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Intravitreal Bevacizumab for Retinopathy of Intravitreal Bevacizumab for Retinopathy of Prematurity: Refractive Error ResultsPrematurity: Refractive Error Results

Journal Reading

Presenter:Presenter:

Olly ConggaOlly Congga

Advisor:Advisor:

Dr. dr. Noor Syamsu, Sp.M(K), Dr. dr. Noor Syamsu, Sp.M(K),

MARS, M.KesMARS, M.Kes

dr. A. M. Ichsan, Ph.D, Sp.M(K)dr. A. M. Ichsan, Ph.D, Sp.M(K)

dr. Marliyanti Akib, Sp.M(K), M.Kesdr. Marliyanti Akib, Sp.M(K), M.Kes

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Abstract

PURPOSEPURPOSE: :

To evaluate refractive error in infants who To evaluate refractive error in infants who underwent intravitreal bevacizumab injection underwent intravitreal bevacizumab injection for treatment of threshold retinopathy of for treatment of threshold retinopathy of prematurity (ROP).prematurity (ROP).

DESIGNDESIGN: :

Retrospective nonrandomized Retrospective nonrandomized interventional comparative study.interventional comparative study.

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METHODS:

The study group included all infants who consecutively received a single intravitreal bevacizumab (0.375mg or 0.625mg) injection for therapy of threshold ROP in fundus zone I or zone II. The control group included infants who had previously undergone retinal argon laser therapy of ROP. The follow-up examination included refractometry under cycloplegic conditions.

Abstract

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RESULTSRESULTS: :

The study group included 12 children (23 eyes; mean birth The study group included 12 children (23 eyes; mean birth weight: 622 ± 153 g; gestational age: 25.2 ± 1.6 weeks) and the weight: 622 ± 153 g; gestational age: 25.2 ± 1.6 weeks) and the control group included 13 children (26 eyes; birth weight: 717 ± control group included 13 children (26 eyes; birth weight: 717 ± 197 g; gestational age: 25.3 ± 1.8 weeks). 197 g; gestational age: 25.3 ± 1.8 weeks).

At the end of follow-up at 11.4 ± 2.3 months after birth, At the end of follow-up at 11.4 ± 2.3 months after birth, refractive error was less myopic in the study group than in the refractive error was less myopic in the study group than in the control group (-1.04 ± 4.24 D vs -4.41 ± 5.50 D ). Prevalence of control group (-1.04 ± 4.24 D vs -4.41 ± 5.50 D ). Prevalence of moderate myopia and high myopia was significantly lower in the moderate myopia and high myopia was significantly lower in the bevacizumab group. Refractive astigmatism was significantly bevacizumab group. Refractive astigmatism was significantly lower in the study group (-1.0 ± 1.04 D vs 1.82 ± 1.41 D). lower in the study group (-1.0 ± 1.04 D vs 1.82 ± 1.41 D).

In multivariate analysis, myopic refractive error and astigmatism In multivariate analysis, myopic refractive error and astigmatism were significantly associated with laser therapy vs bevacizumab were significantly associated with laser therapy vs bevacizumab therapy.therapy.

Abstract

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CONCLUSIONS:

In a 1-year follow-up, a single intravitreal bevacizumab injection as compared to conventional retinal laser coagulation was helpful for therapy of ROP and led to less myopization and less astigmatism.

Abstract

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Journal Theory

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Retinopathy of PrematurityRetinopathy of Prematurity

Retinopathy of prematurity is a Retinopathy of prematurity is a multifactorial vasoproliferative retinal multifactorial vasoproliferative retinal disorder that increases in incidences disorder that increases in incidences with decreasing gestational agewith decreasing gestational age Its a developmental vascular Its a developmental vascular

proliferative disorder that occurs in proliferative disorder that occurs in the incompletely vascularized retina the incompletely vascularized retina of primarily premature infants.of primarily premature infants.

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Retinopathy of PrematurityRetinopathy of Prematurity

• First described by TERRY in 1941First described by TERRY in 1941• Originally known as Retrolental Originally known as Retrolental

fibroplasiafibroplasia• Term RETINOPATHY OF Term RETINOPATHY OF

PREMATURITY was coined by Heath PREMATURITY was coined by Heath in 1952.in 1952.

• Campbell suggested the Campbell suggested the relationship of intensive oxygen relationship of intensive oxygen therapy & subsequent development therapy & subsequent development of ROP.of ROP.

• Kinsey: ROP was inversely Kinsey: ROP was inversely proportional to birth weight.proportional to birth weight.

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Embryogenesis Embryogenesis

Retinal Vascularization begins at optic nerve head Retinal Vascularization begins at optic nerve head by 16 weeks of gestation → migrate from the optic by 16 weeks of gestation → migrate from the optic disc at posterior pole & move towards periphery disc at posterior pole & move towards periphery by 21-22 weeks of gestation.by 21-22 weeks of gestation.

Before the retinal vessels develops the avascular Before the retinal vessels develops the avascular retina receives it oxygen supply by diffusion across retina receives it oxygen supply by diffusion across the retina from choroidal vessels.the retina from choroidal vessels.

Choroidal Vascularization begins at 6Choroidal Vascularization begins at 6thth weeks of weeks of gestation and it is completed by 21 weeksgestation and it is completed by 21 weeks

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Retinal vessels grow out of the Retinal vessels grow out of the optic disc as a wave of optic disc as a wave of mesenchymal spindle cells.mesenchymal spindle cells.

Mesenchymal spindle cells lead Mesenchymal spindle cells lead the shunt, endothelial the shunt, endothelial proliferation and capillary proliferation and capillary formation follow.formation follow.

These new capillaries will form the These new capillaries will form the mature retinal vessels.mature retinal vessels.

Embryogenesis Embryogenesis

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16 weeks 16 weeks → The choroidal vessels → The choroidal vessels supply the rest of the avascularized supply the rest of the avascularized retina.retina.

32 weeks32 weeks → The nasal portion of the → The nasal portion of the retina is completely vascularized to retina is completely vascularized to the ora serrata .the ora serrata .

40-42 weeks40-42 weeks → The larger temporal → The larger temporal area usually is completed area usually is completed

Embryogenesis Embryogenesis

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Temporal side

Nasal side

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PathogenesisPathogenesis

The onset of ROP progresses in two The onset of ROP progresses in two phasesphases::

PHASE 1 : It involves an initial insult such as PHASE 1 : It involves an initial insult such as hyperoxia, hypoxia or hypotension at a critical hyperoxia, hypoxia or hypotension at a critical point in retinal vascularization. Which causes point in retinal vascularization. Which causes vasoconstriction and decreased blood supply to vasoconstriction and decreased blood supply to the developing retina with subsequent arrest in the developing retina with subsequent arrest in vascular development. vascular development.

The relative hyperoxia after birth is The relative hyperoxia after birth is hypothesized to downregulate the production of hypothesized to downregulate the production of growth factor such as VEGF essential for normal growth factor such as VEGF essential for normal development of Retinal vessels.development of Retinal vessels.

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PathogenesisPathogenesis

PHASE 2: during the second phase PHASE 2: during the second phase neovascularization neovascularization occurs. This abberant retinal vessel growth occurs. This abberant retinal vessel growth is thought tois thought tobe driven by excess angiogenic factors be driven by excess angiogenic factors (VEGF) upregulated by hypoxic avascular (VEGF) upregulated by hypoxic avascular retina.retina.

Fig. 5.   Schematic representation of IGF-I/VEGF control of blood vessel development in ROP. New vessels grow through the retina in to the vitreousNew vessels grow through the retina in to the vitreous → → permeable permeable → → hemorrhage & edema occurs.hemorrhage & edema occurs.Extensive and severe extraretinal fibrovascular proliferationExtensive and severe extraretinal fibrovascular proliferation → → retinal retinal detachment.detachment.

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ROP pathogenesis and suggested treatments. (a) Retina vessels in the process of their formation and progressive covering of the retina surface. (b) Hyperoxia at this formative stage suppresses VEGF and, consequently, results in regression of newly formed vessels. (c) Upon return to normal air, the ischemic retina upregulates VEGF to high levels, causing excessive formation of leaky vessels. To antagonize VEGF at this stage has been suggested as a strategy to reduce adverse vessel formation. (d) An alternative strategy proposed by Shih et al. is to protect retina vessels from oxygen-induced obliteration through administration of PlGF-1.

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The International Classification of retinopathy of The International Classification of retinopathy of prematurity (ICROP)prematurity (ICROP)

• ClassificationClassification

ZONEZONE

EXTENTEXTENT

STAGESTAGE

PLUSPLUS

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ZoneZone

Refers to how far the developing retinal vessels have progressed . The retina is divided into three concentric circles or zones :

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Consist of an imaginary circle with optic nerve at the centre and a radius is twice the distance from optic nerve to the macula .

Extents from the edge of zone 1 to the ora serrata on the nasal side of the eye and approximately half the distance to the ora serrata on the temporal side.

Consist of the outer cresent shaped area extending from the Zone 2 out to the ora serrata temporally.

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ExtentExtent

REPORTED AS CLOCK HOURS IN THE APPROPRIATE ZONESREPORTED AS CLOCK HOURS IN THE APPROPRIATE ZONES

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Stage IStage I

Stage I : A demarcation line appears as a Stage I : A demarcation line appears as a thin white line that separates the normal thin white line that separates the normal retina from underdeveloped avascular retina from underdeveloped avascular retinaretina

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Stage IIStage II

Stage II : A ridge of Fibrovascular tissue Stage II : A ridge of Fibrovascular tissue wight height and width replaces the wight height and width replaces the demarcation line. It extends inwards from demarcation line. It extends inwards from the plane of retina .the plane of retina .

Popcorn Popcorn Isolated tufts of neovascular tissue Isolated tufts of neovascular tissue posterior to ridge at the level of retina posterior to ridge at the level of retina

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Stage IIStage II

Fundus photograph showing the ridge between vascularized Fundus photograph showing the ridge between vascularized and avascular retina characteristic of stage 2 retinopathy of and avascular retina characteristic of stage 2 retinopathy of prematurity (single long arrow). Small isolated tufts of new prematurity (single long arrow). Small isolated tufts of new vessels (popcorn) lie on the retinal surface (short arrows). vessels (popcorn) lie on the retinal surface (short arrows). Note also stage 3 retinopathy of prematurity is present in Note also stage 3 retinopathy of prematurity is present in the left hand portion of the photograph (double long the left hand portion of the photograph (double long arrows). arrows).

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Stage IIIStage III

Stage III : The ridge has extraretinal fibrovascular Stage III : The ridge has extraretinal fibrovascular proliferation. Abnormal blood vessels and fibrous proliferation. Abnormal blood vessels and fibrous tissue develop on the edge of the ridge and extend tissue develop on the edge of the ridge and extend in to the vitreous.in to the vitreous.

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Stage IIIStage III

MILD MILD MODERATE MODERATE SEVERESEVERE

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Stage IVStage IV

Stage IV : Partial retinal detachment Stage IV : Partial retinal detachment may result when the scar tissue may result when the scar tissue pulls on the retina.pulls on the retina.

- Exudative, if early- Exudative, if early- Tractional, as part of the change over from - Tractional, as part of the change over from acute to cicatricial disease. acute to cicatricial disease. - Rhegmatogenous detachments, years later- Rhegmatogenous detachments, years later

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Stage IVStage IV

Examples of stages 4A and B retinopathy of prematurity. A, Examples of stages 4A and B retinopathy of prematurity. A, Example of stage 4A, extrafoveal partial retinal detachment. Example of stage 4A, extrafoveal partial retinal detachment. Note also the straightening of temporal vascular arcade. B, Note also the straightening of temporal vascular arcade. B, Fundus photograph of stage 4B, partial retinal detachment Fundus photograph of stage 4B, partial retinal detachment involving macula. Note absence of normal choroidal pattern involving macula. Note absence of normal choroidal pattern in macular region. C, Fundus photograph showing stage 4B in macular region. C, Fundus photograph showing stage 4B retinal detachment with extensive temporal dragging of retinal detachment with extensive temporal dragging of vessels and macula. vessels and macula.

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Stage VStage V

Stage V : Complete retinal detachment occurs. Stage V : Complete retinal detachment occurs. The retina arrange a funnel shaped appearance The retina arrange a funnel shaped appearance and is described as open or narrow in the and is described as open or narrow in the anterior and posterior zone .anterior and posterior zone .

Funnel:

Anterior Posterior

Open Open

Narrow Narrow

Open Narrow

Narrow

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Stage VStage V

Fundus views of stage 5 retinopathy of Fundus views of stage 5 retinopathy of prematurity. A, View of stage 5 retinopathy of prematurity. A, View of stage 5 retinopathy of prematurity, total retinal detachment with open prematurity, total retinal detachment with open funnel configuration. B, View of stage 5 funnel funnel configuration. B, View of stage 5 funnel retinal detachment that is open anteriorly but retinal detachment that is open anteriorly but narrowed posteriorly. narrowed posteriorly.

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Plus DiseasePlus Disease

• Additional designation that refers to the presence Additional designation that refers to the presence of vascular dilation and arteriolar tortuosity of of vascular dilation and arteriolar tortuosity of posterior retinal vessels at least 2 quadrantsposterior retinal vessels at least 2 quadrants

• This indicates the severe form of the diseaseThis indicates the severe form of the disease

• It may be associated with Iris vascular It may be associated with Iris vascular engorgement, pupillary rigidity, and vitreous engorgement, pupillary rigidity, and vitreous haze.haze.

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Plus DiseasePlus Disease

Two fundus photographs with example of plus Two fundus photographs with example of plus disease. A, Another example of plus disease. B, disease. A, Another example of plus disease. B, View of retinopathy of prematurity with plus View of retinopathy of prematurity with plus disease. disease.

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Preplus DiseasePreplus Disease

It’s a vascular abnormalities of the posterior pole It’s a vascular abnormalities of the posterior pole more than normal, less than PLUSmore than normal, less than PLUS

The newly accepted preplus serves as a warningThe newly accepted preplus serves as a warning

Examples of pre-plus disease. A, Pre-plus disease with Examples of pre-plus disease. A, Pre-plus disease with greater tortuosity of posterior pole vessels than normal but greater tortuosity of posterior pole vessels than normal but insufficient to be designated plus disease. B, Another insufficient to be designated plus disease. B, Another example of pre-plus disease. C, Pre-plus disease with example of pre-plus disease. C, Pre-plus disease with insufficient dilatation and tortuosity of vessels to be insufficient dilatation and tortuosity of vessels to be designated plus disease. Stage 2 retinopathy of prematurity designated plus disease. Stage 2 retinopathy of prematurity is present temporally in this image. is present temporally in this image.

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Clinically Significant TermsClinically Significant Terms

• Threshold ROPThreshold ROP: CRYO ROP study: CRYO ROP studyZone I stage III with PlusZone I stage III with PlusZone II Stage III with Plus (5 contigous or total 8 clock hrs)Zone II Stage III with Plus (5 contigous or total 8 clock hrs)

• Prethreshold ROPPrethreshold ROP: ETROP study: ETROP studyHigh risk PrethresholdHigh risk PrethresholdZone I Stage I, II, III with plusZone I Stage I, II, III with plus

Stage III without plusStage III without plusZone II Stage II with plusZone II Stage II with plus

Stage III without plus Stage III without plus Stage III with plus but < 5 contigous or total 8 clock hrsStage III with plus but < 5 contigous or total 8 clock hrs

Plus disease has increased in importance while the Plus disease has increased in importance while the extent (clock hours) of disease has diminishedextent (clock hours) of disease has diminished

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BEAT-ROP studyBEAT-ROP study

• Bevacizumab Eliminates the Angiogenic Threat of Retinopathy Bevacizumab Eliminates the Angiogenic Threat of Retinopathy Of PrematurityOf Prematurity

• Prospective, randomized, US multicentre, controlled clinical Prospective, randomized, US multicentre, controlled clinical trialtrial

• Compared intravitreal Avastin 0.625mg (0.025ml) as primary Compared intravitreal Avastin 0.625mg (0.025ml) as primary therapy with conventional laser therapy for stage 3+ ROPtherapy with conventional laser therapy for stage 3+ ROP

• 150 infants (300 eyes);150 infants (300 eyes);

• 7 died and not included in data (5 in Avastin group, 2 in laser)7 died and not included in data (5 in Avastin group, 2 in laser)

• 67 had zone 1 ROP67 had zone 1 ROP

• 83 had zone 2 posterior ROP83 had zone 2 posterior ROP

• 75 in each treatment group75 in each treatment group

• Higher rate of recurrence for zone 1 disease with laserHigher rate of recurrence for zone 1 disease with laser

• 2 cases (eyes) of recurrence with Avastin, 23 with laser2 cases (eyes) of recurrence with Avastin, 23 with laser

• Significant effect for zone 1 disease, not for zone 2 diseaseSignificant effect for zone 1 disease, not for zone 2 disease

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BEAT-ROP studyBEAT-ROP study

• Avastin significant effect for zone 1 disease, not Avastin significant effect for zone 1 disease, not for zone 2 diseasefor zone 2 disease

• Efficacy shown, safety not provedEfficacy shown, safety not proved• Later recurrence after Avastin: 16±4.6 weeks, Later recurrence after Avastin: 16±4.6 weeks,

laser 6.2 ± 5.7 weekslaser 6.2 ± 5.7 weeks• Avastin treated babies need longer follow-upAvastin treated babies need longer follow-up

•High failure rate with laser, higher than for UKHigh failure rate with laser, higher than for UK•Underpowered - would need 2,800 infants to Underpowered - would need 2,800 infants to establish systemic safetyestablish systemic safety•Follow-up longer/more problematic than laserFollow-up longer/more problematic than laser•The main question is not efficacy but safetyThe main question is not efficacy but safety

ISSUES

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BEAT-ROP studyBEAT-ROP study

Safety concernsSafety concerns• Intravitreal Avastin enters the general circulation, Intravitreal Avastin enters the general circulation,

suppresses plasma VEGF levels and remains in the blood suppresses plasma VEGF levels and remains in the blood for more than 8 weeks in primates.for more than 8 weeks in primates.

• Possible adverse effects on VEGF-dependent Possible adverse effects on VEGF-dependent development must be considered.development must be considered.

(normal angiogenesis, regulation of vascular (normal angiogenesis, regulation of vascular permeability, endothelial differentiation during fetal brain permeability, endothelial differentiation during fetal brain development, signalling between major neural cells, development, signalling between major neural cells, maintenance and development of the blood–brain barrier)maintenance and development of the blood–brain barrier)

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LASERLASER

•LL : Light : Light

•AA : Amplification (by): Amplification (by)

•SS : Stimulated : Stimulated

•EE : Emission (of): Emission (of)

•RR : Radiation : Radiation

Term coined by Gordon Gould. Term coined by Gordon Gould.

Laser means to absorb energy in one form and to Laser means to absorb energy in one form and to emit a new form of light energy which is more emit a new form of light energy which is more useful. useful.

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Continuous and pulsed lasersContinuous and pulsed lasers

• Pulsed – energy delivered in brief Pulsed – energy delivered in brief bursts, more powerbursts, more power

• Examples: Nd YAG, Excimer lasersExamples: Nd YAG, Excimer lasers

• Continuous – Argon, krypton lasers, Continuous – Argon, krypton lasers, diode lasers, and dye lasers diode lasers, and dye lasers

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LASER TISSUE INTERACTIONLASER TISSUE INTERACTION

LASER

TISSUE

Thermal Effect

Photo-chemical

Ionizing Effect

Photocoagulation Photoradiation

Photodisruption Photoablation

Photovaporization

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PhotocoagulationPhotocoagulation

Laser Light

Target Tissue

Generate Heat

Denatures Proteins (Coagulation)

Rise in temperature of about 10 to 20 0C will cause coagulation of tissue.

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Laser indirect ophthalmoscopeLaser indirect ophthalmoscope

Advantages Advantages ::• Wider field(ability to reach periphery).Wider field(ability to reach periphery).• Better visualization and laser application in hazy medium.Better visualization and laser application in hazy medium.• Ability to treat in supine position.(ROP/EUA)Ability to treat in supine position.(ROP/EUA)

DisadvantageDisadvantage : : • difficulty in focusing.difficulty in focusing.• Difficulty to standardize spot size.Difficulty to standardize spot size.• Expensive.Expensive.• Un co-operative patient.Un co-operative patient.• Learning curve.Learning curve.

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Back to Back to JournalJournal

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Retinopathy of Prematurity

Retinal ischemic disease in prematurely born infantsRetinal ischemic disease in prematurely born infants

characterized by retinal and retinovitreal characterized by retinal and retinovitreal neovascularizationneovascularization

Retinal detachment

IntroductionIntroduction

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stage stage 3+ ROP3+ ROP

led to a led to a permanentpermanentdestruction destruction

of the of the peripheral peripheral

retinaretina

significant significant benefit for zone benefit for zone

I disease but I disease but not zone II not zone II

diseasedisease

the peripheral the peripheral retinal vessels retinal vessels continued tocontinued to

developdevelop

Intravitreal Intravitreal Bevaci-Bevaci-zumabzumab

Conven-Conven-tional laser tional laser

therapytherapy

VEGF's important role in the pathogenesis of VEGF's important role in the pathogenesis of

ROPROP

Mintz-Hittner HA, Kennedy KA, Chuang AZ, BEAT-ROP Cooperative Group. Efficacy of intravitreal Mintz-Hittner HA, Kennedy KA, Chuang AZ, BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011; 364(7):603–615bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011; 364(7):603–615

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PROBLEM UNSOLVED :PROBLEM UNSOLVED :

It has remained unclear whether the intravitreal It has remained unclear whether the intravitreal bevacizumab therapy as compared to the bevacizumab therapy as compared to the peripheral retinal laser coagulation leads to the peripheral retinal laser coagulation leads to the same amount of axial myopization.same amount of axial myopization.

How to solve the problem ?How to solve the problem ?

This study conducted to assess the refractive error This study conducted to assess the refractive error of young children who had undergone intravitreal of young children who had undergone intravitreal bevacizumab therapy and compared the refractive bevacizumab therapy and compared the refractive error of children who had previously undergone error of children who had previously undergone laser therapylaser therapy

IntroductionIntroduction

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All children treated with an intravitreal injection of All children treated with an intravitreal injection of bevacizumab (Avastin) for ROP threshold disease in bevacizumab (Avastin) for ROP threshold disease in posterior zone II or zone I or for prethreshold ROP in posterior zone II or zone I or for prethreshold ROP in zone I.zone I.

Clinical data obtained during routine careClinical data obtained during routine care

The diagnosis of ROP → International Committee for The diagnosis of ROP → International Committee for the Classification of Retinopathy of Prematuritythe Classification of Retinopathy of Prematurity

The criterion for therapy → presence of a threshold The criterion for therapy → presence of a threshold disease → disease stage with a 50% likelihood of disease → disease stage with a 50% likelihood of progressing to retinal detachment.progressing to retinal detachment.

Threshold disease → stage 3 ROP in either zone I or Threshold disease → stage 3 ROP in either zone I or zone II → at least 5 continuous or 8 total clock hourszone II → at least 5 continuous or 8 total clock hours

METHODSMETHODSRetrospective Nonrandomized Interventional Comparative StudyRetrospective Nonrandomized Interventional Comparative Study

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RESULTS

CRITERIA STUDY GROUP CONTROL GROUP

SUBJECT NUMBERS 23 EYES (7 , 5 )♂ ♀26 EYES (7 , 6 ♂

)♀BIRTH WEIGHT 622 ± 153 g 717 ± 197 gGESTATIONAL BIRTH AGE 25.2 ± 1.6 weeks 25.3 ± 1.8 weeks

FOLLOW-UP EXAMINATION OF CORRECTED AGE

11.1 ± 3.1 months 11.7 ± 1.6 months

REFRACTIVE ERROR RESULTS -1.04 ± 4.24 D -4.41 ± 5.50 D

REFRACTIVE ASTIGMATISM -1.0 ± 1.04 D 1.82 ± 1.41 D

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STUDY GROUPSTUDY GROUP

• 3 children → acute posterior stage of ROP → 3 children → acute posterior stage of ROP → Early Treatment for Retinopathy of Prematurity Early Treatment for Retinopathy of Prematurity Cooperative Group → received a dosage of 0.625 Cooperative Group → received a dosage of 0.625 mg bevacizumab (W.J.) mg bevacizumab (W.J.)

• 9 children → ROP stage 3+ with 9 children → ROP stage 3+ with neovascularization in 5 adjacent sectors of 30 neovascularization in 5 adjacent sectors of 30 degrees width or 8 nonadherent sectors and degrees width or 8 nonadherent sectors and fulfilled the same criteria for therapy → received fulfilled the same criteria for therapy → received a dosage of 0.375 mg bevacizumab (B.C.H. & a dosage of 0.375 mg bevacizumab (B.C.H. & F.C.S.)F.C.S.)

• All eyes showed a regression of plus disease All eyes showed a regression of plus disease within 2 to 6 days; a decrease in pupillary within 2 to 6 days; a decrease in pupillary rigidity; a resolution of any tunica vasculosa rigidity; a resolution of any tunica vasculosa lentis, if present prior to the injection; and a lentis, if present prior to the injection; and a complete regression of the retinal complete regression of the retinal neovascularization within 2 to 3 weeks.neovascularization within 2 to 3 weeks.

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• One eye of the laser group developed a partial retinal One eye of the laser group developed a partial retinal detachment (stage 4b)detachment (stage 4b)

• The infant who received a primary laser treatment in the right eye The infant who received a primary laser treatment in the right eye and an intravitreal bevacizumab injection 4 weeks later and an intravitreal bevacizumab injection 4 weeks later developed a retinal fold and macular ectopia. developed a retinal fold and macular ectopia.

• The left eye, which had received intravitreal bevacizumab only, The left eye, which had received intravitreal bevacizumab only, showed a regression of the tunica vasculosa lentis and of all showed a regression of the tunica vasculosa lentis and of all retinal neovascularizations without any retinal fold or any other retinal neovascularizations without any retinal fold or any other morphologic abnormality. morphologic abnormality.

• At 29 months of corrected age, refractive error was -10.25 D in At 29 months of corrected age, refractive error was -10.25 D in the right eye and -8.00 D in the left eye.the right eye and -8.00 D in the left eye.

CONTROL GROUPCONTROL GROUP

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DISCUSSIONDISCUSSIONSingle Intravitreal BevacizumabSingle Intravitreal Bevacizumab

• Complete regression of any retinal neovascularization Complete regression of any retinal neovascularization and regression of a tunica vasculosa lentis. and regression of a tunica vasculosa lentis.

• No additional retinal laser coagulation or a repeated No additional retinal laser coagulation or a repeated intravitreal injection needed in any eye. intravitreal injection needed in any eye.

• Refractometry 1 year after birth → significantly lower Refractometry 1 year after birth → significantly lower prevalence of moderate myopia prevalence of moderate myopia

• Small dosage of 0.375 mg (given in 9 of the 12 Small dosage of 0.375 mg (given in 9 of the 12 children) appeared to have had an effect similar to the children) appeared to have had an effect similar to the dosage of 0.625 mgdosage of 0.625 mg

• Less invasive character of the procedure → general Less invasive character of the procedure → general anesthesia is not neededanesthesia is not needed

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• The process of emmetropization in an infant’s The process of emmetropization in an infant’s eye has still not been entirely understoodeye has still not been entirely understood

• Lue et al. → the retina in eyes after ROP is Lue et al. → the retina in eyes after ROP is rendered dysfunctional → affect the eye rendered dysfunctional → affect the eye growth signals, or that ROP might halt or growth signals, or that ROP might halt or delay the normal migration of photoreceptors delay the normal migration of photoreceptors from the fovea → effect on acuity sufficient to from the fovea → effect on acuity sufficient to alter the visually driven feedback mechanism alter the visually driven feedback mechanism in emmetropization.in emmetropization.

DISCUSSIONDISCUSSIONSingle Intravitreal BevacizumabSingle Intravitreal Bevacizumab

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STUDY LIMITATIONSTUDY LIMITATION

• A retrospective study with no randomized control group. A retrospective study with no randomized control group.

• The range follow-up relatively short → 1 year → no The range follow-up relatively short → 1 year → no conclusions might be obtained → long-term effects and conclusions might be obtained → long-term effects and side effects of the therapy.side effects of the therapy.

• No statement can be made about the functional outcome No statement can be made about the functional outcome after the therapy ↓ the infants were still too young for any after the therapy ↓ the infants were still too young for any functional test. functional test.

• the number of children relatively small → any statements the number of children relatively small → any statements on the safety of the therapyon the safety of the therapy

• 3 of 12 children of study group showed an acute 3 of 12 children of study group showed an acute posterior stage of ROP → they underwent therapy at a posterior stage of ROP → they underwent therapy at a high-risk prethreshold stage, in contrast to the children of high-risk prethreshold stage, in contrast to the children of the control groupthe control group

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CONCLUSIONCONCLUSION

In a 1-year follow-up, a single intravitreal low-In a 1-year follow-up, a single intravitreal low-dosage bevacizumab injection as compared to dosage bevacizumab injection as compared to conventional retinal laser coagulation was helpful conventional retinal laser coagulation was helpful for therapy of ROP and led to less myopization for therapy of ROP and led to less myopization and less astigmatism.and less astigmatism.

Future randomized trials may address the same Future randomized trials may address the same topic to strengthen the conclusions of this study, topic to strengthen the conclusions of this study, including the finding that the low dosage of 0.375 including the finding that the low dosage of 0.375 mg bevacizumab may be sufficient for a complete mg bevacizumab may be sufficient for a complete regression of the intraocular neovascularizations regression of the intraocular neovascularizations in ROP.in ROP.

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Thank you !Thank you !

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Studies

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CRYO-ROP (1980’s) Randomized Control Trial study, conducted on 172

preterm infants Peripheral Cryotherapy vs. Observation “Threshold Disease”

Stage 3 (neovascularization) 5 contiguous, 8 noncontiguous clock hours

Zone I or II Plus Disease

Cryotherapy superior to Observation: Reduced unfavorable outcomes Related improved visual acuity results

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ET-ROP (2003)

Randomn control trial study was conducted on (n=317 bilateral; n=84 asymmetric unilateral infants) Early peripheral laser vs conventional treatment “High Risk Prethreshold” ROP disease – Type 1 or Type 2 Type 1 ROP

Zone I: Any Stage, plus / Stage 3, no plus Zone II: Stage 2 or 3, plus Finding: Early Peripheral laser superior to conventional treatment .

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• Type 2 ROP Zone I: Stage 1 or 2, no plus Zone II: Stage 3, no plus Finding: Observation advised until Type 1 or Regression

• Peripheral laser better than conventional treatment for Type 1: It concludes reduced unfavorable anatomic outcome from 15.6% to 9.1% .Reduced unfavorable visual acuity grating from 19.5% to 14.5%

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BEAT-ROP (2011) Bevacizumab Eliminates the Angiogenic Threat in

ROP” Randomn Control Trial was conducted on 150

infants, 300 eyes Stage 3, plus Zone 1 and posterior Zone 2 Comparison : Intravitreal Bevacizumab v/s

Peripheral Laser (ETROP) Summary

Bevacizumab reduced recurrence of ROP Bevacizumab benefit over laser in Zone 1 Bevacizumab allowed continued peripheral

vascularization into avascular retina