We read the paper on non-invasive intracranial pressure determination by Zhang et al(1) with great interest and hope. We fully agree that the search for non-invasive intracranial pressure (ICP) evaluations is of high importance and should be continued. The Bland-Altman plot showing the difference between predicted and intracranially measured pressure looks very impressive. There are, however, still a few points and limits we would like to address concerning the anatomy of the optic nerve, the optic canal, and the basic concept the authors used.
Cerebrospinal fluid (CSF) from the intracranial subarachnoid spaces and the subarachnoid space of the optic nerve (SAS -ON) communicate via the optic canal. Using three-dimensional reconstruction of the optic canal in normal tension glaucoma (NTG) patients, this was found to be narrower than in an age-related cohort of normals,(2) thus questioning the patency of the CSF pathway between the pituitary cistern and the SAS-ON. Further, optic canal dimensions in a normal population are quite variable amongst individuals, and even between orbits within the same individual.(3) These facts largely influence the results the authors present. Further, studies in patients with NTG and patients with elevated ICP (such as patients with idiopathic intracranial hypertension) were shown to have developed an optic nerve sheath compartment syndrome. In such cases, the CSF dynamics between the intracranial CSF and the CSF in...
We read the paper on non-invasive intracranial pressure determination by Zhang et al(1) with great interest and hope. We fully agree that the search for non-invasive intracranial pressure (ICP) evaluations is of high importance and should be continued. The Bland-Altman plot showing the difference between predicted and intracranially measured pressure looks very impressive. There are, however, still a few points and limits we would like to address concerning the anatomy of the optic nerve, the optic canal, and the basic concept the authors used.
Cerebrospinal fluid (CSF) from the intracranial subarachnoid spaces and the subarachnoid space of the optic nerve (SAS -ON) communicate via the optic canal. Using three-dimensional reconstruction of the optic canal in normal tension glaucoma (NTG) patients, this was found to be narrower than in an age-related cohort of normals,(2) thus questioning the patency of the CSF pathway between the pituitary cistern and the SAS-ON. Further, optic canal dimensions in a normal population are quite variable amongst individuals, and even between orbits within the same individual.(3) These facts largely influence the results the authors present. Further, studies in patients with NTG and patients with elevated ICP (such as patients with idiopathic intracranial hypertension) were shown to have developed an optic nerve sheath compartment syndrome. In such cases, the CSF dynamics between the intracranial CSF and the CSF in the SAS-ON differ significantly. This was proven by applying computer-assisted cisternography, diffusion-weighted MRI sequences and gradients of biochemical CSF proteins.(4-6)
In Zhang’s study, CSF pressures (CSFP) larger than 30 mm Hg were excluded. The majority of the patients in whom CSFP needs to be known are those with markedly elevated ICP. Therefore, this study should have been expanded to this group. As the compliance to pressure in the optic nerve sheath is most likely notlinear, this adds a further difficulty to measuring methods.
The authors found that CSF pressure was more significantly correlated with the area of the optic nerve sheath subarachnoid space than with the optic nerve sheath diameter. In an idealized fashion the optic nerve subarachnoid space resembles an annulus with a fractal circumference. The area A itself is not homogeneously filled with CSF but is interspersed with an interindividually variable amount of space-occupying trabeculae. The diameter in an annulus – compared to a circle - is represented twice in the formula for the area. Therefore, the diameter is involved in the SAS area as well. Its therefore difficult to understand why using the area instead of the diameter should render more accurate calculations, especially when the diameter is represented twice in the formula:
A total = π/4 (D2 -d2 ) - A trabecula = π (R2 - r2) - A trabecula
Our prior experience with formulae utilizing biophysical data such as body mass index (BMI), diastolic blood pressure (DBP), and age – all factors known to correlate to CSF pressure to variable degrees – were that they are quite poor at predicting actual CSF pressure.(7) The study excluded the analysis of formulae that utilized anatomic measures of MRI-determined optic nerve sheath width. However, as Zhang’s study is utilizing a similar method except with ultrasonographic determination of nerve sheath width, it would be assumed that the strongest predictor of CSF pressure would be the optic nerve sheath width. This subject has been repeatedly studied, and it does not seem that ultrasonographic evaluation of the optic nerve sheath diameter has ever been able to determine accurate estimates of true CSF pressures, but mostly the determination of normal versus elevated.(8-10)
Lastly, ultrasonography is a subjective method that depends on the user’s ability and reliability. In a study comparing optic nerve sheath diameter measurement between computed tomography, magnetic resonance imaging and ultrasound there was a good comparability between computed tomography and magnetic resonance imaging while the comparability between ultrasound and computed tomography or magnetic resonance tomography seems to be less reliable.(11)
We highly encourage efforts to expand our knowledge of the interrelation of cerebrospinal fluid and ophthalmic disease. But our desire to increase accessibility to study this by using formulae (in which the relationship between the variables is not understood) as opposed to current gold standard measurements of CSF pressure determination should not lead us to the path of using doubtful formulae that will confuse our body of literature.
References:
1) Non-invasive intracranial pressure estimation using ultrasonographic measurement of area of optic nerve subarachnoid space.Zhang Y, Cao K, Pang R, Wang N, Qu X, Kang J, Wang N, Liu H. Br J Ophthalmol. 2022 Aug 24:bjophthalmol-2022-321065.
2) The Optic Canal: A Bottleneck for Cerebrospinal Fluid Dynamics in Normal-Tension Glaucoma?Pircher A, Montali M, Berberat J, Remonda L, Killer HE. Front Neurol. 2017 Feb 23;8:47
3) Evaluation of optic canal anatomy and symmetry. Zhang X, Lee Y, Olson D, Fleischman D. BMJ Open Ophthalmology 2019;4:e000302
4) Cerebrospinal fluid dynamics between the intracranial and the subarachnoid space of the optic nerve. Is it always bidirectional? Killer HE, Jaggi GP, Flammer J, Miller NR, Huber AR, Mironov A. Brain. 2007 Feb;130(Pt 2):514-20
5) Case Report: Cerebrospinal Fluid Dynamics in the Optic Nerve Subarachnoid Space and the Brain Applying Diffusion Weighted MRI in Patients With Idiopathic Intracranial Hypertension-A Pilot Study. Berberat J, Pircher A, Gruber P, Lovblad KO, Remonda L, Killer HE. Front Neurol. 2022 Apr 15;13:862808
6) The optic nerve: a new window into cerebrospinal fluid composition? Killer HE, Jaggi GP, Flammer J, Miller NR, Huber AR. Brain. 2006 Apr;129(Pt 4):1027-30
7) Analysis of cerebrospinal fluid pressure estimation using formulae derived from clinical data. Fleischman D, Bicket AK, Stinnett SS, Berdahl JP, Jonas JB, Wang N, Fautsch MP, Allingham RR. Invest Ophthalmol Vis Sci. 2016;57:5625-5630.
8) Effect of intracranial pressure on the diameter of the optic nerve sheath. Watanabe A, Kinouchi H, Horiokoshi T, Uchida M, Ishigame K. J Neurosurg 2008 109(2): 255-8.
9) Optic nerve ultrasound for the detection of raised intracranial pressure. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Neurocrit Care 2011;15(3):506-15.
10) Sonographic assessment of the optic nerve sheath in idiopathic intracranial hypertension. Bauerle J, Nedelmann M. J Neurol 2011; 258(11):2014-9.
11) Measurement of Optic Nerve Sheath Diameter: Differences between Methods? A Pilot Study. Giger-Tobler C, Eisenack J, Holzmann D, Pangalu A, Sturm V, Killer HE, Landau K, Jaggi GP. Klin Monbl Augenheilkd. 2015 Apr;232(4):467-70
We read with great interest the article of Gokhale et al [1] on their retrospective study of metformin use and risk of age-related macular degeneration (AMD) in individuals with type 2 diabetes mellitus (T2DM). In this study Gokhale and colleagues used data derived from IQVIA Medical Research Data (IMRD-UK), formerly known as The Health Improvement Network (THIN), and found no change in AMD risk in those taking metformin.
An issue with this study is the quality of the GP coding and data on AMD. The authors cite a validation study of THIN data [2] but this study only validated cases identified as having AMD. There was no validation of the quality of data on the absence of AMD. So, the confirmation of positives was high (confirmed AMD cases quoted as 97%) but the false negative rate, is unknown. Also, the validation was by an ophthalmologist reviewing all the GP data, not using recognised diagnostic criteria or a grading scheme for AMD. Furthermore, the authors included a code for “drusen” into their AMD group which was not a code included in the validation study by Vassilev et al [2]. It is likely that this code includes patients with common physiological drusen and not an AMD diagnosis.
We have previously performed a systematic review and meta-analysis [3] of five studies [4–8] on the relationship between metformin use and AMD, which we have now updated to include Gokhale et al [1] and Jiang et al [9]. Including their data, we found a beneficial odds ratio of...
We read with great interest the article of Gokhale et al [1] on their retrospective study of metformin use and risk of age-related macular degeneration (AMD) in individuals with type 2 diabetes mellitus (T2DM). In this study Gokhale and colleagues used data derived from IQVIA Medical Research Data (IMRD-UK), formerly known as The Health Improvement Network (THIN), and found no change in AMD risk in those taking metformin.
An issue with this study is the quality of the GP coding and data on AMD. The authors cite a validation study of THIN data [2] but this study only validated cases identified as having AMD. There was no validation of the quality of data on the absence of AMD. So, the confirmation of positives was high (confirmed AMD cases quoted as 97%) but the false negative rate, is unknown. Also, the validation was by an ophthalmologist reviewing all the GP data, not using recognised diagnostic criteria or a grading scheme for AMD. Furthermore, the authors included a code for “drusen” into their AMD group which was not a code included in the validation study by Vassilev et al [2]. It is likely that this code includes patients with common physiological drusen and not an AMD diagnosis.
We have previously performed a systematic review and meta-analysis [3] of five studies [4–8] on the relationship between metformin use and AMD, which we have now updated to include Gokhale et al [1] and Jiang et al [9]. Including their data, we found a beneficial odds ratio of metformin use for “any AMD” remained (OR 0.75, 95% CI 0.54-0.97, I2=98.5%). This information should be interpreted with caution due to the high heterogeneity between studies including racial differences. We agree that further studies into the potential benefit of metformin for AMD are certainly warranted, including population-based datasets with accurate AMD diagnoses and prospective clinical trials.
Sincerely
References:
1. Gokhale KM, Adderley NJ, Subramanian A, et al. Metformin and risk of age-related macular degeneration in individuals with type 2 diabetes: a retrospective cohort study. British Journal of Ophthalmology Published Online First: 3 February 2022. doi:10.1136/bjophthalmol-2021-319641
2. Vassilev ZP, Ruigómez A, Soriano-Gabarró M, et al. Diabetes, Cardiovascular Morbidity, and Risk of Age-Related Macular Degeneration in a Primary Care Population. Invest Ophthalmol Vis Sci 2015;56:1585–92. doi:10.1167/iovs.14-16271
3. Romdhoniyyah DF, Harding SP, Cheyne CP, et al. Metformin, A Potential Role in Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis. Ophthalmol Ther 2021;10:245–60. doi:10.1007/s40123-021-00344-3
4. Brown EE, Ball JD, Chen Z, et al. The Common Antidiabetic Drug Metformin Reduces Odds of Developing Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2019;60:1470–7. doi:10.1167/iovs.18-26422
5. Stewart JM, Lamy R, Wu F, et al. Relationship between Oral Metformin Use and Age-Related Macular Degeneration. Oph Retina 2020;0. doi:10.1016/j.oret.2020.06.003
6. Blitzer AL, Ham SA, Colby KA, et al. Association of Metformin Use With Age-Related Macular Degeneration: A Case-Control Study. JAMA Ophthalmology Published Online First: 21 January 2021. doi:10.1001/jamaophthalmol.2020.6331
7. Chen Y-Y, Shen Y-C, Lai Y-J, et al. Association between Metformin and a Lower Risk of Age-Related Macular Degeneration in Patients with Type 2 Diabetes. Journal of Ophthalmology. 2019. doi:10.1155/2019/1649156
8. Lee H, Jeon H-L, Park SJ, et al. Effect of Statins, Metformin, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers on Age-Related Macular Degeneration. Yonsei Med J 2019;60:679–86. doi:10.3349/ymj.2019.60.7.679
9. Jiang J, Chen Y, Zhang H, et al. Association between metformin use and the risk of age-related macular degeneration in patients with type 2 diabetes: a retrospective study. BMJ Open 2022;12:e054420. doi:10.1136/bmjopen-2021-054420
Author: Dewi Fathin Romdhoniyyah (1), Nicholas AV Beare (1,2)
(1) Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
(2) St. Pauls Eye Unit, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
Mauschitz et al. (1) conducted a meta-analysis to investigate the association of systemic medications with age-related macular degeneration (AMD) in the general population. A pooled odds ratios (95% confidence intervals [CIs]) of lipid-lowering drugs (LLD) and antidiabetic drugs for any AMD were 0.85 (0.79 to 0.91) and 0.78 (0.66 to 0.91), respectively. In contrast, late AMD was not significantly associated with systemic medications. There is an information that antidiabetics, lipid-lowering agents, and antioxidants could theoretically be repurposed for AMD treatment (2). I present information regarding the effect of antidiabetic medications on the risk of AMD.
Blitzer et al. (3) conducted a case-control study and metformin use was significantly associated with reduced odds of AMD, presenting dose dependent manner. But metformin did not have an effect of protecting diabetic retinopathy. In contrast, Gokhale et al. (4) conducted a retrospective cohort study to evaluate the effect of metformin on the risk reduction of AMD. The adjusted hazard ratio (95% CI) of patients prescribed metformin (with or without other antidiabetic medications) against those prescribed any other antidiabetic medication only for AMD was 1.02 (0.92 to 1.12). Vergroesen et al. (5) conducted a cohort study and a lower risk of AMD was not observed in patients with metformin, but other diabetes medication was significantly associated with a lower risk of AMD.
Mauschitz et al. (1) conducted a meta-analysis to investigate the association of systemic medications with age-related macular degeneration (AMD) in the general population. A pooled odds ratios (95% confidence intervals [CIs]) of lipid-lowering drugs (LLD) and antidiabetic drugs for any AMD were 0.85 (0.79 to 0.91) and 0.78 (0.66 to 0.91), respectively. In contrast, late AMD was not significantly associated with systemic medications. There is an information that antidiabetics, lipid-lowering agents, and antioxidants could theoretically be repurposed for AMD treatment (2). I present information regarding the effect of antidiabetic medications on the risk of AMD.
Blitzer et al. (3) conducted a case-control study and metformin use was significantly associated with reduced odds of AMD, presenting dose dependent manner. But metformin did not have an effect of protecting diabetic retinopathy. In contrast, Gokhale et al. (4) conducted a retrospective cohort study to evaluate the effect of metformin on the risk reduction of AMD. The adjusted hazard ratio (95% CI) of patients prescribed metformin (with or without other antidiabetic medications) against those prescribed any other antidiabetic medication only for AMD was 1.02 (0.92 to 1.12). Vergroesen et al. (5) conducted a cohort study and a lower risk of AMD was not observed in patients with metformin, but other diabetes medication was significantly associated with a lower risk of AMD.
Anyway, clinical trials are needed to specify the inconsistent relationship between antidiabetic medications and the risk reduction of AMD.
References
1. Mauschitz MM, Verzijden T, Schuster AK, et al. Association of lipid-lowering drugs and antidiabetic drugs with age-related macular degeneration: a meta-analysis in Europeans. Br J Ophthalmol 2022 doi: 10.1136/bjo-2022-321985
2. Nadeem U, Xie B, Xie EF, et al. Using advanced bioinformatics tools to identify novel therapeutic candidates for age-related macular degeneration. Transl Vis Sci Technol 2022;11(8):10.
3. Blitzer AL, Ham SA, Colby KA, Skondra D. Association of metformin use with age-related macular degeneration: A case-control study. JAMA Ophthalmol 2021;139(3):302-309.
4. Gokhale KM, Adderley NJ, Subramanian A, et al. Metformin and risk of age-related macular degeneration in individuals with type 2 diabetes: a retrospective cohort study. Br J Ophthalmol 2022 doi: 10.1136/bjophthalmol-2021-319641
5. Vergroesen JE, Thee EF, Ahmadizar F, et al. Association of diabetes medication with open-angle glaucoma, age-related macular degeneration, and cataract in the Rotterdam Study. JAMA Ophthalmol 2022;140(7):674-681.
The paper advises that the population inspected was predominately of white background and is looking to find ways of expanding its knowledge of non-white ethnicity within the sphere of retina testing. Within the following paper : Ethnicity and Type 2 diabetes in the UK by
L. M. Goff; it states that the prevalence of Type 2 diabetes within the non-white community is particularly high. a quote from this paper:
"Among minority ethnic communities, the prevalence is alarmingly high, approximately three to five times higher than in the white British population. "
Which brings me to my response: All UK Type 2 diabetics are offered eye screening during which the retina is photographed every year. These digital photographs are examined by medical staff looking for vein bleeding and are held by the NHS. Given the hign incidence of Type 2 diabetes in non-white citizens a very large number of these records will be available and so allow a useful extension to the work done by Professor Rudnicka.
It is generally believed that retinal neurons stop growing in number after birth in humans.1, 2 But recent research has shown retinal neurogenesis in neonatal 1-3 month old monkeys.3 This poses the question of how the sclera and the retina grow during emmetropization. The ora serrata is reported to be 2 mm wide growing to 6-7mm (approximately 5mm difference) in adult life as the scleral tunic grows more than the retina.4 The vitreous chamber depth in newborns is 10.6mm long and also grows roughly by 6 mm to an adult axial value of 17mm on average.5 It is then possible that during the first 3 months of human life, at that rapid growth phase from 17mm to 19mm in mean axial length,6 the retina could grow at least 1mm to compensate in part for that rapid elongation. The eyes of males and females have only a 0.1mm difference at birth with very small differences in body length and head circumference, but bigger born babies have longer eyes with less powerful corneas,7 so a bigger born girl may have a bigger eye with flatter cornea than a smaller born male. When adulthood is reached, women have eyes shorter than those of men by 0.7mm, with steeper corneas and more powerful crystalline lenses.8 As the cornea stabilizes by ages 2-3 in infants, these differential growth patterns are probably established early in life.4 And as usually happens not only among males and females, emmetropic or low hyperopic eyes that develop low corneal powers are longer than eyes that stay with steep co...
It is generally believed that retinal neurons stop growing in number after birth in humans.1, 2 But recent research has shown retinal neurogenesis in neonatal 1-3 month old monkeys.3 This poses the question of how the sclera and the retina grow during emmetropization. The ora serrata is reported to be 2 mm wide growing to 6-7mm (approximately 5mm difference) in adult life as the scleral tunic grows more than the retina.4 The vitreous chamber depth in newborns is 10.6mm long and also grows roughly by 6 mm to an adult axial value of 17mm on average.5 It is then possible that during the first 3 months of human life, at that rapid growth phase from 17mm to 19mm in mean axial length,6 the retina could grow at least 1mm to compensate in part for that rapid elongation. The eyes of males and females have only a 0.1mm difference at birth with very small differences in body length and head circumference, but bigger born babies have longer eyes with less powerful corneas,7 so a bigger born girl may have a bigger eye with flatter cornea than a smaller born male. When adulthood is reached, women have eyes shorter than those of men by 0.7mm, with steeper corneas and more powerful crystalline lenses.8 As the cornea stabilizes by ages 2-3 in infants, these differential growth patterns are probably established early in life.4 And as usually happens not only among males and females, emmetropic or low hyperopic eyes that develop low corneal powers are longer than eyes that stay with steep corneas (first described by Sorsby9). It is believed that this coordination between ocular components is produced by defocus mechanisms that affect the retino-scleral message that governs ocular growth.10
It has been shown that the limit after which a long axial length ends in myopic maculopathy is shorter in women vs. men.11 One of the believed reasons for myopic maculopathy, besides hypoxia, is retinal thinning as the non-growing retina adapts to an increased rate of myopic scleral elongation during school years. The case is that when environmental triggers (like lagging when reading black text in low illuminated environments) begin to act after age 6 and myopia develops, some of those developing myopic eyes have normal corneas of 43.00D and medium axial lengths of 23mm for 6 year old children, but others have 46.00D corneas with 22mm long eyes, and even some have 40.00D corneas with 24mm long eyes. These ones will grow 1mm in the next 10 years if remaining emmetropic, but about 2-3mm if developing myopia. Following what is suggested about ocular growth, these eyeballs with low powered corneas (or lenses) may be longer eyes which are at higher risk of reaching the threshold for myopic maculopathy.
It is possible that not only the axial length and gender should be monitored with ocular growth curves,12 but the unique data of the keratometry could be split by tertiles in ocular growth curves of boys and girls (as keratometry will not change with growth during school years). This relationship between fundus myopic changes in children and keratometry has been also shown in the recent paper by Gong et al. which has motivated our short report.13 Those children with flatter corneas could be devoted to special care as they are the ones who possibly rank high in axial length dimensions and may be the ones more prone to myopic maculopathy.14
1. Young RW. Cell proliferation during postnatal development of the retina in the mouse. Brain Res 1985;353(2):229-39.
2. Kubota R, Hokoc JN, Moshiri A, et al. A comparative study of neurogenesis in the retinal ciliary marginal zone of homeothermic vertebrates. Brain Res Dev Brain Res 2002;134(1-2):31-41.
3. Tkatchenko AV, Walsh PA, Tkatchenko TV, et al. Form deprivation modulates retinal neurogenesis in primate experimental myopia. Proc Natl Acad Sci U S A 2006;103(12):4681-6.
4. Iribarren R. Crystalline lens and refractive development. Prog Retin Eye Res 2015;47:86-106.
5. Rozema JJ, Herscovici Z, Snir M, Axer-Siegel R. Analysing the ocular biometry of new-born infants. Ophthalmic Physiol Opt 2017.
6. Mutti DO, Mitchell GL, Jones LA, et al. Axial growth and changes in lenticular and corneal power during emmetropization in infants. Invest Ophthalmol Vis Sci 2005;46(9):3074-80.
7. Blomdahl S. Ultrasonic measurements of the eye in the newborn infant. Acta Ophthalmol (Copenh) 1979;57(6):1048-56.
8. Iribarren R, Morgan IG, Hashemi H, et al. Lens power in a population-based cross-sectional sample of adults aged 40 to 64 years in the Shahroud Eye Study. Invest Ophthalmol Vis Sci 2014;55(2):1031-9.
9. Benjamin B, Davey JB, Sheridan M, et al. Emmetropia and its aberrations; a study in the correlation of the optical components of the eye. Spec Rep Ser Med Res Counc (G B) 1957;11(293):1-69.
10. Wallman J, Winawer J. Homeostasis of eye growth and the question of myopia. Neuron 2004;43(4):447-68.
11. Hashimoto S, Yasuda M, Fujiwara K, et al. Association between Axial Length and Myopic Maculopathy: The Hisayama Study. Ophthalmol Retina 2019;3(10):867-73.
12. Tideman JWL, Polling JR, Vingerling JR, et al. Axial length growth and the risk of developing myopia in European children. Acta Ophthalmol 2018;96(3):301-9.
13. Gong W, Cheng T, Wang J, et al. Role of corneal radius of curvature in early identification of fundus tessellation in children with low myopia. Br J Ophthalmol 2022.
14. Galan MM TW, Iribarren R. El rol de la longitud axial y la queratometría en el seguimiento de niños miopes Oftalmologia Clinica y Experimental 2021;14(2).
Randomized controlled trials (RCTs) are considered to be the best method for evaluating the effectiveness of medical interventions.1 Despite their strengths, RCTs have substantial limitations.1 Although RCTs have strong internal validity, they occasionally lack external validity and generalizations of findings outside the study population may be invalid. More specifically in retinal surgery, there are many obstacles to conducting RCTs to address the specific questions asked, so the analysis using real-world data is useful.2 Drs Anguita and Charteris wrote an editorial in the British Journal of Ophthalmology (BJO) on the merits and limitations of studies using real-world data.3 They cited our papers that were recently published in BJO which used the data collected in the Japan Retinal Detachment Registry (J-RD registry), and I would like to comment on with a focus on the retinal surgery.4,5
As correctly stated by Drs Anguita and Charteris, studies using the propensity score matching method cannot be performed well if one is not familiar with the limitations of this technique. 3 However, this is also true for those who do not have a deep understanding of the disease and may make incorrect interpretations. This would be the case for our paper4 cited in the editorial. This study compared pars plana vitrectomy (PPV) and scleral buckling for superior RD without macula detachment using the data from the J-RD registry. The results which were analyzed using propensity score...
Randomized controlled trials (RCTs) are considered to be the best method for evaluating the effectiveness of medical interventions.1 Despite their strengths, RCTs have substantial limitations.1 Although RCTs have strong internal validity, they occasionally lack external validity and generalizations of findings outside the study population may be invalid. More specifically in retinal surgery, there are many obstacles to conducting RCTs to address the specific questions asked, so the analysis using real-world data is useful.2 Drs Anguita and Charteris wrote an editorial in the British Journal of Ophthalmology (BJO) on the merits and limitations of studies using real-world data.3 They cited our papers that were recently published in BJO which used the data collected in the Japan Retinal Detachment Registry (J-RD registry), and I would like to comment on with a focus on the retinal surgery.4,5
As correctly stated by Drs Anguita and Charteris, studies using the propensity score matching method cannot be performed well if one is not familiar with the limitations of this technique. 3 However, this is also true for those who do not have a deep understanding of the disease and may make incorrect interpretations. This would be the case for our paper4 cited in the editorial. This study compared pars plana vitrectomy (PPV) and scleral buckling for superior RD without macula detachment using the data from the J-RD registry. The results which were analyzed using propensity score matching showed that there was no significant difference in the best-corrected visual acuity at 6 months after surgery, but there were significantly fewer surgical failures with scleral buckling than with PPV. Thus, we concluded that, “Although the indications for PPV are becoming broader, PPV may not be the optimal approach for repairing all types of RDs. Therefore, careful considerations are needed when selecting the appropriate surgical technique in treating uncomplicated phakic macula-on RD case”, knowing the limitation of evidence level obtained from real-world data study.4 The editorial by Drs Anguita and Charteris indicated that a major problem with this study was the lack of adjustments for the presence or absence of a posterior vitreous detachment (PVD) which is the most important factor in selecting the surgical method.3 Traditionally, the presence of a PVD has been determined by echography, but its accuracy is inferior to that of optical coherence tomography, and above all, it was found to vary from operator to operator.6 On the other hand, it is widely accepted that almost all cases of retinal tears are caused by a PVD,7 so we decided it would be more objective to adjust the evaluations of PVD by using retinal tear or hole instead. We believed that this analysis, in which preoperative factors were adjusted for retinal tear and/or hole, adjusted for PVD to an acceptable level. Without understanding this background, the findings of this paper might be misinterpreted. On the other hand, we mention in the paper by Funatsu et al, which was also cited in the editorial, on the potential toxic effects of silicone.5 There was a misunderstanding of the intent of our study, however because of space limitation, we will not discuss it here.
We agree that the analysis of real-world data using propensity score matching has its limitations.3 However, there are major problems in implementing RCTs in retinal surgery. First, RCTs are very costly, and the overall cost of an RCT study has skyrocketed to a level that cannot be borne by the surgeons or researchers. In recent years, RCTs are no longer conducted unless they are sponsored by large pharmaceutical companies that can profit from the results of RCTs.8 Additionally, if the drug is not effective, it will not necessarily be published.8 Studies in which the company's profit is not clear, such as retinal surgical treatments, are less likely to be adopted as a topic of study. Second, RCT is time-consuming. It usually takes only a few weeks to complete a study using registry data, but it generally takes years to complete RCT studies from planning, implementation, and analyzation. If prospective RCTs were performed for comparing PPV and scleral buckling for superior RD as in our study, it would have taken several years to accomplish the project. Furthermore, it has been noted that RCTs are virtually impossible to perform to compare existing and new surgical methods because surgeons’ preferences already exist and enrollment does not work.9 In general, surgeons want to know how to save the patient in front of them, often an individual problem, as soon as possible. Not only is it extremely difficult to recruit patients for an RCT who meet the inclusion criteria of individual problem of retinal surgery, and it can take several years to obtain the results.9 Thus, it is not practical to use an RCT for this purpose.
The editorial by Drs Anguita and Charteris is very important and I congratulate that. As they stated, we do not believe that the results obtained from real-world data analysis can replace the evidence of RCTs, either. On the other hand, it is true that RCTs cannot answer all of the surgical questions. Most importantly, RCTs are essentially experimental trials of humans. It is unclear whether it will continue to be ethically acceptable to put a large number of subjects at risk even for medical purposes. In contrast, real-world data analyses are basically retrospective studies so it does not expose patients to any new risks. Until better analysis methods are developed, real-world data analysis will provide certain answers to many problems which surgeons have. Nevertheless, I fully agree with them that the researchers and the readers need to recognize the validity and limitations of propensity score matching studies as well as to know the background of the treatment.
REFERENCES
1. Frieden TR. Evidence for Health Decision Making - Beyond Randomized, Controlled Trials. N Engl J Med 2017;377:465-75.
2. Ryan EH, Ryan CM, Forbes NJ, et al. Primary Retinal Detachment Outcomes Study Report Number 2: Phakic Retinal Detachment Outcomes. Ophthalmology 2020;127:1077-85.
3. Anguita R, Charteris D. Could real-world data replace evidence from clinical trials in surgical retinal conditions? Br J Ophthalmol 2022:bjophthalmol-2022-321759. doi: 10.1136/bjophthalmol-2022-321759. Epub ahead of print. PMID: 35580995.
4. Kawano S, Imai T, Sakamoto T; Japan-Retinal Detachment Registry Group. Scleral buckling versus pars plana vitrectomy in simple phakic macula-on retinal detachment: a propensity score-matched, registry-based study. Br J Ophthalmol 2022:857-62.
5. Funatsu R, Terasaki H, Koriyama C, et al. Silicone oil versus gas tamponade for primary rhegmatogenous retinal detachment treated successfully with a propensity score analysis: Japan Retinal Detachment Registry. Br J Ophthalmol 2021:bjophthalmol-2021-319876. doi: 10.1136/bjophthalmol-2021-319876. Epub ahead of print. PMID: 34373251.
6. Moon SY, Park SP, Kim YK. Evaluation of posterior vitreous detachment using ultrasonography and optical coherence tomography. Acta Ophthalmol 2020;98:e29-e35.
7. Michaels RG, Wilkinson CP, Rice TA. Vitreoretinal precursors of retinal detachment. In Retinal detachment, eds Michaels RG, Wilkinson CP, Rice TA, The CV Mosby Company, St Louis, 1990, pp 29-100.
8. Flacco ME, Manzoli L, Boccia S, et al. Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor. J Clin Epidemiol 2015;68:811-20.
9. Lonjon G, Boutron I, Trinquart L, et al. Comparison of treatment effect estimates from prospective nonrandomized studies with propensity score analysis and randomized controlled trials of surgical procedures. Ann Surg 2014;259:18–25.
We read with interest the manuscript published by Sakamoto et al, on behalf of the Japanese Retina and Vitreous Society, titled: Increased incidence of endophthalmitis after vitrectomy relative to face mask-wearing during COVID-19 pandemic”.[1] In this manuscript, the authors discuss their results after comparing the total prevalence of infectious endophthalmitis among patients that underwent ocular surgery, before and after the peak of the SARS-CoV-2 pandemic in Japan.[1] The authors should be commended due to the level of complexity and significant effort needed to coordinate several centers simultaneously, as well as the detailed description provided in the manuscript regarding the clinical presentation, microbiological results, and outcomes of all cases. Interestingly and despite the low rate of positive vitreous cultures, the authors were able to isolate oral bacteria among several of the cases that developed endophthalmitis during the pandemic, including one caused by Staphylococcus lugdunensis; a pathogen typically hard to eliminate with mechanical washing bacteria, because it accumulates behind the auricle.[1] With all this evidence, the authors provided a compelling argument regarding the inappropriate wearing of face masks could increase the risk of postoperative endophthalmitis. Nevertheless, we believe that there are a few important considerations that the authors may need to address before making such an assumption.
As a start, we ca...
We read with interest the manuscript published by Sakamoto et al, on behalf of the Japanese Retina and Vitreous Society, titled: Increased incidence of endophthalmitis after vitrectomy relative to face mask-wearing during COVID-19 pandemic”.[1] In this manuscript, the authors discuss their results after comparing the total prevalence of infectious endophthalmitis among patients that underwent ocular surgery, before and after the peak of the SARS-CoV-2 pandemic in Japan.[1] The authors should be commended due to the level of complexity and significant effort needed to coordinate several centers simultaneously, as well as the detailed description provided in the manuscript regarding the clinical presentation, microbiological results, and outcomes of all cases. Interestingly and despite the low rate of positive vitreous cultures, the authors were able to isolate oral bacteria among several of the cases that developed endophthalmitis during the pandemic, including one caused by Staphylococcus lugdunensis; a pathogen typically hard to eliminate with mechanical washing bacteria, because it accumulates behind the auricle.[1] With all this evidence, the authors provided a compelling argument regarding the inappropriate wearing of face masks could increase the risk of postoperative endophthalmitis. Nevertheless, we believe that there are a few important considerations that the authors may need to address before making such an assumption.
As a start, we can mention a few methodological irregularities that are hallmarks of any retrospective study and thus unavoidable. However, some may carry a significant relevance to the outcome such as the lack of rigor in the definition of postoperative endophthalmitis in the inclusion/exclusion criteria. In their manuscript, Sakamoto et al considered postoperative endophthalmitis, any intraocular infection that developed within 42 days after surgery. Although we agree with this definition, we must clarify that this definition refers to the maximum time elapsed between the invasion of the intraocular space by the offending bacteria, which is during surgery, and the development of the first clinical symptoms. Which, depending on the bacteria's virulence, could be up to 6 weeks. The latest optical coherence tomography and ultrasound biomicroscopy evidence have shown that sclerotomies after a pars plana vitrectomy seal between 8 and 15 days after surgery, even after a sutureless approach.[2 3] Therefore, it is highly unlikely that the source of infection originated after this time, as the authors seem to imply. Moreover, although the authors’ argument that face masking may increase the contamination of the periocular area makes sense, laboratory evidence has shown that there is no difference between bacterial dispersion toward the ocular surface when comparing different types of masks and masking techniques (tape in the superior border of the mask and no tape).[4] Nevertheless, we do agree that wearing a face mask before or during surgery may induce ocular surface changes such as dry eye disease and subclinical infectious keratitis, which might hypothetically increase the risk of endophthalmitis. If we consider the possible exhaustion of the surgical team (human error), scarcity of surgical disinfectants, and other factors that occurred during the peak of the SARS-CoV-2 pandemic, this should place the source of the infection during surgery and not after it. The high prevalence of Streptococcal endophthalmitis in the SARS-CoV-2 mask period (as defined by the authors), supports indeed the notion that contamination may come from the oral flora, very similar to the reports of post intravitreal injection endophthalmitis. However, bacteria such as Streptococcus mitis and Streptococcus salivarius are usually described as low-virulence or opportunistic pathogens. Therefore, the onset time of the clinical symptoms of endophthalmitis, information not described in the manuscript, could have helped the reader to infer if the contamination occurred during surgery or during the postoperative time.
Finally, the result observed regarding the prevalence of postoperative endophthalmitis in the only-phacoemulsification group, is not consistent with the main hypothesis suggested by the authors, and points in the opposite direction. If how the patient uses the mask during the postoperative period is indeed a determinant factor in endophthalmitis development and, considering that the prevalence of endophthalmitis after vitrectomy is usually lower in comparison to other surgical procedures [5]; we should have expected a proportional increase in the prevalence in all three groups. The latter might be the result of a lack of a sample calculation and therefore an error type 1, which should have been mentioned in the limitation section. A throughout analysis of the surgical circumstance per group is also lacking. Consequently, it is not clear at this time if other significant risk factors (trauma, intraocular foreign body, posterior capsule rupture) for endophthalmitis were present or not during surgery. A multivariate analysis, controlling for several other risk factors should be enough to shed light on this matter.
We congratulate Sakamoto et al for this outstanding contribution. We will look forward to their reply.
References:
1. Sakamoto T, Terasaki H, Yamashita T, et al. Increased incidence of endophthalmitis after vitrectomy relative to face mask wearing during COVID-19 pandemic. Br J Ophthalmol 2022 doi: 10.1136/bjophthalmol-2022-321357[published Online First: Epub Date]|.
2. Keshavamurthy R, Venkatesh P, Garg S. Ultrasound biomicroscopy findings of 25 G Transconjuctival Sutureless (TSV) and conventional (20G) pars plana sclerotomy in the same patient. BMC Ophthalmol 2006;6:7 doi: 10.1186/1471-2415-6-7[published Online First: Epub Date]|.
3. Sawada T, Kakinoki M, Sawada O, Kawamura H, Ohji M. Closure of sclerotomies after 25- and 23-gauge transconjunctival sutureless pars plana vitrectomy evaluated by optical coherence tomography. Ophthalmic Res 2011;45(3):122-8 doi: 10.1159/000318875[published Online First: Epub Date]|.
4. Angaramo S, Law JC, Maris AS, et al. Potential impact of oral flora dispersal on patients wearing face masks when undergoing ophthalmologic procedures. BMJ Open Ophthalmol 2021;6(1):e000804 doi: 10.1136/bmjophth-2021-000804[published Online First: Epub Date]|.
5. AlBloushi B, Mura M, Khandekar R, et al. Endophthalmitis Post Pars Plana Vitrectomy Surgery: Incidence, Organisms' Profile, and Management Outcome in a Tertiary Eye Hospital in Saudi Arabia. Middle East Afr J Ophthalmol 2021;28(1):1-5 doi: 10.4103/meajo.MEAJO_424_20[published Online First: Epub Date]|.
To the editor
We read the article published by Patel et al. with considerable interest [1]. The authors have provided interestingly novel insights into the prevalence and risk factors for chalazion. In their large case-control study comprising 3,453,944 older veteran participants with/without chalazion, the risk factors for chalazion included smoking, conditions of the tear film, conjunctivitis, dry eye, conditions affecting periocular skin, rosacea, allergic conditions, and systemic disorders, such as anxiety. Considering the relationship between chalazion and anxiety, a similar trend as reported in the previous study by Nemet et al. was observed [2]. Moreover, anxiety is generally considered as a psychological reaction to stress [3, 4]. Alsammahi et al. reported that stress is associated with the development of chalazion [5]. In real-world settings, we realize that patients with the onset of chalazion are likely to have anxiety or stress (such as work and examination).
Incidentally, in the c...
To the editor
We read the article published by Patel et al. with considerable interest [1]. The authors have provided interestingly novel insights into the prevalence and risk factors for chalazion. In their large case-control study comprising 3,453,944 older veteran participants with/without chalazion, the risk factors for chalazion included smoking, conditions of the tear film, conjunctivitis, dry eye, conditions affecting periocular skin, rosacea, allergic conditions, and systemic disorders, such as anxiety. Considering the relationship between chalazion and anxiety, a similar trend as reported in the previous study by Nemet et al. was observed [2]. Moreover, anxiety is generally considered as a psychological reaction to stress [3, 4]. Alsammahi et al. reported that stress is associated with the development of chalazion [5]. In real-world settings, we realize that patients with the onset of chalazion are likely to have anxiety or stress (such as work and examination).
Incidentally, in the coronavirus disease 2019 (COVID-19) pandemic era, Silkiss et al. reported that the incidence of chalazion increased with widespread mask wear, possibly resulting from eye dryness and changes in the eyelid microbiome associated with wearing face coverings [6]. Moreover, the widespread COVID-19 vaccinations provide many opportunities to examine the chalazion of patients who had recently received the vaccination at our institution, and most of these patients had anxiety or stress regarding the vaccination. To the best of our knowledge, the association between chalazion and COVID-19 vaccination has not been debated. Moreover, determining whether the chalazion occurred immediately after the vaccination was causation or coincidence is difficult because this disease is common and often observed in unvaccinated patients as well. However, we believe that these cases confirmed the result of Patel et al.’s study, wherein anxiety was associated with the risk of chalazion development. The need for vaccination against COVID-19 will continue because of the increased supply of COVID-19 vaccines for developing nations, recommendation of the third dose of vaccine, and the lowering of the age for vaccination against COVID-19, mainly in developed countries. Therefore, to elucidate the mechanism of chalazion after the vaccination, increasingly reliable care of this symptom following vaccination is warranted.
References
1. Patel S, Tohme N, Gorrin E, Kumar N, Goldhagen B, Galor A. Prevalence and risk factors for chalazion in an older veteran population. Br J Ophthalmol. 2021 Mar 31; bjophthalmol-2020-318420.
doi: 10.1136/bjophthalmol-2020-318420. Online ahead of print.
2. Nemet AY, Vinker S, Kaiserman I. Associated morbidity of chalazia. Cornea 2011; 30: 1376-1381.
3. Robinson L. Stress and anxiety. Nurs Clin North Am 1990; 25: 935-943.
4. American Psychological Association. Stress won’t go away? Maybe you are suffering from chronic stress. Available online: https://www.apa.org/topics/stress/chronic. Accessed March 15, 2022.
5. Alsammahi A, Aljohani Z, Jaad N, Daia OA, Aldayhum M, Almutairi M, Basendwah M, Alzahrani R, Alturki M. Incidence and predisposing factors of chalazion. Int J Community Med Public Health 2018; 5: 4979-4982.
6. Silkiss RZ, Paap MK, Ugradar S. Increased incidence of chalazion associated with face mask wear during the COVID-19 pandemic. Am J Ophthalmol Case Rep 2021; 22: 101032.
We read with interest the article by Sarker et al(1) in which they compared the outcomes of trabeculectomy versus Ahmed glaucoma valve (AGV) implantation in Sturge–Weber syndrome (SWS) patients with secondary glaucoma aged 11-62 years. As it noted in the paper, the authors found that complete success rates after 24 months were 80% and 70% in the AGV and trabeculectomy groups, respectively, and qualified success rates were 90% and 85% at same period in the AGV and trabeculectomy groups, respectively. We were delighted to get the conclusion that both AGV implant and trabeculectomy appeared to be safe and efficacious in controlling glaucoma secondary to SWS.
As it reported by Mohamed et al., the complete success rate and qualified success rate (intraocular pressure≤17mmHg) of trabeculectomy reported were 80% and 100% at 12 postoperative follow-up month, respectively(2). However, the qualified success rate (90%) of AGV implantation in SWS patients with secondary glaucoma is higher than that reported by Hamush et al. (79%)(3) and Kaushik et al. (76%)(4) at 2 years of follow-up. Meanwhile, the trabeculectomy with MMC success rate in this study was comparable to other studies about primary glaucoma(5, 6), but the success rate of tube shunt surgery was higher than in prior reports. The qualified success rate of Baerveldt implantation for patients who not had undergone previous incisional ocular surgery was 73% in Primary Tube Versus Trabeculectomy (PTVT) study(6) and 75% rep...
We read with interest the article by Sarker et al(1) in which they compared the outcomes of trabeculectomy versus Ahmed glaucoma valve (AGV) implantation in Sturge–Weber syndrome (SWS) patients with secondary glaucoma aged 11-62 years. As it noted in the paper, the authors found that complete success rates after 24 months were 80% and 70% in the AGV and trabeculectomy groups, respectively, and qualified success rates were 90% and 85% at same period in the AGV and trabeculectomy groups, respectively. We were delighted to get the conclusion that both AGV implant and trabeculectomy appeared to be safe and efficacious in controlling glaucoma secondary to SWS.
As it reported by Mohamed et al., the complete success rate and qualified success rate (intraocular pressure≤17mmHg) of trabeculectomy reported were 80% and 100% at 12 postoperative follow-up month, respectively(2). However, the qualified success rate (90%) of AGV implantation in SWS patients with secondary glaucoma is higher than that reported by Hamush et al. (79%)(3) and Kaushik et al. (76%)(4) at 2 years of follow-up. Meanwhile, the trabeculectomy with MMC success rate in this study was comparable to other studies about primary glaucoma(5, 6), but the success rate of tube shunt surgery was higher than in prior reports. The qualified success rate of Baerveldt implantation for patients who not had undergone previous incisional ocular surgery was 73% in Primary Tube Versus Trabeculectomy (PTVT) study(6) and 75% reported by Islamaj et al(5)at 2 years of follow-up. The qualified success rates of AGV implantation and Baerveldt implantation for patients with refractory glaucoma were 76% and 68% at 2 years of follow-up, respectively(7).
This more favorable result of AGV implantation relative to previous reports may because this small sample size study excluded 8 patients (16.7%), enrolled patients may uncomplete 2 years of review, or most of them are older than 18 years old compared with other study about SWS patients with secondary glaucoma(3, 4). The study enrolled eyes may at lower risk of surgical failure than that excluded from the study. As the authors mentioned, a total of 48 patients in glaucoma associated with SWS were surgically treated and 8 patients were excluded because of unreliable follow-ups and/or incomplete case records. Substantial differences in the success rate of cases with and without follow-up may overestimate the success rates of two surgeries and prove misleading on interpreting the results in this small sample size, retrospective study. What’s more, mean±SD follow-up in the study was 23.15±2.36 (range, 15–24) and 22.95±2.87 (range, 13–24) in the AGV and trabeculectomy groups, respectively, which may indicate incomplete 2 years of review for some patients. Patients who experienced successful surgical treatment at 15 months may subsequently experience treatment failure at 24 months. It’s better to supplement the number of patients at each follow up visit.
In conclusion, since the small sample size, it is better to supplement the outcomes of eight patients excluded from the study and the number of patients at each follow up visit so as to yield more convincing results.
Reference
1. Sarker BK, Malek MA, Mannaf SMA, Iftekhar QS, Mahatma M, Sarkar MK, et al. Outcome of trabeculectomy versus Ahmed glaucoma valve implantation in the surgical management of glaucoma in patients with Sturge-Weber syndrome. Br J Ophthalmol. 2021;105(11):1561-5.
2. Mohamed T, Salman A, Elshinawy R. Trabeculectomy with Ologen implant versus mitomycin C in congenital glaucoma secondary to Sturge Weber Syndrome. International journal of ophthalmology. 2018;11(2):251-5.
3. Hamush N, Coleman A, Wilson M. Ahmed glaucoma valve implant for management of glaucoma in Sturge-Weber syndrome. American journal of ophthalmology. 1999;128(6):758-60.
4. Kaushik J, Parihar J, Jain V, Mathur V. Ahmed valve implantation in childhood glaucoma associated with Sturge-Weber syndrome: our experience. Eye (London, England). 2019;33(3):464-8.
5. Islamaj E, Wubbels R, de Waard P. Primary baerveldt versus trabeculectomy study after 5 years of follow-up. Acta ophthalmologica. 2020;98(4):400-7.
6. Gedde SJ, Feuer WJ, Lim KS, Barton K, Goyal S, Ahmed IIK, et al. Treatment Outcomes in the Primary Tube Versus Trabeculectomy Study after 3 Years of Follow-up. Ophthalmology. 2020;127(3):333-45.
7. Christakis P, Zhang D, Budenz D, Barton K, Tsai J, Ahmed I. Five-Year Pooled Data Analysis of the Ahmed Baerveldt Comparison Study and the Ahmed Versus Baerveldt Study. American journal of ophthalmology. 2017;176:118-26.
Affiliations:
Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
Conflicts of Interest Disclosure:
APT: Consultant to Ivantis, Sandoz, and Zeiss
Acknowledgment:
APT is supported by an unrestricted departmental grant from Research to Prevent Blindness, NY, NY
Corresponding Author:
Angelo P. Tanna, M.D.
Department of Ophthalmology
Northwestern University Feinberg School of Medicine
645 N. Michigan Ave., Suite 440
Chicago, IL 60611
Telephone: 312-908-8152
Fax: 312-503-8152
E-mail: atanna@northwestern.edu
Dear Editor:
I read with interest the work of Doctor Hashimoto and colleagues on the risk of adverse neonatal outcomes (congenital anomalies, preterm birth, low birth weight) associated with maternal exposure to intraocular pressure-lowering medications during pregnancy.1 They used a large Japanese claims database and state-of-the-art statistical methodology to evaluate the frequency of adverse events in a cohort of live births of 91 women who had “at least one dispensation of IOP-lowering medications during the first trimester,” compared to that observed in 735 women with glaucoma or...
Affiliations:
Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
Conflicts of Interest Disclosure:
APT: Consultant to Ivantis, Sandoz, and Zeiss
Acknowledgment:
APT is supported by an unrestricted departmental grant from Research to Prevent Blindness, NY, NY
Corresponding Author:
Angelo P. Tanna, M.D.
Department of Ophthalmology
Northwestern University Feinberg School of Medicine
645 N. Michigan Ave., Suite 440
Chicago, IL 60611
Telephone: 312-908-8152
Fax: 312-503-8152
E-mail: atanna@northwestern.edu
Dear Editor:
I read with interest the work of Doctor Hashimoto and colleagues on the risk of adverse neonatal outcomes (congenital anomalies, preterm birth, low birth weight) associated with maternal exposure to intraocular pressure-lowering medications during pregnancy.1 They used a large Japanese claims database and state-of-the-art statistical methodology to evaluate the frequency of adverse events in a cohort of live births of 91 women who had “at least one dispensation of IOP-lowering medications during the first trimester,” compared to that observed in 735 women with glaucoma or suspicion of glaucoma who did not have such an exposure.
The authors discuss the previously used and outdated United States Food and Drug Administration (FDA) risk classification system for drugs used during pregnancy. The FDA required the removal of the pregnancy letter categories – A, B, C, D, and X from all drug product labels in 2015. Instead, for systemically absorbed drugs (which includes all ocular hypotensive medications), the FDA requires labeling to include a summary of the risks of using a drug during pregnancy as well as “risk statements based on data from all relevant sources (human, animal, and/or pharmacologic), that describe, for the drug, the risk of adverse developmental outcomes.”2
The investigators observed any adverse outcome in 17.6% of neonates with and in 13.3% without fetal exposure to IOP-lowering medications. The authors concluded that after propensity score adjustment, IOP-lowering medications were not significantly associated with more frequent adverse events. For example, the adjusted odds ratio for congenital anomalies was 1.43 (95% CI, 0.66 to 3.12).
The investigators only evaluated live births; therefore, the potentially increased risk of spontaneous abortion or fetal demise associated with the use of these agents during pregnancy cannot be known from this analysis. It is possible some of the women in the control cohort may have been exposed to ocular hypotensive agent(s) during the first trimester, using medication already in their possession, without necessarily having been dispensed any such agent during the first trimester. This could confound the comparative analysis.
Finally, the authors report their study had a power > 80% for detecting a two-fold increase in the composite outcome (i.e., the risk of any of the adverse neonatal outcomes studied). This begs the question: How much increased risk is a pregnant woman willing to accept? I believe a much lower threshold is necessary to arrive at a meaningful conclusion. In my experience, many women would reject even a 1% increase in the risk of a congenital anomaly. So then, the concluding message in the abstract that “IOP-lowering medications during the first trimester were not significantly associated with increase in congenital anomalies, preterm birth or low birth weight” is not meaningfully supported by the data. The study only supports the concept that the use of these medications is probably not associated with a doubling of the risk. Patients and society are interested in a higher threshold of safety.
Fortunately, pregnancy is often associated with a spontaneous reduction in intraocular pressure (IOP)4; therefore, continued treatment may not be required. Selective laser trabeculoplasty is also an option to consider for some patients. Moreover, many young patients with glaucoma can tolerate nine months of higher IOP.
Glaucoma in pregnancy is a complex problem that requires complex, collaborative decision-making. Pregnant women, their ophthalmologists and obstetricians must evaluate the potential risks associated with continued use of ocular hypotensive agents during pregnancy and weigh those against the risks of modifying or stopping therapy. I congratulate the authors on exploring this important topic and encourage others to conduct similar studies. Eventually, a meta-analysis may yield evidence that can guide clinical decision-making.
REFERENCES:
1. Hashimoto Y, Michihata N, Yamana H, Shigemi D, Morita K, Matsui H, Yasunaga H, Aihara M. Intraocular pressure-lowering medications during pregnancy and risk of neonatal adverse outcomes: a propensity score analysis using a large database. Br J Ophthalmol. 2021 Oct;105(10):1390-1394. doi: 10.1136/bjophthalmol-2020-316198. Epub 2020 Sep 9. PMID: 32907812.
2. Content and Format of Labeling for Human Prescription Drug and Biological Products;
Requirements for Pregnancy and Lactation Labeling. Department of Health and Human Services. Food and Drug Administration 21 CFR Part 201 [Docket No. FDA-2006-N-0515] RIN 0910-AF11. Available online at http://federalregister.gov/a/2014-28241.
3. Mezawa H, Tomotaki A, Yamamoto-Hanada K, Ishitsuka K, Ayabe T, Konishi M, Saito M, Yang L, Suganuma N, Hirahara F, Nakayama SF, Saito H, Ohya Y. Prevalence of Congenital Anomalies in the Japan Environment and Children's Study. J Epidemiol. 2019 Jul 5;29(7):247-256. doi: 10.2188/jea.JE20180014. Epub 2018 Sep 22. PMID: 30249945; PMCID: PMC6556438.
4. Ziai N, Ory SJ, Khan AR, Brubaker RF. Beta-human chorionic gonadotropin, progesterone, and aqueous dynamics during pregnancy. Arch Ophthalmol. 1994 Jun;112(6):801-6. doi: 10.1001/archopht.1994.01090180099043. PMID: 8002840.
Dear Editor:
We read the paper on non-invasive intracranial pressure determination by Zhang et al(1) with great interest and hope. We fully agree that the search for non-invasive intracranial pressure (ICP) evaluations is of high importance and should be continued. The Bland-Altman plot showing the difference between predicted and intracranially measured pressure looks very impressive. There are, however, still a few points and limits we would like to address concerning the anatomy of the optic nerve, the optic canal, and the basic concept the authors used.
Cerebrospinal fluid (CSF) from the intracranial subarachnoid spaces and the subarachnoid space of the optic nerve (SAS -ON) communicate via the optic canal. Using three-dimensional reconstruction of the optic canal in normal tension glaucoma (NTG) patients, this was found to be narrower than in an age-related cohort of normals,(2) thus questioning the patency of the CSF pathway between the pituitary cistern and the SAS-ON. Further, optic canal dimensions in a normal population are quite variable amongst individuals, and even between orbits within the same individual.(3) These facts largely influence the results the authors present. Further, studies in patients with NTG and patients with elevated ICP (such as patients with idiopathic intracranial hypertension) were shown to have developed an optic nerve sheath compartment syndrome. In such cases, the CSF dynamics between the intracranial CSF and the CSF in...
Show MoreWe read with great interest the article of Gokhale et al [1] on their retrospective study of metformin use and risk of age-related macular degeneration (AMD) in individuals with type 2 diabetes mellitus (T2DM). In this study Gokhale and colleagues used data derived from IQVIA Medical Research Data (IMRD-UK), formerly known as The Health Improvement Network (THIN), and found no change in AMD risk in those taking metformin.
An issue with this study is the quality of the GP coding and data on AMD. The authors cite a validation study of THIN data [2] but this study only validated cases identified as having AMD. There was no validation of the quality of data on the absence of AMD. So, the confirmation of positives was high (confirmed AMD cases quoted as 97%) but the false negative rate, is unknown. Also, the validation was by an ophthalmologist reviewing all the GP data, not using recognised diagnostic criteria or a grading scheme for AMD. Furthermore, the authors included a code for “drusen” into their AMD group which was not a code included in the validation study by Vassilev et al [2]. It is likely that this code includes patients with common physiological drusen and not an AMD diagnosis.
We have previously performed a systematic review and meta-analysis [3] of five studies [4–8] on the relationship between metformin use and AMD, which we have now updated to include Gokhale et al [1] and Jiang et al [9]. Including their data, we found a beneficial odds ratio of...
Show MoreMauschitz et al. (1) conducted a meta-analysis to investigate the association of systemic medications with age-related macular degeneration (AMD) in the general population. A pooled odds ratios (95% confidence intervals [CIs]) of lipid-lowering drugs (LLD) and antidiabetic drugs for any AMD were 0.85 (0.79 to 0.91) and 0.78 (0.66 to 0.91), respectively. In contrast, late AMD was not significantly associated with systemic medications. There is an information that antidiabetics, lipid-lowering agents, and antioxidants could theoretically be repurposed for AMD treatment (2). I present information regarding the effect of antidiabetic medications on the risk of AMD.
Blitzer et al. (3) conducted a case-control study and metformin use was significantly associated with reduced odds of AMD, presenting dose dependent manner. But metformin did not have an effect of protecting diabetic retinopathy. In contrast, Gokhale et al. (4) conducted a retrospective cohort study to evaluate the effect of metformin on the risk reduction of AMD. The adjusted hazard ratio (95% CI) of patients prescribed metformin (with or without other antidiabetic medications) against those prescribed any other antidiabetic medication only for AMD was 1.02 (0.92 to 1.12). Vergroesen et al. (5) conducted a cohort study and a lower risk of AMD was not observed in patients with metformin, but other diabetes medication was significantly associated with a lower risk of AMD.
Anyway, clinical trials are nee...
Show MoreThe paper advises that the population inspected was predominately of white background and is looking to find ways of expanding its knowledge of non-white ethnicity within the sphere of retina testing. Within the following paper : Ethnicity and Type 2 diabetes in the UK by
L. M. Goff; it states that the prevalence of Type 2 diabetes within the non-white community is particularly high. a quote from this paper:
"Among minority ethnic communities, the prevalence is alarmingly high, approximately three to five times higher than in the white British population. "
Which brings me to my response: All UK Type 2 diabetics are offered eye screening during which the retina is photographed every year. These digital photographs are examined by medical staff looking for vein bleeding and are held by the NHS. Given the hign incidence of Type 2 diabetes in non-white citizens a very large number of these records will be available and so allow a useful extension to the work done by Professor Rudnicka.
It is generally believed that retinal neurons stop growing in number after birth in humans.1, 2 But recent research has shown retinal neurogenesis in neonatal 1-3 month old monkeys.3 This poses the question of how the sclera and the retina grow during emmetropization. The ora serrata is reported to be 2 mm wide growing to 6-7mm (approximately 5mm difference) in adult life as the scleral tunic grows more than the retina.4 The vitreous chamber depth in newborns is 10.6mm long and also grows roughly by 6 mm to an adult axial value of 17mm on average.5 It is then possible that during the first 3 months of human life, at that rapid growth phase from 17mm to 19mm in mean axial length,6 the retina could grow at least 1mm to compensate in part for that rapid elongation. The eyes of males and females have only a 0.1mm difference at birth with very small differences in body length and head circumference, but bigger born babies have longer eyes with less powerful corneas,7 so a bigger born girl may have a bigger eye with flatter cornea than a smaller born male. When adulthood is reached, women have eyes shorter than those of men by 0.7mm, with steeper corneas and more powerful crystalline lenses.8 As the cornea stabilizes by ages 2-3 in infants, these differential growth patterns are probably established early in life.4 And as usually happens not only among males and females, emmetropic or low hyperopic eyes that develop low corneal powers are longer than eyes that stay with steep co...
Show MoreRandomized controlled trials (RCTs) are considered to be the best method for evaluating the effectiveness of medical interventions.1 Despite their strengths, RCTs have substantial limitations.1 Although RCTs have strong internal validity, they occasionally lack external validity and generalizations of findings outside the study population may be invalid. More specifically in retinal surgery, there are many obstacles to conducting RCTs to address the specific questions asked, so the analysis using real-world data is useful.2 Drs Anguita and Charteris wrote an editorial in the British Journal of Ophthalmology (BJO) on the merits and limitations of studies using real-world data.3 They cited our papers that were recently published in BJO which used the data collected in the Japan Retinal Detachment Registry (J-RD registry), and I would like to comment on with a focus on the retinal surgery.4,5
As correctly stated by Drs Anguita and Charteris, studies using the propensity score matching method cannot be performed well if one is not familiar with the limitations of this technique. 3 However, this is also true for those who do not have a deep understanding of the disease and may make incorrect interpretations. This would be the case for our paper4 cited in the editorial. This study compared pars plana vitrectomy (PPV) and scleral buckling for superior RD without macula detachment using the data from the J-RD registry. The results which were analyzed using propensity score...
Show MoreDear Editor.
We read with interest the manuscript published by Sakamoto et al, on behalf of the Japanese Retina and Vitreous Society, titled: Increased incidence of endophthalmitis after vitrectomy relative to face mask-wearing during COVID-19 pandemic”.[1] In this manuscript, the authors discuss their results after comparing the total prevalence of infectious endophthalmitis among patients that underwent ocular surgery, before and after the peak of the SARS-CoV-2 pandemic in Japan.[1] The authors should be commended due to the level of complexity and significant effort needed to coordinate several centers simultaneously, as well as the detailed description provided in the manuscript regarding the clinical presentation, microbiological results, and outcomes of all cases. Interestingly and despite the low rate of positive vitreous cultures, the authors were able to isolate oral bacteria among several of the cases that developed endophthalmitis during the pandemic, including one caused by Staphylococcus lugdunensis; a pathogen typically hard to eliminate with mechanical washing bacteria, because it accumulates behind the auricle.[1] With all this evidence, the authors provided a compelling argument regarding the inappropriate wearing of face masks could increase the risk of postoperative endophthalmitis. Nevertheless, we believe that there are a few important considerations that the authors may need to address before making such an assumption.
Show MoreAs a start, we ca...
Clinical features of chalazion following COVID-19 vaccination
Yusuke Kameda, Megumi Sugai, Karin Ishinabe, Nichika Fukuoka
Yotsuya-sanchome Ekimae Eye Clinic, Tokyo, Japan
*Corresponding author: Yusuke Kameda, MD, Yotsuya-sanchome Ekimae Eye Clinic, Tokyo, Japan, 3-7-24 Yotsuya, Shinjuku-ku Tokyo 160-0004, Japan.
Phone: 81-3-6380-4101; Fax: 81-3-6380-4133; E-mail: y09025618059@leaf.ocn.ne.jp
To the editor
Show MoreWe read the article published by Patel et al. with considerable interest [1]. The authors have provided interestingly novel insights into the prevalence and risk factors for chalazion. In their large case-control study comprising 3,453,944 older veteran participants with/without chalazion, the risk factors for chalazion included smoking, conditions of the tear film, conjunctivitis, dry eye, conditions affecting periocular skin, rosacea, allergic conditions, and systemic disorders, such as anxiety. Considering the relationship between chalazion and anxiety, a similar trend as reported in the previous study by Nemet et al. was observed [2]. Moreover, anxiety is generally considered as a psychological reaction to stress [3, 4]. Alsammahi et al. reported that stress is associated with the development of chalazion [5]. In real-world settings, we realize that patients with the onset of chalazion are likely to have anxiety or stress (such as work and examination).
Incidentally, in the c...
We read with interest the article by Sarker et al(1) in which they compared the outcomes of trabeculectomy versus Ahmed glaucoma valve (AGV) implantation in Sturge–Weber syndrome (SWS) patients with secondary glaucoma aged 11-62 years. As it noted in the paper, the authors found that complete success rates after 24 months were 80% and 70% in the AGV and trabeculectomy groups, respectively, and qualified success rates were 90% and 85% at same period in the AGV and trabeculectomy groups, respectively. We were delighted to get the conclusion that both AGV implant and trabeculectomy appeared to be safe and efficacious in controlling glaucoma secondary to SWS.
Show MoreAs it reported by Mohamed et al., the complete success rate and qualified success rate (intraocular pressure≤17mmHg) of trabeculectomy reported were 80% and 100% at 12 postoperative follow-up month, respectively(2). However, the qualified success rate (90%) of AGV implantation in SWS patients with secondary glaucoma is higher than that reported by Hamush et al. (79%)(3) and Kaushik et al. (76%)(4) at 2 years of follow-up. Meanwhile, the trabeculectomy with MMC success rate in this study was comparable to other studies about primary glaucoma(5, 6), but the success rate of tube shunt surgery was higher than in prior reports. The qualified success rate of Baerveldt implantation for patients who not had undergone previous incisional ocular surgery was 73% in Primary Tube Versus Trabeculectomy (PTVT) study(6) and 75% rep...
Title: Management of Glaucoma During Pregnancy
Author: Angelo P. Tanna
Affiliations:
Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
Conflicts of Interest Disclosure:
APT: Consultant to Ivantis, Sandoz, and Zeiss
Acknowledgment:
APT is supported by an unrestricted departmental grant from Research to Prevent Blindness, NY, NY
Corresponding Author:
Angelo P. Tanna, M.D.
Department of Ophthalmology
Northwestern University Feinberg School of Medicine
645 N. Michigan Ave., Suite 440
Chicago, IL 60611
Telephone: 312-908-8152
Fax: 312-503-8152
E-mail: atanna@northwestern.edu
Dear Editor:
I read with interest the work of Doctor Hashimoto and colleagues on the risk of adverse neonatal outcomes (congenital anomalies, preterm birth, low birth weight) associated with maternal exposure to intraocular pressure-lowering medications during pregnancy.1 They used a large Japanese claims database and state-of-the-art statistical methodology to evaluate the frequency of adverse events in a cohort of live births of 91 women who had “at least one dispensation of IOP-lowering medications during the first trimester,” compared to that observed in 735 women with glaucoma or...
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