Testing the effectiveness of intravitreal Ranibizumab during 12 months of follow-up in venous occlusion treatment

e413Intravitreal Ranibizumab in venous occlusion treatment

Testing the effectiveness of intravitreal Ranibizumab during

12 months of follow-up in venous occlusion treatmentE. Pacella¹, F. Pacella¹, G. La Torre², D. Impallara¹, K. Malarska¹, C. Brillante¹, P Turchetti³, M. De Giusti²

¹Department of Sense Organs, Faculty of Medicine and Dentistry, Sapienza University of Rome, ²Department of Public Health and

Infectious Diseases, Faculty of Pharmacy and Medicine, Sapienza University of Rome; ³National Institute for Health, Migration and

Poverty (INMP/NIHMP), Rome, Italy

Original article Clin Ter 2012; 163 (6):e413-422

Correspondence: Dr.ssa Elena Pacella. Department of Sense Organs, Faculty of Medicine and Dentistry, Sapienza University of Rome, Viale del

Policlinico, 00161 Rome, Italy. Tel.: +39.06.4997.5303; +39.336.783409; Fax: +39.06.49975304. E-mail: [email protected]

Copyright © Società Editrice Universo (SEU)

Introduction

Retinal vein occlusion (RVO) causes anatomical al-

terations of either an ischemic (ischemic or hemorrhagic

form) or non-ischemic nature (non-ischemic form or venous

stasis) in retinal tissue. We can divide RVO into two types:

branch retinal vein occlusion (BRVO) and central retinal

vein occlusion (CRVO).

Abstract

Aims. To determine the effectiveness and safety of treatment of

intravitreal Ranibizumab for Central Retinal Vein Occlusion.

Patients and Methods. This non-randomized observational clinical

study was comprised of a round of therapy with three IVI. Twenty eyes

affected by CRVO were recruited. The average age was 65.06 ± 15

years and criterion for inclusion: age >18 years, best Corrected Visual

Acuity (BCVA) from 5 to 40 letters and macular edema with thickness

greater than 275 µm. The criteria used for reinjection were: CMT> 150

µm, ETDRS <10 letters and LogMAR <0.2. The statistical analysis

for continuous variables (ETDRS, logMar and CMT) was conducted

calculating median and range (min-max), since these variables, due

to sample size, were not normally distributed.Time trends of these

variables were plotted with boxplot and differences.

Events between T0 and T12 were assessed using the analysis of

variance (ANOVA) for repeated measurements and the F test (Pillai’s

trace). The statistical significance was set at p ≤0.05.

Results. All of the patients showed improvement. In fact, the

ETDRS went from a median of 20.00 to 28.50, LogMAR went from

a median of 0.75 to 0.55 and the values for CMT went from a median

of 556.00 µm to 390.00 µm. The drug reaches maximum effectiveness

after two months of therapy, with T2 remaining constant from the third

injection at T3 until the end of 12 months at T12.

Conclusions. The results produced by our study indicate that Ra-

nibizumab is a valid treatment for CRVO. Clin Ter 2012; 163(6):e413-

422

Key words: Macular edema, Ranibizumab, Retinal vein and

vascular occlusion

International prevalence of RVO, standardized for age

and sex, is equivalent to 0.52% (0.442% for BRVO and

0.08% for CRVO) (1).

The risk of RVO reoccurring in the same eye is 0.9%

within two years and 7.7% in the contralateral eye (2).

Ninety percent of patients are over 50 years of age and this

could be explained by the strong relationship vein occlusion

has with pathologies typically discovered in people over

50: cardiovascular diseases (70% of cases), atherosclerosis

(50% of cases), diabetes mellitus (30% of cases) (3), arterial

hypertension (60%-65% of cases) (4) and glaucoma (20%

of cases).

These listed conditions, along with other risk factors

such as smoking and hyperlipidemia (5), are at the begin-

ning of a series of events that make up the pathogenesis of

vein occlusion. In fact, the first cause is the decrease in the

size of vein lumen followed by turbulence in blood flow

and vein thrombosis. The result is an increase in central

pressure, hemorrhage, ischemia and production of vascular

endothelial growth factor (VEGF) which, in turn, stimulates

capillary neoangiogenesis with the formation of macular

edema due to endothelial damage and rupturing of blood-

retinal membranes (6).

Macular edema results in the accumulation of fluid in the

outer plexiform and inner nuclear layers of the perifoveal

area and is responsible for the increase in macular thickness

and the reduction of visual acuity (7).

In scientific literature, different therapeutic approaches

have been reported especially for handling complications

secondary to macular edema: laser (8), systemic (9-10)

or surgical treatments (11-15); topical steroids (16, 17);

intravitreal injections with steroids (18-20); or intravitreal

injections with anti-VEGF (2).

Our study takes into consideration the intravitreal admi-

nistration of Ranibizumab as an anti-VEGF molecule (21).

Ranibizumab is a humanized antibody fragment directed

towards vascular endothelial growth factor A (VEGF-A)

(22) with high binding affinity for the isoforms VEGF110,

VEGF121 and VEGF165. Its pharmacodynamic action in-

volves blocking the binding of these factors to VEGFR-1 and

e414 E. Pacella, et al.

VEGFR-2 receptors, therefore preventing the proliferation

of endothelial cells, neovascularization, and the increase of

vessel permeability.

The objective of this study is to evaluate the effectiveness

and safety of macular edema treatment secondary to CRVO

during 12 months of follow-up.

Patients and Methods

We conducted a non-randomized clinical study upon

receiving approval from the ethics committee at the Reti-

na Center at the Umberto I General Hospital, “Sapienza”

University of Rome, Italy). In particular, 20 patients were

recruited (for a total of 20 eyes) including: 9 males and 11

females with an average age of 65.06 ± 15 years who had

been suffering from central retinal vein occlusion for 4

weeks to 3 months.

Inclusion criteria

– Willingness to provide signed Informed Consent Form

– Age ≥18 years

– For sexually active women of childbearing potential, use

of an appropriate form of contraception (or abstinence)

for the duration of the study

– Ability and willingness to return for all scheduled visits

and assessments.

Ocular inclusion criteria and injection criteria (Study Eye)

– Foveal center-involved macular edema secondary to

CRVO

– BCVA using ETDRS charts of 20/40 to 20/320 (Snellen

equivalent)

– Mean central subfield thickness ≥ 250 µm on two optical

coherence tomography (OCT) measurements (at scree-

ning [confirmed by the central reading center] and Day

0 [confirmed by the evaluating physician])

– Media clarity, pupillary dilation, and participant coope-

ration sufficient to obtain adequate fundus photographs

with visual acuity from five letters (corresponding to

1/10, LogMar 1.0 or higher) to 40 letters (corresponding

to 5/10, LogMar 0.3 or less) and macular edema with

thickness over 275 µm. Before the first injection (T0),

initial best-corrected visual acuity (BCVA) had a median

of 20 letters (LogMar 0.75) and central macular thickness

(CMT) had a median of 556 µm. An eye exam at T0

showed superficial hemorrhages in the four quadrants,

macular edema, cotton-like snowballs, venous turgidity

and coiling and signs of A-V crossing. Five patients

showed moderate edema of the optic disc.

Intravitreal injection with Ranibizumab was carried out

without distinction between ischemic and non-ischemic

forms of CRVO since the FAG was performed two months

after onset for patients suffering less than four weeks. Me-

anwhile, retinal alterations made it impossible to distinguish

between the type of occlusion in patients who had been

suffering for more than four weeks.

Exclusion criteria

– History of cerebral vascular accident or myocardial

infarction within 3 months prior to Day 0; any anti-

vascular endothelial growth factor (VEGF) or treatment

in the fellow eye within 3 months prior to Day 0; any

systemic anti-VEGF or pro-VEGF treatment within 6

months prior to Day 0; allergy to fluorescein; allergy

to Ranibizumab injection or related molecule

– Relevant systemic disease that may be associated with

increased systemic VEGF levels (namely, all active ma-

lignancies); history of successfully treated malignancies

is not an exclusion criterion.

– Uncontrolled blood pressure

– Pregnancy or lactation

– Any condition that, in the opinion of the investigator,

would preclude participation in the study (e.g., chronic

alcoholism or drug abuse, personality disorder or use

of major tranquilizers, indicated difficulty in long-term

follow-up, and likelihood of survival of less than 1

year)

– Participation in an investigational trial within 30 days

prior to Day 0 that involved treatment with any drug

(excluding vitamins and minerals) or device that has not

received regulatory approval at time of study entry

Ocular exclusion criteria

– Prior episode of retinal vein occlusion (RVO)

– Brisk afferent pupillary defect

– History of radial optic neurotomy or sheathotomy; age-

related macular degeneration (AMD; dry or wet form);

any anti-VEGF treatment in the study eye within 3 mon-

ths prior to Day 0; laser photocoagulation for macular

edema within 4 months prior to Day 0; panretinal scatter

photocoagulation or sector laser photocoagulation within

3 months prior to randomization or anticipated within

the next 4 months following randomization; intraocular

corticosteroid use within 3 months prior to Day 0; pars

plana vitrectomy; intraocular surgery (including cataract

extraction, scleral buckle, etc.) within 2 months prior to

Day 0 or anticipated within the next 7 months following

Day 0; yttrium-aluminum-garnet capsulotomy performed

within 2 months prior to Day 0; herpetic ocular infection,

ocular toxoplasmosis, rhegmatogenous retinal detach-

ment, idiopathic central serous chorioretinopathy

– Previous filtration surgery in the study eye

– Evidence upon examination of vitreoretinal interface

disease (e.g., vitreomacular traction, epiretinal mem-

brane), either on clinical examination or OCT, thought

to be contributing to macular edema

– An eye that, in the investigator’s opinion, would not

benefit from resolution of macular edema, such as eyes

with foveal atrophy, dense pigmentary changes, or dense

subfoveal hard exudates

– Presence of an ocular condition that, in the opinion of the

investigator, might affect macular edema or alter visual

acuity during the study (e.g., uveitis or other ocular in-

flammatory disease, neovascular glaucoma, Irvine-Gass

syndrome, or prior macula-off rhegmatogenous retinal

detachment)

– Visually significant hemorrhage obscuring the fovea and

felt to be a major contributor to reduced visual acuity

– Presence of a substantial cataract that, in the opinion of

the investigator, is likely to be decreasing visual acuity

by 3 lines or more (i.e., a 20/40 cataract)


– Aphakia

– Relevant ocular disease that may be associated with

increased intraocular VEGF levels (namely, uveitis,

neovascular glaucoma, neovascular AMD, diabetic

retinopathy, diabetic maculopathy, or ocular ischemic

syndrome)

– Improvement of >10 letters on best corrected visual

acuity (BCVA) between screening and Day 0.

Medical history

The following was carried out on all patients: a thorough

look at general pre-operative medical history, cardiology

exam, ECG and hematochemical testing. The presence of

possible changes in homocysteine and the Leiden factor

was also particularly evaluated. In no cases were these

factors shown to be pathological. General medical history

highlighted the presence of risk factors such as smoking

(seven patients admitted to being habitual smokers) and

associated pathologies such as diabetes mellitus (in three

patients), essential arterial hypertension (in ten patients),

hypertriglyceridemia (in six patients) and hypercholestero-

lemia (in nine patients) (Table 1).

Treatment

Treatment was administered in the operating room

under sterile conditions injecting 0.5 mg of Ranibizumab

through the pars plana in the inferior-temporal sector, after

preparing the conjunctiva with povidone-iodine 50% solu-

tion, topical anesthesia with Ropivacaine and positioning

of the eyelid.

Re-injection criteria

– A round of therapy included three intravitreal injections

(one injection every four weeks) for all subjects.

– The criteria used for reinjection were: CMT >150 µm,

ETDRS <10 letters and LogMAR <0.2.

Evaluation

During the follow-up all patients underwent slit lamp

biomicroscopy and binocular indirect ophthalmoscopy.

IOP was evaluated using the Goldmann applanation

tonometer.

The BCVA score based on the ETDRS visual acuity

charts (number of correct letters) and assessed at a starting

distance of 4 meters.

Macular thickness and morphology were monitored at

T0- T1- T2- T3- T6- T9- T12 with OCT (OCT Spectralis

HRA-OCT from Heidelberg Engineering with a 512 x 49

volume scan) followed by color fundus photos.

Macular thickness and morphology were monitored

every four weeks (from T0 to T12) in patients with persistent

or recurring macular edema.

Generality

patients

included

General conditions associated INITIAL BCVA

Age Sex Smoking Hypercolesterolemia HypetrigliceridemiaDiabetes

mellitusHyertension

Etdrs

(letters)LogMAR

CMT

( µm)

54 M • • • • • 25 0,6 869

67 M • • • • 20 1 1042

54 M • • • 35 0,5 390

72 M • • • 25 0,7 510

65 M • • 54 0,2 329

59 M • • 19 1 1040

80 F • • • 7 1 900

56 F • • 21 1 1038

69 M • • • 24 0,6 860

57 M • • 26 0,7 506

70 F • • • 53 0,2 327

66 F • • • 18 1 1036

79 M • • • 8 1 902

63 M • • • 35 0,5 391

55 M • • • 25 0,7 503

73 M • • 24 0,6 862

64 F • • • • 20 1 1030

53 M • • • • 53 0,2 325

51 F • • • 18 1 1034

61 F • • • 20 1 1045

Age

average

63.4

±8.623

M/F

13/7

Total

patients

10

Total

patients

11

Total

patients

10

Total

patients

20

Total

patients

9

Average

etdrs

26.50

±

13.387

Average

logmar

0.7 ±

0.295

Average

CMT

746.95

±293.601

Table 1. General conditions.


The study group underwent 12 scheduled follow-ups (at

T0 upon admittance, three follow-ups after one week’s time

from each intravitreal injection at T1, T2 and T3, and nine

follow-ups during the following months after every four weeks

at T4, T5, T6, T7, T8, T9, T10, T11 and T12 respectively).

At T0, the following specific tests were carried out: visual

acuity examination, slit lamp biomicroscopy, tonometry,

direct and indirect ophthalmoscopy of the ocular fundus

and OCT.

Patients underwent ophthalmoscopy and tonometry

testing the day after injections.

During all follow-ups (from T1 to T12), the following

were evaluated: BCVA, biomicroscopy of the anterior and

posterior segments, and tonometry testing.

Safety

We can divide ocular implications related to intravitreal

administration of Lucentis into three categories: preopera-

tive, intraoperative and postoperative. Preoperative compli-

cations (tied to anesthesia by injection) are: perforation of

the ocular bulb, optic nerve lesions, eye muscle lesions and

palpebral, periocular or retrobulbar hemorrhages.

During treatment conjuctival lacerations, lesions of the

crystalline lens and vitreous and choroidal hemorrhage

may occur.

The postoperative complications are as follows: retinal

or choroidal detachment, endophthalmitis, alterations of the

macula, retinal and/or vitreous hemorrhages, vitreoretinal

proliferation, cataract, scleral rupture and scleromalacia,

hypertonia, the permanent or temporary reduction in eye

pressure, reduction of visual acuity, visual field defects,

strabismus, diplopia, myodesopsia, palpebral ptosis, optic

nerve atrophy and glaucoma.

Statistical analysis

The statistical analysis for continuous variables (ET-

DRS®, LogMar and CMT) was conducted calculating me-

dian and range (min-max), since these variables were not

normally distributed due to sample size.

Time trends of these variables were plotted with box plot

and differences between T0 and T12 were assessed using

the analysis of variance (ANOVA) for repeated measure-

ments using the F test (Pillai’s trace) (Table 2). Moreover,

the impact of the following factors was evaluated: gender,

diabetes mellitus, hypertriglyceridemia, hypercholestero-

lemia and arterial hypertension. The statistical significance

was set at p ≤0.05.

Results

Effectiveness

After one week from the first intravitreal injection (IVI)

at T1, visual acuity had a median of 29.50 (LogMar average

of 0.55) and CMT average of 44.60 µm (Fig. 1a and 1b and

Fig. 2).

After the second IVI (after five weeks of follow-up at

T2), we were able to observe a significant improvement in

function along with a consistent reduction of macular thick-

ness (ETDRS with a median of 35.00, LogMar value of 0.40

and CMT with a median of 301.50 µm) (Fig .3).

Following the third IVI (after nine weeks of follow-up

at T3), we found values for ETDRS with a median of 37.50,

LogMar at 0.40 and CMT with a median of 284.00 µm (Fig.

4a and 4b).

Patients, after being re-evaluated after 24 weeks from

the first IVI (after six months of follow-up at T6), were

observed to have values of ETDRS with a median of 35.00,

LogMar at 0.40 and CMT with a median of 313.50 µm (Fig.

5a and 5b).

During the follow-up after 36 weeks from the first IVI

(nine months of follow-up at T9), we found: ETDRS with a

median of 35.00, LogMar at 0.40 and CMT with a median

of 395.00 µm (Fig. 6a and 6b).

At T12 (12 months of follow-up), re-evaluation of all

parameters showed an overall worsening of both anatomic

and functional conditions (ETDRS with a median of 28.50,

LogMar at 0.55 and CMT with a median of 390.00 µm).

The response to treatment was independent of age, sex

and concomitant pathologies. The final reading of data has

allowed us to compare the variations in visual acuity and

CMT from T0 to T6. ETDRS went from a median of 20.00

to 28.50, LogMar went from a median of 0.75 to 0.55 and

CMT went from a median of 556.00 µm to 390.00 µm.

Safety

We did not encounter any preoperative, intraoperative or

postoperative complications in any of the patients.

ANOVA for repeated measurements

The ANOVA for repeated measurements revealed that

differences between T0 and T12 were statistically significant

for all the three variables considered (Table 2) (p <0.001;

Table 2. F-test (Pillai’s trace) and p-values for factor variables influencing trends of ETRDS, LogMAR and CMT.

Variables ETRDS logMAR CMT

Hypercholesterolemia 1.212 (p = 0.286) 0.764 (p = 0.685) 0.444 (p = 0.818)

Hypertriglyceridemia 0.941 (p = 0.510) 0.994 (p = 0.460) 1.151 (p = 0.493)

Diabetes mellitus 0.785 (p = 0.665) 0.585 (p = 0.849) 0.300 p = (0.903)

Hypertension 1.106 (p = 0.364) 0.774 (p = 0.676) 0.567 (p = 0.746)

Gender 0.575 (p = 0.858) 0.381 (p = 0.967) 2.145 (p = 0.284)


1 b

Fig. 1. Images of the right eye at baseline T0: a. Fundus phothograph (3.7); b. fluorescein angiography (3.6); c. optical coherence tomography

Baseline T0 CMT 519 (Number of letters ETDRS 22) (3.3)

Fig. 1

Fig. 1 a

Fig. 2. Images of the right eye at 1 week after I injection, optical coherence tomography CMT 241, (Number of letters ETDRS 31) (3.4)


Fig. 3. Images of the right eye at II injection after 5 weeks CMT 226 ( Number of letters ETDRS 35) (3.5).

Fig. 4a

Fig. 4b

Fig. 4. Images of the right eye at II injection after III injection 9

weeks: a. Fundus phothograph (3.7); b. fluorescein angiography

(3.6); c. optical coherence tomography CMT 228 (Number of letters

ETDRS 36) (3.8).


Fig. 5 Fig. 5a

Fig. 5. Images of the right eye at IV injection after IV injection 24 weeks: a. Fundus phothograph (3.10); b. fluorescein angiography (3.9);

c. optical coherence tomography CMT 365 (Number of letters ETDRS 28) CMT (3.11).

Fig. 6 Fig. 6a


p <0.001 and p =0.017 for ETRDS, LogMar and CMT,

respectively).

None of the considered factors (gender, diabetes mellitus,

hypertriglyceridemia, hypercholesterolemia, arterial hyper-

tension) have an impact on the time trends of the variables

considered (Table 1).

Discussion

The pathogenesis of macular edema secondary to CRVO

is determined by altered vascular permeability and neoangio-

genesis deriving from post-thrombotic hypoxic damage. The

leading cause of the accumulation of intra- and subretinal

fluid is due to the liberation of VEGF and other proinflam-

matory cytokines such as IL-6 and IL-8.

The goal of treatments geared towards stopping and re-

ducing the formation of edema is to increase patients’ visual

acuity and prevent the development of any complications

related to neoangiogenesis.

Available data in scientific literature shows that patients

suffering from CRVO have a higher intravitreal concentra-

tion of VEGF with regards to that of healthy subjects or

subjects suffering from other types of retinal pathologies

(2). These factors have lead to the use of anti-VEGF drugs,

such as Ranibizumab, for treating the pathology under

examination.

The CRUISE study reported that 260 patients treated

with 0.3 mg or 0.5 mg of intravitreal Ranibizumab (or

sham injection) showed an improvement in visual acuity

after six months along with a significant and continuous

reduction of macular edema measured in terms of central

retinal thickness (23).

The study “Ranibizumab for macular edema following

central retinal vein occlusion: six-month primary end point

results of a phase III study” carried out on 392 patients

treated with 0.3 mg or 0.5 mg doses of Ranibizumab (24)

also reported improvements of visual acuity along with a

reduction in macular thickness (23).

The results derived from our study altogether highlight

a clear improvement of BCVA after administration of Ra-

nibizumab accompanied by a reduction of CMT that went

from a median of 556 µm at T0 to a median of 313.5 µm

at T6 (after six months from the beginning of treatment).

Nonetheless, it was necessary to repeat IVI in four patients

(20%) due to a recurrence of edema, and persistent edema

in two other patients (10%).

Specifically, three patients with recurring macular edema

received four injections, one patient with recurring macular

edema received five injections and two patients with per-

sistent macular edema received seven injections (with an

average number of 5.16 injections).

The study “Ranibizumab for macular edema due to

retinal vein occlusions: implication of VEGF as a critical

stimulator” looked at 20 eyes with CRVO observed during

a short follow-up of only three months with the goal of eva-

luating the effectiveness of three consecutive injections of

Ranibizumab with two different doses (0.3 mg or 0.5 mg).

After three months of observation, significant improvements

were seen for visual acuity (a gain >14 letters for the group

that received doses of 0.5 mg and >17 letters for the group

that received doses of 0.3mg) including a reduction of CMT

by 90% (25).

The prospective randomized study “Pieramici-Rabena”

was conducted on ten eyes with CRVO with nine months of

follow-up. The use of Ranibizumab lead to an improvement

of BCVA of 12±20 letters after three months, 3±21 letters

after six months, and 1±24 letters plus a reduction of CMT

(from 272±244 to 119±153 micron) after nine months of

therapy, with respect to pre-treatment values. Nonetheless,

the authors confirm that the effectiveness of treatment is

invalidated by the great variability in data (high standard

deviation) and the excessive number of injections necessary

to maintain the same results that had been obtained with

only one round of therapy (three injections of Ranibizu-

mab) (2).

After looking at results derived from our study, we ob-

served a rapid response to the drug after the first week of

treatment (T1), followed by moderate improvement of visual

acuity and a substantial reduction in macular thickness after

both the first and second injections at T1 and T2. However,

after the third administration (T3), data showed average

Fig. 6. Images of the right eye 36 weeks: a. Fundus phothograph (3.13); b. fluorescein angiography (3.12); c. optical coherence tomography

CMT 244 (Number of letters ETDRS 38) (3.14)


values of ETDRS, LogMar and CMT that were analogous to

previous values observed at T2. When re-evaluating patients

between T4 and T12, the data highlights a slight decline in

the values of the three parameters that were examined when

compared to those from T3 (one week after the third IVI).

Out of the group’s 20 patients, reinjection due to a decline

in conditions was not necessary for 14 patients (70%) during

the 12 months of follow-up.

The remaining six subjects (30%) underwent reinjection

because of a decline in visual acuity and persistent or recur-

ring edema. In fact, regardless of the additional administra-

tions of Ranibizumab, the group’s CMT values at T12 were

the same or had increased with respect to T0 most likely

due to the effectiveness of treatment being correlated to the

great variability of implied factors (correlated pathologies

and risk factors). This study has demonstrated the correlation

between a negative outcome and certain chronic pathologies

such as: essential hypertension (found in 100% of patients)

and diabetes mellitus (found in 33.3% of patients).

In accordance with data found in scientific literature,

Ranibizumab guarantees rapid improvement of patients’

clinical conditions after just the first week of treatment

(T1) and maximum efficacy is reached after two months of

treatment (T2) (2, 26, 27).

After the third intravitreal injection (T3), and with re-

gards to the initial effectiveness of treatment, we observed

a slight decline in results that had been achieved during the

second month as gathered from the average reduction in

visual acuity and the average increase of CMT.

Nonetheless, the final values (obtained at T12) were,

on average, better than initial values recorded (T0), which

demonstrates that, in any case, patients had benefitted from

treatment with Ranibizumab.

The turnaround of progression may most likely be ex-

plained by anti-VEGF drug limitations, such as the limited

vitreal half-life of Ranibizumab (less than nine days), the

lack of a predefined protocol for therapy regarding admi-

nistration procedures, doses and the number of injections

necessary, the possibility of a rebound effect (consistent in

an increase of macular edema secondary to upregulation of

VEGF receptors in the retina caused by the drug’s inhibitory

mechanism) (28), the possible negative effect on the survival

of retinal neurons (VEGF agents are neuroprotective) and

the variability of factors that cause CRVO.

Other than this, we must take into consideration that

VEGF agents do not represent the only factor in the etio-

pathogenesis of the retinal vein occlusion. Other cytokines

(IL-1a, IL-6 and IL-8) and growth factors may have a role

in the formation of pathological neoangiogenesis and an

inflammatory response (29).

In conclusion, the results obtained from this study have

led us to confirm that intravitreal treatment with Ranibizu-

mab represents a valid therapeutic option for retinal vein

occlusion due to the fact that it has shown to immediately

improve all morphofunctional parameters as well as clini-

cal and subjective conditions (Fig. 3 and 4). This has also

resulted in a high level of patient compliance.

In order to most likely achieve higher effectiveness, it

would be ideal to include other therapeutic strategies along

with intravitreal treatment with anti-VEGF agents, such as

laser treatment, as has been reported recently in an interna-

tional case series prospective (with 12 months of follow-

up). Twenty eyes with CRVO were studied. On average,

8.5 injections of Ranibizumab followed by panretinal laser

treatment (PRN) showed to greatly improve visual acuity

(from 45.8 to 64.3 letters) and macular thickness was redu-

ced (from 574 to 186 micron with respect to initial values)

(2), or with intravitreal injection with steroids.

To this end, we believe it is necessary to increase the

number of subjects and the duration of the follow-up.

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Documents

Testing the effectiveness of intravitreal Ranibizumab during 12 months of follow-up in venous occlusion treatment