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Recurrent Diabetic Macular Edema: What to Do

Diabetic macular edema (DME) is a leading cause of blindness in the working population. Herein, we report the case of a patient with recurrent DME for about 6 years, uncontrolled by several medical and surgical treatments, that was successfully treated with a single sustained-release fluocinolone acetonide intravitreal implant in her right eye. The affected eye had presented a visual acuity of 2/10 and a central macular thickness of 488 µm prior to the injection. After treatment with the fluocinolone acetonide intravitreal implant, the patient's right eye presented an improvement in best corrected visual acuity to 6/10 and a reduction of central macular thickness to 198 µm. These functional and anatomical results were continuous and sustained during a follow-up period of more than 12 months, and with an acceptable and manageable safety profile. These results show that fluocinolone acetonide intravitreal implantation is an effective treatment option in DME and should be considered in the DME treatment pathway.


Introduction
Diabetic macular edema (DME) is one of the leading causes of vision loss in the workingage population around the world [1]. It is defined by abnormal collection of extracapillary fluid due to blood-retinal barrier breakdown because of increased production of inflammatory mediators and vascular permeability factors and loss of endothelial tight junctions [2,3]. Because of its complex and multifactorial pathophysiology and chronic nature, it can necessitate ongoing and numerous therapies to maintain vision.
In the past, the standard care for DME was focal/grid laser photocoagulation, but the visual acuity gain was only modest [4,5]. Treatments for DME are rapidly evolving, and today there are numerous alternative therapies to improve patients' vision. Inhibitors of vascular endothelium growth factor (VEGF) are currently considered as the first-line therapy of choice for DME. Several trials have shown that frequent intravitreal injections with anti-VEGF were more effective than laser photocoagulation for the treatment of DME [6][7][8]. However, a large proportion of patients still have a poor response to anti-VEGF agents even with frequently repeated injections. In the phase III ranibizumab studies on DME (RISE and RIDE), between 30.4 and 43.2% of the patients failed to gain ≥10 letters after 3 years of treatment with 0.3 or 0.5 mg ranibizumab [6]. A recent analysis of protocol I data showed that about 40% of the eyes had a suboptimal early response (<5-letter improvement) at 12 weeks, and most of these had suboptimal visual outcomes after 3 years of treatment [9].
Intravitreal corticosteroids have also been evaluated and shown to be effective in achieving visual gain and reduction of DME because of their ability to act on other inflammatory cytokines and pathogenic mechanisms, in addition to those associated with VEGF. Also, they can reduce the frequency of injections needed [10,11]. The currently available intravitreal corticosteroids for the management of DME include triamcinolone (unlicensed for DME in Europe), dexamethasone (Ozurdex ® ; Allergan), and fluocinolone acetonide (FAc) (ILUVIEN ® ; Alimera Sciences). Whilst the treatment effect of dexamethasone implants lasts up to 6 months, the effect of FAc implants is up to 3 years [12]. The FAME study showed that approximately one-third (34%) of their patients with DME for ≥3 years who were treated with a 0.2 μg/day FAc implant experienced a ≥15-letter gain, compared with 13.4% of the sham-treated patients [11].
Here, we present the case report of a patient with recurrent DME uncontrolled by several medical and surgical treatments that showed an anatomical and functional response after treatment with a single intravitreal FAc implant.

Case Report
The patient was a 61-year-old Caucasian woman with type 2 diabetes over the previous 25 years who always had good metabolic control (HbA1c <7.5%). She was first diagnosed in November 2004 with bilateral incipient diabetic retinopathy. Almost 4 years after first presentation, she had decreased vision (3/10 in the right eye and 4/10 in the left eye) due to the development of cystoid macular edema (CME), which was treated at that time with focal argon grid laser in both eyes. Her best corrected visual acuity (BCVA) and CME did not improve ( Fig. 1). Subsequently, the patient was treated by intravitreal injection of triamcino-lone acetonide into both eyes, with improvement of CME. In 2010, panretinal photocoagulation was started in both eyes due to proliferative diabetic retinopathy.
Despite good glycemic control, the patient's DME and proliferative retinopathy continued to develop, with decreasing BCVA. In August 2011, the patient's CME increased and BCVA decreased again (1/10 in both eyes). She underwent multiple triamcinolone acetonide injections into both eyes with partial and transitory responses (Fig. 2). A transient increase in intraocular pressure (IOP) was observed after intravitreal triamcinolone injection.
In November 2012, the left eye underwent pars plana vitrectomy combined with phacoemulsification due to vitreous hemorrhage and cataract development, respectively. After the surgical procedure, the development of central retinal atrophy (central foveal thickness of 195 µm) and a BCVA of 0.5/10 in the left eye were verified, results which remained stable over the follow-up period. The right eye also underwent phacoemulsification due to cataract development, combined with intravitreal triamcinolone. Postoperatively, the right eye's BCVA increased to 6/10 and the macula became dry.
In September 2013, the right eye developed CME again and the BCVA dropped to 2/10. The patient received a loading dose of 3 intravitreal injections of ranibizumab with an increase in BCVA to 5/10, but with recurrence of CME 4 months later. Up to 2015, alternate intravitreal injections of ranibizumab and triamcinolone acetonide were performed on the right eye, without sustained functional or anatomical results.
In September 2015, an FAc intravitreal implant was placed in the right eye, with resolution of the CME (the central foveal thickness decreased from 488 µm prior to the injection to 198 µm after treatment) and an increase in BCVA (from 2/10 to 6/10 after the injection) 1 month later, results that remain stable 12 months later (Fig. 3). Table 1 summarizes the treatments performed on the right eye for DME, and the respective outcomes, from the diagnosis of diabetic retinopathy to the present date.
As in the last year intercurrences occurred in the right eye, we reported the occurrence of vitreous hemorrhage after posterior vitreous detachment, which resolved spontaneously. Additional laser treatment was performed for enhancement of the panretinal photocoagulation. Moreover, we reported ocular hypertension in the right eye (max. IOP = 27 mm Hg), which was effectively controlled with hypotensive eye drops and selective laser trabeculoplasty (SLT) ( Table 1), without any documented damage to the optic nerve.

Discussion
Due to its chronic nature and persistence, DME can be difficult to manage. Combined medical and even surgical procedures may be the best way to achieve DME control in patients. Use of an FAc intravitreal implant, a slow-release low-dose corticosteroid implant, is indicated for the treatment of vision impairment associated with chronic DME considered insufficiently responsive to available therapies, and it is the only treatment available with a treatment regimen of 1 single injection for up to 36 months [11], which suggests a reduced treatment burden.
The patient whose case we reported is a challenge to any ophthalmologist that treats DME. Despite having good metabolic control and despite the various treatments administered, which included both laser treatment and intravitreal injections of anti-VEGF agents and short-term-efficacy corticosteroids, she had not responded sufficiently, and chronic DME over a period of about 6 years as well as progressive aggravation of her visual function were observed. Thus, an alternative treatment was required, since the right eye was the only one with potential visual function and prolonged intraretinal fluid accumulation might have caused irreversible damage resulting in permanent visual loss. In this case, the switch to an FAc intravitreal implant in the right eye appears to have been an excellent therapeutic option, with rapid resolution of the CME and a significant increase in BCVA after injection of the implant. It also allowed the patient to remain free of DME and to achieve a good functional vision of 6/10 for more than 12 months, with an acceptable and manageable safety profile.
In recent years, there have been numerous clinical studies reporting the efficacy and safety of the FAc implant in patients whose DME has been insufficiently responsive to laser therapy and intravitreal anti-VEGF agents [13][14][15][16][17]. As an example, Alfaqawi et al. [14] showed, at 12 months, a mean improvement of +8 letters from baseline and a gain of ≥15 ETDRS letters in 25% of their patients. This kind of emerging evidence has been vital for clinicians to justify the use of the FAc implant in those patients who have not responded to the first-line therapy of DME.
This case report also demonstrates the potential effectiveness of the FAc intravitreal implant in a real-world clinical setting and suggests that it should be considered if a patient does not respond optimally to other available therapies. Notably, in this case, we observed that a prior steroid response to intravitreal triamcinolone predicted a subsequent response to the FAc implant, including patient IOP outcomes. Recently, Bailey et al. [18] have already shown that emergent IOP-lowering medication or IOP elevation above 30 mm Hg following treatment with FAc was more frequently reported in patients with prior IOP-related events. In our case, SLT was successfully utilized in the management of ocular hypertension, which may suggest a potential role for SLT as a less-invasive treatment for the management of IOP elevation associated with FAc treatment.

Statement of Ethics
Patient consent and hospital ethics committee approval were obtained.

Disclosure Statement
The authors report no conflicts of interest.