

-RRB-

controls

-LRB-

without

TA

-RRB-

days

in

TA-group

days

in

controls

VA

-LRB-

logMAR

-RRB-

In

TA-group

improvement

from

to

-LRB-

p

-RRB-

No

significant

change

of

VA

in

controls

Significant

reduction

of

ME

in

TA-group

-LRB-

P

-RRB-

Chen

et

al.

Case

report

eye

-LRB-

mg

TA

-RRB-

months

Improvement

in

VA

from

counting

fingers

to

Eye

with

macular

ischaemia

Chen

et

al.

Prospective

interventional

non-controlled

case

series

eyes

-LRB-

mg

TA

-RRB-

All

patients

completed

months

eyes

completed

months

VA

-LRB-

logMAR

-RRB-

improved

from

to

-LRB-

p

-RRB-

after

months

no

significant

difference

in

VA

after

and

months

Eye

with

macular

ischaemia

All

eyes

with

macular

ischaemia

Tsujikawa

et

al.

Prospective

interventional

non-controlled

case

series

eyes

-LRB-

vitrectomy

mg

TA

intravitreal

-RRB-

eyes

of

them

with

recurrent

ME

received

sub-tenon

mg

TA

months

of

eyes

rapid

resolution

of

ME

within

months

-LRB-

p

-RRB-

eyes

-LRB-

-RRB-

received

sub-tenon

TA

because

of

recurrent

ME

Final

VA

-LRB-

logMAR

-RRB-

improved

from

to

-LRB-

p

-RRB-

eyes

with

vitrectomy

underwent

additional

phacoemulsification

with

lens

implantation

Karacorlu

et

al.

Prospective

interventional

non-controlled

case

series

eyes

-LRB-

mg

TA

-RRB-

All

eyes

with

serous

macular

detachment

months

After

TA

regression

of

ME

and

serous

macular

detachment

in

all

eyes

After

months

recurrence

in

eyes

-LRB-

-RRB-

re-treatment

occurred

Final

VA

improved

in

eyes

-LRB-

-RRB-

Krepler

et

al.

Prospective

interventional

non-controlled

case

series

eyes

-LRB-

mg

TA

-RRB-

months

Significant

improvement

in

reading

VA

only

after

month

-LRB-

p

-RRB-

No

significant

improvement

in

VA

for

distance

No

significant

reduction

in

macular

thickness

eyes

non-ischaemic

BRVO

eyes

ischaemic

BRVO

Degenring

et

al.

Case

report

patients

eye

BRVO

eye

CRVO

-LRB-

mg

TA

-RRB-

weeks

Patient

with

BRVO

improved

VA

from

to

Patient

with

CRVO

from

to

Wakabayshi

et

al.

Prospective

interventional

non-controlled

case

series

eyes

with

CRVO

eyes

with

BRVO

All

eyes

received

sub-tenon

injection

of

mg

TA

months

eyes

-LRB-

-RRB-

improved

VA

and

eyes

-LRB-

-RRB-

had

worsening

of

VA

at

the

time

of

final

examination

Reduction

of

ME

of

initial

thickness

in

eyes

-LRB-

-RRB-

Because

of

recurrent

ME

in

eyes

repeated

sub-tenon

application

of

TA

eye

with

BRVO

pretreated

with

laser

photocoagulation

because

of

retinal

ischemia

Salinas-Alaman

et

al.

Retrospective

interventional

case

series

eyes

-LRB-

mg

TA

-RRB-

months

Improvement

of

VA

in

eyes

eye

underwent

re-injection

after

months

because

of

recurrent

ME

Hirano

et

al.

Retrospective

interventional

comparative

case-control

study

eyes

TA-injected

group

-LRB-

simultaneous

intravitreal

and

sub-tenon

TA

injection

-RRB-

eyes

vitrectomy

with

TA

group

-LRB-

treated

by

vitrectomy

and

intravitreal

or

sub-tenon

TA

-RRB-

months

VA

improved

significantly

from

baseline

in

both

the

TA-injected

-LRB-

p

-RRB-

and

vitrectomy

with

TA

groups

-LRB-

p

-RRB-

There

was

no

significant

difference

in

VA

and

macular

thickness

between

the

two

groups

Kuppermann

et

al.

Randomized

interventional

clinical

trial

-LRB-

with

venous

occlusion

-RRB-

eyes

in

each

group

I.

μg

Posurdex

II

μg

Posurdex

III

controls

months

Improvement

of

VA

of

lines

-LRB-

ETDRS

-RRB-

eyes

in

group

μg

Posurdex

in

μg

Posurdex

and

in

control

group

-LRB-

p

versus

μg

group

p

versus

μg

group

-RRB-

Preliminary

report

eyes

with

retinal

venous

occlusion

include

eyes

with

CRVO

and

BRVO

Most

published

studies

on

intravitreal

TA

for

BRVO

however

suffer

from

two

serious

flaws

either

the

designs

are

not

randomized

or

they

often

do

not

clearly

differentiate

between

nonischemic

types

and

ischemic

types

of

occlusion

To

compare

the

effectiveness

and

safety

of

standard

care

versus

TA

injection

in

the

treatment

of

ME

in

patients

with

CRVO

and

BRVO

the

multicenter

randomized

study

SCORE

is

ongoing

-LRB-

-RRB-

In

each

of

the

two

disease

areas

participants

will

be

randomized

in

a

ratio

to

one

of

three

groups

standard

care

intravitreal

mg

of

TA

or

mg

of

TA

The

follow-up

is

planned

for

years

The

results

are

not

published

as

yet

Biodegradable

intravitreal

implants

may

allow

steroid

delivery

over

a

more

sustained

period

permitting

longer

duration

of

action

A

multicenter

randomized

clinical

trial

which

evaluates

implantation

of

dexamethasone

μg

or

μg

-LRB-

Posurdex

-RRB-

versus

observation

-LRB-

no

therapy

-RRB-

for

ME

secondary

to

a

variety

of

retinal

disorders

-LRB-

including

BRVO

-RRB-

has

been

reported

The

preliminary

results

of

all

evaluated

patients

showed

that

an

improvement

in

VA

of

letters

or

more

-LRB-

in

ETDRS

-RRB-

was

achieved

by

a

greater

proportion

of

patients

treated

with

dexamethasone

μg

-LRB-

-RRB-

or

μg

-LRB-

-RRB-

than

untreated

patients

-LRB-

p

versus

μg

group

p

versus

μg

group

-RRB-

The

results

were

similar

for

patients

with

diabetic

retinopathy

retinal

vein

occlusion

or

uveitis

or

Irvine-Gass

syndrome

In

total

patients

with

BRVO

were

randomized

to

receive

μg

or

μg

dexamethasone

or

observation

-LRB-

no

therapy

-RRB-

In

the

case

of

RVO

the

effect

of

the

treatment

was

evaluated

only

in

a

common

group

-LRB-

CRVO

and

BRVO

patients

together

-RRB-

an

improvement

in

VA

of

letters

or

more

was

achieved

in

of

untreated

patients

versus

of

patients

treated

with

dexamethasone

μg

The

number

of

patients

with

an

increase

in

intraocular

pressure

of

more

than

mmHg

from

baseline

anytime

during

the

study

was

for

μg

for

μg

and

for

the

untreated

controls

Periocular

Application

of

Triamcinolone

Acetonide

Kawaji

et

al.

evaluated

in

patients

the

effectiveness

and

safety

of

trans-tenon

retrobulbar

injection

of

mg

of

TA

for

ME

associated

with

BRVO

after

vitrectomy

Improvement

in

VA

was

seen

in

-LRB-

-RRB-

eyes

Hayashi

et

al.

compared

in

a

randomized

clinical

trial

the

short-term

effect

of

intravitreal

versus

retrobulbar

injection

of

TA

for

the

treatment

of

ME

caused

by

BRVO

Sixty

patients

received

either

a

single

intravitreal

injection

-LRB-

mg

-RRB-

or

repeated

retrobulbar

injections

-LRB-

mg

three

times

-RRB-

of

TA

The

first

injection

in

the

retrobulbar

group

was

given

approximately

one

week

after

focal

laser

photocoagulation

Foveal

thickness

macular

volume

and

improvement

in

VA

were

significantly

better

after

intravitreal

injection

than

after

repeated

retrobulbar

injections

The

need

for

re-injections

was

significantly

greater

in

the

retrobulbar

group

than

in

the

intravitreal

group

Intravitreal

Injection

of

VEGF

Inhibitors

VEGF

inhibitors

are

a

treatment

option

for

ME

associated

with

RVO

that

target

the

disease

at

the

causal

molecular

level

Randomized

studies

evaluating

the

results

of

treatment

of

all

available

VEGF

inhibitors

-LRB-

bevacizumab

ranibizumab

and

pegaptanib

-RRB-

are

ongoing

Case

reports

small

retrospective

or

prospective

non-controlled

studies

of

VEGF

inhibitors

in

the

treatment

of

ME

and

retinal

neovascularizations

secondary

to

BRVO

have

been

published

Rosenfeld

et

al.

first

reported

improved

VA

and

reduced

ME

measured

by

optical

coherent

tomography

-LRB-

OCT

-RRB-

following

intravitreal

injection

of

bevacizumab

for

recurrent

ME

secondary

to

CRVO

in

an

eye

previously

treated

by

intravitreal

TA

injection

In

a

short-term

study

Iturralde

et

al.

treated

eyes

of

CRVO

with

ME

that

had

failed

intravitreal

corticosteroid

therapy

and

nearly

every

eye

showed

some

anatomic

or

VA

improvement

following

bevacizumab

injection

In

various

reports

doses

from

to

mg

bevacizumab

have

been

intravitreally

administrated

The

most

recently

published

studies

evaluated

the

results

in

a

group

of

patients

with

BRVO

combined

with

patients

with

CRVO

In

all

of

these

studies

bevacizumab

injection

improved

VA

and

reduced

macular

thickness

measured

by

OCT

within

the

first

to

weeks

Few

studies

are

available

for

BRVO

patients

alone

Rabena

et

al.

reported

a

significantly

increased

VA

and

reduced

macular

thickness

after

treatment

with

mg

bevacizumab

in

a

retrospective

study

of

patients

with

BRVO

Recurrent

ME

was

observed

in

-LRB-

-RRB-

patients

an

average

of

months

after

the

initial

injection

These

patients

were

reinjected

and

all

showed

moderate

to

complete

reduction

in

ME

The

limitations

of

this

retrospective

study

are

short

follow-up

and

lack

of

control

group

Additionally

most

of

the

eyes

in

the

study

were

previously

treated

and

thus

failed

standard

treatment

and

perhaps

represent

a

group

unlikely

to

benefit

from

any

treatment

All

published

reports

provide

evidence

that

this

treatment

is

well

tolerated

The

most

common

adverse

events

were

conjunctival

hyperemia

and

subconjunctival

hemorrhage

at

the

injection

site

However

the

duration

of

reduced

ME

after

bevacizumab

administration

is

currently

unknown

Frequent

repeated

injections

are

required

to

prevent

a

rebound

effect

with

no

clearly

defined

endpoint

Campochiaro

et

al.

presented

preliminary

results

of

a

randomized

study

in

the

treatment

of

BRVO

with

intravitreal

injection

of

ranibizumab

at

the

Annual

Meeting

of

Association

on

Research

and

Vision

in

Ophthalmology

-LRB-

ARVO

-RRB-

Patients

with

ME

due

to

CRVO

or

BRVO

were

randomized

to

receive

monthly

injections

of

or

mg

of

ranibizumab

Interim

results

without

regard

to

treatment

assignment

which

is

unknown

showed

that

randomized

patients

with

BRVO

gained

an

improvement

in

VA

-LRB-

in

ETDRS

-RRB-

from

to

letters

and

a

reduction

in

ME

from

to

μm

after

months

of

treatment

The

endpoint

results

are

expected

to

clarify

any

differences

between

the

treatment

groups

Another

indication

for

anti-VEGF

drugs

are

retinal

neovascularizations

rubeosis

iridis

and

neovascular

glaucoma

Rapid

regression

of

neovascularizations

and

compensation

of

intraocular

pressure

have

been

described

in

several

studies

Intracameral

application

of

bevacizumab

as

successful

treatment

of

rubeosis

iridis

and

neovascular

glaucoma

has

also

been

reported

Prospective

controlled

studies

are

mandatory

to

develop

standardized

treatment

protocols

that

allow

safe

and

effective

application

of

anti-VEGF

drugs

Laser

Treatment

Laser

treatment

is

an

established

method

for

use

in

patients

with

BRVO

A

large

number

of

publications

concerning

the

role

of

photocoagulation

in

the

management

of

BRVO

have

appeared

Various

laser

techniques

can

be

used

macula

grid

photocoagulation

and

the

method

of

arterial

crimping

for

treatment

of

ME

and

peripheral

scatter

photocoagulation

for

treatment

of

retinal

and/or

disc

neovascularization

Macular

Grid

Laser

Photocoagulation

The

Branch

vein

occlusion

study

group

remains

the

largest

randomized

prospective

trial

that

has

evaluated

the

efficacy

of

grid-pattern

laser

photocoagulation

for

the

treatment

of

ME

in

BRVO

In

this

study

only

eyes

with

recent

BRVO

perfused

ME

resolved

foveal

hemorrhage

VA

or

worse

and

no

other

ocular

comorbidities

were

included

After

a

follow-up

period

of

treated

eyes

gained

improvement

of

or

more

lines

from

baseline

as

opposed

to

of

untreated

eyes

The

number

of

eyes

that

lost

or

more

lines

was

not

significantly

different

in

the

two

groups

Parodi

et

al.

published

two

randomized

controlled

studies

in

which

no

significant

benefit

of

MLG

on

VA

was

found

MLG

is

recommended

as

an

effective

treatment

to

reduce

the

ME

in

BRVO

after

a

period

of

to

months

after

onset

and

following

absorption

of

the

majority

of

hemorrhage

if

VA

is

or

worse

If

the

fluorescein

angiogram

reveals

macular

nonperfusion

laser

therapy

is

not

warranted

Subramanian

et

al.

recommended

laser

treatment

in

patients

with

poor

VA

-LRB-

or

worse

-RRB-

secondary

to

ME

due

to

BRVO

before

more

aggressive

approaches

-LRB-

as

intravitreal

TA

-RRB-

Argon

MLG

is

usually

used

for

this

purpose

However

diode

laser

-LRB-

nm

-RRB-

and

krypton

red

laser

-LRB-

nm

-RRB-

also

can

be

used

Scatter

Photocoagulation

The

randomized

controlled

study

by

Branch

vein

occlusion

study

reported

that

peripheral

scatter

laser

photocoagulation

significantly

reduced

the

development

of

retinal

neovascularization

and

vitreous

hemorrhage

This

study

also

demonstrated

that

if

all

eyes

with

large

retinal

nonperfusion

were

treated

of

these

patients

would

never

develop

neovascularization

If

only

the

eyes

that

develop

neovascularization

were

treated

the

events

of

vitreous

hemorrhage

would

decrease

from

to

Since

loss

in

the

lower

part

of

the

visual

field

can

produce

marked

disability

and

BRVO

involving

the

superior

retina

is

common

a

significant

worsening

of

visual

fields

with

laser

treatment

becomes

a

very

important

clinically

relevant

finding

Therefore

waiting

is

generally

advocated

until

neovascularization

actually

develops

before

scatter

photocoagulation

is

considered

Arteriolar

Constriction

An

alternative

type

of

laser

treatment

involves

arteriolar

constriction

-LRB-

called

also

crimping

technique

-RRB-

and

may

be

considered

in

order

to

reduce

the

inflow

into

the

affected

area

if

the

ME

is

excessive

This

procedure

was

first

described

by

in

It

may

lead

to

a

decrease

in

arterial

pressure

in

the

occluded

region

resulting

in

better

drainage

of

the

ME

due

to

reduced

blood

inflow

The

technique

is

employed

by

placing

coagulations

at

approximate

intervals

of

disc

diameter

-LRB-

using

the

green

beam

of

argon

laser

-RRB-

through

the

afferent

arteriole

in

the

region

of

venous

blockage

In

Jalkh

et

al.

proposed

their

own

modification

of

this

method

and

published

the

results

obtained

in

eyes

In

this

study

arterial

constriction

was

applied

in

the

treatment

of

the

chronic

stage

of

BRVO

Rehak

et

al.

published

several

studies

describing

the

modified

arteriolar

constriction

in

patients

with

BRVO

This

technique

consists

of

the

application

of

coalescent

coagulation

spots

through

the

afferent

arteriole

that

supports

the

occluded

venous

region

of

patients

treated

by

this

method

within

the

first

months

after

the

onset

of

occlusion

achieved

a

final

VA

or

better

In

a

study

by

Erdol

and

Akyol

the

improvement

in

VA

was

higher

in

a

group

of

patients

receiving

the

MLG

combined

with

arteriolar

constriction

than

in

a

group

treated

by

MLG

only

However

the

difference

in

the

resolution

of

ME

between

the

groups

was

not

statistically

significant

The

authors

suggest

that

arteriolar

constriction

in

addition

to

grid

pattern

laser

photocoagulation

is

more

effective

for

resolving

ME

in

patients

with

BRVO

CONCLUSIONS

The

pathogenesis

of

BRVO

is

multifactorial

Its

resulting

visual

loss

is

due

primarily

to

ME

macular

nonperfusion

and

retinal

neovascularization

A

large

number

of

treatments

have

been

advocated

in

its

management

Unfortunately

almost

all

of

these

lack

sufficient

evidence

for

their

effectiveness

Randomized

prospective

trials

are

essential

The

only

one

established

treatment

for

ME

is

macular

grid

photocoagulation

in

patients

with

BRVO

longer

than

months

and

a

VA

of

or

worse

Additionally

the

initial

VA

may

play

a

crucial

role

in

the

prognosis

of

BRVO

and

determinates

the

final

VA.

branch retinal vein occlusion
pathogenesis
risk factors
treatment
visual prognosis


Cancer screening in France : subjects ' and physicians ' attitudes Objective Since screening for cancer has been advocated , funded , and promoted in France , it is important to evaluate the attitudes of subjects in the general population and general practitioners -LRB- GPs -RRB- toward cancer screening strategies . Introduction Early detection of cancer can theoretically prolong overall survival of the screened subjects . Reductions in cancer-related mortality have been demonstrated for mammography for breast cancer -LRB- BC -RRB- and fecal occult blood test -LRB- FOBT -RRB- for colorectal cancer -LRB- CRC -RRB- -LSB- 1 , 2 -RSB- . For these two cancers , mass-screening programs are implemented in France , in which targeted subjects are contacted by mail . The US Preventive Services Task Force guidelines rate CRC screening as `` A '' -LRB- strongly recommended -RRB- , BC screening as `` B '' -LRB- recommended -RRB- , and both prostate cancer -LRB- PC -RRB- and lung cancer -LRB- LC -RRB- screenings as `` I '' -LRB- evidence insufficient to come down in favor or against screening -RRB- -LSB- 3 -RSB- . The objectives of the nationwide EDIFICE opinion poll carried out in France were to collect data at the national level -LRB- the level of funding -RRB- about -LRB- 1 -RRB- subjects ' individual access to cancer screening procedures -LRB- through organized programs or on subjects ' own initiative -RRB- and -LRB- 2 -RRB- about general practitioners ' -LRB- GPs -RRB- attitudes toward cancer screening . Four frequent cancer types were selected on the grounds of their different screening statuses : BC and CRC for evidence of efficacy of screening and existence of a national screening program and prostate and lung cancers for neither evidence of efficacy of screening nor official screening program . Methods General population opinion poll The population-based EDIFICE opinion poll was carried out by telephone from 18 January to 2 February , 2005 among a representative sample of 1,504 subjects living in France and between 40 and 75 years old -LRB- 1,609 subjects minus 105 who had already been affected by cancer -RRB- . Sample representativeness was assessed , in relation to the statistics of the French Employment Survey in year 2002 -LSB- 4 -RSB- , based on the following criteria : sex , age -LRB- five categories -RRB- , profession -LRB- eight categories -RRB- , community size -LRB- five categories -RRB- , and regional distribution -LRB- nine categories -RRB- . General practitioner opinion poll A nationwide opinion poll was carried out by telephone from 31 January to 18 February , 2005 among a representative sample of 600 GPs practicing in France . Sample representativeness was assessed based on the following criteria : age -LRB- four categories -RRB- and regional distribution -LRB- five categories -RRB- . Results The main results of EDIFICE opinion poll are summarized in Fig. 1 . Almost all -LRB- 93 % -RRB- interviewed women stated that they had undergone at least one mammography . In contrast , 25 % , 36 % , and 6 % of the interviewed subjects stated that they had undergone screening tests for CRC , PC , and LC , respectively . Fig. 1Adherence to cancer screening strategies according to the French nationwide EDIFICE opinion poll -LRB- 1,504 subjects , 600 general practitioners -RRB- . In France , there are organized mass-screening programs for breast cancer by mammography -LRB- 100 % of the population covered at the time of the opinion poll -RRB- and for colorectal cancer using Hemoccult -LRB- almost 30 % of the population covered -RRB- . In contrast , there is no mass-screening program for prostate cancer and lung cancer . For subjects in the general population , figures indicate the rates of subjects stating that they had undergone at least one screening test . For general practitioners , figures indicate the rates of general practitioners stating that they systematically recommended cancer screening The corresponding percentages of GPs who stated that they recommended cancer screening tests to their patients were consistent with the proportions of subjects who had undergone screening tests for each tumor type : 68 % , 18 % , 58 % , and 4 % of the interviewed GPs stated that they systematically recommended screening for BC , CRC , PC and LC , respectively . Reasons given to explain why screening tests had not been performed Physicians and subjects provided contrasting answers as to why cancer-screening tests had not been performed . Physicians mainly focused on subjects ' fears while subjects denied this reason . Fear of results was cited by 44 % of physicians as the main explanation why subjects did not undergo BC screening tests versus only 18 % of subjects . For CRC screening , the figures were 16 % and 3 % , respectively . The corresponding odds ratios for fear being elicited by subjects versus GPs as the reason for not undergoing BC or CRC screening tests were 0.29 and 0.15 , respectively -LRB- Table 1 -RRB- . Furthermore , subjects focused on a lack of advice on cancer screening from their physicians whereas GPs rarely did so . Lack of advice from the physicians was cited by 11 % of subjects as the main explicative factor for subjects not undergoing BC screening tests versus only 1 % of GPs . For CRC screening , the figures were 16 % and 9 % , respectively . The corresponding odds ratios for lack of medical advice being elicited by subjects versus GPs as the reason for subjects not undergoing BC or CRC screening tests were 11.65 and 1.93 , respectively -LRB- Table 1 -RRB- . Table 1Reasons cited by subjects in the general population and general practitioners why subjects did not undergo screening tests for breast cancer -LRB- BC -RRB- or colorectal cancer -LRB- CRC -RRB- Reasons citedFor not undergoing BC screening testsFor not undergoing CRC screening testsFemale subjects N = 38General practitioners N = 600Subjects N = 725General practitioners N = 600Subjects fearing the result n -LRB- % -RRB- 7 -LRB- 18 -RRB- 264 -LRB- 44 -RRB- 20 -LRB- 3 -RRB- 96 -LRB- 16 -RRB- OR -LRB- CI95 % -RRB- 0.29 -LRB- 0.12 -- 0.66 -RRB- 0.15 -LRB- 0.09 -- 0.24 -RRB- Lack of physician 's advice n -LRB- % -RRB- 4 -LRB- 11 -RRB- 6 -LRB- 1 -RRB- 116 -LRB- 16 -RRB- 54 -LRB- 9 -RRB- OR -LRB- CI95 % -RRB- 11.65 -LRB- 3.14 -- 43.23 -RRB- 1.93 -LRB- 1.37 -- 2.71 -RRB- OR indicates odds ratio ; CI95 % indicates confidence interval at the risk α = 0.05 Discussion In the present study , we describe the adherence to different screening programs for four types of cancers -LRB- BC , CRC , PC , and LC -RRB- in France . It is important to point out that this opinion poll does not report an accurate incidence of subjects actually screened for cancer but indeed the proportion of subjects stating that they had undergone at least one screening test . It is also worth mentioning that the French national health insurance system currently makes the corresponding screening tests -LRB- FOBT , mammography , prostate specific antigen -- PSA -- testing and X-ray -RRB- available for free -LRB- or almost free -RRB- to all affiliates . The major finding of this report is the obvious disagreement between evidence-based official recommendations and actual practice is both subjects in the general population and GPs in France . Despite a high level of evidence of reduction in cancer-related mortality of similar magnitude -LRB- ∼ 15 -- 20 % -RRB- with both BC and CRC mass-screenings -LSB- 1 , 2 -RSB- , 93 % of women undergo mammography screening whereas only 25 % of subjects in the same age range have access to CRC screening tools . In contrast , 36 % of men aged between 50 and 74 years have undergone a screening test for PC -LRB- mainly PSA testing -RRB- even though the benefit of PC screening remains unknown -LSB- 5 -RSB- . EDIFICE showed , on the one hand , two `` rational rates '' of screening -- high rate of women having undergone mammography and low rate of subjects having performed LC screening -- and , on the other hand , two `` inadequate rates '' of screening -- abnormally low rate of CRC screening -LRB- nationwide coverage by the on-going program is expected by the end of 2007 -RRB- and abnormally high rate of PC screening . Even more striking , the French GPs ' behavioral pattern of recommending individual cancer screening exhibited the same inconsistencies . Three reasons can be suggested to explain the observed relationships between subjects ' and GPs ' behaviors . First , subjects in the general population may be influenced by medical counseling . Alternatively , physicians may endorse their patients ' views and agree `` under pressure '' -LSB- 6 -RSB- . Lastly , both subjects and GPs are exposed to similar not evidence-supported recommendations/information , with the `` magic touch '' of blood analysis for PC screening being attractive to them . Appropriate information of subjects and physicians , including the possible benefits and risks of PC screening through PSA testing , could make these erroneous behaviors less frequent -LSB- 7 -RSB- . Whereas GPs ' and subjects ' statements in EDIFICE appeared in rather good agreement with respect to the proportions of interviewed subjects having undergone cancer screening tests and of GPs recommending cancer screening to their patients , the reasons put forward why screening tests were not performed are different , indeed even opposite : based on their statements , GPs overestimated the negative impact of fear of the results on subjects ' participation in cancer screening and they underestimated their own role . Nevertheless , both GPs and subjects interestingly seem to attach a more dreadful meaning to the result of BC screening than to the result of CRC screening . Indeed , fear of the result acting as a check upon carrying out cancer screening tests was cited by 18 % of the subjects for BC screening whereas only 3 % cited this reason for not undergoing CRC screening tests . Comparatively , 44 % and 16 % of GPs cited fear of the result as the reason for subjects not undergoing BC and CRC screening tests , respectively . It thus appears that there is a need for more research in social science as well as in biology and public health to improve the effectiveness of cancer screening in the framework of a national health system .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

mass-screening
compliance
health care opinion poll
health services research
health services misuse


The effect of moderate alcohol consumption on adiponectin oligomers and muscle oxidative capacity : a human intervention study Aims/hypothesis The aim of this study was to investigate whether moderate alcohol consumption increases plasma high molecular weight -LRB- HMW -RRB- adiponectin and/or muscle oxidative capacity . Introduction Moderate alcohol consumption is associated with a decreased risk of type 2 diabetes compared with abstention -LSB- 1 -RSB- , which could be explained by improved insulin sensitivity -LSB- 2 -RSB- . The underlying mechanism for this is not clear , but several pathways may be involved . First , moderate alcohol consumption increases plasma adiponectin concentrations , which could precede changes in insulin sensitivity -LSB- 2 -RSB- . Adiponectin improves insulin sensitivity by increasing muscle fat oxidation and/or decreasing intramyocellular triacylglycerols -LRB- IMTGs -RRB- -LSB- 3 -RSB- . Adiponectin is present in plasma as a trimer , hexamer or high molecular weight -LRB- HMW -RRB- form , the latter possibly being the most relevant in the aetiology of insulin resistance -LSB- 4 -RSB- . Second , moderate alcohol consumption acutely affects energy expenditure , diet-induced thermogenesis , lipolysis and lipid oxidation -LSB- 5 -RSB- . These changes may result from acetate production from ethanol , which is converted to acetyl-CoA mainly in peripheral tissue such as muscle -LSB- 5 -RSB- . Such acute changes could cumulatively affect oxidative capacity and insulin sensitivity . This is the first human study to investigate whether chronic moderate alcohol consumption affects plasma adiponectin oligomers and muscle oxidative capacity . Materials and methods In a randomised , controlled , crossover trial , conducted at TNO Quality of Life , 19 healthy , moderate-drinking , lean -LRB- BMI 18 -- 25 kg/m2 , n = 11 -RRB- and overweight -LRB- BMI ≥ 27 kg/m2 , n = 8 -RRB- men -LRB- aged 18 -- 40 years -RRB- , consumed 100 ml whisky -LRB- 32 g alcohol per day ; Famous Grouse Scotch Whisky , 40 % vol , Perth , Scotland -RRB- or mineral water -LRB- Spa Reine , Spa , Belgium -RRB- daily for 4 weeks . For the last 7 days of each treatment period the diet was fully controlled , and treatments were separated by a 2 day wash-out period . This sample size was sufficient to detect ∼ 15 % difference of β-3-hydroxyacyl-CoA dehydrogenase -LRB- β-HAD -RRB- and citrate synthase activity in this crossover trial and correlation coefficients of 0.55 or higher with 80 % power and accepting an alpha of 0.05 . At the end of each treatment period , muscle biopsies from the vastus lateralis muscle were taken to assess β-HAD , cytochrome c oxidase and citrate synthase activity -LSB- 6 -RSB- , IMTG -LSB- 7 -RSB- and succinate dehydrogenase activity -LSB- 8 -RSB- . Fasting blood samples were collected and an OGTT was performed to calculate whole-body insulin sensitivity . Subjects gave written informed consent and the University Medical Center Utrecht Medical Ethics Committee approved the protocol . The study was conducted according to the Declaration of Helsinki -LRB- 2000 -RRB- and the International Conference on Harmonisation Guidelines for Good Clinical Practice . Data were analysed using the SAS statistical software package -LRB- SAS/STAT version 8 , SAS Institute , Cary , NC , USA -RRB- . Treatment effects were assessed by ANOVA , using general linear modelling , with BMI , period , treatment and treatment order included in the model . Two-sided p values below 0.05 were considered statistically significant . Results Compliance to treatments was good as assessed by measurements of urinary ethyl glucuronide every 5 days , showing one negative sample during the whisky-drinking and no positive samples during the water-drinking period . Another indication was the 11 % increase -LRB- p < 0.001 -RRB- of serum HDL-cholesterol after whisky compared with water consumption . Table 1 shows results on insulin sensitivity , adiponectin and muscle enzyme activities . Insulin sensitivity was not changed after moderate alcohol consumption , but plasma adiponectin concentrations increased from 7.9 ± 0.2 mg/l after water to 9.0 ± 0.2 mg/l -LRB- means ± SEM -RRB- after whisky consumption . Moderate alcohol consumption tended to increase HMW and medium molecular weight -LRB- MMW -RRB- adiponectin , but not low molecular weight -LRB- LMW -RRB- adiponectin . Differences in insulin sensitivity and adiponectin and its oligomers tended to be more pronounced among lean than overweight men -LRB- Table 2 -RRB- . Muscle oxidative capacity measured by β-HAD , cytochrome c oxidase and citrate synthase activity did not differ between treatments . A borderline significant interaction between treatment and BMI was observed for cytochrome c oxidase -LRB- p = 0.072 -RRB- and citrate synthase -LRB- p = 0.102 -RRB- activity . Moderate alcohol consumption tended to increase cytochrome c oxidase -LRB- +23.7 % ; 95 % CI − 3.9 to +51.2 % , p = 0.08 -RRB- and citrate synthase -LRB- +24.7 % ; 95 % CI − 7.7 to +57.2 % , p = 0.11 -RRB- activity among lean , but not overweight men -LRB- Table 2 -RRB- . Succinate dehydrogenase activity in mixed muscle fibres decreased -LRB- p = 0.03 -RRB- by 15 % after moderate alcohol consumption . IMTGs did not differ , despite a 15 -- 20 % difference between both treatments . These results were not different for lean and overweight men -LRB- Table 2 -RRB- . After whisky consumption , HMW correlated positively with activities of citrate synthase -LRB- r = 0.64 , p = 0.004 -RRB- , cytochrome c oxidase -LRB- r = 0.59 , p = 0.009 -RRB- and β-HAD -LRB- r = 0.46 , p = 0.056 -RRB- . Activities of citrate synthase -LRB- r = 0.44 , p = 0.07 -RRB- , cytochrome c oxidase -LRB- r = 0.32 , p = 0.20 -RRB- and β-HAD -LRB- r = 0.44 , p = 0.07 -RRB- also tended to correlate with MMW adiponectin , but not LMW adiponectin . A similar pattern was observed for correlations of adiponectin oligomers with HDL-cholesterol -LRB- HMW : r = 0.55 , p = 0.014 ; MMW : r = 0.55 , p = 0.014 ; LMW : r = 0.21 , p = 0.38 -RRB- . Table 1Insulin sensitivity index , adiponectin oligomer concentrations , HbA1c and enzyme activities after 4 weeks of consumption of whisky or mineral water in 19 lean or overweight men Mineral waterWhisky % Changep valueInsulin sensitivity indexa10 .6 ± 1.39.6 ± 1.3 − 9.40.61 Adiponectin -LRB- mg/l -RRB- 7.9 ± 0.29.0 ± 0.212.50.0008 HMW0 .7 ± 0.11.1 ± 0.157.1 0.074 MMW4 .0 ± 0.24.5 ± 0.212.50.065 LMW3 .2 ± 0.33.5 ± 0.39.40.442 HbA1c -LRB- % -RRB- 4.9 ± 0.024.8 ± 0.02 − 2.00.023 Muscle β-HAD -LRB- mol/μg protein -RRB- 4.22 ± 0.484.37 ± 0.493.60.827 Muscle citrate synthase -LRB- mol/μg protein -RRB- 0.66 ± 0.050.75 ± 0.0513.60.262 Muscle cytochrome c oxidase -LRB- mol/μg protein -RRB- 1.48 ± 0.121.67 ± 0.1212.80.262 Intramyocellular triacylglycerols -LRB- AU -RRB- Type 10.027 ± 0.0040.022 ± 0.004 − 18.50.339 Type 20.010 ± 0.0020.008 ± 0.002 − 20.00.489 Mixed0 .019 ± 0.0030.016 ± 0.002 − 15.8 0.429 Succinate dehydrogenase activity -LRB- AU -RRB- Type 10.084 ± 0.0050.075 ± 0.004 − 10.70.122 Type 20.057 ± 0.0030.052 ± 0.003 − 8.80.221 Mixed0 .073 ± 0.0030.062 ± 0.003 − 15.10.028 Data are presented as means ± SEM or % AU Arbitrary unitsaInsulin sensitivity according to Matsuda and DeFronzo -LSB- 15 -RSB- Table 2Insulin sensitivity index , adiponectin oligomer concentrations , HbA1c and enzyme activities -LRB- means ± SEM -RRB- after 4 weeks of consumption of whisky or water in lean and overweight subjects Lean groupOverweight groupWaterWhisky % Changep valueWaterWhisky % Changep valueInsulin sensitivity indexa13 .3 ± 1.913.0 ± 1.9 − 2.30.937.8 ± 1.64.6 ± 1.6 − 41.0 0.21 Adiponectin -LRB- mg/l -RRB- 8.1 ± 0.39.4 ± 0.316.10.017.7 ± 0.28.5 ± 0.210.40.08 HMW0 .8 ± 1.21.2 ± 0.250.00.120.8 ± 0.10.8 ± 0.100.62 MMW4 .2 ± 0.34.8 ± 0.314.30.133.9 ± 0.24.1 ± 0.25.10.52 LMW3 .2 ± 0.43.4 ± 0.46.30.693.1 ± 0.43.5 ± 0.412.90.50 HbA1c -LRB- % -RRB- 4.9 ± 0.024.8 ± 0.02 − 2.00.044.9 ± 0.024.9 ± 0.0200.53 Muscle β-HAD -LRB- mol/μg protein -RRB- 4.67 ± 0.505.10 ± 0.459.20.553.46 ± 0.903.69 ± 1.016.70.87 Muscle citrate synthase -LRB- mol/μg protein -RRB- 0.73 ± 0.080.92 ± 0.0726.00.110.60 ± 0.050.54 ± 0.06 − 10.00.51 Muscle cytochrome c oxidase -LRB- mol/μg protein -RRB- 1.72 ± 0.152.12 ± 0.1423.30.081.33 ± 0.131.13 ± 0.15 − 15.00.36 Intramyocellular triacylglycerols -LRB- AU -RRB- Type 10.022 ± 0.0060.016 ± 0.005 − 27.30.500.032 ± 0.0060.028 ± 0.006 − 12.50.61 Type 20.006 ± 0.0020.008 ± 0.00233.30.410.013 ± 0.0030.007 ± 0.003 − 46.20.14 Mixed0 .014 ± 0.0040.013 ± 0.003 − 7.10.860.024 ± 0.0040.019 ± 0.004 − 20.80.40 Succinate dehydrogenase activity -LRB- AU -RRB- Type 10.086 ± 0.0050.080 ± 0.005 − 7.00.400.084 ± 0.0090.069 ± 0.008 − 17.90.29 Type 20.060 ± 0.0050.055 ± 0.005 − 8.30.500.054 ± 0.0050.048 ± 0.004 − 11.10.34 Mixed0 .076 ± 0.0050.066 ± 0.005 − 13.20.160.069 ± 0.0050.057 ± 0.004 − 17.40.15 Data are presented as means ± SEM or % AU Arbitrary unitsaInsulin sensitivity according to Matsuda and DeFronzo -LSB- 15 -RSB- Discussion This study showed that moderate alcohol consumption increases adiponectin concentrations , consistent with previous reports -LSB- 2 -RSB- . We have now observed that the alcohol-induced increase of adiponectin may be oligomer specific . Moderate alcohol consumption increased particularly HMW adiponectin , MMW adiponectin to a lesser extent , but not LMW adiponectin . These results are in line with those of Bobbert et al. -LSB- 9 -RSB- showing a similar pattern of changes in adiponectin oligomers after moderate weight reduction . Studies with thiazolidinedione or rigorous weight reduction show similar , but more pronounced results -LSB- 10 -RSB- . HDL-cholesterol concentrations correlated particularly with HMW adiponectin , as previously shown -LSB- 9 -RSB- . We have now also observed that HMW and MMW adiponectin are correlated with markers of muscle oxidative capacity , in line with reports of increased fat oxidation after adiponectin infusion -LSB- 3 -RSB- and a recent study showing that adiponectin increases muscle oxidative capacity -LSB- 11 -RSB- . Our results tend to confirm these findings and show that these relationships may be specific to HMW adiponectin . Altogether , this could provide an underlying mechanism for the proposed importance of HMW adiponectin in the aetiology of insulin resistance -LSB- 4 -RSB- . Despite this , the alcohol-induced increase of adiponectin and specifically HMW adiponectin did not affect muscle oxidative capacity , IMTG content and insulin sensitivity . As some subtle differences were present , we can not completely rule out the hypothesis that changes in IMTG content and/or oxidative capacity could occur . Although it did not reach significance , we observed a 15 -- 20 % lower IMTG content after whisky than water consumption , which is of similar magnitude to that observed for a weight loss and physical activity intervention -LSB- 12 -RSB- . Furthermore , moderate alcohol consumption tended to increase muscle citrate synthase activity among lean men , but succinate dehydrogenase activity declined after moderate alcohol consumption in mixed muscle fibres . All citric acid cycle and respiratory chain enzymes are thought to change in parallel to perturbation -LSB- 13 -RSB- . Our findings with citrate synthase and succinate dehydrogenase , however , are contradictory to this notion . This could simply be due to the measurement of ex vivo oxidative capacity or to chance . Alternatively , moderate alcohol consumption could differentially affect various enzymes in oxidative pathways such as the citric acid or glyoxylate cycle as suggested by Kokavec and Crowe -LSB- 14 -RSB- . Because acetyl-CoA from ethanol oxidation is generated independently from activation of pyruvate dehydrogenase complex , it may not affect the citric acid cycle . Alcohol may instead affect the glyoxylate cycle that bypasses part of the citric acid cycle , including succinate dehydrogenase -LSB- 13 , 14 -RSB- . Strengths of this study are its randomised , controlled crossover design . We assessed compliance to study treatments several times throughout the study and observed no significant deviations . It is therefore unlikely that our results are confounded by diet or lifestyle . Our study was , however , limited by a slightly small sample size for certain contrasts such as analyses in subgroups of lean and overweight men or of IMTG content . Therefore these results may be somewhat preliminary and need to be confirmed with larger sample sizes . Second , because insulin sensitivity was not the primary endpoint of this study , an OGTT was used to assess insulin sensitivity . However , we used an insulin sensitivity index that correlates well with the gold standard , the hyperinsulinaemic -- euglycaemic clamp technique -LSB- 15 -RSB- . In addition , our results on insulin sensitivity do not differ from our previous studies using the clamp technique -LSB- 2 -RSB- . We therefore believe that using this insulin sensitivity index has not influenced our results to a large extent . In conclusion , this study shows that 4 weeks of daily moderate alcohol consumption increases adiponectin concentrations and particularly HMW adiponectin concentrations , but does not affect insulin sensitivity and oxidative capacity . Concentrations of HMW and MMW adiponectin were positively associated with muscle oxidative capacity .

O O O B I I O B O O B I I O O O O O O O O O O O O O O O B I I O O O O O O O O B O B I I O O B I I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I I O O B O O O O O O O B I O O O O B O B I O O O O O O O B I O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I I O O B O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O B I O O O O B I I O O O B O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O B O O O O O O O O O B O O O B I O B O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O B O O O O O O O O O O O O O O O O O O O B O O O O O B I I O O O B O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O B I I O O O O O O O O O O B O O O O O O O O O O B O B I I O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O B O O O B I I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I I O B O O O O B O O O O O O B I O O O O O O O O O B O O O O B I I O

adiponectin
insulin sensitivity
intramyocellular triacylglycerols
moderate alcohol consumption
muscle oxidative capacity