Changing from pro re nata treatment regimen to a treat and extend regimen with ranibizumab in neovascular age-related macular degeneration Dan Calugaru, Mihai Calugaru Department of Ophthalmology, Univ of Medicine Cluj-Napoca/Romania

Re: Changing from pro re nata treatment regimen to a treat and extend regimen with ranibizumab in neovascular age-related macular degeneration. Hatz and Prunte. Br J Ophthalmol 2016; http:/dx. doi.org/10.1136/bjophthalmol-2015-307299.

Dear Editor We would like to address several limitations arisen from the interesting study by Hatz and Prunte (1) and which can be specifically summarized as follows:

1. The article was retrospectively conducted with the existence of a selection bias due to the inclusion in the final analysis only those patients who completed treat and extend (TE) follow-up of 12 months. Of note, only patients with active disease during the last 3 months of the pro re nata (PRN) phase were transitioned to TE treatment.

2. With the exception of data concerning the baseline choroidal neovascularization (CNV), there were no details on the anatomical types of neovascular maculopathy (CNV/serous and/or hemorrhagic detachment of the neurosensory retina or retinal pigment epithlium [RPE]/retinal hard exudates/subretinal and sub-RPE fibrovascular proliferation/disciform scar [subretinal fibrosis]), at baseline visit, as well as before and after switching from a PRN to a TE treatment regimen.

3. There were no data referring to the proportion of eyes considered "dry" on optical coherence tomography as per criterion of central retinal thickness (CRT) < 320 microns (2), before and after switching to a TE algorithm.

4. The comparative analysis of the visual and morphologic outcomes of the two treatment regimens was fairly inconclusive. Thus, there was a mean visual acuity (VA) gain of approximately 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in comparison with the baseline VA at the end of the PRN phase; this value increased subsequently by an average of approximately 5 letters until the month 12 of the TE phase. The CRT decreased by a mean of 86 microns in relation to the baseline value, up to the end of the PRN phase; this CRT reduction increased thereafter by a mean of 35 microns until the month 12 of the TE phase. Importantly, during the TE period of this study, patients received approximately two more injections over a 12-month period than during 12 months of PRN treatment.

5. Implementation of the 2-sequence, 2-period, 2-treatment algorithm design in which each patient was assigned to a sequence of treatment, did not provide the answer to the question which of the 2 treatment approaches was more efficiently. On the contrary, the disadvantages of such a study could not be avoided. Thus, the washout period, which is essential between periods of such a study in terms of aliased effects, was not precisely delimited and the impact of the significant carryover effects may be confounded with direct treatment effects, in the sense that these effects could not be estimated separately being able to bias the interpretation of data analysis.

Altogether, regardless of the treatment approaches chosen (TE/PRN algorithm), the efficacy of therapy depends primarily on the promptness of the therapy after neovascular age-related degeneration diagnosis (3,4).

References 1. Hatz K, Prunte C. Changing from pro re nata treatment regimen to a treat and extend regimen with ranibizumab in neovascular age-related degeneration. Br J Ophthalmol 2016; http:/dx. doi.org/10.1136/bjophthalmol -2015-307299. 2. Grover S, Murthy RK, Brar VS, and Chalam KV. Normative data for macular thickness by high-definition spectral-domain optical coherence tomography (spectralis). Arch Ophthalmol 2009;148-271. 3. Calugaru D, Calugaru M. Treat-and-extend intravitreal bevacizumab for branch retinal vein occlusion. Ophthalmic Surg Lasers Imaging Retina 2015;46:994. 4. Calugaru D, Calugaru M. Comment on:"Central retinal vein occlusion:modyfing current treatment protocols." Eye 2016; http:/dx.doi.org/10.1038/eye.2016.83.

Conflict of interest: None declared

Conflict of Interest:

None declared

Outcomes of intravitreal anti-VEGF therapy in eyes with both neovascular age-related macular degeneration and diabetic retinopathy Dan Calugaru, Mihai Calugaru Department of Ophthalmology, Univ of Medicine Cluj-Napoca/Romania

Re: Outcomes of intravitreal anti-VEGF therapy in eyes with both neovascular age-related macular degeneration and diabetic retinopathy. Bandello et al. Br J Ophthalmol 2016; http:+/dx. doi.org/10.1136/bjophthalmol-2015-308400.

Dear Editor We would like to address several challenges arisen from the interesting study by Bandello et al [1] and which can be summarized specifically as follows:

1. The article was retrospectively conducted with the existence of a selection bias due to previous treatments applied for diabetic retinopathy (DR) in 12% of the patients (eg., paretinal photocoagulation [PRP] in 5% and grid laser in 7% of the patients). Moreover, there were other treatments than those with the antivascular endothelial growth factor (VEGF) agents which were administered during follow-up (eg., dexamethasone implant in 12%, PRP in 2%, photodynamic therapy in 15%, and stereotactic radio in 2% of the eyes).

2. We analyzed the results of this study taking into account the current assertion whereby the assessment should be guided by anatomical measure data with visual changes as a secondary guide [2]. Thus, best corrected visual acuity improved significantly at 1 year but returned to baseline values at the end of the follow-up, while mean central macular thickness (CMT) significantly decreased from 408 to 335 microns at last follow-up visit. Of note, this CMT value is more than the cutoff (315.2 microns) for the upper level of normal foveal thickness (270+/- 22.5) [3] plus 2 standard deviations and highlights unresolved macular edema indicating that the disease process is still active and progressive requiring further treatment.

3. The final anatomic results in eyes with both neovascular age- related macular degeneration (AMD) and DR were poor. They revealed 39% of the eyes with active choroidal neovascularization, 22% with predominantly atrophic scar, and 39% of the eyes with predominantly fibrotic scar. Additionally, one eye graded as severe non-proliferative DR progressed to proliferative DR and finally was inactivated due to PRP.

4. The results of this series can be explained by the low frequency of injections (a mean of 9.2) as well as the long duration of diabetes (a mean of 22 years). Most likely there was a chronic retinal capillaropathy due to permanent breakdown of the inner and outer blood-retinal barriers following ischemic changes to the macular ganglion cell complex, close to the foveola.

Altogether, the specific anti-VEGF agents represent the front-line therapy for AMD and DR. Because o lot of cytokines, chemokines, and growth factors may be associated with DR pathophysiology [4,5], the addition of a non-specific anti-VEGF substance, eg., a corticosteroid implant, which inhibits the up-regulation of the VEGF and suppresses the expression of the whole panoply of the proinflammatory and proangiogenic factors, is mandatory.

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. 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. 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. 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 Ophthalmol

2011;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;http:/dx.doi.org/10.1097/IAE

0000000000001038.

Conflict of interest: None declared

Conflict of Interest:

None declared

eLetter Comment on: The impact of donor age and endothelial cell density on graft survival following penetrating keratoplasty Parul Chawla Gupta, MS; Jagat Ram, MS, FAMS Department of Ophthalmology Post Graduate Institute of Medical Education and Research, Chandigarh, India, 160012 Corresponding author Dr. Jagat Ram, MS, FAMS Professor and Head Department of Ophthalmology Post Graduate Institute of Medical Education and Research, Chandigarh, India, 160012 Email id: drjagatram@gmail.com Conflict of interest and source of funding- None declared

Dear Editor, We read with interest the recent paper by Wakefield and associates [1] analysing if donor age and preoperative endothelial cell density (ECD) affects corneal endothelial failure following penetrating keratoplasty (PK). While the study is indeed interesting, we herein address important issues, some of which warrant further discussion. First, the authors have determined the overall 5-year graft survival rate due to endothelial failure in all recipients. No mention has been made of the endothelial cell density/loss at 5 years after surgery in all age groups. Was there any significant difference in the endothelial cell density in all groups? Second, diabetic status has been few of the factors affecting corneal endothelial cell counts. In patients with diabetes (after adjusting age), the cell count is lesser by 66 cells (95% CI, 6.3-125.9) compared with controls [2]. Did the authors take into consideration the presence or absence of diabetes mellitus in all groups since higher prevalence of diabetes in the younger age group donors could have decreased the graft survival ultimately making it comparable with the graft survival of corneas from elderly donors. Third, cigarette smoking reduces endothelial cell counts [3]. Smoking history should also have been considered while comparing the graft survival rates in all the groups. Moreover, advanced nuclear cataract and chronic pulmonary disease are significant risk factors for reduced endothelial density. Although the mechanisms are unknown, patients with these risk factors may have a poor endothelial reserve [4]. The authors should therefore rule out all the aforementioned factors before analyzing the results. References 1. Wakefield MJ, Armitage WJ, Jones MNA, et al. Br J Ophthalmol 2016;100:986-989. 2. Sudhir RR, Raman R, Sharma T. Changes in the Corneal Endothelial Cell Density and Morphology in Patients With Type 2 Diabetes Mellitus: a Population Based Study, Sankara Nethralaya Diabetic Retinopathy And Molecular Genetics Study (SN-DREAMS, Report 23). Cornea 2012; 0:1-4. 3. Ilhan N, Ilhan O, Coskun M, et al. Effects of Smoking on Central Corneal Thickness and the Corneal Endothelial Cell Layer in Otherwise Healthy Subjects. Eye Contact Lens. 2015; 10.1097/ICL.0000000000000212 4. Ishikawa A. Risk factors for reduced corneal endothelial cell density before cataract surgery. J Cataract Refract Surg. 2002;28(11):1982-92.

Conflict of Interest:

None declared

Dear Editor,

I read with interest the article by Kuroda et al.[1] The authors explored new possibilities of anterior segment imaging using a posterior segment swept-source optical coherence tomography device without noteworthy modifications. Interestingly, it was possible to obtain high- resolution images of the conjunctiva, episclera, and the sclera near the limbus that seemingly allow unequivocal identification of anatomical boundaries. The authors used this technique to examine eyes with anterior scleritis/episcleritis.

However, I was not so impressed when I read through the methods section of the paper. Contralateral eyes of patients were included as controls. This is certainly problematic, considering that some of the subjects had systemic inflammatory disease. In patients with overt bilateral disease, both eyes were included in the analysis. As a result, the measurements are not independent,[2] and the use of basic statistical tests such as the Mann-Whitney or Kruskal-Wallis tests is not legitimate. All these tests require independence of observations. Advanced statistical methods[3] such as generalized estimating equations[4] or paired comparison[5] would be necessary to obtain statistically valid results.

Another significant weakness of the methodology is that the thickness of tissues was not measured perpendicularly to the ocular surface. This makes data prone to bias and increases the variability. Moreover, the internal limits of the sclera in Figures 2B and 4B are not very distinct, and one wonders how accurate the measurements of this boundary are in other eyes in the study, if these photos are representative.

To sum up, the images displayed are promising, yet, the scientific rigour of the paper is much less compelling.

References

1. Kuroda Y, Uji A, Morooka S, et al. Morphological features in anterior scleral inflammation using swept-source optical coherence tomography with multiple B-scan averaging. Br J Ophthalmol Published Online First: 7 July 2016. doi: 10.1136/bjophthalmol-2016-308561

2. Ray WA, O'Day DM. Statistical analysis of multi-eye data in ophthalmic research. Invest Ophthalmol Vis Sci 1985; 26:1186-8.

3. Fan Q, Teo YY, Saw SM. Application of advanced statistics in ophthalmology. Invest Ophthalmol Vis Sci 2011; 52:6059-65.

4. Hanley JA, Negassa A, Edwardes MD, et al. Statistical analysis of correlated data using generalized estimating equations: an orientation. Am J Epidemiol 2003; 157:364-75.

5. Murdoch IE, Morris SS, Cousens SN. People and eyes: statistical approaches in ophthalmology. Br J Ophthalmol 1998; 82:971-3.

Conflict of Interest:

None declared