rop seminar

RETINOPATHY OFPREMATURITY

INTRODUCTIONRetinopathy of prematurity is a multifactorial vasoproliferative retinal disorder that increases in incidences with decreasing gestational age . Its a developmental vascular proliferative

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

• First described by TERRY in 1942• Originally known as Retrolental fibroplasia• Term RETINOPATY OF PREMATURITY was coined by

Health in 1951.

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

• Kinsey: ROP was inversely proportional to birth weight.

EMBRYOGENESIS• Retina is a thin, semitransparent, multilayered

sheet of neural tissue that lines the inner aspect of the posterior two-thirds of the wall of the globe.

• It is a thin delicate layer of nervous tissue of surface area 266mm2.

• It extends from optic disc to ora serrata

Normal retinal vascularisation

Choroid vascularises at 6 weeksRetinal vascularisation starts at optic

nerve head at 16 weeks gestationProceeds outward to the peripheryVascularisation is almost complete by

term

Vasculogenesis: primitive plexus formed from precursor cells, not VEGF dependant

Angiogenesis: new vessels from pre existing vasculature, VEGF dependant

Retinal Vascularization begins at optic nerve head by 16weeks of gestation, which migrate from the optic discat posterior pole and move towards periphery by 21-22 weeks of gestation.

Before the retinal vessels develops the avascular retinareceives it oxygen supply by diffusion across the retinafrom choroidal vessels.

Choroidal Vascularization begins at 6th weeks ofgestation and it is completed by 21 weeks

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

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

These new capillaries will form the mature retinal vessels.

6 wks- The choroidal vessels supply the rest of the avascularized retina.

32 Wks- The nasal portion of the retina is completely vascularized to the ora serrata .

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

PATHOGENESISClassical theory

Arthon & PatzO2Vasoconstriction-vasoocclusion-endothelial cell

proliferation-neovascularizationSpindle cell theory

Kretzer Spindle cell exposure to hyperoxic environment- spindle

cell insult- spindle cell stops to migration & canalization

PATHOPHYSIOLOGY

•ROP progresses in two phases.

•The first phase - delayed retinal vascular growth after birth and partial regression of existing vessels due to hyperoxia.

•Second phase - hypoxia-induced pathological vessel growth.

Kretzer and hittner

Extra uterine hyperoxia

Gap junctions in mesenchymal spindle

cells

Abnormal vacularisation

Ashton theory {bi-phasic model}

hyperoxia Retinal vasoconstriction

ischemiaEndothelial cell injury

Release of angiogenic

factors

neovaascularisation

Immature vessels

Fibrotic intravitrial bands

Retinal detachment

Risk factors

• Three crucial risk factors: • Birth weight • Gestational age • Number of days oxygen administered

• Other risk factors:• Multiple births • Blood transfusions • Respiratory Distress Syndrome (RDS) • Sepsis • Intra Ventricular Hemorrhage (IVH)• Intra Uterine Growth Retardation (IUGR)• Vit E deficiency• Anemia • Seizures.

ClassificationsThe International Classification of retinopathy of prematurity (ICROP).The classification consists of four components: Location Severity Extent Plus Disease

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

Zone 1:

Zone 2 :

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.

Zone 3 : Consist of the outer cresent shaped area extending from the Zone 2 out to the ora serrata temporally.

Severity: It refers to the stage of the diesease :

Stage 1A demarcation line appears as a thin white line that separates the normal retina from underdeveloped avascular retina

Stage 2A ridge of Fibrovascular tissue wight height and width replaces the demarcation line . It extends inwards from the plane of retina .

Ridge of fibrovascular tissue

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

Stage 3The ridge has extraretinal fibrovascular proliferation . Abnormal blood vessels and fibrous tissue develop on the edge of the ridge and extend in to the vitreous.

Stage 4Partial retinal detachment may result when the scar tissue pulls on the retina.

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

STAGE 4 AMacula Spared

STAGE 4 B Macula involved

Stage 5

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

EXTENT

PLUS DISEASE• Additional designation that refers to the presence

of vascular dilation and arteriolar tortuosity of posterior retinal vessels at least 2 quadrants

• This indicates the severe form of the disease

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

PREPLUS DISEASE It’s a vascular abnormalities of the posterior pole

more than normal, less than PLUS

The newly accepted preplus serves as a warning

CLINICALLY IMPORTANT DEFINATIONS

THRESHOLD ROP:

• CRYO ROP study• Zone I stage III with Plus• Zone II Stage III with Plus• ( 5 contigous or total 8 clock hours)• Risk of blindness is 50%

PRETHRESHOLD ROP : ETROP study

• High risk Prethreshold• Zone I Stage I, II, III with plus• Stage III without plus• Zone II Stage II and III with plus

SCREENING

WHOM TO SCREEN ?

• In US• The recommendation is to screen all babies with a

Birth Weight < 1500gm• Gestational age < 32 weeks• Babies born after 32 weeks of gestation may be

considered for screening if they have been ill ( RDS, hypotension, surgery ) .

• In INDIA

• Should be performed in all preterm neonates who are

• < 34 weeks gestation and / or < 1750 grams birth weight.

• 34 to 36 weeks gestational age or a birth weight between 1750

and 2000 grams with risk factors.

• First screen should be performed not later than 4 weeks of age or

30 days of life in infants ≥ 28 weeks of gestational age.

• Infants <28 weeks or <1200 grams birth weight should be screened

early at 2-3 weeks of age, for early diagnosis of AP-ROP.

• Patients are screened every 2 weeks until their vessels have grown out to the ora Serrata and the retina is considered mature.

• If ROP is diagnosed the frequency of the examination depends on the severity and

rapidity of the progression of the disease.

How to screen ?

• The procedure is performed in NICU by pediatric opthalmologist , under the supervision of neonatologist so that complication can be handled.

• The pupil are dilated with a mixture of phenyl phrine 2.5% and tropicamide or cyclopentolate 1% instilled 2 times at 15min intervals before the scheduled examination.

• Indirect opthalmoscopy is performed with 20D / 30D lens using fresh sterile instruments.

• Scleral depression is done to stabilize the eye , rotate it , indent it, and contrast retina.

• RETCAM can be used to provide real time video display of images

• Tropical anesthetic should be used to reduce discomfort.

• Atleast two fundal examination should be performed after dilatation using binocolor indirect opthalmoscope.

• When ROP is diagnosed the frequency of examination depends severity and rapidity of disease.

RETCAM Wide angle digital paediatric retinal imaging

system Mobile, self contained system for use in

nursery, ICU, O.T Easily used by technicians or nurses Provide retinal images at 130 degree Avoids stress & expertise of I/O examination &

indentation, but as specific and sensitive as I/O Useful for diagnosis, telemedicine &

documentation

When can the Retinal examination be terminated ?

• COMPLETE VASCULARIZATION• VASCULARIZATION in ZONE III (till 1 DD of temporal

ora) – if no previous ROP in zone I & II• REGRESSED ROP ( b/w 40 -44 weeks PCA)– no active

disease left• 45 weeks PCA with less than pre threshold disease

TREATMENT Cryotherapy ( mostly outdated)

Laser treatment (gold standard)

Anti-VEGF (adjuvant) before laser and surgery

Surgery

Cryotherapy significantly improves the outcome of severe ROP

Superceded by laser photocoagulation.

Cyroprobe is applied to the external surface of the sclera and areas peripheral to the ridge are frozen until in avascular retina has been treated.

The procedure is done general anesthesia.

CRYOTHERAPY

End point of cryotherapy is the appearance of mild whitening.

multiple white cryo burns (black arrows) in avascular retina anterior to ridge (white arrow).

Complications of cryotherapy Eyelid edema, laceration of the conjunctiva, and pre-retinal and vitreous haemorrhage as well as systemic complications like bradycardia, cyanosis and respiratory depression

Procedure of choice, being less invasive, less traumatic and causes less discomfort to the infant.

Laser treatment is delivered through an indirect opthalmoscope .

It can be performed in NICU and under local anesthesia

Easy to treat posterior located lesion. Argon green and Diode red LASER has

been used

LASER THERAPY

An average of 1000 to 2000 spots of 100 mm size 1½ burn width apart can be placed in each eye.

Entire avascular retina till ora, avoid the ridge.

Fundus picture of RE showing laser scars (black arrows)

Complications of laser therapy Burns in cornea and iris. Other complications include cataract, and retinal and vitreous haemorrhage. Development of cataracts and glaucoma or anterior segment ischemia following laser has been reported.

Monotherapy Single injections Multiple injections for recurrenceLess desirable if periphery not perfused

Adjunctive therapy Injections to allow regression beyond Zone 1

Laser for recurrent ROP Anti-VEGF as a Bridge to laser peripherally

Treatment after laser / cryotherapy failure Perioperative therapy before surgery

Reduce bleeding Promote regression of neovascularization Vitrectomy and scleral buckles

Anti VGEF therapy

SURGERY

RETINAL REATTACHMENT• Once the macula detaches in stage 4b or 5 ROP retinal

reattachment is done.

• It may include vitrectomy with or without lensectomy.

• Membrane peeling is done to remove the tractional force causing the retinal detachment.

• A Scleral buckling procedure is useful for perpheral detachments with drainage of subretinal fluid for effusional detachment.

• Sucessful retinal reattachment outcome of the visual acuity is in the range of the Legal blindness.

• Despite low vision outcome it is considered superior to untreated stage 5 .

SCLERAL BUCKLE It is done under GAPeritomy2.5 mm encircling band passed beneath 4 RectiOne anchoring mattress suture applied in all quadrantsRemoval after 3-6 months

VITRECTOMYNecessary in advanced casesLensectomy avoidedPeeling of membranesRelieve of tractionNo attempt to drain Sub Retinal Fluid

AIM : Ambulatory vision ie being able to see objects and move around a room without stumbling or bumping into obstacles.

Follow up

• ROP management doesn’t end with laser or surgery.

• Once treated, lifelong followup (yearly) is mandatory.

• All other premature infants irrespective of having ROP - yearly followup till the age of 5 years is advisable.

• To rule out - refractive errors (most common), squint and amblyopia.

STUDIES

LANDMARK STUDIESCorroborative study for role of O2 -

1950s

ICROP - 1984, 1987, 2005

CRYO ROP

ETROP

LIGHT ROP

STOP ROP

HOPE ROP

PHOTO ROP

BEAT ROP

CRYO-ROP (1980’S) Randomn 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

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 .

• 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%

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

Pegaptanib and ROP (2012)

• 152 eyes with Zone 1, posterior Zone 2 ROP Stage 3, plus disease • Group 1 (68 eyes)

• Pegaptanib (0.3 mg) with laser • Follow up 19.3 months

• Group 2 (84 eyes) • Laser / cryotherapy • Follow up 21.5 months

• Primary Outcome: absence of recurrent Stage 3+ ROP • Results

• Group 1 89.7% regression; 85.4% no recurrence • Group 2 60.8% regression; 50% no recurrence

THANK YOU