Displaying 1-10 letters out of 519 published
Comment on: Changes observed in diabetic retinopathy: eight-year follow-up of a Spanish population
I read with great interest the article by Romero- Aroca et al. titled "Changes observed in diabetic retinopathy: eight-year follow-up of a Spanish population" . Insulin usage has found to be a risk factor for progression of DRP. Authors conclude this result as relaxation of patients in metabolic control. Beside this conclusion, insulin analogues may directly cause progression of DRP. Insulin and its analogues stimulate insulin like growth hormone-1 (IGF-1) receptors, like growth hormone. There is a strong relationship between growth hormone and progression of DRP. Diabetic retinopathy regresses after surgical ablation or spontaneous infarction of pituitary gland . Growth hormone deficiency is a protective factor for development of diabetic retinopathy in dwarfs . Development of diabetic retinopathy is significantly higher in pubertal subjects than pre -pubertal subjects, despite the same glycemic control . Thus, insulin analogues may cause progression of DRP through growth hormone-like effect. But I hypothesize that insulin analogues may cause progression of DRP only after deterioration of inner blood retinal barrier . Hyperglycemia is a major risk factor for development of DRP. High blood glucose levels cause inner blood-retinal barrier deterioration by polyol pathway, non-enzymatic protein glycation and oxidative stress. Insulin analogues decrease blood glucose level and protect pericytes and inner blood-retinal barrier. When inner blood-retinal barrier is intact, insulin analogues may pass into the retinal tissue in very small amounts. After impairment of inner blood retinal barrier, insulin analogues may pass into the retinal tissue in much more amounts. Thus, insulin analogues may pass retinal tissue after impairment of inner blood retinal barrier and cause progression of DRP by growth hormone like effect. But before impairment, analogues can not pass through inner blood retinal barrier to cause progression of DRP, even delay onset of DRP by decreasing high blood glucose that impair pericytes.
References 1. Romero-Aroca P, de la Riva-Fernandez S, Valls-Mateu A, Sagarra-Alamo R, Moreno-Ribas A, Soler N. Changes observed in diabetic retinopathy: eight- year follow-up of a Spanish population. Br J Ophthalmol. 2016 Jan 14. 2. Adams, D.A., Rand, R.W., Roth, N.H., Dashe, A.M., Gipstein, R.M., Heuser, G. Hypophysectomy in diabetic retinopathy. The relationship between the degree of pituitary ablation and ocular response. Diabetes. 1974;23:698???707. 3. Merimee, T.J. A follow-up study of vascular disease in growth-hormone-deficient dwarfs with diabetes. N Engl J Med. 1978;298:1217???1222. 4. Murphy, R.P., Nanda, M., Plotnick, L., Enger, C., Vitale, S., Patz, A. The relationship of puberty to diabetic retinopathy. Arch Ophthalmol. 1990;108:215???218. 5. Kaya A, Kar T, Aksoy Y, Ozalper V, Basbug B. Insulin analogues may accelerate progression of diabetic retinopathy after impairment of inner blood-retinal barrier. Med Hypotheses. 2013 Dec;81(6):1012-4. 4.
Conflict of Interest:
Comment on: Short-term choroidal thickness changes in patients treated with either ranibizumab or aflibercept: a comparative study
We have read and reviewed the article entitled as "Short-term choroidal thickness changes in patients treated with either ranibizumab or aflibercept: a comparative study'' by Kim et al. with interest.1 The authors analyzed 240 eyes of 240 treatment-naive neovascular AMD patients who treated with three-monthly injections of either ranibizumab (ranibizumab group) or aflibercept (aflibercept group). They analyzed the choroidal thickness (CT) alterations between the time of diagnosis and 3 months later, and compared them between two groups. They demonstrated a greater decrease in CT in eyes treated with aflibercept compared to the eyes treated with ranibizumab. We would like to ask for further details, and contribute to the article.
As mentioned in the discussion section of the paper, a number of factors including diurnal variation, refractive error, axial length (AL), diabetes mellitus, hypertension, and consumption of water or coffee might affect CT. However, we wonder intraocular pressure (IOP), use of local or systemic drugs, smoking, sleep and exercise status, consumption of alcohol before optical coherence tomography (OCT), and whether body mass index, and systemic blood pressure of the patients were taken into consideration. We also wonder lightening of the test room since all of the aforementioned factors have been shown to affect CT significantly.2 3
For instance, Sanchez-Cano et al. demonstrated a strong negative correlation between subfoveal CT and AL in healthy adults.4 In addition Saeedi et al. showed a negative correlation between mean CT and IOP.5 On the other hand, intravitreal ranibizumab and aflibercept may cause a significant increase in IOP6-8, and a significant alteration in CT. Therefore, IOP must be analyzed on control examinations just before OCT measurements. Additionally CT shows a significant diurnal variation. The choroid could increase its thickness by 50% in an hour, and quadruple its thickness in a few days.4 Kee et al. found that the choroid could thin very rapidly, by about 100 micron, in 3-4 h in young chicks.9 Usui et al. showed that CT might show a diurnal variation up to 65 micron in healthy individuals.10
It is highly likely that all those parameters could affect the data obtained from the study, and the results of the statistical tests. Therefore, one should act with suspicion towards the results of this study.
1 Kim JH, Lee TG, Chang YS, et al. Short-term choroidal thickness changes in patients treated with either ranibizumab or aflibercept: a comparative study. Br J Ophthalmol 2016. doi: 10.1136/bjophthalmol-2015- 308074. [Epub ahead of print].
2 Akay F, Gundogan FC, Yolcu U, et al. Choroidal thickness in systemic arterial hypertension. Eur J Ophthalmol 2016;26:152-7.
3 Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010; 29:144-68.
4 Sanchez-Cano A, Orduna E, Segura F, et al. Choroidal thickness and volume in healthy young white adults and the relationships between them and axial length, ammetropy and sex. Am J Ophthalmol 2014;158:574-83.e1.
5 Saeedi O, Pillar A, Jefferys J, et al. Change in choroidal thickness and axial length with change in intraocular pressure after trabeculectomy. Br J Ophthalmol 2014;98:976-9.
6 Dedania VS, SJ Bakri. Sustained elevation of intraocular pressure after intravitreal anti-vegf agents: What is the evidence? Retina 2015;35:841-58.
7 Freund KB, Hoang QV, Saroj N. Intraocular pressure in patients with neovascular age-related macular degeneration receiving intravitreal aflibercept or ranibizumab. Ophthalmology 2015;122:1802-10.
8 Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal anti-vascular endothelial growth factor therapy. Retina 2013;33:179-87.
9 Kee CS, Marzani D, Wallman J. Differences in time course and visual requirements of ocular responses to lenses and diffusers. Invest Ophthalmol Vis Sci 2001;42:575-83.
10 Usui S, Ikuno Y, Akiba M, et al. Circadian changes in subfoveal choroidal thickness and the relationship with circulatory factors in healthy subjects. Invest Ophthalmol Vis Sci 2012;53:2300-7.
Conflict of Interest:
Comparison of trabeculectomy versus Ex-PRESS: 3-year follow-up.Gonzalez-Rodriguez et al.doi:10.1136/bjophthalmol-2015-307161.
We read with great interest the study titled as "Comparison of trabeculectomy versus Ex-PRESS: 3-year follow-up" by Gonzalez-Rodriguez et al .We congratulate their efforts for conducting the study with a follow up of 3 years, making the results more significant.They concluded that success rates, mean IOP, number of anti-glaucoma medications and final visual acuities were similar between the two groups after 3 years. The positive points in favour of Ex-PRESS implant, are its standardized pore size leading to more predictable filtration and consequently avoidance of hypotony & other complications and a shorter learning curve.
Interestingly many studies have also claimed that Ex-PRESS has a faster visual recovery. In fact, the authors showed from their first year data that by one month the Ex-PRESS group reached the baseline acuity whereas in the trabeculectomy group, acuity remained significantly lower from baseline at each study visit from day 1 to 6 months. However, when excluding patients who needed a repeat glaucoma procedure, the acuity was found to be better in Ex-PRESS group compared to Trabeculectomy group at all time points. In our opinion, this data would have been more promising had the authors mentioned the test-retest variability as well as the confidence intervals of the visual acuity measurements in either group. The e?ects of the Ex-PRESS device on cornea were previously evaluated by the authors in their 1 year results . We are keen to know their findings with regards to corneal health at last follow-up.
The results of this study are consistent with other published reports, proving that, there is actually no difference in success rates between Ex-PRESS and trabeculectomy [3,4]. Though Ex-PRESS implant is considered to be another good option in our surgical armamentarium, the significant cost difference needs to be considered in conjunction with e?cacy and safety, if Ex-PRESS is to supersede trabeculectomy .
1. Gonzalez-Rodriguez JM, et al. Br J Ophthalmol 2015
2. Wagschal et al. Prospective Randomized Study Comparing Ex-PRESS to Trabeculectomy: 1-Year Results. J Glaucoma 2015;24:624-629.
3. Netland PAet al. Randomized, prospective, comparative trial of EX- PRESS glaucoma filtration device versus trabeculectomy (XVT study). Am J Ophthalmol 2014;157:433-40.e3.
4. Dahan E, Ben Simon GJ, Lafuma A. Comparison of trabeculectomy and Ex-PRESS implantation in fellow eyes of the same patient: a prospective, randomised study. Eye (Lond) 2012;26:703-10.
5. Buys YM. Trabeculectomy with ExPRESS: weighing the benefits and cost. CurrOpin Ophthalmol 2013;24:111-18.
Conflict of Interest:
Characteristics and quantification of vascular changes in macular telangiectasia type 2 on optical coherence tomography angiography
With great interest,We have read the article by Chidambara1 and partners on characteristics and quantification of vascular changes in macular telangiectasia type 2( MacTel 2) on optical coherence tomography angiography(OCTA).The authors concluded that OCTA helps understand the pathology and disease progression better in MacTel 2.We commend their interesting and important work on this subject.However, we have a question for the authors concerning intra- and inter-observer variation and the reproducibility of the OCTA examination.
As far as I know, reproducibility and repeatability are indicators of the applicability of any instrument as a diagnostic tool in clinical practice2.OCTA is extremely sensitive to motion, some images had significant artifacts even with the motion correction algorithm. Operator learning curve, media opacity, and patient cooperation were factors in poor-quality images3.If the subjects had repeated instances of unstable fixation,the image would appear with white ambiguous lines.The analysis software would mistake these white ambiguous lines for blood vessels and would overestimate the retinal vessel density.Therefore,intra- and inter- observer variation would be relatively large. I think the authors should perform a reproducibility analysis to prove the stability of the OCTA system examination.If such an analysis had been performed and intra- and inter- observer variation exceeded a certain percent,the results of this study might have been shown to be unreliable.
REFERENCES 1. Chidambara L, Gadde SGK, Yadav NK, et al. Characteristics and quantification of vascular changes in macular telangiectasia type 2 on optical coherence tomography angiography. Br J Ophthalmol 2016:2015- 307941. 2. Carpineto P, Mastropasqua R, Marchini G, et al. Reproducibility and repeatability of foveal avascular zone measurements in healthy subjects by optical coherence tomography angiography. Br J Ophthalmol 2015. 3. Hwang TS, Gao SS, Liu L, et al. Automated Quantification of Capillary Nonperfusion Using Optical Coherence Tomography Angiography in Diabetic Retinopathy. JAMA OPHTHALMOL 2016:1-7.
Conflict of Interest:
Cigarette smoke extract-mediated oxidative stress and fibrotic-related genes expression may contribute to poor response to steroids therapy in Graves' ophthalmopathy
We read with great interest the article entitled "Smoking was associated with poor response to intravenous steroids therapy in Graves' ophthalmopathy" by Xing et al . Cigarette smoking is known to be the most important risk factor for the development or deterioration of GO, and it is associated with poor response to treatment for GO. However, the exact mechanisms which prove deleterious effect of cigarette smoking on GO remain poorly understood.
It has been suggested that smoke-induced generation of reactive oxygen species (ROS) may play a role in the pathogenesis of GO, either through direct contact with the paranasal sinuses, or indirectly through the bloodstream . Previously, we had revealed that smokers had significant higher urinary 8-OHdG (product of oxidative DNA damage) than never smokers in GO patients . Recently , we observed that cigarette smoke extract (CSE)-induced more cytotoxicity and ROS accumulation in a dose-dependent manner in the GO orbital fibroblasts as compared to those of normal controls. The increased generation of ROS, especially the superoxide anions and hydrogen peroxide, can stimulate orbital fibroblasts proliferation and induce the production of pro-inflammatory cytokines, being key pathological features of GO . More importantly, we also noted that cigarette smoke-mediated oxidative stress could induce fibrotic-related genes expression, including apolipoprotein J, fibronectin, and connective tissue growth factor (CTGF) in the GO orbital fibroblasts (169%, 180%, and 170%, respectively) , and these inductions could be inhibited by pretreatment with antioxidants.
Apolipoprotein J, fibronectin, and CTGF are all important fibrogenic factors. Especially, CTGF is critical for TGF-beta-mediated fibroblast-myofibroblast transdifferentiation and subsequent extracellular matrix deposition , which may contribute to the tissue remodeling and fibrosis process in GO. Besides, CSE has been reported to stimulate adipocyte differentiation in GO orbital fibroblasts either by synergizing with ROS or interleukin -1 [2,6]. Collectively, previous reports and our current findings may explain, in part, why smoking is associated with poor response to immunosuppressive therapy in GO.
1. Xing L, Ye L, Zhu W, Shen L, Huang F, Jiao Q, Zhou X, Wang S, Wang W, Ning G. Smoking was associated with poor response to intravenous steroids therapy in Graves' ophthalmopathy. Br J Ophthalmol. 2015;99:1686- 91.
2. Yoon JS, Lee HJ, Chae MK, Lee SY, Lee EJ. Cigarette smoke extract- induced adipogenesis in Graves' orbital fibroblasts is inhibited by quercetin via reduction in oxidative stress. J Endocrinol. 2013;216:145- 56.
3. Tsai CC, Cheng CY, Liu CY, Kao SC, Kau HC, Hsu WM, Wei YH. Oxidative stress in patients with Graves' Ophthalmopathy: Relationship between oxidative DNA damage and clinical evolution. Eye (Lond). 2009;23:1725-30.
4. Tsai CC, Cheng CY, Liu CY, Kao SC, Kau HC, Hsu WM, Wei YH. Oxidative stress in patients with Graves' Ophthalmopathy: Relationship between oxidative DNA damage and clinical evolution. Eye (Lond). 2009;23:1725-30.
5. Folger PA, Zekaria D, Grotendorst G, Masur SK. Transforming growth factor-beta-stimulated connective tissue growth factor expression during corneal myofibroblast differentiation. Invest Ophthalmol Vis Sci. 2001;42; 2534-41.
6. Cawood TJ, Moriarty P, O'Farrelly C, O'Shea D. Smoking and thyroid -associated ophthalmopathy: a novel explanation of the biological link. Journal of Clinical Endocrinology and Metabolism. 2007;92:59-64.
Conflict of Interest:
Increased expression of connective tissue growth factor play a role in the pathogenesis of thyroid eye disease
We read with great interest the article entitled "Pathogenesis of thyroid eye disease: review and update on molecular mechanisms" by Khong et al . We would like to contribute to the article with our novel findings.
In our previous study, we first demonstrated the up-regulation of mRNA and protein expression of fibrosis-related genes including fibronectin, apolipoprotein J and connective tissue growth factor (CTGF), in the orbital fibroblasts from patients with TED, as compared with those of normal controls . In addition, the expression of CTGF in orbital fibroblasts can be modulated by oxidative stress. Recently, we further revealed that the enhanced expression of CTGF in TED orbital fibroblasts correlated with the clinical activity score and ophthalmopathy index, suggesting that increased levels of CTGF are pathologically significant [unpublished data].
CTGF, a cysteine-rich matricellular protein of the CCN family, has been implicated in mediating various cellular processes, including adhesion, proliferation, differentiation, and migration, and extracellular matrix production, all of which are common features of tissue remodelling and fibrosis. Evidence has been increased suggesting that over-expression of CTGF has been noted in numerous fibrotic disorders, including pulmonary, renal, hepatic, skin, cardiac, and ocular fibrosis.
Inflammation often dominates the early course of TED, followed by remodeling of orbital connective tissue, including accumulation of extracellular matrix and fibrosis. Fibrosis process represents a relative quiescent stage in the disease course of TED; however, it may cause much of the substantial morbidity of the patients including severe lid retraction, restrictive strabismus, proptosis, exposure keratopathy, and compressive optic neuropathy. Current knowledge about the inflammatory process of TED has been rapidly expanding, however, only limited studies have addressed the fibrosis process of this disease. Elucidation of the molecular mechanisms that initiate and regulate the process of fibrosis, especially the role of CTGF in TED, is crucial for the development of novel treatments.
1. Khong JJ, McNab AA, Ebeling PR, Craig JE, Selva D. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol 2016;100:142-50.
2. Tsai CC, Wu SB, Chang PC, Wei YH. Alteration of Connective Tissue Growth Factor (CTGF) Expression in Orbital Fibroblasts from Patients with Graves' Ophthalmopathy. PLoS One 2015;10:e0143514.
Conflict of Interest:
Optic disc edema in astronauts following long-duration space flight
Optic disc edema in astronauts following long-duration space flight
We commend Morgan and colleagues for their discussion of optic disc changes during and after long-duration space flight (LDSF). 1 They note that astronauts after LDSF have developed clinical features (disc edema, globe flattening) similar to those of idiopathic intracranial hypertension (IIH) that may persist for many months post flight and suggest that these changes result from increased intracranial pressure (ICP) "which persists for months and years after their return to Earth."1
Cephalad microgravity fluid shifts may increase head and neck venous pressure, thus inhibiting cerebrospinal fluid (CSF) drainage into the venous system, increasing CSF pressure and leading to changes similar to those seen in patients with IIH. However, lumbar puncture opening pressure (LPOP) has been only moderately elevated (21 to 28.5 cm H20) in the 4 astronauts examined from 12 to 60 days post-mission.2 Although LPOP may have been higher during the mission, we doubt these post-flight pressures are sufficiently high to sustain disc edema for months post-mission.
As Morgan et al. note, microgravity exposure may disrupt flow within the orbital optic nerve subarachnoid space (ONSAS), causing accumulation of toxic metabolites and creating a ball-valve like effect that allows CSF to enter the ONSAS but inhibits outflow, thus increasing pressure within that compartment.3 In theory, either one or both ON sheaths may be affected in a given astronaut, with or without increased ICP. Of seven astronauts with disc edema, four have displayed disc asymmetry. One of these had unilateral disc edema associated with an LPOP of 18 cmH20 1 week after space flight.4 We also have observed persistent asymmetric disc edema 6 months following LDSF in an astronaut with LPOP's of 22 and 16 cm H20 performed 7 days and 1 year post mission respectively, again suggesting ON sheath compartmentalization (manuscript in preparation). We thus believe that increased ICP may not be the sole, or even primary, cause of persistent optic disc changes post LDSF.
Thomas H. Mader MD C. Robert Gibson OD Andrew G. Lee MD Prem S. Subramanian, MD, PhD Neil R. Miller MD
1. Morgan WH, Balaratnasingam C, Lind CRP, Colley S, Kang MH, House PH, Yu D. Cerebrospinal fluid pressure and the eye. Br J Ophthalmol 2015; 0:1-7.
2. Mader TH, Gibson CR, Pass AF, et al. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. Ophthalmology 2011;118:2058-69.
3. Killer HE, Subramanian PS. Compartmentalized cerebrospinal fluid. Internat Ophthalmol Clin 2014;54(1):95-102.
4. Mader TH, Gibson CR, Pass AF, et al. Optic disc edema in an astronaut after repeat long-duration space flight. J Neuroophthalmol 2013;33:249-55.
Conflict of Interest:
RE: Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Kapetanakis, et al. 100:1 86-93 doi:10.1136/bjophthalmol-2015-307223
We thank Cheng and Tham for their interest in our systematic review of global variations and time trends in primary open angle glaucoma (POAG). The comments raise some important issues relating to the assimilation of evidence from observational studies, particularly in summarising estimates of chronic disease prevalence.
Cheng and Tham have questioned our inclusive approach, which resulted in us having a greater number of studies, number of POAG cases and population denominator, and led to more precise estimates of POAG prevalence compared to their earlier review. The purpose of our more complex approach was to explicitly model and quantify the heterogeneity between population surveys, which used different survey methods and case definitions of POAG. By quantifying these differences we are able to provide estimates of POAG prevalence standardised to studies which use optimal methods, i.e., that did not rely on intraocular pressure and routinely performed visual field assessments on all participants, while allowing studies with suboptimal methods to contribute to overall estimates by accounting for the differences in study methods. This is particularly important when attempting to appreciate time trends in POAG, given changes in study methods over time. Moreover it allows greater global representation of studies, allowing more recent studies, particularly from less developed countries often with suboptimal methods, to contribute. This would not have been the case if a more exclusive approach had been adopted.
Cheng and Tham also raise the issue of examining response rates. However, we examined differences in response rates in our earlier review, and found that these had little effect on our prevalence estimates. We acknowledge in the paper the difficulty of extracting response rates, as these are not routinely reported, and sometimes confused with participation rates, i.e., the number who took part and completed an examination out of those who agreed to take part. In general, our experience is that assessment of study quality of observational studies is complex, compared to established methods in experimental studies. Attempts were made to judge the quality of studies on criteria such as response rates and methods used. However, it is difficult to extract measures of study quality in a meaningful way; for example well- designed studies may have low response rates. Our experience suggests that subjective assessments of study quality can sometimes be arbitrary and may not capture characteristics which may influence the outcome of interest. Hence, we have chosen an approach which seeks to understand variability by explicitly modelling differences in study methods. We believe that this makes for a fuller assessment, providing evidence based guidance for the conduct of future studies. For instance, our work suggests that a recent shift away from routine visual field testing, perhaps as an inadvertent consequence of recent ISGEO guidelines, may have artefactually influenced prevalence estimates; such an effect would not have been identified and quantified by a more exclusive approach.
Cheng and Tham also question whether our more inclusive strategy may have led to lower global estimates of POAG prevalence; 2.2% (95% CrI 1.8% to 2.8%) in our study  versus 3.1% (1.7% to 5.3%) in their earlier review. However, we would like to point out that these estimates are not dissimilar, with our more precise estimate being encapsulated within the much wider confidence interval of their earlier estimate. That our estimate is marginally lower may in part be attributable to our different ethnic/regional categorization of studies, particularly amongst Asians. The earlier review simply treated Asians as one population. However, we found evidence suggesting that the age specific prevalence differed across Asian populations, which needs to be accounted for when deriving global estimates, especially given the large population size of Asia. Moreover, our review includes more recent studies from Asian populations, where POAG numbers are high given the large population, but age-specific prevalence is actually lower compared to other ethnic groups. We feel that our modelling approach is justified and provides an important corrective to earlier work. For example, the earlier review suggested urban-rural differences in disease prevalence, where we showed no effect as urban- rural associations were inextricably linked to ethnicity and the ethnic specific associations with age.
We hope that these estimates provide greater certainty and transparency so we understand how the global and regional estimates of POAG prevalence are derived. Greater precision allows for more accurate and appropriate planning of health care service needed to care for those with the condition. We also believe that our work will assist with the design of future population based studies, which seek to describe the population prevalence of glaucoma.
Authors: Dr Alicja R Rudnicka,* Dr Venediktos V Kapetanakis,* Miss Michelle P Y Chan,# Professor Paul J Foster,#** Professor Derek G Cook,* Professor Christopher G Owen
*Population Health Research Institute, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK
#Division of Genetics and Epidemiology, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
**NIHR Biomedical Research Centre Moorfields Eye Hospital NHS Foundation Trust, 162 City Road, London EC1V 2PD, UK.
1. Kapetanakis VV, Chan MP, Foster PJ, Cook DG, Owen CG, Rudnicka AR. Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Br J Ophthalmol 2015.
2. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 2014; 121(11):2081- 2090.
3. Rudnicka AR, Mt-Isa S, Owen CG, Cook DG, Ashby D. Variations in primary open-angle glaucoma prevalence by age, gender, and race: a Bayesian meta-analysis. Invest Ophthalmol Vis Sci 2006; 47(10):4254-4261.
4. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002; 86(2):238-242.
Conflict of Interest:
Re: Global variations and time trends in the prevalence of primary open-angle glaucoma: a systemic review and meta-analysis
We read with interest the article by Kapetanakis et al. The authors presented a systemic review of published population-based surveys to provide estimates of global and regional prevalence of primary open- angle glaucoma (POAG). The authors claimed that this review provided the most precise estimates of POAG prevalence thus far, as they adopted a more "inclusive" approach, compared to previous review. As a result of this inclusive approach, more publications were included in this review with greater total number of cases and participants, and thus the authors believed that these estimates provided greater certainty compared to previous reviews.[2 3]
Nevertheless, while an 'inclusive' approach adopted in this review generated a 'seemingly' more precise estimate (slightly narrower credible intervals), it may not necessarily provide estimates which 'accurately' reflect the trends of POAG prevalence. This is mainly because, the review also included older studies with improper definition/ diagnosis of POAG which used raised IOP (i.e. greater than 21mmHg) as a key diagnostic criterion for POAG. It has been widely recognized that using IOP as a diagnostic criterion is not appropriate and may miss POAG cases with lower levels of IOP. This point has also been reiterated and acknowledged by the authors themselves in the manuscript. Furthermore, in Table 2, the authors showed that reliance on IOP in POAG diagnosis was associated with lower POAG prevalence. This finding befittingly concurs with the point that studies which used IOP as a diagnostic criterion would indeed underestimate the prevalence of POAG. Thus, inclusion of older studies with improper POAG definition in the meta-analysis would naturally result in an underestimated overall pooled estimate despite having a seemingly narrower range of credible intervals (mainly due to higher number of POAG cases). This is evident when comparing the global POAG prevalence in this review (2.2%) with the prevalence estimated in our group's recent meta- analysis project (3.05%).
The idea to include more studies in order to have 'greater power' but at the expense of compromised study quality inclusion criteria, is fundamentally flawed in the context of conducting a reliable meta- analysis. Estimation errors caused by inclusion of poor quality studies may not be sufficiently accounted for by using modeling method to adjust for study design factor. Thus, the authors' claim that 'more precise and accurate estimates were produced in this review' appears to be unconvincing and overly stated.
Secondly, response rate was not taken into account when identifying studies to be included in this meta-analysis. It was noticed that studies of low response rates (i.e. less than 60% or 70%) were also included in the analysis. It should be noted that population-based studies with suboptimal response rate can give rise to sampling bias even though random sampling method was adopted. Thus, estimates from these studies may not be accurately representative of their respective underlying populations. Inclusion of such studies may further introduce error to the overall pooled estimate. Furthermore, if greater weights were attributed by studies which relied on IOP diagnostic criterion or by studies with poor response rate in this meta-analysis, the impact on the overall pooled estimate would be even greater. With regards to this, a forest plot ought to be included in this meta-analysis to illustrate the effect size and the weight rendered by each study. Such illustration with additional sensitivity analyses (stratified by study design factors or response rate) may help to further validate or refute the approach adopted in this analysis.
Taken together, we humbly opine that a more 'inclusive' approach but without adequate screening of study quality, may not necessarily yield more accurate estimates. The seemingly more precise estimate (i.e. slightly narrower credible intervals) was simply due to increase in sheer number of POAG cases from studies of inadequate quality. Robust and comprehensive assessments of study quality are central to a valid, high quality meta-analysis.
1. Kapetanakis VV, Chan MP, Foster PJ, et al. Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Br J Ophthalmol 2015.
2. Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta- analysis. Ophthalmology 2014;121(11):2081-90.
3. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90(3):262-7.
4. Quigley HA. Glaucoma. Lancet (London, England) 2011;377(9774):1367 -77.
Conflict of Interest:
Real life visual improvements with anti vascular endothelial growth factor treatment for wet age-related macular degeneration - Absolute or relative?
We congratulate Holz et al.1 on their most important contribution to anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration (n-AMD). We think it is important to note that their main finding "visual acuity improved until about day 120; thereafter visual acuity changes were not maintained" does not contradict the findings of the MARINA2 [Ranibizumab Vs sham injection] clinical trial. We have previously re-evaluated3 the published results of the MARINA study to assess the absolute risk reduction (The absolute difference of outcome between experimental - i.e. ranibizumab treated - and control participants in the MARINA trial). This being the approach specified in The ABPI Code of Practice4 Clause 7; Information, Claims and Comparisons "Referring only to relative risk, especially with regard to risk reduction, can make a medicine appear more effective than it actually is. In order to assess the clinical impact of an outcome, the reader also needs to know the absolute risk involved. In that regard relative risk should never be referred to without also referring to the absolute risk. Absolute risk can be referred to in isolation." We set out in the graph below our evaluation of mean letter change from baseline (visual acuity change) derived from MARINA Figure 2 A results page 14262. The published change in letter score is at 3 month intervals rather than for each monthly injection as our efforts to acquire the raw data from the authors of the MARINA study2 have been unsuccessful. The best we can do is to show the letter change for the ranibizumab treated patients (we have confined our analysis to 0.5 mg group) letter score is in green, sham injection is in blue and the difference between the groups is in pink - this being the absolute risk reduction at every time we have data for. Our re-analysis seemingly confirms Holtz's findings1; ranibizumab is apparently most beneficial in the initial stages of treatment of n-AMD and visual gains cease between 3 - 6 months.
Figure 1 - Green line - Ranibizumab treated patients (0.5mg) - change in letters read since last injection. Blue line - Sham-injection treated patients - change in letters read since last injection. Pink line - Absolute risk reduction (The arithmetic difference between the Ranibizumab and sham groups for each 3-monthly time point.)
We note that Holtz and colleagues presented the mean change in visual acuity score after start of anti-VEGF as their primary endpoints. Our graph demonstrates the change in visual acuity score since previous visit and we note the striking resemblance in that both the analysis plots a very similar graph. While the patient demographics include the various subsets of n-AMD, we could not find any mention of visual acuity outcomes for these subset groups of patients. As MARINA showed visual benefits (stabilization or improvement of letters read) due to Ranibizumab treatment was achieved in only 27.6% of patients, we ask the authors if they are able to predict likely responders based on any base-line characteristics that would distinguish them from non-responders. Also would the authors be able to share if available their analysis of change in visual acuity from the previous visit. This could help in the early identification of those patients unlikely to benefit either prior to treatment or as the treatment progresses and avoid exposing patients unlikely to benefit to the risks of treatment.
1. Frank G Holz, Ramin Tadayoni, Stephen Beatty et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration.Br J Ophthalmol doi:10.1136/bjophthalmol-2014-305327
2. Philip J. Rosenfeld, M.D., Ph.D., David M. Brown, M.D., Jeffrey S. Heier, M.D. et al. for the MARINA Study Group. N Engl J Med 2006; 355:1419-1431.
3. B. Ramasamy, S Tiew, J Wason, L Clearkin . Absolute Risk Reduction and Natural Frequencies of Ranibizumab treatment in neovascular Age-Related Macular Degeneration (nvAMD). Poster and rapid fire presentation, Oxford Ophthalmological Congress ( 7/7/2015)
4. ABPI Code of Practice for The Pharmaceutical Industry https://www.bsped.org.uk/resources/docs/ABPIguidelines
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