|Year : 2015 | Volume
| Issue : 4 | Page : 237-243
Zone I and posterior zone II retinopathy of prematurity
Gloria Isaza, Milad Modabber, Sourabh Arora, Varun Chaudhary
Department of Surgery, Division of Ophthalmology, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
|Date of Web Publication||16-Oct-2015|
McMaster University Medical Centre, 3V2 Clinic, 1200 Main Street West, Hamilton, Ontario L8N 3Z5
Source of Support: None, Conflict of Interest: None
Background: There is a paucity of literature describing the stages in zone I and posterior zone II retinopathy of prematurity (ROP). Aims: The aim was to describe and compare the clinical presentation and progression to the treatment of infants with zone I and posterior zone II ROP. Settings and Design: Retrospective case series at a single tertiary care Neonatal Intensive Care Unit. Subjects and Methods: Patient information collected included: Gestational age, birth, weight, postmenstrual age (PMA) at first ROP diagnosis, and PMA at treatment. Digital retinal photographs were also analyzed when available. Statistical Analysis Used: Student's t-test, Chi-square analysis. Results: Totally, 14 of 47 (29.8%) infants were classified with zone I ROP and 33 (70.2%) as posterior zone II ROP. The mean PMA at first ROP diagnosis was 33 weeks in both zones. The incidence of treatment was higher in the zone I ROP (85.7%) compared to posterior zone II ROP (48.6%). About 50% of infants with zone I ROP had an elapsed time of 1 week from first presentation to a disease requiring treatment, compared with 6.25% of posterior zone II ROP infants. By 2 weeks, the proportion of posterior zone II infants requiring treatment rose to 56%. Sequential and nonsequential analysis of retinal images illustrated the similar atypical presentation of ROP in both zones. Conclusion: The presentation of infants with ROP in the zone I and posterior zone II are very similar. The clinical course in the zone I ROP is faster and more aggressive than posterior zone II. Due to their atypical morphology and rapid progression, appropriate recognition, and classification of ROP is needed for adequate and timely treatment.
Keywords: Laser ablation, pediatrics, retinopathy of prematurity
|How to cite this article:|
Isaza G, Modabber M, Arora S, Chaudhary V. Zone I and posterior zone II retinopathy of prematurity. J Clin Neonatol 2015;4:237-43
| Introduction|| |
Retinopathy of prematurity (ROP) remains a significant morbidity in extremely premature infants, and as the survival rate continues to increase, this may result in a growing incidence of posterior ROP., Therefore, recognition of the atypical morphology and rapid progression of the posterior disease is crucial. In 2002, The Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study described the natural course of zone I ROP. The International Committee for the Classification of Retinopathy of Prematurity (ICROP) published in 2005 a revised classification of ROP indicating stage 1, as a demarcation line, which separates the avascular retina localized anteriorly from the posterior vascularized retina. Stage 2, as a ridge that has height and width. Stage 3, as an extraretinal fibrovascular proliferation that extends into the vitreous. Stage 4, as a partial retinal detachment that is divided into partial extrafoveal retinal detachment (stage 4A) and partial foveal retinal detachment (stage 4B). Stage 5, as a total retinal detachment.
Retinopathy of prematurity, which is located in the posterior retina has been associated with the unusual clinical presentation and rapid progression as compared to classic ROP., The revised ICROP also importantly identified Aggressive Posterior ROP (APROP) as characterized by severe plus disease, flat neovascularization in zone I or posterior zone II, with a rapid progression to retinal detachment in absence of intervention. They also noted that an important feature of APROP was that it typically does not progress through the classic stages (1-3) of ROP. Zone I and posterior zone II ROP, especially with signs of plus disease, and APROP have been identified as the most difficult to treat and have a high incidence of recurrence after treatment, warranting additional treatment.,,, The CRYO-ROP Cooperative Study reported that 77.8% of zone I disease treated with cryotherapy had unfavorable outcomes and the early treatment for ROP Cooperative Group reported a 55.2% unfavorable outcome rate using laser photocoagulation in zone I disease., The objectives of this study are to describe and compare clinical presentation and progression for infants classified with zone I and posterior zone II ROP.
| Subjects and Methods|| |
This was a retrospective longitudinal study conducted at at McMaster University Medical Centre in Hamilton, Ontario. The study was approved by the McMaster University Health Research Ethics Board. Inclusion criteria in this study were infants who had ROP in zone I or posterior zone II; being inpatients at the Neonatal Intensive Care Unit (NICU); and having been screened for ROP between July 2006 and December 2012. Demographic and neonatal clinical course data were extracted from the Canadian Neonatal Database, which maintains clinical information about neonates. This database did not contain the longitudinal information specific to ROP screening, disease development or treatment, therefore the individual patient charts of 115 premature infants who had a gestational age (GA) 28 weeks and BW 1000 g were reviewed to obtain this information. It was based on previous studies conducted at the same NICU by the same investigator who found that any infant that had GA >28 weeks and BW >1000 g did not have zone I ROP and did not require laser treatment.
Patient information collected and analyzed included: GA, BW, gender, singleton or multiple births, postmenstrual age (PMA) atfirst ROP exam, PMA atfirst ROP diagnosis and PMA at treatment, and ROP examination results. Patient records were used to calculate the PMA, which was defined as the time elapsed between the 1st day of the last menstrual period and birth (GA) plus the chronological age (time elapsed since birth). The endpoint of data collection relevant to this study was defined as the time when ROP regressed or progressed to the stage of requiring treatment. PMA was not used in defining the endpoint of data collection.
Infants born with GA 27 weeks werefirst examined at 31 weeks PMA. Beyond 27 weeks GA, thefirst exam was done at 4 weeks after birth. Zone I was defined as the circle of retina extending from the optic disk with a radius of twice the distance from the disk to the macula and posterior zone II was defined as one disk diameter peripheral to the anterior border of zone I. Posterior zone II was defined as one disk diameter peripheral to the anterior border of zone I. Anterior zone II is a circle with the inner border defined by posterior zone II and the outer border defined by zone III. Eyes with ROP involving both zones were classified as having zone I ROP. ROP status was classified based on the diagnosis recorded by three ophthalmologists. The examinations were performed every 1 to 2 weeks, or twice per week depending on the severity of disease present and the ophthalmologist's clinical judgment criteria. The examination was performed under topical anesthesia using 0.5% proparacaine eye drops (Ophthetic, Allergan, Markham, Ontario, Canada) and supportive oral sucrose. Pupils were dilated with topical cyclopentolate 0.2% and phenylephrine 1% (Cyclomydril, Alcon, Mississauga, Ontario, Canada) applied 60 min and 30 min prior to the eye examination. Indirect ophthalmoscopy was performed using a binocular indirect ophthalmoscope and a 28-diopter lens. A speculum for infants and a scleral depressor were also used to perform the examination.
When available, sequential ROP retinal imaging was performed, using a wide-angle digital imaging system (RetCam Clarity Medical Systems, Pleasanton, California, USA) and the saved images were later analyzed by one pediatric ophthalmologist (GI) using clinical judgment. Digital images of posterior pole vessels and of mid-peripheral retina were taken using wide field (130°) imaging and included five images per se ssion (posterior pole, temporal, nasal, superior and inferior retinal area). Retinal images were analyzed to determine zone, stage, extension, clinical presentation, and progression of ROP, and the retinal images were compared to chart records. If discrepancies between retinal images and chart records were found or if there was missing information on the chart records, further analysis of retinal images were made to obtain more precise ROP status. If clarification could not be made after the analysis of the retinal images and/or chart records, infants were excluded from analysis. For those infants who did not have sequential ROP retinal images available, photographs of individual sessions were also examined and the results were included in the batch analysis of infants with the closest PMA. Images with poor quality were not included in the analysis.
Data were extracted from medical charts, input into Excel and analyzed using SPSS 20 (IBM Corp., Armonk, NY). Continuous variables (GA, BW, PMA at various intervals) were compared between zones using Student's t-test, after performing Levene's test for Equality of Variances. Categorical variables (gender, ROP zone, ROP stage, treatment required, multigestational) were compared between groups using Chi-square analysis. A P <0.05 was considered significant.
| Results|| |
The individual charts of 115 premature infants screened for ROP in the NICU at McMaster University Medical Center from July 2006 to December 2012 with a GA 28 weeks, and BW 1000 g were reviewed. Of those patients, 47 met the inclusion criteria of having ROP in the zone I or zone II ROP. Subsequently, 68 patients were excluded from the study: 1 did not survive to be screened; 10 infants did not have complete ROP clinical data; 57 infants were excluded because they were subsequently found to be in anterior zone II ROP upon further analysis of the charts and/or retinal images. The remaining 47 infants were included in this study and results can be found in [Table 1].
Of the 47 included patients, 14 (29.8%) infants were classified as zone I ROP and 33 (70.2%) infants as posterior zone II ROP. Overall, 22 of the infants were male (46.8%), seven males (50%) in the zone I ROP. All included infants presented with bilateral ROP.
Of the 47 infants, the mean GA at birth was 24.5 ± 0.87 weeks, and the mean BW was 655.8 ± 80 g. The mean GA of infants in the zone I ROP was 24.13 ± 0.81, and the mean GA for a posterior zone II ROP was 24.6 ± 0.87 weeks (P = 0.105). The mean BW for zone I ROP was 617 ± 79, and 672 ± 76 g in zone II ROP infants (P = 0.032). The difference in BW was statistically significant between the two zones. The mean PMA atfirst ROP exam was 31 weeks across both zones, as per our clinical guidelines. The mean PMA at thefirst appearance of any ROP was 33 ± 1.27 weeks (32.98 ± 1.35 for zone I vs. 33.18 ± 1.25 for posterior zone II, P = 0.630), with no statistical difference between the two zones (P = 0.630).
Twenty-eight of 47 infants (59.6%) required treatment for ROP. The incidence of treatment was significantly higher in infants with zone I ROP (85.7%) compared to posterior zone II ROP (48.4%) (P = 0.017). The mean overall PMA at the time of treatment was 35.6 ± 2.54 weeks, which was comparable across the two ROP zones (35.17 ± 2.04 vs. 35.97 ± 2.85, P = 0.369, NS). None of the infants in this cohort progressed to retinal detachment.
There was no difference in the ROP zone (P = 0.781) and staging of ROP (P = 0.168) between males and female patients.
Six infants (12.8%) were born from multigestational pregnancies (twins). Single versus multigestational patients exhibited similar GA at birth (P = 0.666) and BW (P = 0.573). No significant differences in the zone (P = 0.843) and staging (P = 0.577) of ROP was observed between single versus twin births.
A total of 34 patients had their retinas imaged via the RetCam (Clarity Medical Systems; Pleasanton, California, USA), Sequential and nonsequential analysis of the retinal images illustrated the atypical presentation of ROP in both zones.
Thefirst appearance of any ROP in both zones was the dilation of the superior and inferior temporal arcades [Figure 1]. Remnants of the pupillary membrane and vitreous haziness made vascular dilation difficult to be seen in some cases. Then, in stage 2, there was a demarcation between the vascular and avascular retinal area usually created by a vascular shunting, which developed a vascular ridge. We found some differences in the presentation of the demarcation in stage 2, whereby the vascular ridge was made by shunting of the superior and inferior temporal arcades, and it was circular [Figure 2]. Notably, in some of our cases, the vascular ridge was not always clear and/or complete and there was not a discernible or orderly vascular pattern making the demarcation ill-defined and usually there was a temporal indentation toward the fovea with a no circular shape [Figure 3]. At this stage choroid vessels can be seen anterior to the vascular/avascular ridge but could be mistaken for vascularized retina due to the absence of a clear vascular ridge. This stage may progress to a more severe stage 3 ROP, similar in both zones, presenting with flat retinal neovascularization posterior to the vascular/avascular ridge. There was also in this stage a significant contrast in color between the velvet color of the neovascularized retina posterior to the vascular/avascular ridge and the pale grayish color anterior to the ridge, which may cause difficulty in identification of the choroidal vessels [Figure 4]. If treatment is not performed in a timely manner, plus disease may develop, making it difficult to differentiate arteries from veins [Figure 5].
|Figure 1: Fundus photographs in cases of stage 1 retinopathy of prematurity in zone I. Note dilated superior and inferior temporal arcades. Vitreous haziness makes difficult view in some cases|
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|Figure 2: Fundus photograph of stage 2, zone I retinopathy of prematurity. Note the circular vascular ridge and prominent choroidal vessels, which may be mistaken for vascularized retina. Furthermore, note retinal hemorrhage|
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|Figure 3: Fundus photograph of stage 2, posterior zone II retinopathy of prematurity. Note the ill-defined vascular ridge with temporal indentation to fovea and the prominent choroidal vessels|
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|Figure 4: Fundus photograph of preplus stage 3, posterior zone I retinopathy of prematurity. An ill-defined avascular ridge and a velvet hue suggestive of flat neovascularization. Stark color contrast between the vascular and avascular retina makes identification of choroid vessels difficult|
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|Figure 5: Fundus photograph of stage 3 plus, anterior zone I retinopathy of prematurity. An ill-defined border with temporal indentation toward the fovea. Note the contrast in color between the anterior and posterior ridge areas|
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| Discussion|| |
Posterior ROP, particularly in the zone I, is characterized by rapidly progressive vascular changes, flat neovascularization, intraretinal shunting without ridge tissue, hemorrhages, and the tendency to progress without evolving through the typical stages 1-3.,,, These eyes may also advance to late stages including retinal detachment if it is not treated in a timely manner. Prior randomized trials have demonstrated an increased likelihood of an unfavorable outcome in eyes with the posterior disease; however the reasons are somewhat unclear.,,,,
In this study, the presence and progression of ROP in the zone I and posterior zone II were made by clinical examination and by comparison when available with sequential and nonsequential retinal images.
It remains speculative as to why the presentation of ROP in posterior zones is different when compared with a classic ROP presentation. Alteration of the mechanisms involved in the vascularization of the retina may partially explain these differences. Particularly, it may explain the differences found in the presentation of stage 2 ROP found in this study. If vasculogenesis exists in an early phase and is responsible only for the formation of the four major arterial arcades in the posterior retina, its alteration may result in the arterial shunting, forming the arcade vascular ridge. If this early mechanism is injured, it could also explain the result of a more aggressive and faster posterior ROP presentation. If angiogenesis, in a later phase, is responsible for increasing capillary density of the central retina and forming and completing the peripheral vessels, when altered, it may result in a more ill-defined demarcation between the vascular and avascular retina as a consequence of a more altered formation of vessels and their shunting leading to a nonuniform demarcation.
Overlapping presentation of a circular ridge and an ill-defined area was found in some infants in this study [Figure 6]. Furthermore, a classic ROP presentation as described in zones II and III by the ICROP was found in some infants, when a more anterior-posterior ROP was present or when an ill-defined demarcation converted to a classic stage 2 ROP. An overlapping of the mechanisms involved in the vascularization of the retina that differs in time and location and its alteration may explain a combined ROP presentation or the conversion from an unusual ROP presentation to a more classic presentation.
|Figure 6: Fundus photograph of overlapping presentations of a circular vascular ridge zone I and an ill-defined demarcation in posterior zone II|
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In the study by Andres Kychenthal at the Hospital de Niños in Chile (1996–2002), 44 infants with threshold zone I ROP, two anatomic subgroups within zone I (anterior and posterior), were defined. Although they did not compare the morphologic presentation of ROP in both subgroups in zone I, they reported an appearance of a peripheral arteriovenous arcade separating the vascular retina from the avascular retina which could be similar to the circular ridge that we report in this study. They also reported the contrast in color between the vascular and avascular retina.
Recognition of earlier ROP stages was sometimes difficult due to media opacities such as remnant pupillary membrane and vitreous haziness. Despite this, we found that an increase in the width of the vessels presented as stage 1 ROP in both zones. A significant percentage of stage 1 ROP was not observed in both zones in this study: About 64.2% of infants who were classified zone I ROP and 63.6% of posterior zone II had stage 2 or higher at the time of the initial screening. This may be partially explained by the characteristic rapid progression of ROP in posterior zones. Another reason why the earliest stages of ROP and progression were missed could be due to the adherence to the ETROP screening criteria, which suggests a 2 weeks follow-up if ROP is not detected. Another possible explanation is that stage 1 may have been misdiagnosed as another stage as a result of the unclear classification of stages of ROP in APROP.
We found a definite contrast between the velvet color of the neovascularized retina, posterior to the vascular/avascular ridge and the pale grayish color anterior to the ridge, which appeared to be a sign of activity and progression of ROP. It was initially detected in stage 2 and even more noticeable in stage 3 because of a more abrupt contrast in color, whereby making the identification of choroidal vascularization more difficult.
No significant difference existed in mean GA between zone I and posterior zone II, thus we cannot predict, based on GA alone, which infants would be in the zone I or posterior zone II. We found statistically significant lower BW in infants classified with zone I ROP when compared with posterior zone II ROP (617 ± 79 vs. 672 ± 76 g). Not surprisingly, we can predict from this study, that smaller infants have a higher risk of having a more immature retina.
The overall mean GA (24.5 weeks) found in this study was lower than the mean GA in the zone I reported in the CRYO-ROP (26.5 weeks) and the ETROP (25.6 weeks) studies., The overall mean BW (645 g) was also lower when compared with the CRYO-ROP (831 g) and ETROP (703 g) studies., The overall mean PMA weeks at the time of treatment of 35.6 weeks in this study was also lower when compared to the mean PMA of 36 weeks at prethreshold treatment in the CRYO-ROP and ETROP studies. We found that infants with a lower GA and BW had an increased risk of APROP and needed for treatment.
In this study, seven infants (50%) had stage 3 ROP at the time offirst appearance of any ROP; 5 infants who were classified as zone I ROP, two of them with plus disease. Two infants in posterior zone II, none, had the plus disease. Two out of the 7 infants who had stage 3 at thefirst appearance of any ROP had GA of 32 weeks. This has caused us to speculate that posterior ROP may start even before screening protocols are set to commence.
A significant number of infants who underwent treatment had more rapid ROP progression with an elapsed time from thefirst ROP diagnosis to treatment of 1 weeks: It was significantly higher for infants with ROP in zone I (50%) compared to infants with ROP in posterior zone II (6.25%). By week 2, the number of infants in posterior zone II rose dramatically to 56%. The clinical course in the zone I was faster and more aggressive than posterior zone II in this study.
Eight out of 28 infants who underwent treatment had stage 2 at time of treatment: Three infants had stage 2 ROP in both eyes at the time of treatment and five infants had stage 2 ROP in one eye and stage 3 in the other eye at the time of treatment. We acknowledge that some infants were treated earlier than recommended by ETROP guidelines. No infants in this study went on to retinal detachment.
We found some similarities between our study when compared to the study conducted by Soh et al. at Osaka Medical Center and Research Institute for Maternal and Child Health in Japan from 2000 to 2006 in 23 infants (46 eyes) with zone I ROP. In our study, we found that 50% of the infants classified zone I ROP had a rapid ROP progression with an elapsed time from thefirst ROP diagnosis to treatment of 1 weeks: They also reported a rapid progression in zone I ROP from stage 1 to stage 3 ROP with a mean period of 1.3 weeks and 60.9% of all the cases were treated within 10 days after stage 1 diagnosis. In both this study, and their study some infants were treated earlier than the ETROP treatment criteria (8 and 4 infants, respectively).
There were several limitations in our study. First of all, it is a retrospective study. The individual patient chart review to obtain information for infants with posterior ROP was based on a GA 28 weeks and BW 1000 g, based on criteria established from previous studies completed in the same NICU from the same investigator, which created a possibility of missing bigger and older infants with posterior ROP. ROP classification and follow-up criteria also differed between the examiners. Some infants had posterior zone II ROP with temporal zone I making difficult to establish the exact location of vascularization. Some infants were treated prior to the observation of flat neovascularization (stage 3), whereby missing the evaluation of ROP progression. Remnants of the pupillary membrane and vitreous' opacities also made difficult to obtain a good view of very early signs of ROP in some infants. Not all infants had retinal images and not all infants who had retinal images had a full series of sequential images, which may have demonstrated early stages of ROP. All retinal images were interpreted by only one ophthalmologist (GI).
In this study, there were no differences in the clinical presentation of ROP in infants classified with ROP in the zone I when compared with posterior zone II ROP. Progression of ROP in the zone I was faster and more aggressive than posterior zone II ROP. Earlier signs of ROP and its progression to treatment were seen during thefirst 2 weeks following the initiation of screening and it could potentially be overlooked if there is not close and careful follow-up of extremely premature infants. We recommend that screening in extremely premature infants should occur at least every week when no signs of ROP are present and twice weekly if any signs of ROP are observed. Posterior ROP can have good outcomes if screening is done early and treatment is timely. Further studies need to be conducted in order to validate findings and ensure prediction of consistent results. A unique set of guidelines to screen and manage posterior ROP should be considered.
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Conflict of Interest:
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]