Dear Editor, We read and reviewed the article entitled as "Predicting outcomes to anti- vascular endothelial growth factor (VEGF) therapy in diabetic macular oedema: a review of the literature'' by Ashraf et al. with great interest [1]. In that comprehensive study, the authors reviewed the studies that investigated demographic, clinical, optical coherence tomography (OCT), and fluorescein angiography results that could predict the outcomes of the anti-VEGF agents in patients with diabetic macular edema.

Ashraf et al. suggested that choroidal thickness (CT) might also be utilized as a novel marker to predict outcomes of the treatment with anti- VEGF agents in patients with diabetic macular edema. However, we disagree with the authors at some important points.

As Ashraf et al. have already indicated in their paper, CT is significantly variable in the patients with diabetic retinopathy. Although some studies stated that CT increased significantly, some others demonstrated that CT decreased significantly in patients with diabetic retinopathy. Even in some studies, CT has been found to be the same in the diabetic patients and the normal control group. Then what may be the causes of such conflicting results in CT measurements?

First, choroid has a unique vascular anatomy and physiology [2]. It is one of the tissues that has the most excessive per-gram blood supply in the body. Therefore, various local, systemic, and environmental factors significantly affect CT [2,3].

Second, various anatomic and pathological factors associated with eye significantly affect CT. In the literature, it has been indicated that local factors such as intraocular pressure, axial length, and refractive errors may affect CT [2,3]. Moreover, glaucoma, amblyopia, strabismus, and many other eye diseases and their treatments may affect CT.

Third, many neurologic, rheumatologic, inflammatory, hematologic, endocrine, and vascular disease and their medications may significantly affect CT [3]. Additionally, physiologic conditions such as pregnancy and menstrual cycle also affect CT.

Fourth, smoking, alcohol and caffeinated/decaffeinated beverages, diurnal variations as well as lightening conditions of the room where the CT measurement is performed may significantly affect CT [2,3].

In contrast to Ashraf et al., we do not suggest CT as a suitable marker for patient follow-up, or a predictor for treatment outcomes. If the CT would be considered as a criterion, all local, systemic, and environmental factors should be standardized and optimized.

References 1 Ashraf M, Souka A, Adelman R. Predicting outcomes to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular oedema: a review of the literature. Br J Ophthalmol. 2016; doi: 10.1136/bjophthalmol-2016-308388. 2 Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010;29:144-68. 3 Tan KA, Gupta P, Agarwal A, Chhablani J, Cheng CY, Keane PA, et al. State of science: Choroidal thickness and systemic health. Surv Ophthalmol 2016; doi: 10.1016/j.survophthal.2016.02.007.

Conflict of Interest:

None declared

Intravitreal bevacizumab for diabetic macular oedema: 5-year results of the Pan-American collaborative retina study group. Dan Calugaru, Mihai Calugaru Department of Ophthalmology, Univ of Medicine Cluj-Napoca/Romania

Re: Intravitreal bevacizamab for diabetic macular oedema: 5-year results of the Pan-American collaborative retina study group. Arevalo et al. Br J Ophthalmol published online on February 24, 2016;doi:10.1136/bjophthalmol-2015-307950.

Dear Editor The article by Arevalo et al [1] has several shortcomings that prevent the validation and extrapolation of their results and that can be specifically summarized as follows:

1. The study was retrospectively conducted with the existence of a selection bias due to the lack of a uniform clear treatment schedule for injections and reinjections, the decision to treat being left at the discretion of the treating physicians. Additionally, a total of 113 eyes were diagnosed with proliferative diabetic retinopathy and treated with panretinal photocoagulation at least 6 months before undergoing intravitreal bevacizumab (IVB) for diabetic macular oedema (DME).

2. The assessment of the final outcomes should be made taking into account the current assertion whereby evaluation of the outcomes has to be guided by the anatomical measure data with the visual changes as a secondary guide [2]. Accordingly, the visual and anatomic improvements of this study were poor. Thus, while early visual gains due to IVB were not maintained 5 years after treatment, the central macular thickness (CMT) decreased significantly from 403.5 to 313.7 microns over 5 years follow- up. Importantly, this value is much more than the cutoff (252 microns) for the upper level of normal foveal thickness (212 ? 20 ?m)(3) plus 2 standard deviations. Of note, the proportion of eyes considered "dry" on optical coherence tomography as per criterion of foveal thickness ? 260 ?m was 29.4%, the rest of the eyes having unresolved macular oedema.

3. The results of this study could be explained by the low frequency of injections (a mean of 8.4 IVB injections per eye over 5 years) as well as the long duration of diabetes (a mean of 15.8 years). Most likely there was a chronic retinal capillaropathy due to permanent irreversible breakdown of the inner and outer blood retinal barriers. The vascular endothelial growth factor (VEGF) is one proven contributor to macular oedema in diabetic retinopathy. Besides, a panoply of proinflammatory and proangiogenic cytokines, chemokines, and growth factors may be associated with pathophysiology of DME [4,5].

Altogether, the specific anti-VEGF drugs represent the front-line therapy for the treatment of DME but VEGF inhibition only may not be sufficient to decrease inflammatory response. Therefore, addition of a non -specific anti-VEGF substance, i.e., intravitreal steroid injection is mandatory. Otherwise, patients will be impeded to achieve maximal visual and anatomic benefits. References 1. Arevalo JF, Lasave AF, Wu L, et al. Intravitreal bevacizumab for diabetic macular oedema: 5-year results of the Pan American collaborative retina study group. Br J Ophthalmol 2016, online first published on February 24, 2016; doi:10.1136/bjophthalmol-2015-307950. 2. Freund KB, Korobelnik JF, Deveny R, et al. Treat-and-extend regimens with anti-VEGF agents in retinal diseases. A literature review and consensus recommendations. Retina 2015;35:1489-1506. 3. Chan A, Duker JS, Ko TH, et al. Normal macular thickness measurements in healthy eyes using optical coherence tomography. Arch Ophthalmol 2006;124:193-198. 4. Sohn HJ, Han DH, Kim IT, et al. Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am J Ophthalmol2011;152:686-694. 5. Shah SU, Harless A, Bleau L, et al. Prospective randomized subject- masked study of intravitreal bevacizumab monotherapy versus dexamethasone implant monotherapy in the treatment of persistent diabetic macular edema. Retina 2016, online first published on April 27, 2016; doi:10.1097/IAE 0000000000001038.

We thank Drs Calugaru M. and Calugaru D. for their interest in our article,1 and we welcome this opportunity to address their concerns. The purpose of our study was to investigate the outcomes of intravitreal antivascular endothelial growth factor (VEGF) therapy in eyes with both neovascular age-related macular degeneration (AMD) and diabetic retinopathy (DR) as higher levels of VEGF due to concomitant DR in eyes with active neovascular AMD may lead to a higher consumption of anti-VEGF molecules, thus impairing the efficacy of treatment.1 As pointed out, in our series we included patients that had undergone other treatments for DR, either before or during administration of anti- VEGF drugs for neovascular AMD. This is an obvious limitation of our retrospective study, even though all the patients included were treatment na?ve for anti-VEGF agents. We recorded that best corrected visual acuity, after a significant improvement at 1 year, returned to baseline values at the last follow-up visit, while mean central macular thickness (CMT) significantly decreased from 408 ?m to 335 ?m. As pointed out, these results may suggest that disease process could be still active and progressive requiring further treatment. 2 In fact, at the end of follow up, CNV was still active in 39% eyes, while 61% eyes developed an atrophic/fibrotic scar with no signs of activities. On the other hand, CMT could have been influenced by the two concomitant diseases, the diabetic retinopathy and the choroidal neovascularization. In particular, we cannot exclude that some patients underwent anti-VEGF treatment, DR-related macular edema. We agree that, a lot of cytokines, chemokines, and growth factors may be associated with DR pathophysiology.3,4 Further prospective studies should consider the effects of these molecules and the use of non-specific anti- VEGF substances which inhibits the up-regulation of the VEGF and suppresses the expression of the whole panoply of the proinflammatory and proangiogenic factors.

References 1. Bandello F, Corvi F, La Spina C, et al. Outcomes of intravitreal anti- VEGF therapy in eyes with both neovascular age-related macular degeneration and diabetic retinopathy. Br J Ophthalmol 2016; http:/dx.doi.org/10.1136/bjophthalmol-2016- 308400. 2. Gover S, Murthy RK, Brar VS, et al. Normative data for macular thickness by high-definition spectral-domain optical coherence tomography (spectralis). Am J Ophthalmol 2009;148:266-271. 3. Sohn HJ, Han DH, Kim IT, et al. Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am J Ophthalmol 2011;152:686-694. 4. Shah SU, Harless A, Bleau L, et al. Prospective randomized subject- masked study of intravitreal bevacizumab monotherapy versus dexamethasone implant monotherapy in the treatment of persistent diabetic macular edema. Retina. 2016 Apr 27. [Epub ahead of print]

Conflict of Interest:

None declared

Response to e-letter to the editor

We thank Dr. Mourits and co-workers for their interest and comments regarding our manuscript on impression-free three-dimensional (3D) printed anophthalmic socket, and appreciate their recognition of its value in the manufacturing of an ocular prosthesis.(1)

Dr. Mourits and co-workers propose an alternative technique, impression mould through silicon injection in the anophthalmic socket, which is subsequently scanned with magnetic resonance imaging (MRI), and further 3D processed. This technique, however, renews the manual step of impression moulding, which reintroduces a non-digital procedure in the digital domain.

We confirm the benefit of MRI over cone-beam computed tomography (CBCT) as radiation-free option.(2) However, we would like to highlight our concerns on the current use of MRI for the purpose of imaging the anophthalmic socket. First, spatial resolution of MRI is lower than CBCT, since MRI is characterized by geometric distortion produced by magnetic susceptibility, particularly at the air-tissue interface.(3,4) Second, longer acquisition times in MRI potentially result in more variable delineation.(5) Manual delineation in MRI, in contrast to computer- assisted delineation in CT, requires expertise and is time-consuming. Third, adequate MRI protocols and preferred coils for orbital scanning with high resolution and signal-to-noise ratio within reasonable measurement times are as yet not established.(6) By contrast, in CT, the process of delineation of soft tissue for calculation of orbital soft tissue volume is validated, reliable and accurate.(7) Finally, MRI in children requires general anaesthesia, which is associated with increased morbidity.(8)

Continuous improvement in MRI imaging will help to further develop this innovative concept. We encourage Dr. Mourits et al to publish the data they shared on the use of a mould and special MRI orbital scanning.

Bibliography

1. Ruiters S, Sun Y, de Jong S, et al. Computer-aided design and three-dimensional printing in the manufacturing of an ocular prosthesis. Br J Ophthalmol 2016 ;100:879- 881.

2. Brenner DJ, Hall EJ. Computed tomography--an increasing source of radiation exposure. N Engl J Med 2007;357(22):2277-84.

3. Ludwig U, Eisenbeiss AK, Scheifele C, et al. Dental MRI using wireless intraoral coils. Sci Rep 2016;6:23301.

4. Sumanaweera TS, Glover GH, Binford TO, et al. MR susceptibility misregistration correction. IEEE Trans Med Imaging 1993;12(2):251-9.

5. Karlo C, Reiner CS, Stolzmann P, et al. CT- and MRI-based volumetry of resected liver specimen: comparison to intraoperative volume and weight measurements and calculation of conversion factors. Eur J Radiol 2010;75(1):e107-11.

6. Georgouli T, James T, Tanner S, et al. High-resolution microscopy coil MR-Eye. Eye (Lond) 2008;22(8):994-6.

7. Regensburg NI, Kok PH, Zonneveld FW, et al. A new and validated CT -based method for the calculation of orbital soft tissue volumes. Invest Ophthalmol Vis Sci 2008;49(5):1758-62.

8. Cot? CJ, Wilson S. Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures: Update 2016. Pediatr Dent 2016;38(4):13-39.

Conflict of Interest:

None declared