In this study, we investigated for IOP elevation after anti-VEGF injections and Ozurdex implant in diabetic patients without prior OAG treated for DME during a follow-up of 2 months. Since anti-VEGFs have been used to treat nAMD for ten years, some localised long-term negative effects have been documented. Studies measuring sustained IOP elevation in nAMD patients receiving anti-VEGF injections have found that it occurs in 4–11% of patients, and the factors that have been found to be predisposing include the quantity of injections (over 20) and the short time between injections (20–22). These studies' large prevalence heterogeneity is likely caused by various IOP elevation criteria. It's important to evaluate these phenomena in DME, which has a younger prevalence (65 years (23), compared to 77.5 years in nAMD (24), and for which less long-term injections are necessary. In our study excluded cases that received any previous intravitreal injections and we selected cases with DME that only need 1 intravitreal according to OCT finding so we could rule the previous theory that assume that IOP elevation post intravitreal injections could be cumulative effect of repeated injections as Tseng et al21 and Hoang et al15 showed an association between the total number of injections and IOP elevation.
Studies investigating the relationship between diabetes and glaucoma have produced conflicting findings. Although there is no universal agreement, the majority of studies point to an increased incidence of OAG in diabetes patients. Therefore estimating the increased IOP values while receiving anti-VEGF therapy for DME is interesting. Previous studies had stated increased IOP values post intravitreal injections (25). We may presume that this rate was higher than our study because the term "IOP elevation" was defined differently. We used the definition of raised IOP provided by Al-Abdullah et al who conducted single center retrospective study in 486 patients assessing 760 eyes treated for DME but due of the low baseline IOP in our trial (mean IOP = 15.6 mmHg), we did not include the 20% rise from baseline IOP that Al-Abdullah et al. did(23).
In our study we injected the patient once to overcome the loading effect produced by repeated intravitreal injections as was noted in previous studies of Kim et al (26) and Al-Abdullah et al (23) who found that the mean number of injections per eye was significantly higher in the group with sustained IOP elevation than in the group without it, patients received a greater number of injections (mean number of six injections per eye versus three respectively).
Different theories have been postulated to explain post intravitreal elevation of IOP including the anti-direct VEGF's inhibitory effect on the trabecular meshwork's cells (27), the silicone oil micro-droplets and protein aggregates that accumulated in the syringes during storage's toxic effects (28), the trabecular lesion caused by volume changes brought on by repeated injections, and the anti-inhibition VEGF's of nitric oxide synthesis in the trabecular meshwork.
However according to Al-Abdullah et al., most eyes with DME and IOP elevation following intravitreal anti-VEGF injections suffer a temporary IOP rise that doesn't need to be treated. Additionally, even when the elevation is sustained, most eyes only experience modest IOP elevations, while 2% of eyes experience substantial IOP elevations 33. In fact, also Wehrli et al.'s study about NVAMD (29), which compared the incidence of IOP elevation in eyes with NVAMD that received bevacizumab and/or ranibizumab with control eyes that did not receive either, demonstrated such a low level of IOP elevation. Additionally, the results of this study support the idea that age may be a confounding factor in the association between IOP elevation and intravitreal injections in patients with NVAMD. These results were consistent with our results that reported no increase in IOP to be marked as “elevated IOP” as defined with our inclusion criteria upon comparing means of IOP values of the 3 groups in either of the 3 follow up periods (1week, 1 months and 2 months) indicating that 1 intravitreal injection of any of the 2 included anti VEGFs or the Ozurdex implant in the study.
The specific intravitreal medication used may also play a role in IOP elevation after therapy. For instance, one study found that the IOP elevation rate was three times higher after bevacizumab compared to ranibizumab alone, with a rate of 9.9% and 3.1% respectively. (30,31,32) The direct toxicity of an anti-VEGF drug on the TM is a potential IOP-increasing mechanism. This was consistent with our results as regard Ranibizumab intravitreal injection we found no IOP elevation occurred among our cases for over a period of 2 months.
Our results showed significance (P value < 0.001) upon comparing pre op baseline IOP and IOP values 1 week post injection. However over 2 month follow up IOP returns to be non significance (P value = 0.054) with the pre op values as regard ranibizumab and aflibercept. However with aflibercept we noticed that the range of return of IOP to near baseline pre op values after one month was less than that of ranibizumab, we can correlate this difference to the longer half life of aflibercept than that of ranibizumab. These results came to agree with Khalil et al who also stated that no significant increase in IOP measured one month after injection from the baseline IOP in group (33)
As regard Ozurdex Lazic et al investigated ozurdex efficacy in DME (34) and found In 3 of 16 eyes over the follow-up period (19%). These three eyes were treated with topical glaucoma medicine, and the condition was well controlled. After 4 months the mean IOP increased to 16.25 mmHg (range, 14-18 mmHg), but not significantly compared to the baseline IOP of 15.38 mmHg (range, 12-19 mmHg) (P = 0.24).
Choi et al conducted (35) a retrospective observational study on 540 eyes who received Ozurdex implant injection and were diagnosed with macular oedema (ME) IOP was measured prior to injection and at 1 week, 1 month, 2 months, 3 months, 6 months and
12 months after injection. They found that the mean baseline IOP was (13.45±2.95) gradually increased until 2 months post injection (IOP=16.85±5.96 mm Hg, p<0.001) and then gradually decreased until 12 months postinjection (IOP=13.80±4.04mm Hg, p=0.16).
To the best of our knowledge we are one of the earliest studies to compare anti-VEGFs (Ranibizumab and Aflibercept). During the first week IOP follow up no significant difference was noted between Ozurdex and the 2 anti-VEGF. But at the first month we found a significance difference in IOP values between Ozurdex and Ranibizumab (P value 0.033) and also between Ozurdex and Aflibercept (P vaue 0.022) but no significant value between IOP values between Ranibizumab and Aflibercept (P value 0.853) . Moving forward at 2 months follow up IOP values decreased to be no statistical difference found between IOP with Ozurdex versus anti- VEGF.
In conclusion, the current study confirms the results of previous studies which showed the safety of IV injection of anti-VEGF agents for IOP elevation in post-injection first 2 month in non glaucomatous patients. However, there might be a tendency to increased IOP in glaucoma cases and repeated injections, so further studies about safety of repeated injections, in glaucomatous patients and for different retinal disorders should be carried out. Our study for intravitreal injections recommends “monitoring of IOP after injection and providing therapy when elevated IOP warrants intervention”.
Although with Ozurdex the IOP elevation peaked between 1 and 2 months post injection. Assuming that the duration of intravitreal ozurdex implantation effect lasts approximately 4–6 months, it is noteworthy that the duration of IOP increase lasted only until 2 months post injection in our study. These results may suggest measures for safe patient management after ozurdex implantation, such as the need for more careful IOP follow-up until at least 3 months after injection, and especially between 1 and 2 months post injection.
The results suggest that the rate of significant and persistent IOP elevation in patients with DME after intravitreal anti-VEGF injections is lower than that reported for the NVAMD population. However, the limitations of this study, lack of a control group, variations in baseline characteristics between groups, such as duration of diabetes (the value of which remains unknown), and absence of gonioscopic documentation of the angle in most of our patients, make this conclusion speculative. Age and the quantity of injections each eye received may be significant factors in this variance, while there may be other contributing factors as well. Clinicians should be aware of the possibility for IOP elevation after intravitreal anti-VEGF therapy in eyes with DME, particularly when the patients require a higher number of injections. Although more research is required to determine whether such an association even exists, given the apparent low rate seen in this study, clinicians should be aware of the possibility. There are still many issues about this subject that need to be answered, so more future comparison research with big numbers is required.