Retinopathy of prematurity Narciso F. Atienza, Jr. MD. DPBO Legaspi Eye Center Chief of Section - Vitreo-Retinal Surgery - Cardinal Santos Medical Center St. Lukes Medical Center
PATS - American Society of Retina Specialists - 2005
PATS - American Society of Retina Specialists - 2005
Historical prespective First described by Terry (1942) Designated as “retrolental fibroplasia” Thought to be caused by a primary change in the proliferation of the embryonic hyaloid system.
Historical prespective Oxygen as the culprit (1950’s) Reported decrease in incidence of RLF, but increased neonatal mortality and cerebral palsy rates. Kinsey, VE: Retrolental fibroplasia. Cooperative study of retrolental fibroplasia and the use of oxygen, Arch Ophthalmol 56:481-543, 1956
Incompletely vascularized retina was susceptible to oxygen. The more immature the vascularization, the greater the response to oxygen. Ashton, N, Ward, B, and Serpell, G: Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia, Br J Ophthalmol 38:397-432, 1954
Mechanism of oxygen effects on immature retina Primary stage - Retinal vasoconstriction and vascular occlusion.
Secondary stage – Retinal neovascularization. Marked endothelial proliferation from residual vascular complexes driven by hypoxia.
The occurrence of Retinopathy of prematurity was: Not related to arterial oxygen levels. Duration of oxygen exposure was a risk factor. Kinsey, VE, Arnold, HJ, Kalina, RE, Stern, L, Stahlman, M, Odell, G, Driscoll, JM Jr, Elliott, JH, and Patz, A: PaO2 levels and retrolental fibroplasia: a report of the cooperative study, Pediatrics 60:655-668, 1977
Postulates on the following sequenceof events in the development of ROP Injury to the endothelium occurs after differentiation from mesenchyme to form the primitive capillary meshwork. After injury to the vascular endothelium, the mesenchyme and mature arteries and veins "survive" the toxic injury and "unite" via the few remaining vascular channels, replacing the destroyed or damaged capillary bed.
The mesenchymal arteriovenous shunt is located at the demarcation between the avascular anterior retina and the vascularized posterior retina.
Cells inside the shunt differentiate into normal capillary endothelium, forming capillaries towards the avascular retina. This represents regression, which he observed to occur in more than 90% of cases of early stage of ROP.
Primitive cells inside the shunt proliferate and erupt through the internal limiting membrane, into the surface of the retina and into the vitreous body. This is the chief event in the process of membrane proliferation leading to traction detachment.
Involvement of GF in growth phases VEGF is required for normal blood vessel growth – Phase I Normal retinal development anteriorly causes increased oxygen demand and localized hypoxia Induced physiologic hypoxia the precedes vessel growth As hypoxia is relieved by oxygen, VEGF mRNA is suppressed, moving the wave forward.
What does supplemental oxygen do in the cycle? Oxygen interferes with the normal development, causing cessation of normal vessel growth through suppresion of VEGF mRNA. Causes loss of the physiologic wave of VEGF anterior to the growing vascular front.
VEGF and oxygen plays are role the development of retinal blood vessels Other chemical mediators are involved ROP is multifactorial, as other factors pertaining to prematurity itself are at work
GH and IGF-1 – potential candidates in mediators involved in Phase II. IGF is usually provided by the placenta and amniotic fluid. Lack of IGF is associated with poor vascular growth and with subsequent proliferative ROP. VEGF alone may not be sufficient for promoting vigorous retinal angiogenesis.
Blood vessel growth is dependent on both IGF-1 and VEGF. In premature infants, absence of IGF stops blood vessel growth. Causes oxygen starvation, mediating increased production of VEGF As infants mature, IGF levels rise again, suddenly allowing VEGF to produce new blood vessels.
Clinical implications Early inhibition of either VEGF or IGF early after birth can prevent normal blood vessel growth development and precipitate disease. Replacement of IGF may promote normal retinal development Inhibition at phase II might prevent destructive neovascularization. Late supplementation may exacerbate the disease.
Who are at risk of developing ROP? Prematurity Low birth weight Complex hospital course Prolonged supplemental oxygen
Criteria for examination Screening currently is suggested for children less than 1500 grams birth weight. Instituted prior to a postmenstrual age of 31 weeks and continue until 50 weeks PMA. It is important to examine the child Two-week intervals if no retinopathy of prematurity is present One week intervals if retinopathy of prematurity is present.
Onset of ROP events in postconceptional age (weeks)Stage 5th Median 95th percentile percentile1 + 34.3 39.12 32 35.4 40.7Threshold 33.6 36.9 42
Stages in ROPStage No. Characteristics1 Demarcation line2 Ridge3 Ridge with extraretinal fibrovascular proliferation4 Subtotal RD A. Extra-foveal B. Foveal involvement5 Total retinal detachment Funnel: Anterior Posterior open open narrow narrow open narrow narrow open
Treatment for ROP Cryotherapy – investigated by the Cryo- ROP group (1988) Studied the outcomes of treated eyes v.s. controlled eyes.
Factors influencing the risk of developing threshold disease Lower birth weight Younger gestational age White race Multiple birth Being born outside a Cryo-ROP study nursery
Factors the influence risk of having unfavorable macular outcomes Zone 1 ROP Plus disease Severity of Stage of ROP Amount of circumferential involvement of ROP Rapid rate of progression of prethreshold disease
Results of Cryo-ROP study after 10 years Treated eyes Untreated eyesdistance visual 44.4% 62.1%acuityfundus status 27.2% 47.9%Retinal status 22.0% 41.4%
Cryotherapy on the avascular portion of the retina
Laser ablation Does not have any large multistage trials reported Results from studies show it has same efficacy as cryotherapy, but with less tissue destruction.
When to treat? Optimal timing – with 72 hours of diagnosis of threshold disease. Threshold disease Five or more contiguous clock hours Eight or more cumulative clock hours Stage 3 Zone 1 or 2 Plus disease
Regression of ROP Cryo-ROP study 94% of ROP patients will have regression while 6% will progress to threshold disease
Regressed ROP-Anterior Changes Vascular Failure to vascularize peripheral retina Abnormal, nondichotomous branching of retinal vessels Vascular arcades with circumferential interconnection Telangiectatic vessels
Regressed ROP-Anterior Changes Retinal Pigmentary changes Vitreoretinal interface changes Thin retina Peripheral folds Vitreous membranes with or without attachment to retina Latticelike degeneration Retinal breaks Traction or rhegmatogenous retinal detachment
Regressed ROP-Posterior changes Vascular Vascular tortuosity Straightening of blood vessels in temporal arcade Decrease in angle of insertion of major temporal arcade
Regressed ROP-Posterior changes Retinal Pigmentary changes Distortion and ectopia of macula Stretching and folding of retina in macular region leading to periphery Vitreoretinal interface changes Vitreous membrane Dragging of retina over disc
Late complications of ROP Angle closure glaucoma Late traction retinal detachment
ETROP – Early Treatment of Retinopathy of Prematurity Advocates the treatment of patients with retinopathy of prematurity before Threshold stage.
Criteria for ETROP Zone I, any stage of ROP less than threshold. Zone II, stage 2 with (+), stage 3 without (+), or stage 3 with (+) disease but less than threshold
Infants less than 1500 grams at birth Infants less than 28 weeks at birth Infants between 1500 grams to 2000 grams with a complicated clinical course.
1st examination should be between 4 to 6 weeks chronological age (post-natal). Within 31st to 33rd week of post- conceptional or post-menopausal age (gestational age at birth + chronological age)