Discussion
In this post hoc analysis, we report the integrity of the EZ in subjects enrolled in the OASIS trial over time after ocriplasmin or sham injection. We observed that while an increase in the severity of EZ abnormalities may be observed at week 1 and month 1 after treatment, this abnormality appears to resolve in nearly all subjects by month 3 and this was sustained out to month 24.
A number of previous smaller studies have assessed the EZ in the setting of ocriplasmin. Tibbets et al11 demonstrated a disruption of the EZ associated with reduced ERG amplitudes with symptoms of darkening of the vision that persisted for at least 4 months. Margo et al12 reported EZ and ERG abnormalities that persisted for 14 months after ocriplasmin treatment. Tschuppert S et al reported on a series of 12 consecutive patients with VMT treated with ocriplasmin, and observed subfoveal fluid after injection in 9 of these cases which was associated with vision loss, but resolved by 6 weeks in 8 of the 9 cases.13 Freund et al14 reported EZ disruption 1 week after treatment of an FTMH with ocriplasmin, but already noted some recovery of the EZ by 3 weeks. Cereda et al15 used widefield OCT (55°) to better evaluate the extent of EZ changes and observed evidence of EZ attenuation throughout the scanning field (they termed ‘panretinal’) in 8 of 15 eyes, with recovery of the photoreceptors in 7 of 8 eyes. Itoh et al6 7 used an ellipsoid mapping technique and observed subretinal fluid and EZ attenuation in 7 of 19 treated patients at 1 week with recovery of the EZ by 3 months. The ASRS Therapeutic Surveillance Committee also summarised initial postmarketing experience with ocriplasmin but described only eight cases (0.18% of cases) with EZ alterations, of which at least six resolved.16
The various studies have highlighted that the EZ may be impacted by ocriplasmin in some cases, but as they were small retrospective series or case reports or incomplete post-marketing surveys, it was difficult to establish the true frequency and time course of the problem. The prospective Phase 3b OASIS trial offered an opportunity to study this problem more precisely, in greater detail and with use of available SD-OCT. Previously, we reported on a substudy of subjects from the OASIS trial who underwent MP to better understand the impact on visual function.9 This MP sub study only included 27 subjects, but demonstrated a consistently better sensitivity in ocriplasmin treatment patients. However, a transient reduction in sensitivity in the ocriplasmin group was noted at week 1 and month 1. The previous analysis, however, did not focus on the OCT data to see if it demonstrated a similar pattern. Unlike the MP data, the OCT data were available for the entire cohort and was the subject of the analysis in this report.
Overall, the anatomic EZ analysis from the OCT appeared to parallel the previous MP findings. In particular, a transient increase in EZ disruption/abnormality was observed by 1 week after ocriplasmin treatment in a small percentage of subjects and this abnormality appeared to persist through month 1, but had returned to approximately baseline by month three and remained stable through the final assessment at month 24. This general pattern was apparent in all zones (CS, PAA, PEA), though it was more difficult to discern in the CS. This is not surprising since the CS, and to a lesser extent the PAA, could be directly involved by an FTMH; or in the absence of FTMH, and were more likely to be significantly impacted by the vitreomacular traction process. Although the vitreous adhesion was present on the epiretinal surface, the tractional effects could impact the entire thickness of the retina. This is readily apparent, when one considers the frequency of abnormal or discontinuous EZ in CS at baseline in both the ocriplasmin and sham groups. The baseline presence of EZ abnormality is a potential confounder in our understanding of the impact of ocriplasmin. The perifoveal region (PEA), in contrast, was relatively normal at baseline—in fact the EZ was assessed to be completely normal in this region in 96%–97% of cases. Thus, the PEA may be best location to evaluate for the potential direct effect of ocriplasmin treatment on the EZ. In the PEA, an additional 7 percent of subjects developed EZ abnormalities at week 1. The same frequency was observed at month 1, and by month 3, the frequency of EZ abnormality had returned nearly to the baseline level.
Overall, our findings would seem to highlight that EZ alterations only occur in a minority of ocriplasmin patients and that in vast majority of these patients the alterations resolve over time, typically by 3 months. These findings are very much in line with previously reported electrophysiologic and microperimetric findings.9
Our study is not without limitations, including most notably the loss of subjects over time which was by virtue of the design of the study which permitted subjects who did not experience release of traction to be exited and undergo vitrectomy or other procedures per their treating physician. The loss of subjects was especially problematic in the sham group where most patients did not demonstrate a spontaneous release. Because of this loss to follow-up, the comparisons between ocriplasmin and sham patients might be confounded. Another limitation is that the EZ was assessed qualitatively and categorically which precludes a more granular assessment of the time course of recovery. The EZ was also assessed on a single horizontal B-scan. While it is possible this may have missed localised EZ abnormalities in other sectors, that situation is probably unlikely based on Cereda’s widefield OCT analysis which showed diffuse alterations throughout the retina in affected eyes.15 An en face EZ mapping approach as described by Itoh et al may be more informative, but this would require dense OCT scanning. In addition, as the EZ reflectivity was assessed qualitatively, it is unknown whether more subtle reflectivity abnormalities may have been present in eyes with an otherwise normal appearing EZ. Lastly, although we do show anatomic improvement of the EZ following treatment with ocriplasmin, functional assessment (eg, MP or ERG assessment) to correlate with the anatomic changes would have been of interest, but this was not available.
An important strength of this study is the use of experienced masked reading centre graders to assess the EZ. Thus, compared with previous studies, we believe the present study provides greater insight into the true frequency, severity and durability of the impact of ocriplasmin on the outer retina. Additionally, as compared with previous studies on this topic, SD-OCT (performed by certified evaluators) was available for evaluation.
In summary, in the OASIS study, ocriplasmin treatment was associated with a transient disruption of the EZ in <10% of subjects that was evident by 1 week after treatment and recovered in nearly all subjects by 3 months after treatment. This recovery was sustained out to 24 months.