This study assessed the associations between pre-injection VA, post-injection VA, and clinical and SD-OCT characteristics in NIU MO eyes treated with intravitreal DEX. We identified EZ damage, the presence of DRIL, and a thicker macula as biomarkers of worse pre-injection VA. EZ disruption and DRIL were also predictors of poor visual outcomes, and their prevalence increased significantly in eyes requiring multiple treatments. Older age, longer MO duration, higher CRT, and the presence of HRF were risk factors for persistent MO after each DEX.
According to randomized clinical trials and real-life data, the magnitude of visual improvement in eyes being treated for NIU and MO varies widely. In the HURON trial, the percentage of 15-letter gainers after intravitreal DEX was 42% at 3 months and 38% at 6 months.4 Real-world studies showed that up to 40% of eyes failed to improve 3 EDTRS lines after DEX treatment.5,19,20 The patients included in this study globally gained vision after each DEX, but visual gains were heterogenous, with 60% of eyes improving less than 5 letters. There is limited data availability on morpho-functional correlations in eyes with NIU MO.21 Studies examining the effect of single or repeated DEX in NIU were based on a small number of eyes, and only a few analyzed morphologic predictors of visual and anatomic outcomes.6,8,22,23 Our study is uniquely positioned to analyze data from nearly 200 DEX in NIU patients undergoing serial SD-OCT imaging in an attempt to identify the factors affecting DEX response.
Ciulla et al. investigated the relationship between VA and CRT in eyes with NIU MO.12 The authors found VA and CRT were weakly associated, and CRT values accounted only for a negligible part of VA scores variability.12 We found that pre-injection VA and CRT values followed an exponential relationship, suggesting that very low (e.g., < 300 µm) and very high (e.g., > 600 µm) CRT values were both associated with poor VA. While high CRT values suggest worse MO, low CRT values may correspond to macular atrophy with extensive retinal damage, a common end-stage disease of exudative macular disorders.24 Nonetheless, CRT values alone (considering either linear or quadratic fits) explained less than 7% of the pre-injection VA variance in our cohort, implying the existence of other structural biomarkers contributing to VA.
DRIL and EZ disruption were associated with worse VA, before and after DEX. DRIL indicates the loss of inner retinal layers' lamination on SD-OCT, and it is a surrogate of irreversible damage of amacrine, bipolar, and horizontal cells.17 Conversely, the EZ band reflects the integrity of the photoreceptor outer segments. DRIL correlates with poorer treatment response in eyes with DMO,25,26 RVO,14,27 and idiopathic ERM.28 The presence of DRIL and its extent has also been associated with worse visual outcomes in eyes with NIU treated with systemic IMT (Adalimumab).17 On the other hand, the posthoc analysis of the PEACHTREE and AZALEA trials assessing the efficacy of suprachoroidal triamcinolone acetonide in NIU eyes showed the EZ status had the strongest association with baseline and post-treatment VA (explaining up to 25% of the total variation).29 Our data confirmed the robustness of DRIL and EZ disruption as independent negative prognostic biomarkers for VA in real-life practice.
A multicenter French study observed that patients who were naïve at baseline (n = 6/22, 27%) had a higher chance of visual improvement after DEX than previously treated patients (n = 8/46, 17%).30 MO duration was not directly correlated with VA in our study; however, the chance of at least 5-letter improvement was higher after the first DEX than subsequent DEX. A regression toward the mean plausibly biases this finding. However, we speculate progressive retinal damage occurs with recurrent MO. In fact, the prevalence of DRIL and EZ disruption increased with repeated DEX. Moreover, we found a possible inverse association between systemic IMT and pre-injection VA, suggesting worse vision in subjects not receiving systemic IMT. Prolonged inflammation and, probably, undertreatment is the most likely cause of cumulative retinal damage.
The effect of DEX was lower in eyes with ERM. Epiretinal membranes are relatively common in NIU, with an estimated prevalence of 41%.31 Eyes with ERM tend to have worse VA than eyes without ERM,31 and may obtain limited visual gains after surgical ERM removal.32 Munk et al. and Khurana and Porco investigated the treatment outcomes in NIU MO presenting with ERM. Both groups found that intravitreal treatments had limited visual effects in eyes with ERM compared to eyes without ERM.6,33 Our data also showed a possible interaction between VA and ERM, with eyes with ERM and poor pre-injection VA having worse post-injection vision than eyes without ERM. We hypothesize ERM may exert additive harm on the macular structures, which does not revert with medical treatment.
A delayed anatomic response was associated with suboptimal visual recovery after suprachoroidal triamcinolone acetonide treatment.29 In our study, the persistence of intraretinal or subretinal fluid was associated with worse post-injection VA. A few studies reported the rate of persistent or recurrent MO in NIU.5,7,8,10A retrospective case series of 18 eyes treated with DEX found MO resolved in 72% of cases,6 comparable to our study rate of 67%. Older age, longer MO duration, and a higher pre-injection CRT were associated with a lower chance of MO regression. The presence of HRF was also a risk factor for less responsive MO. Although there is no definitive consensus, HRF may derive from lipoproteins extravasation from a halted inner blood-retinal barrier. HRF may also represent microglial activation, and their presence may imply active intraretinal inflammation.34 The presence of SF was associated with a 6-fold higher chance of MO regression, in line with a US retrospective study of 101 eyes with uveitic MO.35 SF tends to occur in MO of shorter duration and may suggest intact connections between Müller cells and foveal cones.33 Therefore, it may be regarded as a sign of good response to local or systemic treatments.
We acknowledge the retrospective design and the presence of missing data as limitations of this study. Patients seen at tertiary uveitis centres could have worse expected outcomes by the referring physicians, and the study may be limitedly generalizable. There was heterogeneity in patients' follow-up time due to discrepancies in post-injection visits scheduled between centres. In fact, post-injection SD-OCT scans were available in 75% of the cases. We cannot exclude data were not missing at random; patients not returning for follow-up SD-OCT could be those with very good or very poor responses to DEX. Similarly, we defined persistent MO as intraretinal or subretinal fluid on follow-up SD-OCT. The post-injection assessment was done at 3 months, so we could not discern eyes with persistent fluid from those with early MO recurrence. We did not include clinical variables potentially affecting VA in the regression analyses, such as anterior segment inflammation, cataract grading, and vitritis severity. Hence, a large quote of VA variability was still not explained by our models.
In conclusion, this study assessed the relationship between clinical and SD-OCT biomarkers and VA in NIU patients with MO treated with DEX. Our analysis revealed that integrity of the inner and outer retina is associated with a better visual response to treatment, independently from the severity of macular thickening. Long-standing and recurrent MO are likely to cause cumulative retinal damage and are associated with less chance of both visual and anatomic improvement. We conclude that timely treatment with local and systemic IMT is necessary to maximize the outcomes of MO in NIU patients.