Dear editor, we have read with great interest the article presented by Melo et al.1 The authors provide good evidence of silicone oil release in injections from lubricated syringes. However, the likelihood of false-negative data may have been high because of lack of a staining method (Sudan III, for example) to differentiate and highlight small droplets, as previously described.2
Although injectable fluid contamination with syringe silicone oil has been known for decades,3,4 the lack of awareness of all medical specialties about this problem is impressive. The most concerning, still controversial long-term effect of silicone oil exposure is the development of an autoimmune/inflammatory syndrome induced by adjuvants, also known as ASIA syndrome.5
Given the massive amount of injections given worldwide, silicone oil injected seems safer than one would imagine, however, it is worth remembering that if the physician is unaware of the fact of the silicone oil injection, the diagnosis is omitted as a possible hypothesis. Enlarged lymph nodes or skin nodules with evidence of granulomas are assumed as sarcoidosis, and lumps in the abdomen of diabetic patients are all diagnosed as insulin fat hypertrophy, and if a biopsy is performed, the likely cause of the granuloma would be the injected therapeutic protein or an autoimmune phenomenon. If the physicians are informed that a patient received silicone oil injections the diagnoses change to silicone oil induced granuloma...
Dear editor, we have read with great interest the article presented by Melo et al.1 The authors provide good evidence of silicone oil release in injections from lubricated syringes. However, the likelihood of false-negative data may have been high because of lack of a staining method (Sudan III, for example) to differentiate and highlight small droplets, as previously described.2
Although injectable fluid contamination with syringe silicone oil has been known for decades,3,4 the lack of awareness of all medical specialties about this problem is impressive. The most concerning, still controversial long-term effect of silicone oil exposure is the development of an autoimmune/inflammatory syndrome induced by adjuvants, also known as ASIA syndrome.5
Given the massive amount of injections given worldwide, silicone oil injected seems safer than one would imagine, however, it is worth remembering that if the physician is unaware of the fact of the silicone oil injection, the diagnosis is omitted as a possible hypothesis. Enlarged lymph nodes or skin nodules with evidence of granulomas are assumed as sarcoidosis, and lumps in the abdomen of diabetic patients are all diagnosed as insulin fat hypertrophy, and if a biopsy is performed, the likely cause of the granuloma would be the injected therapeutic protein or an autoimmune phenomenon. If the physicians are informed that a patient received silicone oil injections the diagnoses change to silicone oil induced granulomas and lymphatic migration of silicone oil.
If patients had the option to choose between receiving injections with or without silicone oil, which would they choose? Would the regulatory agencies and manufacturers listen to their option?
The generalized adoption of silicone oil free syringes is likely the future. Meanwhile, the flush technique can be adopted to minimize the possibility of adverse reactions,2 which can occur decades after an injection.
References:
1. Melo GB, Emerson GG, Dias Jr CS, Morais FB, Lima Filho A de S, Ota S, et al. Release of silicone oil and the off-label use of syringes in ophthalmology. Br J Ophthalmol 2019. doi:10.1136/bjophthalmol-2019-313823.
2. Wambier CG, Assis de Andrade E, Cruz LS, et al. Flush technique to minimize adverse reactions from syringe lubricant (silicone oil). J Am Acad Dermatol. December 2018. doi:10.1016/j.jaad.2018.12.014
3. Chantelau EA, Berger M. Pollution of Insulin With Silicone Oil, a Hazard of Disposable Plastic Syringes. Lancet. 1985;325(8443):1459. doi:10.1016/S0140-6736(85)91892-6
4. Baldwin RN. Contamination of insulin by silicone oil: a potential hazard of plastic insulin syringes. Diabet Med. 1988;5(8):789-790.
5. Perricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects. J Autoimmun. 2013;47:1-16. doi:10.1016/j.jaut.2013.10.004
We have read the paper written by Avila MY et al “Randomised prospective clinical trial of platelet-rich plasma injection in the management of severe dry eye” . Authors have evaluated the effectiveness of platelet-rich injection in lacrimal gland plus free-demand topical lubricants drops in Sjögren’s syndrome severe dry eye patients . Diagnosis was based on Schirmer I, break-up time(BUT), ocular surface staining (Oxford grid) and OSDI . Achieved results in interventional group showed a Schirmer I (6,7+/-0,9 vs 9,2+/-1 mm, p<0,002), BUT (6,4+/-0,4 vs 4,4+/-0,3 secs p=0,0005), staining (2,15+/-0,15 vs 1,2+/-0,18 p<0,001) and OSDI (59+/-0,4 VS 34+/-4, p<0,001). Surprisingly authors have not included the lacrimal osmolarity test, the most valuable diagnostic tool to rule in/out this disease (S and Sp >90%) . Unfortunately Schirmer I (without anesthesia) evaluates not just basal lacrimal tearing, it also measures reflex response giving confounding bias in measured result. Surface staining (a qualitative variable) was mistakenly analyzed with a t-paired student test. Regarding OSDI, PRP patients showed a test improvement (pre 59+/- 4,0 vs post 34+/-4,0) without change in disease severity. Finally, this trial enrolled a low number of patients (n=15) that according to authors assumptions we would expect a much greater sample size (Epidat 4.1 n=417 eyes). In conclusion, a novel and interesting new treatment for Sjögren’s dry eye patients that must be confirmed in the f...
We have read the paper written by Avila MY et al “Randomised prospective clinical trial of platelet-rich plasma injection in the management of severe dry eye” . Authors have evaluated the effectiveness of platelet-rich injection in lacrimal gland plus free-demand topical lubricants drops in Sjögren’s syndrome severe dry eye patients . Diagnosis was based on Schirmer I, break-up time(BUT), ocular surface staining (Oxford grid) and OSDI . Achieved results in interventional group showed a Schirmer I (6,7+/-0,9 vs 9,2+/-1 mm, p<0,002), BUT (6,4+/-0,4 vs 4,4+/-0,3 secs p=0,0005), staining (2,15+/-0,15 vs 1,2+/-0,18 p<0,001) and OSDI (59+/-0,4 VS 34+/-4, p<0,001). Surprisingly authors have not included the lacrimal osmolarity test, the most valuable diagnostic tool to rule in/out this disease (S and Sp >90%) . Unfortunately Schirmer I (without anesthesia) evaluates not just basal lacrimal tearing, it also measures reflex response giving confounding bias in measured result. Surface staining (a qualitative variable) was mistakenly analyzed with a t-paired student test. Regarding OSDI, PRP patients showed a test improvement (pre 59+/- 4,0 vs post 34+/-4,0) without change in disease severity. Finally, this trial enrolled a low number of patients (n=15) that according to authors assumptions we would expect a much greater sample size (Epidat 4.1 n=417 eyes). In conclusion, a novel and interesting new treatment for Sjögren’s dry eye patients that must be confirmed in the future with a more robust trial.
Reference:
1. Avila MY, et al. Br J Ophthalmol 2019;103(648653)
2. Aqrawi L, Chen X, Jensen J, Morthen M, Thiede B et al. Severity of clinical dry eye manifestations influences protein expression in tear fluid of patients with primary Sjögren’s syndrome. PlosOne. 2018; Oct:1-14
3. Karakus S, Akpek E, Agrawal D, Massof R. Validation of an objective measure of dry eye severity. Trans Vis Sci Tech. 2018;7(5):26
4. Wolffsohn J.S. TFOS DEWS II Diagnostic Methodology Report. The Ocular Surface 15 (2017);539-574
We appreciate the interest in our paper by Kumawat and Kumar, and the opportunity to address their comments. With regards to axial length, it is certainly known to be correlated with choroidal thickness. However, this information was not routinely obtained in our retina clinic and was not available for most patients in the study. We were able to account for spherical equivalent in our multivariate model, which may serve as a proxy for axial length. We agree that accounting for at least one of these variables is required for studies on choroidal thickness. We appreciate the Kumawat and Kumar’s suggestion to categorize patients based on stage of disease (proliferative vs nonproliferative). We had considered this approach, however the small number of patients with proliferative disease (only 4) made this less ideal from a statistical standpoint. Subretinal neovascularization was included in our univariate analysis but was not found to be statistically significant with regard to choroidal thickness, so it was not further considered in our multivariate assessments. Lastly, while inter-ocular asymmetry in choroidal thickness may exist, eye laterality was not found to be a significant variable affecting choroidal thickness in our univariate analysis (p = 0.87) and thus was also not included in multivariate models. We once again thank Dr. Kumawat and Dr. Kumar for their interest in our work.
Dear Editor,
We have read with great interest the article by Singhal et al 1 on 'Clinical presentation and management of corneal fistula'. The authors have rightly highlighted the point that failure to perform simple test like Seidel test in cases of corneal ulcer, can lead to missing the diagnosis of corneal fistula, which in turn can lead to serious complications like endophthalmitis, panophthalmitis and phthisis bulbi.
One of the complications of persistent corneal fistula is the formation of anterior capsular cataract. It would have been more insightful if the authors had mentioned as to how many patients had developed anterior capsular cataract during follow up, as this can lead to a change in the future management of the eye.
Also, the authors have not mentioned the type of anaesthesia for doing the procedure. As creating the grooves around perforation to tuck in the tenons graft is difficult due to the friability of corneal tissue, the type of anaesthesia has a bearing on the intra operative surgical procedure. As doing the technique in topical anaesthesia will be technically challenging and administration of peribulbar block could lead to extrusion of the intraocular contents or extension of the perforation.
Although the study mentions the surgical technique for closing the fistula with a tenons patch graft, it does not mention the regimen of postoperative medical management.
In the discussion, the authors have mentioned that...
Dear Editor,
We have read with great interest the article by Singhal et al 1 on 'Clinical presentation and management of corneal fistula'. The authors have rightly highlighted the point that failure to perform simple test like Seidel test in cases of corneal ulcer, can lead to missing the diagnosis of corneal fistula, which in turn can lead to serious complications like endophthalmitis, panophthalmitis and phthisis bulbi.
One of the complications of persistent corneal fistula is the formation of anterior capsular cataract. It would have been more insightful if the authors had mentioned as to how many patients had developed anterior capsular cataract during follow up, as this can lead to a change in the future management of the eye.
Also, the authors have not mentioned the type of anaesthesia for doing the procedure. As creating the grooves around perforation to tuck in the tenons graft is difficult due to the friability of corneal tissue, the type of anaesthesia has a bearing on the intra operative surgical procedure. As doing the technique in topical anaesthesia will be technically challenging and administration of peribulbar block could lead to extrusion of the intraocular contents or extension of the perforation.
Although the study mentions the surgical technique for closing the fistula with a tenons patch graft, it does not mention the regimen of postoperative medical management.
In the discussion, the authors have mentioned that the cyanoacrylate glue application can lead to iritis. But all the cases included in the study had fistula size of not more than 3 mm. There is enough evidence to state that perforations and fistulas of sizes 2-3 mm can be closed safely with cyanoacrylate glue without any migration of the glue into the anterior chamber and obviate the need for other surgical treatment.2,3
References :
1. Singhal D, Sahay P, Maharana PK, et al. Clinical presentation and management of corneal fistula. Br J Ophthalmol. 2019 ;103:530-533.
2. Jhanji V, Young AL, Mehta JS, et al. Management of corneal perforation. Surv Ophthalmol. 2011 ;56:522-38.
3. Korah S, Selvin SS, Pradhan ZS, et al. Tenons Patch Graft in the Management of Large Corneal Perforations. Cornea 2016;35:696–9
We would like to thank Dr. Tarannum Mansoori for the interest in our study, “Intraocular pressure change after injection of intravitreal dexamethasone (Ozurdex) implant in Korean patients” and highlighting important issues about the intraocular pressure (IOP) measurement methods and the correlation of IOP with age.1
We used KT-800 Non-Contact Tonometer (Kowa, Tokyo, Japan) to measure IOP initially and rechecked with GAT if necessary. Unless the patient was diagnosed with glaucoma, NCT was initially used to measure both pre- and post-injection IOP.
As Dr. Tarannum Mansoori has pointed out, we also agree that GAT is the gold standard for IOP measurement. If the IOP measured with NCT was found to be high, it was always rechecked with GAT. GAT was used in 2 situations in our study. First, when the patients had a previous history of glaucoma, and second, when the patients’ IOP as measured with NCT was high (greater than 20). Thus, in cases of high IOP, the measurement involved NCT and was also always double checked with GAT. Moreover, multiple IOP measurements were obtained with GAT in cases of high IOP, and the average value of the measurements was regarded as the final IOP.
The range of age of the patients for injection of intravitreal dexamethasone was broad, from 16 to 88 years. We know that very young age (less than six years) or an older age are risk factors for steroid-induced glaucoma.2 However, regrettably, we have not performed any further analysis...
We would like to thank Dr. Tarannum Mansoori for the interest in our study, “Intraocular pressure change after injection of intravitreal dexamethasone (Ozurdex) implant in Korean patients” and highlighting important issues about the intraocular pressure (IOP) measurement methods and the correlation of IOP with age.1
We used KT-800 Non-Contact Tonometer (Kowa, Tokyo, Japan) to measure IOP initially and rechecked with GAT if necessary. Unless the patient was diagnosed with glaucoma, NCT was initially used to measure both pre- and post-injection IOP.
As Dr. Tarannum Mansoori has pointed out, we also agree that GAT is the gold standard for IOP measurement. If the IOP measured with NCT was found to be high, it was always rechecked with GAT. GAT was used in 2 situations in our study. First, when the patients had a previous history of glaucoma, and second, when the patients’ IOP as measured with NCT was high (greater than 20). Thus, in cases of high IOP, the measurement involved NCT and was also always double checked with GAT. Moreover, multiple IOP measurements were obtained with GAT in cases of high IOP, and the average value of the measurements was regarded as the final IOP.
The range of age of the patients for injection of intravitreal dexamethasone was broad, from 16 to 88 years. We know that very young age (less than six years) or an older age are risk factors for steroid-induced glaucoma.2 However, regrettably, we have not performed any further analysis regarding the correlation with age in our study. We plan to perform further analysis and look forward to sharing our results in the near future.
References
1 Choi W, Park SE, Kang HG, et al. Intraocular pressure change after injection of intravitreal dexamethasone (Ozurdex) implant in Korean patients. Br J Ophthalmol 2018.
2 Lam DS, Fan DS, Ng JS, et al. Ocular hypertensive and anti-inflammatory responses to different dosages of topical dexamethasone in children: a randomized trial. Clin Exp Ophthalmol 2005;33:252-8.
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 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 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 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.
Dear editor, we have read with great interest the article presented by Melo et al.1 The authors provide good evidence of silicone oil release in injections from lubricated syringes. However, the likelihood of false-negative data may have been high because of lack of a staining method (Sudan III, for example) to differentiate and highlight small droplets, as previously described.2
Although injectable fluid contamination with syringe silicone oil has been known for decades,3,4 the lack of awareness of all medical specialties about this problem is impressive. The most concerning, still controversial long-term effect of silicone oil exposure is the development of an autoimmune/inflammatory syndrome induced by adjuvants, also known as ASIA syndrome.5
Given the massive amount of injections given worldwide, silicone oil injected seems safer than one would imagine, however, it is worth remembering that if the physician is unaware of the fact of the silicone oil injection, the diagnosis is omitted as a possible hypothesis. Enlarged lymph nodes or skin nodules with evidence of granulomas are assumed as sarcoidosis, and lumps in the abdomen of diabetic patients are all diagnosed as insulin fat hypertrophy, and if a biopsy is performed, the likely cause of the granuloma would be the injected therapeutic protein or an autoimmune phenomenon. If the physicians are informed that a patient received silicone oil injections the diagnoses change to silicone oil induced granuloma...
Show MoreWe have read the paper written by Avila MY et al “Randomised prospective clinical trial of platelet-rich plasma injection in the management of severe dry eye” . Authors have evaluated the effectiveness of platelet-rich injection in lacrimal gland plus free-demand topical lubricants drops in Sjögren’s syndrome severe dry eye patients . Diagnosis was based on Schirmer I, break-up time(BUT), ocular surface staining (Oxford grid) and OSDI . Achieved results in interventional group showed a Schirmer I (6,7+/-0,9 vs 9,2+/-1 mm, p<0,002), BUT (6,4+/-0,4 vs 4,4+/-0,3 secs p=0,0005), staining (2,15+/-0,15 vs 1,2+/-0,18 p<0,001) and OSDI (59+/-0,4 VS 34+/-4, p<0,001). Surprisingly authors have not included the lacrimal osmolarity test, the most valuable diagnostic tool to rule in/out this disease (S and Sp >90%) . Unfortunately Schirmer I (without anesthesia) evaluates not just basal lacrimal tearing, it also measures reflex response giving confounding bias in measured result. Surface staining (a qualitative variable) was mistakenly analyzed with a t-paired student test. Regarding OSDI, PRP patients showed a test improvement (pre 59+/- 4,0 vs post 34+/-4,0) without change in disease severity. Finally, this trial enrolled a low number of patients (n=15) that according to authors assumptions we would expect a much greater sample size (Epidat 4.1 n=417 eyes). In conclusion, a novel and interesting new treatment for Sjögren’s dry eye patients that must be confirmed in the f...
Show MoreDear Editor,
We appreciate the interest in our paper by Kumawat and Kumar, and the opportunity to address their comments. With regards to axial length, it is certainly known to be correlated with choroidal thickness. However, this information was not routinely obtained in our retina clinic and was not available for most patients in the study. We were able to account for spherical equivalent in our multivariate model, which may serve as a proxy for axial length. We agree that accounting for at least one of these variables is required for studies on choroidal thickness. We appreciate the Kumawat and Kumar’s suggestion to categorize patients based on stage of disease (proliferative vs nonproliferative). We had considered this approach, however the small number of patients with proliferative disease (only 4) made this less ideal from a statistical standpoint. Subretinal neovascularization was included in our univariate analysis but was not found to be statistically significant with regard to choroidal thickness, so it was not further considered in our multivariate assessments. Lastly, while inter-ocular asymmetry in choroidal thickness may exist, eye laterality was not found to be a significant variable affecting choroidal thickness in our univariate analysis (p = 0.87) and thus was also not included in multivariate models. We once again thank Dr. Kumawat and Dr. Kumar for their interest in our work.
Dear Editor,
Show MoreWe have read with great interest the article by Singhal et al 1 on 'Clinical presentation and management of corneal fistula'. The authors have rightly highlighted the point that failure to perform simple test like Seidel test in cases of corneal ulcer, can lead to missing the diagnosis of corneal fistula, which in turn can lead to serious complications like endophthalmitis, panophthalmitis and phthisis bulbi.
One of the complications of persistent corneal fistula is the formation of anterior capsular cataract. It would have been more insightful if the authors had mentioned as to how many patients had developed anterior capsular cataract during follow up, as this can lead to a change in the future management of the eye.
Also, the authors have not mentioned the type of anaesthesia for doing the procedure. As creating the grooves around perforation to tuck in the tenons graft is difficult due to the friability of corneal tissue, the type of anaesthesia has a bearing on the intra operative surgical procedure. As doing the technique in topical anaesthesia will be technically challenging and administration of peribulbar block could lead to extrusion of the intraocular contents or extension of the perforation.
Although the study mentions the surgical technique for closing the fistula with a tenons patch graft, it does not mention the regimen of postoperative medical management.
In the discussion, the authors have mentioned that...
We would like to thank Dr. Tarannum Mansoori for the interest in our study, “Intraocular pressure change after injection of intravitreal dexamethasone (Ozurdex) implant in Korean patients” and highlighting important issues about the intraocular pressure (IOP) measurement methods and the correlation of IOP with age.1
Show MoreWe used KT-800 Non-Contact Tonometer (Kowa, Tokyo, Japan) to measure IOP initially and rechecked with GAT if necessary. Unless the patient was diagnosed with glaucoma, NCT was initially used to measure both pre- and post-injection IOP.
As Dr. Tarannum Mansoori has pointed out, we also agree that GAT is the gold standard for IOP measurement. If the IOP measured with NCT was found to be high, it was always rechecked with GAT. GAT was used in 2 situations in our study. First, when the patients had a previous history of glaucoma, and second, when the patients’ IOP as measured with NCT was high (greater than 20). Thus, in cases of high IOP, the measurement involved NCT and was also always double checked with GAT. Moreover, multiple IOP measurements were obtained with GAT in cases of high IOP, and the average value of the measurements was regarded as the final IOP.
The range of age of the patients for injection of intravitreal dexamethasone was broad, from 16 to 88 years. We know that very young age (less than six years) or an older age are risk factors for steroid-induced glaucoma.2 However, regrettably, we have not performed any further analysis...
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...
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 MoreTo 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 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 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...
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