Cicatricial Retrolental Fibroplasia Research Articles

The Retina as a Window to the Brain in Vulnerable Neonates

Fifty years ago, Kinsey1 published the results of a cooperative study of what was then called retrolental fibroplasia (RLF) and the use of oxygen. Infants who weighed <1.5 kg and survived the first 48 hours were enrolled in this multicenter study. Of the 590 survivors who had an adequate eye examination, 533 infants had received curtailed oxygen and 53 had received routine oxygen. Of those infants who received routine oxygen, 38 (75%) had vascular changes of RLF (stage 1–3 retinopathy of prematurity [ROP]) and 12 (25%) had cicatricial RLF (stage 4–5 ROP). Among the 533 infants with curtailed oxygen, 178 had vascular changes (33%) of RLF and 35 (7%) had cicatricial RLF. This trial, sponsored by the National Society for the Prevention of Blindness and the National Institute of Neurologic Disease and Blindness, was notable for providing a multicenter clinical trial that halted the indiscriminate use of oxygen, which had been responsible for the blinding of thousands of children. This therapeutic misadventure had occurred because of medicine's ability to introduce the technology of supplemental oxygen in incubators without ways of measuring the physiologic impact on the preterm infant. At that time, there was no consistent ability to measure arterial blood gases, no uniform classification system for ROP, and limited opportunities for collaboration between neonatologists, ophthalmologists, neurodevelopmentalists, and epidemiologists.2–4 From this study, as well as the tort legal system that was quickly and vigorously pursued by the American Bar, a <40% restricted–supplemental oxygen policy was implemented in NICUs. In 1960, Avery5 demonstrated the down side of this restricted-oxygen era by … Address correspondence to Michael E. Msall MD, University of Chicago Pritzker School of Medicine, Kennedy Mental Retardation Center, Comer Children's and LaRabida Children's Hospitals, 5841 S Maryland Ave, MC0900, Chicago, IL 60637. E-mail: mmsall{at}peds.bsd.uchicago.edu

Retinopathy of Prematurity in Extremely Low Birthweight Infants

Hyperoxia is still believed to be the main cause of retmopathy of prematurity, and it has been claimed that vitamin E. because of its antioxidant effect, reduces the severity of the disorder when administered in large doses. The present authors report the results of a study of ocular morbidity in 108 infants of extremely low birth weight (less than 1000 gm). all of whom received only small doses of vitamin E for maintenance of their hemotological status. The arterial oxgyen tensions were kept, when possible. below 80 mm Hg. The authors have followed the recent trend in using the term “retinopathy of prematurity” to replace the term developing or acute retrolental fibropla-sia.“ The term ”retrolental fibroplasia“ now replaces the term cicatricial retrolental fibroplasia.” The various degrees of retrolental fibroplasia severity were: grade 1. mild peripheral changes; grade 2. slight dragging of temporal vessels, heterotopia of macula, per-etmal fibrosis. and myopia: grade 3. dragged disc with

Handicaps and health problems in 2 year old children of birth weight 500 to 1500 g.

Fifty-nine infants of birthweight 500 to 999 g born in 1977 to 1980 and 132 infants of birthweight 1000 to 1500 g born in 1977 to 1978 were reviewed at two years corrected age. For the whole cohort, cerebral palsy was found in 12.6%, bilateral deafness in 1%, blindness in 1% and severe developmental delay in 12%. There was no significant difference in these disabilities between the groups of larger and smaller infants; 37.7% of the cohort was readmitted to hospital on at least one occasion, 35.6% of children had wheezing episodes and/or lower respiratory tract infections which together accounted for 51% of hospitalizations. The infants of birthweight 500 to 999 g tended to require more frequent and prolonged hospitalizations. Dolicocephalic head shape, chest deformities, iatrogenic sequelae from intensive care, poor growth and cicatricial retrolental fibroplasia were significantly more frequent in children of birthweight 500 to 999 g. Parents reported that 39% of their children had 'colic', 31.6% had sleep disturbance and 25% had multiple behavioural problems. Low frustration tolerance, inability to wait, hypo- or hyperactivity and an inappropriate relationship with the mother as measured by the psychologist all occurred significantly more frequently in children of birthweight of less than 1000 g. This report confirms the belief that a comprehensive follow-up is required for very low birthweight (VLBW) children because significant health problems continue after primary hospitalization.

Lensectomy for Secondary Angle-closure Glaucoma in Advanced Cicatricial Retrolental Fibroplasia

A study of 15 patients with secondary angle-closure glaucoma associated with advanced cicatricial retrolental fibroplasia is presented. Eight patients developed glaucoma acutely, while 7 showed a chronic course. In four patients the fellow eye became involved acutely within 1 month of the first eye. Seven others were also bilateral, but on a chronic basis. Twelve of the 15 presented after age 2. All were treated with lensectomy which cured the glaucoma. All have extremely poor vision in the range of light perception to hand motion, but have retained their eyes on a pain-free basis.

Retrolental Fibroplasia in Full-Term Infants Without Exposure to Supplemental Oxygen

We observed retinal folds identical in appearance to Grade 3 cicatricial retrolental fibroplasia in three infants at birth. In two of them we observed the active lesion of acute retrolental fibroplasia in the fellow eye at birth. These observations lead us to suggest that the active lesion of retrolental fibroplasia can occur in utero and progress to cicatrization in the absence of any obvious precipitating factor.

Ocular morbidity in infants of very low birth weight.

In the years 1977-8,258 infants weighing less than 1500 g were born at, or transferred to, the Royal Women's Hospital, Melbourne; 177 (68.5%) survived, and 111 of these attended for an ophthalmic examination. Significant ocular lesions were found in 37 (33%): 21 (19%) children had squint, 19 (17%) had a significant refractive error, 11 (10%) had cicatricial retrolental fibroplasia (RLF), and 3 (2.7%) had very poor vision due to optic atrophy associated with cerebral palsy. No children were blind owing to RLF, indicating that the recent increase in survival rate of infants of very low birth weight has not been accompanied by an increase in the prevalence of severe RLF. In those children with neither cerebral palsy nor RLF the prevalence of squint was 11% and of refractive errors 13%. Myopia was found mainly in children who had shown RLF changes in the neonatal period. It is recommended that infants of very low birth weight continue to be screened in the premature nursery for RLF, and also at the age of 2, for the detection of refractive errors and squint.

Infants Weighing 1,000 Grams or Less at Birth: Developmental Outcome for Ventilated and Nonventilated Infants

The neurodevelopmental outcome at a mean age of 40 months was investigated in 23/25 surviving infants of birth weights less than or equal to 1,000 gm. Eight infants required intubation and assisted ventilation and 17 were not ventilated. One ventilated infant was lost to follow-up and one nonventilated infant was a victim of sudden infant death syndrome at age 6 months. Fifteen (65%) had a good outcome but the differences between ventilated and nonventilated infants were striking. Thirteen (81%) of the nonventilated group were normal, but only two ventilated survivors (28%) were normal (P less than 0.05). Cicatricial retrolental fibroplasia occurred in three (43%) of the ventilated survivors and in none of the nonventilated infants (P less than .02). The requirement for assisted ventilation in these very low-birth-weight infants is associated with significant morbidity. Improvement in outcome may depend as much upon better understanding and management of prenatal events as upon improvements in neonatal care.

THE SIGNIFICANCE OF OCULAR MORBIDITY IN VERY‐LOW‐BIRTHWEIGHT INFANTS TO THE AUSTRALIAN HEALTH SERVICE

The survival rate of very-low-birthweight (VLBW) infants has greatly increased due to the introduction of intensive-care methods to neonatal nurseries. It was feared that this would also cause an increase in the amount of ocular morbidity associated with prematurity. In order to estimate this, 111 very-low-birthweight infants (birthweights less than or equal to 1500 g) were reviewed at two years of age. They comprised 63% of the total number of long-term surviving babies born at, or transferred in the neonatal period to, the Royal Women's Hospital, Melbourne, in 1977 and 1978. In 33% a significant ocular problem was detected; 19% had strabismus, 17% had a significant refractive error, 10% had cicatricial retrolental fibroplasia (RLF), and 2.7% were blind, due to optic atrophy associated with cerebral palsy. Other studies have shown that 7% of VLBW infants develop severe (Stage III) RLF, and 18% of these (1.26% of VLBW infants) will be socially or totally blind. In order to estimate the significance of VLBW infants to the ophthalmic health services, and to the organisations for the care of the visually handicapped, these figures can be extrapolated. Based on 1980 figures, it would be expected that approximately 1105 VLBW infants would survive annually, and nine would become blind from RLF, while 110 would have been affected by RLF. Thirty-three children would be blind from optic atrophy associated with cerebral palsy, 210 would have strabismus, and at least 187 would have a significant refractive error. VLBW infants will contribute significantly to the number of children requiring ocular care, and because of the high incidence of ocular abnormalities, it is recommended that routine screening of all VLBW infants be carried out at one year and two years of age.

Parenteral indomethacin for closure of the patent ductus arteriosus. Clinical experience with 67 preterm infants.

During a 19-month period, 23% of preterm infants had symptomatic patent ductus arteriosus (PDA). Intravenous indomethacin was administered to 67 infants with successful closure in 91% of the patients and in 83% of those with birth weights less than 1,000 g. No differences were found between the number of doses required and birth weight, gestational age, or age at initial therapy. Transient alterations in renal function were common after therapy, but mild renal failure occurred in only four infants. The incidence of intraventricular hemorrhage and necrotizing enterocolitis in treated infants was similar to that in the total preterm population. Cicatricial retrolental fibroplasia developed in one patient. Bronchopulmonary dysplasia occurred more frequently in infants with PDA, but a decreased incidence was found after early ductal closure. Intravenous indomethacin administration successfully effects ductal closure without major complications in preterm infants.

Vitrectomy in Infants and Children with Retinal Detachments Caused by Cicatricial Retrolental Fibroplasia

Four infants and one child with retinal detachments from cicatricial retrolental fibroplasia involving traction judged too severe to be relieved by scleral buckling alone underwent lensectomy and vitrectomy. Three retinas were successfully reattached. Because of the incomplete development of the pars plana in infants and the manner in which peripheral retina is pulled anteriorly to a position near or in contact with the posterior lens capsule, entry through the pars plana can create iatrogenic tears in the peripheral retina or introduction of irrigation fluid under the retina. Our experience has shown that a small contact lens makes it possible to work in the posterior vitreous cavity through the limbal approach in these infants. The circumferential traction produced by the ring of fibrovascular proliferation behind the lens can be relieved and tractional bands running forward from the posterior pole can be cut. Fibrovascular proliferative tissue lying on the posterior pole, however, proved resistant to membrane peeling or dissection, and its severity seemed to determine the success or failure of the surgery.

Vitamin E and Retrolental Fibroplasia in 1982

The retrolental fibroplasia (RLF) blind are an increasingly tragic shadow in the otherwise brightening picture for extremely premature infants1,2; thus, it is natural to feel eager anticipation at the report of vitamin E as an effective prophylactic.3 However, in seeking a solution to this frustrating disease, we must remain cautious about the price to be paid for prevention. I believe the time is ripe to ask "Where do we stand in our current knowledge of RLF; what is the history of vitamin E in this disorder; what is the strength of the evidence for its efficacy and safety; and finally is the risk/benefit ratio tipped in favor of treating the estimated 37,000 susceptible infants born annually in the United States, or must we await further evidence?" RLF OR RETINOPATHY OF PREMATURITY Through the combination of meticulous clinical observations4-7 and innovative studies in animal models,8,9 we have come to understand that acute, proliferative RLF occurs when the retina becomes ischemic following oxygen-related vaso-obliteration of immature, developing retinal arterioles. In the most immature infants (weight &amp;lt; 1 kg) this occurs as frequently as 75% of the time.7 There, however, our understanding of RLF ends inasmuch as cicatricial RLF (or retinopathy of prematurity with idiopathic fibrosis10), the scarred, occasional sequelae of acute RLF, is the output from a classic "black box." Prematurity, illness, and acute retinopathy go into one side, but we have no idea what determines healing vs cicatrix, the outputs on the far side. Animal models offer no help in this regard as none progress from acute vasculopathy to cicatricial sequelae (with perhaps one promising11).

EFFECT OF INTRAMUSCULAR VITAMIN E ON FREQUENCY AND SEVERITY OF RETROLENTAL FIBROPLASIA: A Controlled Trial

126 appropriate-for-gestational age neonates born in hospital with birth-weights of 750 g-1500 g were prospectively studied in a randomised trial to determine the effect of intramuscular vitamin E on the frequency and severity of retrolental fibroplasia (RLF). In the 99 who lived for more than one month the frequency of active RLF in the vitamin E and control groups in the nursery (18·8% vs 23·5%) and at discharge (8·3% vs 19·6% was not significantly different. Vitamin E had significantly reduced the severity of RLF at follow-up eye examination 6-33 months after discharge (p<0·01). 3 control infants (760 g, 780 g, 1020 g) were blind in both eyes (grade V cicatricial RLF), whereas the most severe grade of disease in the vitamin E infants was grade II cicatrix. Infants in whom RLF developed were gestationally younger (p = 0·005), required a longer period of mechanical ventilation (p = 0·035), had a greater exposure to oxygen (p = 0·03), and had a greater number of arterial PO 2 values between 75 and 99 mm Hg (p = 0·004). Early administration of vitamin E, while not affecting the frequency of RLF, will significantly reduce its severity and subsequent eye damage, and such treatment is recommended for all low-birth-weight infants of less than 1250 g who require supplementary oxygen.

Lensectomy-Vitrectomy for Stage V Cicatricial Retrolental Fibroplasia

Ten infants (18 eyes) blind from stage V cicatricial retrolental fibroplasia were examined from January 1978 to January 1981 at North Carolina Memorial Hospital. The early perinatal factors which may have predisposed to the binding end-stage cicatrix are identified. To increase their visual potential and to prevent secondary angle closure glaucoma, 12 lensectomy-vitrectomies were performed on 12 eyes (eight infants). One eye (one infant) had a pars plana vitrectomy without lensectomy. Seven eyes (seven infants) were not operated. Five of these eyes (five infants) had stage VRLF while two eyes (two infants) remained stable at stage II RLF. All retinas remained detached immediately after surgery. Secondary vitrectomies with air injections (three eyes, two infants) similarly failed to attach any retinas. Adherence of ciliary epithelium to clear lens and retrolental membrane as visualized within the dilated pupil (Eifrig-Merritt sign) was an intra-operative indicator of imminent surgical failure. Two eyes (two infants) developed early vitreous hemorrhages, hyphemas, secondary glaucoma, and phthisis bulbi within 12 months. Follow-up data were unavailable on two infants. Blindness secondary to cicatricial retrolental fibroplasia is increasing due to increased survival of low birthweight premature infants. Since surgical visual rehabilitation is not possible after the retrolental cicatrix has formed, the risk factors common to this high risk population should prompt preventive therapies.

Retrolental Fibroplasia: Experience Over Two Decades in One Institution

We examined 1,849 consecutively admitted premature infants weighing 2000 gm or less at birth for retrolental fibroplasia (RLF). Proliferative RLF was diagnosed frequently in low birth weight infants who were more likely to survive with modern neonatal intensive care. Cicatricial RLF was more likely to result from proliferative RLF and to be more severe in lower birth weight infants, but most affected eyes retained useful vision. Comparison of eases diagnosed over the 20 years of this study suggest that cicatricial RLF in recent years is less likely to result in severe visual disability. Improving survival rates for lower birth weight infants mandate continued surveillance for RLF and study of improved oxygen monitoring techniques.

Retrolental Fibroplasia and Blood Transfusion in Very Low-Birth-Weight Infants

The relative contribution of transfusions of adult blood to the development of retrolental fibroplasia (RLF) in very low-birth-weight infants was examined. Five years of experience with the expanded use of replacement and exchange transfusions in 90 infants with birth weight less than or equal to 1,250 gm was reviewed. Twenty percent of the infants developed cicatricial RLF. Exchange transfusion was not related to development of cicatricial RLF. The incidence of RLF in infants receiving greater or equal to 130 ml of packed red blood cells per kilogram of birth weight as replacement blood transfusion (RBT) was significantly higher (42.9%) than that in infants receiving 61 to 131 ml of packed red blood cells per kilogram (15.4%) and infants receiving less than or equal to 60 ml of packed red blood cells per kilogram (0%), P less than .001. The need for RBT, however, was strongly correlated (r = .85, P less than .001) with increasing duration of O2 therapy. When O2 therapy was controlled for, the association between RBT and RLF did not achieve statistical significance (P = .07). The association between RBT and RLF remained significant when adjusted for duration of therapy in fractional inspired oxygen (FIO2) greater than 0.4. Further detailed studies of large numbers of susceptible infants are warranted to assess the magnitude of the contribution of transfusions of adult blood to development of RLF.

Retrolental Fibroplasia: Evidence for a Role of the Prostaglandin Cascade in the Pathogenesis of Oxygen-Induced Retinopathy in the Newborn Beagle

Aspirin administration, at a dosage producing plasma levels within the human therapeutic range, caused marked inhibition of production of both vascular prostacyclin (a vasodilator) and platelet thromboxane (a vasoconstrictor) in beagle puppies. In addition, aspirin-treated, oxygen-exposed puppies developed retinopathy of significantly greater severity than their unmedicated, oxygen-exposed littermates. Direct ophthalmoscopic observations indicated that whereas sustained oxygen breathing produced retinal vasoconstriction in unmedicated puppies, retinal vessels of aspirin-treated littermates became more dilated or remained unchanged. It is postulated that retinal vasoconstriction may be a normal physiologic mechanism to protect the immature retina from damaging effects of high blood oxygen levels; i.e., it may be a protective rather than a pathologic process in response to hyperoxia. Many vascular anomalies which characterize the human disease were present in the retinas of the puppies. Several of the most severely affected puppies treated with aspirin even displayed grade III cicatricial retinopathy (falciform retinal fold). Thus, a major criticism of the retrolental fibroplasia animal model has been addressed by producing cicatricial retrolental fibroplasia in puppies, and the confidence with which results from experimental animal studies might be extrapolated to the clinical situation is thereby strengthened.

Risk Factors in Retrolental Fibroplasia

Possible determinant factors that may increase the risk of the occurrence of retrolental fibroplasia (RLF) were analyzed in 80 infants born in 1975 and 1976 with birth weights between 501 and 1,500 gm and who survived. Active and/or cicatricial RLF occurred in 27 (33.8%) infants and the factors significantly associated with RLF were: gestational age (P less than .001); apnea requiring bag and mask resuscitation with oxygen (P less than .001); septicemia (P less than .005); degree of illness; blood transfusion; and mechanical ventilation. Severe cicatricial RLF developed in eight (10%) infants (grades 2 to 5). In the group of infants all of whom had apnea which required resuscitation, septicemia was also significantly associated with RLF (P less than .01). A highly significant association between RLF and severe myopia (P less than .001) was found in follow-up in all infants. Data show a resurgence and high incidence of RLF in low birth weight infants who survived. Infants with these factors should be considered to have greater risk for the occurrence of RLF and ophthalmologic examination prior to, and within three months following discharge is recommended.

Secondary Angle-Closure Glaucoma in Cicatricial Retrolental Fibroplasia

Five patients had cicatricial retrolental fibroplasia with a complication of secondary angle-closure glaucoma. In all the patients, the glaucoma occurred after age 2 years. All were treated with a pars plana lensectomy and anterior vitrectomy, which alleviated the glaucoma. They all achieved normal intraocular pressure and a pain-free eye. However, visual acuity was poor, in the range of light perception to hand motions. All patients have been followed up for one year and in only one patient has the fellow eye developed secondary angle-closure glaucoma.

Retinal detachment in retrolental fibroplasia.

Problems of retinal detachment in retrolental fibroplasia (RLF) based on observations during 10 years of 92 premature children treated with supplemental oxygen in incubators are discussed. Two essential types of retinal detachment can be distinguished: the oedematous type in the stages III-V of the active phase of RLF and the rhegmatogenous type of cicatricial RLF. In our material 2 cases of oedematous detachment, which regressed spontaneously, were found. The case of a 10-year-old boy with total retinal detachment in cicatricial RLF, which was diagnosed too late, is presented. Since good results have been described after scleral buckling procedures in cases diagnosed early enough, all children with RLF should remain under steady control.

Sequelae of caffeine treatment in preterm infants with apnea

Growth, neurologic, and ophthalmologic assessments were done in 21 low-birth-weight infants given caffeine for neonatal apnea and in 21 matched control infants. Caffeine significantly decreased the need for and the duration of mechanical ventilation. No difference in growth and development was noted between the control and caffeine-treated infants. A high incidence of cicatricial retrolental fibroplasia was observed in both control (10/21) and caffeine-treated infants (7/18).