Discussion
For patients with DME, the current treatment options include intravitreal anti-VEGF injections, intraocular steroids and focal/grid lasers in an attempt to treat and prevent vision loss.2 12–16 25 26 Focal/grid laser was the gold-standard treatment for DME for many years, but a high rate of recurrent oedema was shown, and trials such as RESTORE and the READ-2 studies have demonstrated the superiority of intravitreal anti-VEGF over focal laser.2 26 27 Comparing a recent DRCR study which showed that 18% of patients with DME treated with focal laser experienced a 3-line improvement in BCVA,28 DRCR Protocol T showed that after 2 years of anti-VEGF treatments with aflibercept, bevacizumab or ranibizumab, 39%, 35% and 37% of patients with DME had a 3-line improvement in the BCVA, respectively.15 Furthermore, the RISE/RIDE studies established the efficacy of ranibizumab as monotherapy, with the RISE trial demonstrating that at 36 months, 51.2% of patients receiving 0.3 mg ranibizumab gained ≥15 ETDRS letters compared with 22.0% in the sham injection group, while in the RIDE cohort 36.8% of the group receiving 0.3 mg ranibizumab gained ≥15 ETDRS letters compared with 19.2% in the sham injection group.25 29 Based on these promising outcomes, anti-VEGF therapy has become the new gold standard treatment for DME. Last, steroids can play a major role in the treatment of DME and provide longer-lasting treatments such as with the intravitreal 0.7 mg dexamethasone implant (Ozurdex) which provides continuous treatment for up to 3 months, and the 0.2 µg/day FAc intravitreal implant (Iluvien) which acts in a similar manner for 36 months.18 30
However, for patients with DME and for their treating physicians, the intensive regimen of frequent examinations and numerous intravitreal injections is a burden to both parties. The DME anti-VEGF treatment cycle is expensive for the healthcare system. Juxtaposed to monthly visits and treatments for DME seen in trials such as the RISE/RIDE studies,29 less intensive injection algorithms have been proposed and studied such as PRN treatments or treat-and-extend.31–33 In a study assessing the treat-and-extend protocol, at 2 years, there was a significant improvement in the BCVA, and reduction in the central macular thickness.31 In these protocols, OCT with CRT measurements is a mainstay imaging modality used to monitor treatment response and to guide further management decisions. Several studies have shown at least a modest correlation between CRT values and visual function following therapy for DME, and this correlation has been demonstrated with macular laser, bevacizumab and intravitreal dexamethasone21–23; In a DRCR study of 251 eyes, a correlation coefficient for visual acuity versus CRT on OCT was 0.52, 0.49, 0.36 and 0.38 at baseline, 3.5 months, 8 months and 12 months following laser photocoagulation, respectively.21 Another study assessing treatment of DME with an intravitreal steroid delivery system showed a modest inverse correlation between the macular thickness and BCVA, with a significant correlation of 0.53 at 90 days from baseline with 700-µg dexamethasone.23
In this study, when treating eyes with chronic DME, the authors noted an increased variability of the measured CRT values taken at each visit prior to administration of FAc. However, when converting to continuous steroid therapy via the FAc implant, the CRT amplitudes between visits were profoundly reduced by an average of 123.8 µm compared with before FAc administration. These results are especially impressive as this patient population had DME recalcitrant to traditional management requiring a switch in therapy to the FAc implant.
To the author’s knowledge, no published studies have evaluated the change in CRT amplitudes before and after a given treatment for DME. While the clinical relevance and long-term effects on visual prognosis remain unclear and need to be studied, information gleaned from basic science analyses demonstrate the negative impact that macular oedema plays on photoreceptor viability.8–10 The presence of macular oedema leads to a diminished photoreceptor directional sensitivity due to changes in cone alignment and structure, with a possible end-result of photoreceptor cellular loss.9 In DME, a study revealed that disruption in the inner and outer segment layer of the retina with oedema was associated with a 3.28 dB decrease in the retinal point sensitivity as measured by fundus microperimetry.8 Furthermore, the integrity of this layer is an important determinant of the effect of macular thickness on the visual acuity,9 and a strong relationship exists between the point thickness of the macula and a decreased macular sensitivity.10 One may surmise that frequent, large changes in macular thickness, as measured by the amplitude can further hinder photoreceptor alignment and structure, and the recurrent stretching and shrinking of photoreceptor cells can possibly negatively impact long-term function. Lardenoye and colleagues demonstrated that non-damaged photoreceptors that have been misaligned structurally by macular oedema can have a return to normal directional sensitivity following resolution of the macular oedema. Furthermore, improved visual acuity were correlated with these findings.9 A significant decrease in macular thickness amplitude following FAc was shown in our cohort of patients with DME, and we surmise that the decreased fluctuations in macular thickness have a positive, long-term effect on photoreceptor viability, and ultimately visual function.
From a clinical practice standpoint, the decreased amplitude changes of the CRT seen following FAc correlated with a decreased treatment frequency where the number of treatments required per month significantly decreased from an average of 1 treatment every 2.7 months to 1 treatment every 6 months. After switching from discontinuous DME therapies such as anti-VEGF, focal/grid laser and/or intravitreal dexamethasone implants, the switch to continuous steroid therapy via the FAc intravitreal implant decreased the treatment burden on the patient and treating physician, and also decreased is the possibility of complications associated with frequent intravitreal injections such as endophthalmitis.
A limitation of this study is its retrospective nature without randomisation, and there were a relatively small number of eyes included in the study. Furthermore, the concept of studying change in macular thickness amplitudes before and after a given treatment is novel in the current literature, so we are unable to compare our findings. Conversely, the idea of macular amplitude changes is a potential new avenue to investigate further, with the possibility of correlating these results with macular sensitivities. Nevertheless, this is a unique real-world evaluation of FAc treatment for DME in that all DME treatments (anti-VEGF, steroids and focal laser) were compared pre-FAc and post-FAc.
In conclusion, our real-world results highlight that in eyes with DME, a significant reduction in the mean CRT amplitude occurs after treatment with FAc. Concurrently, a reduction in treatment burden while maintaining BCVA was observed. Further studies are needed to evaluate these interesting findings and the long-term effects of decreased CRT amplitudes.