The main finding from this study is that the use of SChI-TA after surgery is a repeatable and safe procedure that provides significant recovery of BCVA and reduction of macular CRT and EIFL-T. In addition, TA was more effective when administered suprachoroidally than intravitreally.
TA is a synthetic lipophilic intermediate-acting corticosteroid. Because of its low solubility in aqueous solution, it can be used in sustained-release crystalline form, making it suitable for local depot injection. TA has been known to reduce inflammation and suppress cell proliferation increasing the production of basic fibroblast growth factor (bFGF) and decreasing the production of transforming growth factor beta (TGF-β) by human fibroblasts [13].
Until recently, the only method to deliver high doses of TA to the retina after vitrectomy was by intravitreal injection. However, IVTA can be associated with risks as direct contact and toxicity to the sensory retina, risks of infection, and of increased IOP. Studies in vitrectomized eyes have reported that the average elimination half-life of a 4 mg IVTA is 2–3 days, so the drug remains in the vitreous for less than 10 days [7, 14].
After vitrectomy, the anti-inflammatory effect of IVTA wanes rather quickly and is sometimes followed by a rebound effect of macular edema [15]. The duration of IVTA can reach several weeks raising the dosage to 20 mg, but with the risk of major complications such as glaucoma [8].
The efficacy of intravitreal corticosteroids after vitrectomy for iERM can be increased by using a sustained release dexamethasone intravitreal implant (Ozurdex® 0.7 mg-Allergan-Irvine-CA) [16].
The effect of Ozurdex® in a vitrectomized eye lasts for several months, and its use after vitrectomy for iERM has shown positive results with faster improvement in visual acuity and faster resolution of macular edema compared to untreated patients [17].
However, Ozurdex® is not always routinely available, is expensive, and injection into a vitrectomized eye may cause some complications. There is a possibility of retinal injury due to impact; mobility of the implant in the vitreous chamber may cause floaters, migration into the anterior chamber, corneal decompensation, etc.
A new route of drug delivery into the eye has recently been discovered: the injection into the SChS, a virtual space located between the sclera and the choroid [18]. TA is one of the best preparations that can be injected into the SChS due to its lower solubility and prolonged release [19,20,21].
Animal and human studies have shown that TA administered suprachoroidally remains in the ocular tissues for at least 3 months, longer than the intravitreal route, and is unaffected by whether the eye has undergone vitrectomy. SChI-TA induces significant concentrations of steroid in the retina, choroid and sclera, with small amounts reaching the lens and anterior chamber.
Numerous trials have confirmed the clinical validity of this procedure in the treatment of macular edema caused by uveitis, diabetes or retinal vascular accidents [22,23,24].
Idiopathic ERM is a macular disorder characterized by fibrocellular proliferation and contraction on the central retina. Müller cells are the major cellular components of iERM. Müller cells become ‘reactive’ in response to virtually every pathological stimulation of the retina. This reaction is called Müller cells gliosis or, precisely in iERM: glial to mesenchymal transition (GMT) that is a transdifferentiation process characterized by the downregulation of Müller cells glial markers, paralleled by the upregulation of pro-fibrotic myofibroblast markers [25].
Various cytokines and growth factors act as modulators by triggering Müller cells swelling, transdifferentiation, proliferation, collagen production and contraction. TGF β appears to be the major cytokine driving GMT in iERM [26].
Recently, Govetto et al. introduced the new SD-OCT-based ERM staging scheme based on the presence or absence of EIFL. EIFL is defined as the presence of a continuous hyporeflective (extension of the inner nuclear layer) or hyperreflective (extension of the inner plexiform layer) band across the fovea [11].
Gliosis and straightening of the perifoveal Müller cells due to the anteroposterior and centripetal traction forces of the ERM are thought to be responsible for the progressive displacement of the inner nuclear and plexiform layers through the foveal centre, creating the EIFL.
The classification of ERM is divided into four stages: in S-3 the retinal layers are clearly visible under EIFL, in S-4 the retinal layers are not clearly distinguishable. The presence of EIFL is a sign of increased Müller cell activation and GMT and an independent predictor of worse postoperative visual acuity [27]. Accordingly, we chose to treat patients with S-3 and S-4 iERM with TA. Surgical removal of the iERM eliminates the mechanical stimulus that maintains and worsens Müller cell GMT over time, leading to slow and often incomplete recovery of macular structure and improvement in BCVA.
However, in the early postoperative period surgery cannot modify the concentration of cytokines within the retinal parenchyma, which maintains the reactivity of Müller cells. Pre-existing pathologic edema due to ERM may be slow to disappear, persist, or even worsen following the trauma of mechanical peeling of the membrane.
Although ILM peeling in iERM surgery is controversial [28], ILM peeling may be considered a recommended procedure in the treatment of advanced iERM with severe macular distortion, as it reduces the risk of re-intervention.
In our experience, if ILM peeling is not performed in the advanced stages of iERM, recurrence of macular pucker is quite common [29], so we always perform this procedure, even though it may be one of the causes of the onset of CME in the postoperative period. In fact, surgical trauma to the retinal tissue during ILM peeling causes postoperative macular changes such as thickening, thinning or dimpling [30]. Disruption of adhering Müller cell end-feet during ILM peeling may cause a transient increase in local production of inflammatory cytokines that in some cases can cause CME [31].
The rationale for using TA that inhibits cell proliferation and inflammation is to both to inhibit the production of local modulators, including TGFβ, responsible of retinal gliosis, and to reduce the incidence of CME. IVTA used intraoperatively during vitrectomy for iERM removal has shown mixed results. Some authors demonstrated that intraoperative IVTA had a beneficial effect on the rapidity of visual recovery due to faster fluid absorption, prevention of postoperative inflammation and neuroprotective action on the photoreceptors [2,3,4], while others have not found differences in final results between treated and untreated patients [5, 6].The conflicting results between authors may be explained by the rapid clearance of TA in vitrectomized eyes [7].
In this study, 4 mg SChI-TA was advantageous compared to 4 mg IVTA because it offered a longer duration of action, possibly corresponding to a higher intraocular TA level. This is consistent with studies using Ozurdex® during iERM surgery [16].
At the end of the study, G-1 had a mean reduction in CRT and EIFL-T of − 131 μm (− 26.4%) and − 104 μm (− 46.6%), respectively, while G-2 had a significantly greater reduction in both parameters: − 222 μm (− 39.1%) and − 200 μm (− 68%). (Table 3).
This correlated with greater increase in BCVA in patients undergoing SCh-TA. (Fig. 4).
Graphs A Central retinal thickness (CRT), B Ectopic inner foveal layer thickness (EIFL-T), and C—Best corrected visual acuity (BCVA) in patients who underwent vitrectomy and intravitreal injection of triamcinolone acetonide (IVTA, blue dots) or suprachoroidal injection of triamcinolone acetonide (SCHi-TA, red triangles), mean ± SD
Our results support that changes in macular thickness after iERM peeling have a significant inflammatory component; therefore, prolonged anti-inflammatory medication is useful. EIFL-T was significantly affected by the sustained release of TA: at the end of the study, the EIFL was no longer measurable in 10 cases of G-2 (43%) and 4 cases of G-1 (16%). Prolonged inhibition of local cytokine and TGF-β production, which results in immune activation of Müller cells, was able to partially or completely regress the gliotic responses of Müller cells.
We were unable to determine with certainty how long the iERM had been present in most cases. It is possible that in cases where the iERM has recently formed, the reactive inflammatory component predominates over the structural component, and therefore surgery added to TA may be more effective in restoring macular integrity in the early stages.
Further studies should be conducted to determine the benefits of early surgery for iERM compared to watchful waiting and late surgery.
According to the literature, postoperative CME occurs in 13–47% of patients after ERM/ILM peeling and is a serious event responsible for the delay in visual recovery in these patients [31, 32].
Within 3 months of surgery, 16% of G-1 patients and no G-2 patients developed signs of CME. However, one patient in G-2 (4.3%) developed CME after 3 months. This indicates that the TA was washed out from the suprachoroidal space; that is a warning that the rebound effect of CME is possible even after SChI-TA. We remind that all the patients of the study were pseudophakic. Regarding IOP, the prevalence of ocular hypertension after SChI-TA was comparable to that after IVTA (~ 4%), transient and controllable with topical therapy.
A major limitation of the current study was the small sample size and relatively short follow-up. However, postoperative changes in CRT, EIFL-T, IOP and incidence of CME occur mainly in the first 6 months after iERM removal, whereas changes after 6 months were reported to be minimal. Inaccuracy of manual measurement of CRT and EIFL-T was another confounding factor in this study. However, the measurement was performed in a masked fashion by three different authors, and the reduction in both parameters was undoubtedly greater in G-2.
In conclusion, SChI-TA promoted a greater reduction of CRT and EIFL-T than IVTA after vitreoretinal surgery for severe iERM. With SChI-TA, 43% of patients (compared to 16% with IVTA) had a recovery of foveal depression. This was associated with a greater improvement in BCVA. Patients treated with SChI-TA had fewer cases of postoperative CME than those treated with IVTA. However, the rebound effect of CME may also occur after SChI-TA. Finally, SChI-TA did not increase the risk of ocular hypertension compared to IVTA.
These data may support the routine use of SChI-TA in combination with standard vitrectomy and peeling for the treatment of advanced stage iERMs.
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