Retinopathy of Prematurity Kristin E. Hubert, MD December, 2011

Retinopathy of Prematurity Pathologic retinal neovascularization Related to Prematurity 84% of infants less than 28 weeks gestation will develop ROP 11% of these will require treatment Oxygen exposure Therapy Ablative-Laser Avastin Approximately 10-15% of treated eyes progress to blindness

Historical Perspective First case described in 1942 Grey, blood vessel-covered membranes behind the pupil Termed Rentrolental Fibroplasia (RLF)

Historical Perspective Epidemic of ROP in 1940s and 1950s No ventilators, IV fluids, or laboratory blood tests were available Why? Oxygen was introduced to treat apnea of prematurity Common to fill incubator with oxygen for first several weeks of life The idea was basically that more oxygen is better!

Kinsey VE, Arch Ophthalmol. 1956;56:481-547 Implicating Oxygen 1956 NIH funded Infants <1500 g who survived 48 hours Randomized by telegraph Control Experimental 50% oxygen for 28 days Oxygen reduced to RA unless cyanotic If cyanotic, oxygen increased up to 50%. Kinsey VE, Arch Ophthalmol. 1956;56:481-547

Kinsey VE, Arch Ophthalmol. 1956;56:481-547 Implicating Oxygen Findings Resulting changes in practice Oxygen was restricted (40% rule) ROP virtually disappeared Survival ROP Stage 3 to 5 Blind Control 22% 72% 23% 11% Experimental 25% 33% 6% 2% Kinsey VE, Arch Ophthalmol. 1956;56:481-547

Famous Musician with ROP

Historical Perspective ROP re-emerged in 1970s Improved survival of premature infants IV fluids, exchange transfusions, ability to measure serum electrolytes, ventilators But oxygen was being well controlled… Interest in the disease process sparked

www.amdcanada.com/images/

ROP Pathogenesis Phase 1 Immature retina exposed to hyperoxia Vasoconstriction of immature retinal vessels Vaso-obliteration and vaso-prevention with continued hyperoxia

Effect of Oxygen on Mouse Retinas 12 day old mouse kept in room air 12 day old mouse exposed to 75% oxygen from day of life 7-12 (Mice lose blood vessels centrally, humans lose them in the periphery)

ROP Pathogenesis Phase 2 Retinal ischemia upon withdrawal of high levels of oxygen Vasoproliferation with preretinal neovascularization VEGF (1995) Retinal hemorrhage, folds, detachment

Who gets screened? (AAP Criteria) All Infants born at <30 weeks All infants with birth weight <1500 grams Any other infant at neonatologist’s discretion Typically infants with an unstable clinical course not meeting the above criteria

When do they get screened? 1st exam when infant is BOTH 4 weeks from birthdate AND 31 weeks PMA GA at birth PMA Chronologic age 24 31 7 25 6 26 5 27 4 28 32 29 33 30 34 31* 35 32* 36 * If indicated Adapted from AAP Policy Statement, February 2006

Classification of ROP Zone Stage Plus Disease Extent Location Severity Blood vessel characterization Extent Amount of retina involved

Classification of ROP Zone

Classification of ROP Stage-Indicator of severity Stage 1-Demarcation line is thin, white. Separates normal retina from undeveloped, avascular retina www.ropard.org

Classification of ROP Stage 2-Demarcation line is a ridge of scar tissue with height and width. www.ropard.org

Classification of ROP Stage 3-Ridge has extraretinal, proliferation. Abnormal vessels and fibrous tissue extend from ridge into vitreous www.ropard.org

Classification of ROP Stage 4-Scar tissue pulls on retina and causes partial retinal detachment 4A-Partial detachment outside the macula (good chance for vision when reattaches) 4B-Partial detachment involving the macula (limiting likelihood of favorable outcome) www.ropard.org

Classification of ROP Stage 5-Complete retinal detachment. Retina is funnel shaped www.ropard.org

www.ropard.org

Classification of ROP Plus Disease Refers to appearance of blood vessels in retina Defined as the presence of dilated and tortuous vessels in the posterior retina. Indicator of more severe disease. If seen in Zone 1 ROP, termed “rush disease” and is likely to progress very rapidly www.ropard.org

Classification of ROP Extent Refers to the circumferential extent of disease Reported as the number of “clock hours” within the zone of disease

http://www.nei.nih.gov/ROP/photos.asp

Laser Ablation Goal is to ablate the AVASCULAR area of the retina The AVASCULAR area is secreting VEGF, producing the stimulus to grow new blood vessels which are causing ROP By ablating the VEGF-secreting region, the signal to grow new vessels goes away. This gives the retina a chance to remodel the abnormal vessels that are already there…and ROP can regress.

Post-Laser Ablation This is an example of how NOT to do laser ablation. Each laser “zap” should overlap with half of the prior “zap”. The ablated retina should be confluently white (ie ablated).

Avastin (Bevacizumab) Binds VEGF Inhibits signal for the retina to grow new vessels Stops abnormal blood vessel growth Allows for remodeling of abnormal vessels Benefits: No ablation of the retina Blood vessels can grow later Easier to administer Less sedation Concerns Lacking large scale safety data

Avastin (Bevacizumab) Mintz-Hittner, et al. NEJM 2011; 364: 603-615 Compared laser therapy to Avastin injection Stage 3+ in Zone I or Zone II Posterior Results: Avastin had more favorable outcomes in Zone I and there was no difference in Zone II More favorable = fewer retreated eyes and more normal pattern of blood vessel growth at 54 weeks corrected

Avastin (Bevacizumab) Some practitioners have begun using Avastin instead of Laser Ablation due to this data. Safety trials have not been performed yet What happens to the Avastin that leaks into the systemic circulation? There are a lot of blood vessels in the preemie’s growing body that need to grow….!

LEH Smith, IOVS 2008