We read with interest the article written by Creuzot-Garcher and colleagues that was published in the June 2018 issue of your journal. 1 The authors retrospectively reviewed billings codes from a national database in France from January 2004 to December 2014 to examine acute postoperative endophthalmitis (POE) rates. They reported an incidence of acute POE in stand-alone phacoemulsification of 0.102% over this 11-year period. In contrast, combined surgery in which phacoemulsification was performed with another intraocular procedure had an overall higher incidence of 0.149%. The incidence of acute POE in combined phacoemulsification and glaucoma surgery, corneal surgery, and vitreoretinal surgery was found to be 0.089%, 0.142%, and 0.223% respectively.
As Creuzot-Garcher and colleagues mention, many phakic patients who undergo either glaucoma surgery, corneal surgery, or vitreoretinal surgery, are elderly and likely will require cataract extraction at some point.1 In addition, it is well established that these surgeries promote cataract formation in phakic eyes, and therefore patients who do not undergo combination surgery will likely require stand-alone cataract surgery in the future.
Hence, it would be instructive to compare the risk of acute POE in combined surgery with the total risk conferred by separately performing the two surgeries. We made the assumption that the chance of endophthalmitis in each surgery is independent. Using the...
We read with interest the article written by Creuzot-Garcher and colleagues that was published in the June 2018 issue of your journal. 1 The authors retrospectively reviewed billings codes from a national database in France from January 2004 to December 2014 to examine acute postoperative endophthalmitis (POE) rates. They reported an incidence of acute POE in stand-alone phacoemulsification of 0.102% over this 11-year period. In contrast, combined surgery in which phacoemulsification was performed with another intraocular procedure had an overall higher incidence of 0.149%. The incidence of acute POE in combined phacoemulsification and glaucoma surgery, corneal surgery, and vitreoretinal surgery was found to be 0.089%, 0.142%, and 0.223% respectively.
As Creuzot-Garcher and colleagues mention, many phakic patients who undergo either glaucoma surgery, corneal surgery, or vitreoretinal surgery, are elderly and likely will require cataract extraction at some point.1 In addition, it is well established that these surgeries promote cataract formation in phakic eyes, and therefore patients who do not undergo combination surgery will likely require stand-alone cataract surgery in the future.
Hence, it would be instructive to compare the risk of acute POE in combined surgery with the total risk conferred by separately performing the two surgeries. We made the assumption that the chance of endophthalmitis in each surgery is independent. Using the data presented by Creuzot-Garcher, we found the following:
(i) In the scenario where glaucoma surgery is performed and, at a separate date cataract surgery is done, the total risk of developing acute POE would be 0.171%. This is higher than the risk of 0.089% in combined surgery quoted in the article.
(ii) In the scenario where corneal surgery is performed and, at a separate date cataract surgery is done, the total risk of developing acute POE would be 0.236%. This is higher than the risk of 0.142% in combined surgery quoted in the article.
(iii) In the scenario where vitreoretinal surgery is performed and, at a separate date cataract surgery is done, the total risk of developing acute POE would be 0.292%. This is higher than the risk of 0.223% in combined surgery.
Hence, while combined surgery may be associated with a higher incidence of acute POE as compared to a stand-alone procedure, multiple surgeries on the same eye but performed at different sittings may yield an overall higher risk. This information should be taken into consideration when planning surgery in phakic eyes.
R. Rishi Gupta MD, FRCSC1
Mark E. Seamone MD, FRCSC2
Marcelo Nicolela MD, FRCSC1
Jayme Vianna MD1
Daniel O’Brien MD, FRCSC1
1 Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, NS, Canada
2 Department of Ophthalmology, University of Alberta, Edmonton, AB, Canada
References:
1. Creuzot-Garcher CP, Mariet AS, Benzenine E, Daien V, Korobelnik JF, Bron AM, Quantin C. Is combined cataract surgery associated with acute postoperative endophthalmitis? A nationwide study from 2005 to 2014. Br J Ophthalmol. 2018 Jun 20.
In their report, entitled “Intravitreal chemotherapy in retinoblastoma: expanded use beyond intravitreal seeds“, Abramson and corkers report on the successful use of intravitreal chemotherapy in 52 patients for subretinal seeds and recurrent retinal tumours [1]. They state that, prior to their experience, intravitreal chemotherapy had been used exclusively to control persistent or recurrent vitreous seeding in retinoblastoma that had been refractory to systemic intravenous or intra-arterial chemotherapy.
In fact, intravitreal chemotherapy as an adjuvant treatment for both subretinal seeds and recurrent retinal tumours, including its use instead of systemic chemotherapy in the setting of chemothermotherapy for small unresponsive primary retinoblastomas, has been in regular use already for a decade at the Ocular Oncology Service, Helsinki University Eye Hospital. Indeed, three of the first four patients that we reported during the congress of the International Society of Ocular Oncology in 2009 [2], and published in 2011 [3], received intravitreal methotrexate for reasons other than vitreous seeds. Subsequent experience with intravitreal chemotherapy with methotrexate and, later, with melphalan has strengthened our initial findings, as does the comprehensive report of Abramson and coworkers.
1. Abramson DH, Ji X, Francis JH, et al. Intravitreal chemotherapy in retinoblastoma: expanded use beyond intravitreal seeds. Br J Ophthalmol 2018 Jun 6. pii: bjophthalmol-...
In their report, entitled “Intravitreal chemotherapy in retinoblastoma: expanded use beyond intravitreal seeds“, Abramson and corkers report on the successful use of intravitreal chemotherapy in 52 patients for subretinal seeds and recurrent retinal tumours [1]. They state that, prior to their experience, intravitreal chemotherapy had been used exclusively to control persistent or recurrent vitreous seeding in retinoblastoma that had been refractory to systemic intravenous or intra-arterial chemotherapy.
In fact, intravitreal chemotherapy as an adjuvant treatment for both subretinal seeds and recurrent retinal tumours, including its use instead of systemic chemotherapy in the setting of chemothermotherapy for small unresponsive primary retinoblastomas, has been in regular use already for a decade at the Ocular Oncology Service, Helsinki University Eye Hospital. Indeed, three of the first four patients that we reported during the congress of the International Society of Ocular Oncology in 2009 [2], and published in 2011 [3], received intravitreal methotrexate for reasons other than vitreous seeds. Subsequent experience with intravitreal chemotherapy with methotrexate and, later, with melphalan has strengthened our initial findings, as does the comprehensive report of Abramson and coworkers.
1. Abramson DH, Ji X, Francis JH, et al. Intravitreal chemotherapy in retinoblastoma: expanded use beyond intravitreal seeds. Br J Ophthalmol 2018 Jun 6. pii: bjophthalmol-2018-312037. doi: 10.1136/bjophthalmol-2018-312037.
2. Kivelä T, Eskelin S, Lindahl P, Majander A. Intravitreal methotrexate monotherapy as salvage treatment for recurrent retinoblastoma after standard chemoreduction. In: ISOO Metting 2009: Programme and Abstracts, p. 279. http://www.xcdsystem.com//isoo/webimages/pdf%20%236%20isoo%202009%20camb... (accessed on November 1, 2018)
3. Kivelä T, Eskelin S, Paloheimo M. Intravitreal methotrexate for retinoblastoma. Ophthalmology 2011;118(8):1689, 1689.e1-6. doi: 10.1016/j.ophtha.2011.02.005.
We thank the authors of the article “Intravitreal Methotrexate for Retinoblastoma” published in Ophthalmology in 2011 for their letter to the editor and adjustment of our discussion in our paper. As was found in your experience, as well as ours, intravitreal chemotherapy plays an important role in the treatment of retinoblastoma outside of its currently accepted use for intravitreal seeds. We look forward to hearing about your continued successful experience with intravitreal melphalan for use beyond intravitreal seeds.
To the Editor,
Intravitreal antivascular endothelial growth factor (VEGF) agents undeniably have many clinical applications and we read with great interest the recent meta-analysis published in your journal by Low et al1 comparing the effectiveness and harms of these agents in three retinal disorders.
We would first like to thank the authors for their exhaustive review and synthesis of the evidence in this area. The conclusions they reached served to confirm what many of us had already suspected.2 Nevertheless, the article features some important methodological flaws and inadequate reporting of data that we would like to highlight to ensure that readers are in a position to interpret the findings of the meta-analysis correctly.
In relation to reporting issues, we were surprised to see that Table 1, which is quite creative and unique in terms of systematic review tables, does not include a list of the studies analyzed for each section. The authors, for example, state that they included two clinical trials comparing aflibercept and ranibizumab, but they do not specify which ones. This detracts from the transparency of the study and makes it difficult to review the findings. We also noticed a lack of uniformity within the figures, as some of the studies are listed by author name and others by author name and year of publication. In addition, Figure 3 shows data from the 2011 study by Biswas P, Sengupta S, Choudhary R, et al for the 18-24–month but not the 12...
To the Editor,
Intravitreal antivascular endothelial growth factor (VEGF) agents undeniably have many clinical applications and we read with great interest the recent meta-analysis published in your journal by Low et al1 comparing the effectiveness and harms of these agents in three retinal disorders.
We would first like to thank the authors for their exhaustive review and synthesis of the evidence in this area. The conclusions they reached served to confirm what many of us had already suspected.2 Nevertheless, the article features some important methodological flaws and inadequate reporting of data that we would like to highlight to ensure that readers are in a position to interpret the findings of the meta-analysis correctly.
In relation to reporting issues, we were surprised to see that Table 1, which is quite creative and unique in terms of systematic review tables, does not include a list of the studies analyzed for each section. The authors, for example, state that they included two clinical trials comparing aflibercept and ranibizumab, but they do not specify which ones. This detracts from the transparency of the study and makes it difficult to review the findings. We also noticed a lack of uniformity within the figures, as some of the studies are listed by author name and others by author name and year of publication. In addition, Figure 3 shows data from the 2011 study by Biswas P, Sengupta S, Choudhary R, et al for the 18-24–month but not the 12-month period, and there is no explanation for this omission in the text.
We also detected some methodological issues that depart from international recommendations.3,4 On replicating the meta-analysis using the data provided by Low et al1 in the STATA statistical package, we did not find the same results as those reported. In Figure 2, the mean difference (95% CI) given for months in the GEFAL study is 2.36 (-0.72 to 5.44), whereas we obtained a difference of 1.90 (95 CI%: -0.73 to 4.53). This modifies the magnitude of the overall measure (in our case, -0.25; 95% CI: -1.39 to 0.89), but not its direction or interpretation. We observed a similar finding for the 18-24 month period for the CATT study, as Figure 2B shows a difference of -1.00 (95% CI: -3.54 to 1.54), whereas we observed an overall difference of -0.51 (9 5CI% :-1.91 to 0.88).
Another aspect that caught our attention is that some of the meta-analysis subgroup analyses were underpowered (<50%), but this is not mentioned in the results or discussed as an important limitation. The authors also make no mention of publication bias, which is normally evaluated using a funnel plot or Egger’s plot, as per reporting guidelines.3,4 Finally, Low et al1 reported that they analyzed the quality of the individual studies included in their systematic review and show the corresponding results in Table 1. However, they did not report on any sensitivity analyses to identify lower-quality studies that should have possibly been excluded or studies that might have significantly affected results.
The authors clearly attempted to cover many aspects in their systematic review, from the effectiveness and harms to the cost and cost-effectiveness of three VGEF agents in three conditions: neovascular age-related macular degeneration, diabetic macular oedema (DME), and branch retinal vein occlusion. It is not our place to comment on the wisdom or not of analyzing so many aspects, but we would like to point out that just one study was analyzed to assess the evidence on the cost-effectiveness of bevacizumab versus aflibercept versus ranibizumab in DME. Despite the commendable efforts of the authors, they failed to report on some key methodological aspects from the PRISMA (Preferred Reported Items for Systematic Review and Meta-Analyses) checklist3 and the Cochrane Handbook for Systematic Reviews of Interventions.4
REFERENCES
1. Low A, Faridi A, Bhavsar KV, Cockerham GC, Freeman M, Fu R, et al. Comparative effectiveness and harms of intravitreal antivascular endothelial growth factor agents for three retinal conditions: a systematic review and meta-analysis. Br J Ophthalmol. 8 de noviembre de 2018;
2. Cai S, Bressler NM. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T. Curr Opin Ophthalmol. noviembre de 2017;28(6):636-43.
3. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 21 de julio de 2009;339:b2535.
4. Higgins JP, Green, Sally. Cochrane Handbook for Systematic Reviews of Interventions [Internet]. The Cochrane Collaboration. Disponible en: https://handbook-5-1.cochrane.org/
We appreciate Francisco-Javier Carrera-Hueso, Pedro Vazquez-Ferreiro, and Jaime Poquet-Jornet's careful reading of this paper. This commissioned review had a necessarily broad scope in order to summarize benefits and harms across three available therapies for the most common clinical indications. We agree there was quite a bit of information to present and that doing so in a succinct format is a challenge. However, we disagree with their contention that we did not follow current methodologic systematic review standards. We did indeed follow PRISMA reporting guidelines, as described in the Methods.
Regarding Table 1, the studies included in the summary table are the same as those described within the text and meta-analyses; we apologize for any confusion. In terms of format for the listing of studies in the meta-analyses, since studies are known primarily by their acronym, we used them in the figures whenever possible. The trials without specific names or acronyms were listed according to author and year.
Biswas 2011 only reported the percentage of patients gaining ≥15 letters at the 18-month endpoint, not at 12 months, so the study could not be included in the 12-month analysis for this outcome. The study did report mean change in BCVA at both endpoints, so it is included in both the 12 month and 18-24 month analyses in Figure 2. In terms of analyzing cost-effectiveness, only two trials meeting inclusion criteria (CATT and DRCR) di...
We appreciate Francisco-Javier Carrera-Hueso, Pedro Vazquez-Ferreiro, and Jaime Poquet-Jornet's careful reading of this paper. This commissioned review had a necessarily broad scope in order to summarize benefits and harms across three available therapies for the most common clinical indications. We agree there was quite a bit of information to present and that doing so in a succinct format is a challenge. However, we disagree with their contention that we did not follow current methodologic systematic review standards. We did indeed follow PRISMA reporting guidelines, as described in the Methods.
Regarding Table 1, the studies included in the summary table are the same as those described within the text and meta-analyses; we apologize for any confusion. In terms of format for the listing of studies in the meta-analyses, since studies are known primarily by their acronym, we used them in the figures whenever possible. The trials without specific names or acronyms were listed according to author and year.
Biswas 2011 only reported the percentage of patients gaining ≥15 letters at the 18-month endpoint, not at 12 months, so the study could not be included in the 12-month analysis for this outcome. The study did report mean change in BCVA at both endpoints, so it is included in both the 12 month and 18-24 month analyses in Figure 2. In terms of analyzing cost-effectiveness, only two trials meeting inclusion criteria (CATT and DRCR) directly compared cost outcomes between any of the 3 agents; both were included in our review.
Regarding the differing figures for mean difference calculated by the letter authors, we state in the Data Synthesis and Analysis portion of the text that “we used the mean difference (MD) between arms reported in the study whenever available; otherwise, mean between-group differences were calculated based on reported data.” For example, Kodjikian 2013 reported a mean difference of 2.36 (95% CI, -0.72 to 5.44) analysis for the GEFAL study, so that data was used in our analyses.
The use of quantitative estimation of publication bias is controversial and not without its own drawbacks (1). Publication bias is a type of reporting bias in which positive (often smaller) studies are preferentially published over negative studies. We examined the possibility of including unpublished research by searching, as mentioned in the manuscript, trial registries, and regulatory agency sites to identify all relevant registered and in-progress trials. We also requested unpublished data from drug manufacturers, but did not identify any additional trials.
We describe qualitatively the results contributed by each study according to its risk of bias. We found no indication of consistent differences in results according to ROB. Statistical measures also suggested minimal heterogeneity in the meta-analytic estimates presented.
We thank the authors of the letter for their interest in our article, and appreciate the opportunity to respond to their concerns.
Sincerely,
Allison Low
Devan Kansagara
References:
1. Guyatt GH, Oxman AD, Montori V, et al. GRADE guidelines: 5. Rating the quality of evidence—publication bias. J Clin Epidemiol. 2011;64(12):1277-1282.
We thank the authors for their careful perusal of our study report and thoughtful observations. We agree that as demonstrated by the large population study1,2 referenced by us and by them, the rate of complications with cataract surgery is non-homogenous and increases dramatically with advanced stage cataracts – as much as 200%+ increase in rate of PCT in cases with high grade cataract, pseudoexfoliation and other comorbidities. In fact, with the co-existence of multiple factors, the compound rate can be even higher.
Our pilot study was in patients with advanced cataracts and multiple co-existing ocular pathologies and given the small sample size we are not surprised that the study point estimate for the PCT rate may be on the higher end of the overall range demonstrated by the larger population study. In addition, the randomized control design of the clinical trial further validates a PCT rate which was similar for both treatment and control groups. Certainly, an informed reader would appreciate that such a small trial is underpowered to be conclusive regarding the small difference between the two groups so no claims should be made about the slightly better rate of PCT and lower trend demonstrated in the miLOOP group.
What is important to appreciate from both the population study and our pilot data is that the rate of PCT is not the same for all cataract surgeries and there is a multiplier effect in certain subgroups and subpopulations. Our authorship team...
We thank the authors for their careful perusal of our study report and thoughtful observations. We agree that as demonstrated by the large population study1,2 referenced by us and by them, the rate of complications with cataract surgery is non-homogenous and increases dramatically with advanced stage cataracts – as much as 200%+ increase in rate of PCT in cases with high grade cataract, pseudoexfoliation and other comorbidities. In fact, with the co-existence of multiple factors, the compound rate can be even higher.
Our pilot study was in patients with advanced cataracts and multiple co-existing ocular pathologies and given the small sample size we are not surprised that the study point estimate for the PCT rate may be on the higher end of the overall range demonstrated by the larger population study. In addition, the randomized control design of the clinical trial further validates a PCT rate which was similar for both treatment and control groups. Certainly, an informed reader would appreciate that such a small trial is underpowered to be conclusive regarding the small difference between the two groups so no claims should be made about the slightly better rate of PCT and lower trend demonstrated in the miLOOP group.
What is important to appreciate from both the population study and our pilot data is that the rate of PCT is not the same for all cataract surgeries and there is a multiplier effect in certain subgroups and subpopulations. Our authorship team felt that for investigational transparency and authenticity it is important to report all results, including the ones we don’t like and the ones that give us pause in order to stimulate thoughtful discourse such as the one unfolding through the comments in your letter.
Sean Ianchulev, MD MPH
Professor of Ophthalmology
New York Eye and Ear Infirmary of Mount Sinai
References
1. Jaycock P, Johnston RL, Taylor H, et al. The Cataract National Dataset electronic multi-centre audit of 55,567 operations: updating benchmark standards of care in the United Kingdom and internationally. Eye 2009 23(1):38-49.
2. Narendran N, Jaycock P, Johnston RL, et al. The Cataract National Dataset electronic multicenter audit of 55,567 operations: risk stratification for posterior capsule rupture and vitreous loss. Eye 2009 23(1):31-7.
We are interested in the work of Ianchulev et al in their recent interventional randomized controlled trial.[1] What piqued our interest was the rate of posterior capsular tears (PCT). 4/53 (7.5%) patients in the miLOOP+phaco group experienced PCT, and 5/48 (10.4%) phaco-alone controls with PCT. These rates are much higher than standard phacoemulsification reports. The authors refer to a large study that identified advanced cataracts increased risk of PCT at comparable levels.[2] That same group published investigations expounding upon this.[3-4] Advanced cataracts were specifically identified as brunescent/white cataracts, contrasting Grade 3-4 in the miLOOP study (curiously described as LOCSIII classification in the manuscript).
Using the risk calculation,[3] the range of composite adjusted odds ratio (aOR) for the miLOOP study was 49.93 (25-28% risk) to an aOR of 0.87 (<1% surgical risk). The average patient from the miLOOP investigation had an aOR of 4.43, thus <5% PCT risk.
Our concerns: First, the authors state that “There was a trend towards a lower rate of capsular tear during the phaco portion with miLOOP-assisted phaco (7.5%) compared to standard phaco (10.4%).” Given the numbers representing these percentages this is an inappropriate description of this relationship.
Let us assume that a control group presented with a PCT rate similar to that reported in literature: <5%. Here, miLOOP-phaco PCT rate would be higher than the control...
We are interested in the work of Ianchulev et al in their recent interventional randomized controlled trial.[1] What piqued our interest was the rate of posterior capsular tears (PCT). 4/53 (7.5%) patients in the miLOOP+phaco group experienced PCT, and 5/48 (10.4%) phaco-alone controls with PCT. These rates are much higher than standard phacoemulsification reports. The authors refer to a large study that identified advanced cataracts increased risk of PCT at comparable levels.[2] That same group published investigations expounding upon this.[3-4] Advanced cataracts were specifically identified as brunescent/white cataracts, contrasting Grade 3-4 in the miLOOP study (curiously described as LOCSIII classification in the manuscript).
Using the risk calculation,[3] the range of composite adjusted odds ratio (aOR) for the miLOOP study was 49.93 (25-28% risk) to an aOR of 0.87 (<1% surgical risk). The average patient from the miLOOP investigation had an aOR of 4.43, thus <5% PCT risk.
Our concerns: First, the authors state that “There was a trend towards a lower rate of capsular tear during the phaco portion with miLOOP-assisted phaco (7.5%) compared to standard phaco (10.4%).” Given the numbers representing these percentages this is an inappropriate description of this relationship.
Let us assume that a control group presented with a PCT rate similar to that reported in literature: <5%. Here, miLOOP-phaco PCT rate would be higher than the control raising safety concerns. Yet the study showed a similarly high complication rate in the control group, statistically maintaining the miLOOP’s safety.
Finally, this occurs in the setting of considerable financial interest.
Regardless of the opportunities not otherwise afforded to these patients by their generous work, ethical standards and protection against bias is essential to protect patients. The complication rate was unacceptably high, and the trial should have been stopped and the study should not have been published.
References
1. Ianchulev T, Chang DF, Koo E, et al. Microinterventional endocapsular nucleus disassembly: novel technique and results of first-in-human randomized controlled study. Br J Ophthalmol 2019 103(2):176-180.
2. Jaycock P, Johnston RL, Taylor H, et al. The Cataract National Dataset electronic multi-centre audit of 55,567 operations: updating benchmark standards of care in the United Kingdom and internationally. Eye 2009 23(1):38-49.
3. Narendran N, Jaycock P, Johnston RL, et al. The Cataract National Dataset electronic multicenter audit of 55,567 operations: risk stratification for posterior capsule rupture and vitreous loss. Eye 2009 23(1):31-7.
4. Johnston RL, Taylor H, Smith R, et al. The Cataract National Dataset Electronic Multi-center audit of 55,567 operations: variation in posterior capsule rupture rates between surgeons. Eye 2010 24(5):888-93.
We thank Drs. Robert and Vidal for their comments. After carefully reading their original series of 5 patients and observing their videos [1], our impression was that both series could definitely refer to the same unique phenomenon.
As stated before [2], a drawback of our series was the inability to acquire eye movement recordings for any of our patients due to technical obstacles and parental refusal. We found Robert and Vidal’s ability to do so in one of their patients very important to the understanding and definition of the phenomenon [1]. Clearly their recordings demonstrate an upbeating nystagmus that would be expected in patients with tonic downgaze, assuming the eyes drift down while saccadic correcting movements are upward towards primary gaze. Hopefully, additional supporting recordings will be added to the literature in the future, allowing us to conclude that this is a representing finding for all of these patients.
This condition was apparently described under different titles over the years owing to scarce descriptions in the literature and difficulty providing convincing support for one definition over the other. This is an important step in that direction. We agree that with their addition of data, the term should include “upbeat nystagmus” and therefore suggest the term “benign infantile positional tonic downgaze with upbeat nystagmus”.
1. Robert MP, Michel S, Adjadj E, Boddaert N, Desguerre I, Vidal PP. Benign intermittent upbeat nystag...
We thank Drs. Robert and Vidal for their comments. After carefully reading their original series of 5 patients and observing their videos [1], our impression was that both series could definitely refer to the same unique phenomenon.
As stated before [2], a drawback of our series was the inability to acquire eye movement recordings for any of our patients due to technical obstacles and parental refusal. We found Robert and Vidal’s ability to do so in one of their patients very important to the understanding and definition of the phenomenon [1]. Clearly their recordings demonstrate an upbeating nystagmus that would be expected in patients with tonic downgaze, assuming the eyes drift down while saccadic correcting movements are upward towards primary gaze. Hopefully, additional supporting recordings will be added to the literature in the future, allowing us to conclude that this is a representing finding for all of these patients.
This condition was apparently described under different titles over the years owing to scarce descriptions in the literature and difficulty providing convincing support for one definition over the other. This is an important step in that direction. We agree that with their addition of data, the term should include “upbeat nystagmus” and therefore suggest the term “benign infantile positional tonic downgaze with upbeat nystagmus”.
1. Robert MP, Michel S, Adjadj E, Boddaert N, Desguerre I, Vidal PP. Benign intermittent upbeat nystagmus in infancy: a new clinical entity. Eur J Paediatr Neurol. 2015; 19: 262-5.
2. Sternfeld A, Lobel D, Leiba H, Luckman J, Michowiz S, Goldenberg-Cohen N. Long-term follow-up of benign positional vertical opsoclonus in infants: retrospective cohort. Br J Ophthalmol. 2018; 102: 757-60.
We thank Dr. Bunce et al for their interest in our paper.1 We would like to apologize for not mentioning the Statistics Notes Series2-12 from the UK Ophthalmology Research Section of the NIHR Statistics group. Given that our paper’s purpose is to evaluate whether the correlated eye data were analyzed properly in published ophthalmic clinical science papers, we did not cite these papers because we think most of them serve as introductions of general statistical methods instead of specific statistical methods for correlated eye data.
We agree these Statistics Notes Series are very helpful to the vision research community to improve the statistical analysis and interpretation of ophthalmic data. We applaud the UK Ophthalmology Research Section of the NIHR Statistics group for their collaborative efforts in improving the quality of statistics for ophthalmic research through these series of publications and workshops. Similarly in the USA, we have been promoting the proper analysis of correlated eye data through tutorial papers13-14 and the ARVO short course. We believe all these efforts will lead to improvement in the statistical practice for ophthalmic data.
We also agree that there are varying degrees of misuse of statistical methods in analyzing correlated eye data. Ignoring the inter-eye correlation when data from both eyes are analyzed is very bad practice as it can lead to the invalid conclusion, while analyzing correlated ocular data at person-level does...
We thank Dr. Bunce et al for their interest in our paper.1 We would like to apologize for not mentioning the Statistics Notes Series2-12 from the UK Ophthalmology Research Section of the NIHR Statistics group. Given that our paper’s purpose is to evaluate whether the correlated eye data were analyzed properly in published ophthalmic clinical science papers, we did not cite these papers because we think most of them serve as introductions of general statistical methods instead of specific statistical methods for correlated eye data.
We agree these Statistics Notes Series are very helpful to the vision research community to improve the statistical analysis and interpretation of ophthalmic data. We applaud the UK Ophthalmology Research Section of the NIHR Statistics group for their collaborative efforts in improving the quality of statistics for ophthalmic research through these series of publications and workshops. Similarly in the USA, we have been promoting the proper analysis of correlated eye data through tutorial papers13-14 and the ARVO short course. We believe all these efforts will lead to improvement in the statistical practice for ophthalmic data.
We also agree that there are varying degrees of misuse of statistical methods in analyzing correlated eye data. Ignoring the inter-eye correlation when data from both eyes are analyzed is very bad practice as it can lead to the invalid conclusion, while analyzing correlated ocular data at person-level does not take full advantage of data and may lead to the inefficient conclusion.
We are saddened by the death of Professor Altman. We have learnt and benefited so much from the papers published by him. Professor Altman’s death is an immense loss to the applied statistics community.
References
1. Zhang HG, Ying GS. Statistical approaches in published ophthalmic clinical science papers: a comparison to statistical practice two decades ago. Br J Ophthalmol. 2018 Sep;102(9):1188-1191.
2. Stephenson J, Bunce C, Doré CJ, Freemantle N; Ophthalmic Statistics Group. Ophthalmic statistics note 11: logistic regression. Br J Ophthalmol. 2016 Dec;100(12):1594-1595.
3. Bunce C, Stephenson J, Doré CJ, Freemantle N; Ophthalmic Statistics Group.Ophthalmic statistics note 10: data transformations.Br J Ophthalmol. 2016 Dec;100(12):1591-1593.
4. Skene SS, Bunce C, Freemantle N, Doré CJ; Ophthalmic Statistics Group. Ophthalmic statistics note 9: parametric versus non-parametric methods for data analysis. Br J Ophthalmol. 2016 Jul;100(7):877-878.
5. Bunce C, Quartilho A, Freemantle N, Doré CJ; Ophthalmic Statistics Group. Ophthalmic statistics note 8: missing data--exploring the unknown. Br J Ophthalmol. 2016 Mar;100(3):291-4.
6. Cipriani V, Quartilho A, Bunce C, Freemantle N, Doré CJ; Ophthalmic Statistics Group. Ophthalmic statistics note 7: multiple hypothesis testing—to adjust or not to adjust. Br J Ophthalmol. 2015 Sep;99(9):1155-7.
7. Cook JA, Bunce C, Doré CJ, Freemantle N; Ophthalmic Statistics Group. Ophthalmic statistics note 6: effect sizes matter. Br J Ophthalmol. 2015 May;99(5):580-1.
8. Saunders LJ, Zhu H, Bunce C, Doré CJ, Freemantle N, Crabb DP; Ophthalmic Statistics Group. Ophthalmic statistics note 5: diagnostic tests—sensitivity and specificity. Br J Ophthalmol. 2015 Sep;99(9):1168-70.
9. Nash R, Bunce C, Freemantle N, Doré CJ, Rogers CA; Ophthalmic Statistics Group.
Ophthalmic Statistics Note 4: analysing data from randomised controlled trials with baseline and follow-up measurements. Br J Ophthalmol. 2014 Nov;98(11):1467-9.
10. Ophthalmic statistics note: the perils of dichotomising continuous variables. Cumberland PM, Czanner G, Bunce C, Doré CJ, Freemantle N, García-Fiñana M; Ophthalmic Statistics Group.Br J Ophthalmol. 2014 Jun;98(6):841-3.
11. Bunce C, Patel KV, Xing W, Freemantle N, Doré CJ; Ophthalmic Statistics Group. Ophthalmic statistics note 2: absence of evidence is not evidence of absence. Br J Ophthalmol. 2014 May;98(5):703-5.
12. Bunce C, Patel KV, Xing W, Freemantle N, Doré CJ; Ophthalmic Statistics Group Ophthalmic statistics note 1: unit of analysis. Br J Ophthalmol. 2014 Mar;98(3):408-12.
13. Ying GS, Maguire MG, Glynn R, Rosner B. Tutorial on Biostatistics: Linear regression analysis of continuous correlated eye data. Ophthalmic Epidemiology 2017;24:130-140.
Ying GS, Maguire MG, Glynn R, Rosner B. Turtorial on biostatistics: Statistical analysis for correlated binary eye data. Ophthalmic Epidemiology 2018;25:1-12.
We congratulate the authors for bringing out an ingenious theory regarding pathogenesis of cupping in glaucomatous (GC) and non-glaucomatous (NGC) eyes using this optical coherence tomography (OCT) model. (1) Differentiating a NGC from GC has been a point of discussion for decades and to finally have an objective parameter “anterior laminar depth (ALD)” which appears specific for glaucomatous cupping from this study is indeed beneficial. The authors have used a linear regression model to compare the GC and NGC eyes with healthy controls with adjustment of age, axial length and peripapillary choroidal thickness (PCT). However, it remains to be further studied, how the ALD is to be used for an individual patient, for eg., what cut-off of ALD above which a patient can be labelled as falling in the glaucomatous range. In this regard, we had a doubt regarding inclusion of PCT in ALD calculation. Since the authors have finally adjusted for PCT in the end, we wonder how the results will turn out if they would remove PCT from ALD measurement and compare the remainder measurement (ALD - PCT) between NGC and GC groups.
Finally, we observed that in this sentence “No significant difference was found in visual field mean deviation (MD) <0.001).”, there is a typographical error and an inadequacy of explanation. No significant difference in visual field MD was indeed seen between NGC and GC groups (p should be >0.99 and not <0.001, as seen in Table...
We congratulate the authors for bringing out an ingenious theory regarding pathogenesis of cupping in glaucomatous (GC) and non-glaucomatous (NGC) eyes using this optical coherence tomography (OCT) model. (1) Differentiating a NGC from GC has been a point of discussion for decades and to finally have an objective parameter “anterior laminar depth (ALD)” which appears specific for glaucomatous cupping from this study is indeed beneficial. The authors have used a linear regression model to compare the GC and NGC eyes with healthy controls with adjustment of age, axial length and peripapillary choroidal thickness (PCT). However, it remains to be further studied, how the ALD is to be used for an individual patient, for eg., what cut-off of ALD above which a patient can be labelled as falling in the glaucomatous range. In this regard, we had a doubt regarding inclusion of PCT in ALD calculation. Since the authors have finally adjusted for PCT in the end, we wonder how the results will turn out if they would remove PCT from ALD measurement and compare the remainder measurement (ALD - PCT) between NGC and GC groups.
Finally, we observed that in this sentence “No significant difference was found in visual field mean deviation (MD) <0.001).”, there is a typographical error and an inadequacy of explanation. No significant difference in visual field MD was indeed seen between NGC and GC groups (p should be >0.99 and not <0.001, as seen in Table 1), however, both MD of NGC and GC were individually significantly different from the control group (p<0.001).
References
1. Fard MA, Moghimi S, Sahraian A, et al Optic nerve head cupping in glaucomatous and non-glaucomatous optic neuropathy British Journal of Ophthalmology Published Online First: 23 May 2018. doi: 10.1136/bjophthalmol-2018-312161
Dear Editor,
We read with interest the article written by Creuzot-Garcher and colleagues that was published in the June 2018 issue of your journal. 1 The authors retrospectively reviewed billings codes from a national database in France from January 2004 to December 2014 to examine acute postoperative endophthalmitis (POE) rates. They reported an incidence of acute POE in stand-alone phacoemulsification of 0.102% over this 11-year period. In contrast, combined surgery in which phacoemulsification was performed with another intraocular procedure had an overall higher incidence of 0.149%. The incidence of acute POE in combined phacoemulsification and glaucoma surgery, corneal surgery, and vitreoretinal surgery was found to be 0.089%, 0.142%, and 0.223% respectively.
As Creuzot-Garcher and colleagues mention, many phakic patients who undergo either glaucoma surgery, corneal surgery, or vitreoretinal surgery, are elderly and likely will require cataract extraction at some point.1 In addition, it is well established that these surgeries promote cataract formation in phakic eyes, and therefore patients who do not undergo combination surgery will likely require stand-alone cataract surgery in the future.
Hence, it would be instructive to compare the risk of acute POE in combined surgery with the total risk conferred by separately performing the two surgeries. We made the assumption that the chance of endophthalmitis in each surgery is independent. Using the...
Show MoreIn their report, entitled “Intravitreal chemotherapy in retinoblastoma: expanded use beyond intravitreal seeds“, Abramson and corkers report on the successful use of intravitreal chemotherapy in 52 patients for subretinal seeds and recurrent retinal tumours [1]. They state that, prior to their experience, intravitreal chemotherapy had been used exclusively to control persistent or recurrent vitreous seeding in retinoblastoma that had been refractory to systemic intravenous or intra-arterial chemotherapy.
In fact, intravitreal chemotherapy as an adjuvant treatment for both subretinal seeds and recurrent retinal tumours, including its use instead of systemic chemotherapy in the setting of chemothermotherapy for small unresponsive primary retinoblastomas, has been in regular use already for a decade at the Ocular Oncology Service, Helsinki University Eye Hospital. Indeed, three of the first four patients that we reported during the congress of the International Society of Ocular Oncology in 2009 [2], and published in 2011 [3], received intravitreal methotrexate for reasons other than vitreous seeds. Subsequent experience with intravitreal chemotherapy with methotrexate and, later, with melphalan has strengthened our initial findings, as does the comprehensive report of Abramson and coworkers.
1. Abramson DH, Ji X, Francis JH, et al. Intravitreal chemotherapy in retinoblastoma: expanded use beyond intravitreal seeds. Br J Ophthalmol 2018 Jun 6. pii: bjophthalmol-...
Show MoreTo the editor and auther Kivela et al.:
We thank the authors of the article “Intravitreal Methotrexate for Retinoblastoma” published in Ophthalmology in 2011 for their letter to the editor and adjustment of our discussion in our paper. As was found in your experience, as well as ours, intravitreal chemotherapy plays an important role in the treatment of retinoblastoma outside of its currently accepted use for intravitreal seeds. We look forward to hearing about your continued successful experience with intravitreal melphalan for use beyond intravitreal seeds.
To the Editor,
Show MoreIntravitreal antivascular endothelial growth factor (VEGF) agents undeniably have many clinical applications and we read with great interest the recent meta-analysis published in your journal by Low et al1 comparing the effectiveness and harms of these agents in three retinal disorders.
We would first like to thank the authors for their exhaustive review and synthesis of the evidence in this area. The conclusions they reached served to confirm what many of us had already suspected.2 Nevertheless, the article features some important methodological flaws and inadequate reporting of data that we would like to highlight to ensure that readers are in a position to interpret the findings of the meta-analysis correctly.
In relation to reporting issues, we were surprised to see that Table 1, which is quite creative and unique in terms of systematic review tables, does not include a list of the studies analyzed for each section. The authors, for example, state that they included two clinical trials comparing aflibercept and ranibizumab, but they do not specify which ones. This detracts from the transparency of the study and makes it difficult to review the findings. We also noticed a lack of uniformity within the figures, as some of the studies are listed by author name and others by author name and year of publication. In addition, Figure 3 shows data from the 2011 study by Biswas P, Sengupta S, Choudhary R, et al for the 18-24–month but not the 12...
To the Editor,
We appreciate Francisco-Javier Carrera-Hueso, Pedro Vazquez-Ferreiro, and Jaime Poquet-Jornet's careful reading of this paper. This commissioned review had a necessarily broad scope in order to summarize benefits and harms across three available therapies for the most common clinical indications. We agree there was quite a bit of information to present and that doing so in a succinct format is a challenge. However, we disagree with their contention that we did not follow current methodologic systematic review standards. We did indeed follow PRISMA reporting guidelines, as described in the Methods.
Regarding Table 1, the studies included in the summary table are the same as those described within the text and meta-analyses; we apologize for any confusion. In terms of format for the listing of studies in the meta-analyses, since studies are known primarily by their acronym, we used them in the figures whenever possible. The trials without specific names or acronyms were listed according to author and year.
Biswas 2011 only reported the percentage of patients gaining ≥15 letters at the 18-month endpoint, not at 12 months, so the study could not be included in the 12-month analysis for this outcome. The study did report mean change in BCVA at both endpoints, so it is included in both the 12 month and 18-24 month analyses in Figure 2. In terms of analyzing cost-effectiveness, only two trials meeting inclusion criteria (CATT and DRCR) di...
Show MoreWe thank the authors for their careful perusal of our study report and thoughtful observations. We agree that as demonstrated by the large population study1,2 referenced by us and by them, the rate of complications with cataract surgery is non-homogenous and increases dramatically with advanced stage cataracts – as much as 200%+ increase in rate of PCT in cases with high grade cataract, pseudoexfoliation and other comorbidities. In fact, with the co-existence of multiple factors, the compound rate can be even higher.
Our pilot study was in patients with advanced cataracts and multiple co-existing ocular pathologies and given the small sample size we are not surprised that the study point estimate for the PCT rate may be on the higher end of the overall range demonstrated by the larger population study. In addition, the randomized control design of the clinical trial further validates a PCT rate which was similar for both treatment and control groups. Certainly, an informed reader would appreciate that such a small trial is underpowered to be conclusive regarding the small difference between the two groups so no claims should be made about the slightly better rate of PCT and lower trend demonstrated in the miLOOP group.
What is important to appreciate from both the population study and our pilot data is that the rate of PCT is not the same for all cataract surgeries and there is a multiplier effect in certain subgroups and subpopulations. Our authorship team...
Show MoreWe are interested in the work of Ianchulev et al in their recent interventional randomized controlled trial.[1] What piqued our interest was the rate of posterior capsular tears (PCT). 4/53 (7.5%) patients in the miLOOP+phaco group experienced PCT, and 5/48 (10.4%) phaco-alone controls with PCT. These rates are much higher than standard phacoemulsification reports. The authors refer to a large study that identified advanced cataracts increased risk of PCT at comparable levels.[2] That same group published investigations expounding upon this.[3-4] Advanced cataracts were specifically identified as brunescent/white cataracts, contrasting Grade 3-4 in the miLOOP study (curiously described as LOCSIII classification in the manuscript).
Using the risk calculation,[3] the range of composite adjusted odds ratio (aOR) for the miLOOP study was 49.93 (25-28% risk) to an aOR of 0.87 (<1% surgical risk). The average patient from the miLOOP investigation had an aOR of 4.43, thus <5% PCT risk.
Our concerns: First, the authors state that “There was a trend towards a lower rate of capsular tear during the phaco portion with miLOOP-assisted phaco (7.5%) compared to standard phaco (10.4%).” Given the numbers representing these percentages this is an inappropriate description of this relationship.
Let us assume that a control group presented with a PCT rate similar to that reported in literature: <5%. Here, miLOOP-phaco PCT rate would be higher than the control...
Show MoreWe thank Drs. Robert and Vidal for their comments. After carefully reading their original series of 5 patients and observing their videos [1], our impression was that both series could definitely refer to the same unique phenomenon.
As stated before [2], a drawback of our series was the inability to acquire eye movement recordings for any of our patients due to technical obstacles and parental refusal. We found Robert and Vidal’s ability to do so in one of their patients very important to the understanding and definition of the phenomenon [1]. Clearly their recordings demonstrate an upbeating nystagmus that would be expected in patients with tonic downgaze, assuming the eyes drift down while saccadic correcting movements are upward towards primary gaze. Hopefully, additional supporting recordings will be added to the literature in the future, allowing us to conclude that this is a representing finding for all of these patients.
This condition was apparently described under different titles over the years owing to scarce descriptions in the literature and difficulty providing convincing support for one definition over the other. This is an important step in that direction. We agree that with their addition of data, the term should include “upbeat nystagmus” and therefore suggest the term “benign infantile positional tonic downgaze with upbeat nystagmus”.
1. Robert MP, Michel S, Adjadj E, Boddaert N, Desguerre I, Vidal PP. Benign intermittent upbeat nystag...
Show MoreWe thank Dr. Bunce et al for their interest in our paper.1 We would like to apologize for not mentioning the Statistics Notes Series2-12 from the UK Ophthalmology Research Section of the NIHR Statistics group. Given that our paper’s purpose is to evaluate whether the correlated eye data were analyzed properly in published ophthalmic clinical science papers, we did not cite these papers because we think most of them serve as introductions of general statistical methods instead of specific statistical methods for correlated eye data.
We agree these Statistics Notes Series are very helpful to the vision research community to improve the statistical analysis and interpretation of ophthalmic data. We applaud the UK Ophthalmology Research Section of the NIHR Statistics group for their collaborative efforts in improving the quality of statistics for ophthalmic research through these series of publications and workshops. Similarly in the USA, we have been promoting the proper analysis of correlated eye data through tutorial papers13-14 and the ARVO short course. We believe all these efforts will lead to improvement in the statistical practice for ophthalmic data.
We also agree that there are varying degrees of misuse of statistical methods in analyzing correlated eye data. Ignoring the inter-eye correlation when data from both eyes are analyzed is very bad practice as it can lead to the invalid conclusion, while analyzing correlated ocular data at person-level does...
Show MoreDear authors,
We congratulate the authors for bringing out an ingenious theory regarding pathogenesis of cupping in glaucomatous (GC) and non-glaucomatous (NGC) eyes using this optical coherence tomography (OCT) model. (1) Differentiating a NGC from GC has been a point of discussion for decades and to finally have an objective parameter “anterior laminar depth (ALD)” which appears specific for glaucomatous cupping from this study is indeed beneficial. The authors have used a linear regression model to compare the GC and NGC eyes with healthy controls with adjustment of age, axial length and peripapillary choroidal thickness (PCT). However, it remains to be further studied, how the ALD is to be used for an individual patient, for eg., what cut-off of ALD above which a patient can be labelled as falling in the glaucomatous range. In this regard, we had a doubt regarding inclusion of PCT in ALD calculation. Since the authors have finally adjusted for PCT in the end, we wonder how the results will turn out if they would remove PCT from ALD measurement and compare the remainder measurement (ALD - PCT) between NGC and GC groups.
Show MoreFinally, we observed that in this sentence “No significant difference was found in visual field mean deviation (MD) <0.001).”, there is a typographical error and an inadequacy of explanation. No significant difference in visual field MD was indeed seen between NGC and GC groups (p should be >0.99 and not <0.001, as seen in Table...
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