Some previous studies analyzed the treatment reasons of non-Type 1 ROP (seen in Table 5)3,5,11,16, but the main treatment method in these studies was laser coagulation. No literature had been studied the effect of intravitreal injection of anti-VEGF drugs on the treatment of non-type 1 ROP currently.
Of the 263 eyes treated in this study, 65 eyes (24.8%) were non-type 1 ROP, showing a higher proportion than that in previous studies (9.5–13.7%)3,5,11. Because that the treatment for ROP cases in this study was intravitreal injection of anti-VEGF drugs, which are simpler and more minimally invasive than laser coagulation14. Some lesions in critical conditions at risk of aggravation were suggested to be treated. In this study, lesions in all eyes with non-type 1 ROP were relieved after treatment, which was similar to the results of previous studies 11. It was also found that the treatment effect of non-type 1 ROP eyes was better than that of type 1 ROP eyes, which may be related to the mild condition and the use of different types of anti-VEGF drugs. In this study, the proportion of fusion protein drugs used was higher in the non-type 1 ROP group (87.2%) than that in the type 1 ROP group (54.5%). This might be other potential reason for statistically significant difference in treatment effects between the two groups. Some studies found that the recurrence rate of ROP eyes treated with fusion protein drugs (conbercept or aflibercept) was lower than that of ROP eyes treated with ranibizumab 12,13. The drug selection in our study was associated with the time to market in China.
Table 5
Studies of non-type 1 ROP treatment.
Investigator
|
Time published
|
Country
|
Method
|
Case
|
Treatment
|
Reasons of treatmentβ
|
Gupta MP et al3
|
2016
|
USA
|
multicenter retrospective study
|
A total of 137 eyes treated,13 eyes with non-Type 1 ROP
|
laser
|
①concerning structural changes; ②persistent ROP at an advanced PMA (41w); ③ vitreous hemorrhage; ④ active ROP with the fellow eye being treated for type 1 ROP
|
LiuT et al 5
|
2019
|
USA
|
multicenter retrospective study
|
A total of 1004 eyes,126 eyes with non-Type 1 ROP
|
Laser in 122 eyes and IVRα in 4 eyes
|
①fellow eye with type 1 ROP;②stage 3 ROP with pre-plus;③others: concerning structural changes in the retina; persistent stage 3 for ≥ 6 weeks without regression; stage 3 with no plus; stage 3, zone III with plus; logistical considerations; stage 2 disease.
|
Rajan RP et al11
|
2020
|
India
|
retrospective study
|
A total of 241eyes treated,33eyes with non-Type 1 ROP
|
Laser in 32 eyes, IVRαin 1 eye
|
①structural changes;② pre-plus disease;③persistent stage 3 ROP that did not show any sign of regression for 6 weeks; ④active ROP with fellow eye being treated.
|
Koucheki R et al16
|
2020
|
Canada
|
retrospective study
|
2,356 Cases, and 115 cases (172 eyes) with stage-3 ROP persisting ≥ PMA 40w
|
Of 21 cases (33 eyes) treated by laser, 17 eyes with non-type 1 ROP
|
≥ 2 continuous clock hours of persistent stage 3 crossing the temporal horizontal midline and pre-plus
|
αIVR: intravitreal injection of bevacizumab. |
βReasons of treatment were arranged in descending order of proportion. |
Of eyes with non-type 1 ROP treated in this study, 63 cases (96.9%) had more lesions in zone II, and 41 eyes (63.1%) and 22 eyes (33.8%) had more lesions in stages 2 and 3, respectively. The characteristics of pathological manifestation were similar to those of the finding of Gupta MP et al 3, in which, 11 eyes (84.6%) had lesions in zone II, and 12 eyes (92.3%) had lesions in stages 2 and 3. While in the study of Liu T et al5, most eyes (66%) had pre-plus lesions in zone II stage 3. The above evidence suggests that ROP should be checked carefully about the changes of lesions at stage 2 or 3 in zone II.
The main treatment reason for non-type 1 ROP eyes in this study was the pre-plus disease (89.2%), which was different from previous studies. In the study of Gupta MP et al and Rajan RP et al., the most important treatment reason was structural changes in the fundus caused by the traction of the ridge (69.2% and 72.7%, respectively) 3,11. Pre-plus disease (33.3%) was the second reason in the study of Rajan RP et al11. The major reason in Liu et al’s study was the contralateral eye with type 1 ROP (43%), followed by stage 3 ROP with pre-plus (30%)5. As for pre-plus and plus disease, ICROP3 defined it as a continuous spectrum of retinal vascular changes from normal, to pre-plus, and finally to plus disease. Consistent judgments of different scholars only in the normal and last plus stages10. This suggests a high possibility of clinical disagreement over pre-plus lesions, resulting in no typical plus lesions in some ROP eyes and further risk of retinal traction with progressive worsening of the ridge. Due to the use of anti-VEGF drugs, we paid more attention to the judgment of pre-plus in the ROP examination.
The second cause of treatment in this study was ridge changes (33.8%), shown as more obvious or/and more extent, or thickened and widened locally. Actually, the ridge changes were often accompanied by pre-plus (Fig. 1). Koucheki R et al confirmed that pre-plus was significantly correlated with increased ridges (≥2 continuous clock hours of persistent stage 3 crossing the temporal horizontal midline) in the eyes with stage-3 ROP persisting ≥40 weeks of PMA16. The ridge changes in this study were slightly lighter than the structural fundus changes mentioned in previous studies3,5,11, and no macular traction, retinal traction, or folds were produced due to the tangential traction caused by the straightening of the temporal vessels in the fundus. Under these proliferation conditions, intravitreal injection of anti-VEGF drugs may not be recommended because of the risk of aggravated proliferation17,18.
In this study, the simultaneous treatment of contralateral eyes accounted for 13.8%. Most previous studies considered that acute ROP commonly occurs in both eyes. For example, 79.1% of ROP infants have high-risk pre-threshold disease in both eyes at the time of enrollment in an ETROP study1. A study on Telemedicine Approaches to Evaluating of Acute-Phase Retinopathy of Prematurity (e-ROP) found that 72.7% of infants had the same severity of ROP in both eyes among ROP image sessions15.
However, our study does not recommend arbitrary early treatment for non-type 1 ROP. Previous studies suggested that ROP with stage 3 can be treated when no regression is found after 41 weeks of PMA3 or continuous 6 weeks of follow-up5,11. In this study, the average time of the first treatment for eyes with type 1 ROP was 38.6 weeks, while the follow-up of another 6 weeks was 44 weeks for non-type I ROP eyes with some of the above particular retinal features. Meanwhile, due to the use of anti-VEGF drugs, in order to avoid obvious fibrosis, we paid attention to the progression of lesions at stage 2 and stage 3. Therefore, our study considered a treatment for ROP infants with lesions at persistent stages 2 and 3 without regression at the corrected gestational age of 44 weeks or more, and whether there were other retinal manifestations was also taken into consideration. In this study, 4 cases (8 eyes) (12.3%) were followed up for ≥ 44 weeks and then received drug treatment, but the fundus was accompanied by pre-plus lesions or ridge aggravation or logistical considerations before treatment.
In this study, 4 eyes (6.2%) were treated for the logistical considerations that result in not timely follow-up. The logistical considerations of Liu T et al ’s study were the difficulty in follow-up or general anesthesia for non-ROP surgery (3%)5. The intravitreal injection for ROP infants in this study was performed under topical anesthesia and there was no treatment under general anesthesia due to other diseases. For some ROP cases with difficulty in follow-up, detailed communication with the family before treatment is recommended to emphasize the importance of follow-up, especially after anti-VEGF drug treatment that requires longer follow-up.
This study still had some limitations. To avoid medical disputes caused by delayed treatment during clinical practice, no control group was set. So, it was unable to accurately judge the progression of non-type 1 ROP that did not receive treatment. The sample in the study group shall gradually be increased to collect untreated cases with non-type 1 ROP so as to investigate reasonable treatment methods in the future.
To summarize, non-type 1 ROP with some characteristics, such as pre-plus, ridge changes, treatment with contralateral eyes, no regression in persistent stage 2 or 3 for follow-up time ≥ 44 weeks, and logistical considerations, were cured or improved after intravitreal injection of anti-VEGF drugs. It is suggested that in clinical practice, personalized treatment can be carefully considered for some ROP in critical conditions based on expert consensus or guidelines.