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• Response to the e-letter to editor by Bonnet et al on “The Central corneal basal cell density and nerve parameters in ocular surface disease and limbal stem cell deficiency: a review and meta-analysis”.
  Pradipta Bhattacharya
  Published on: 5 May 2020
• Letter to the Editor
  Clemence Bonnet
  Published on: 9 April 2020

• Published on: 5 May 2020

  Response to the e-letter to editor by Bonnet et al on “The Central corneal basal cell density and nerve parameters in ocular surface disease and limbal stem cell deficiency: a review and meta-analysis”.

  • Pradipta Bhattacharya, Optometrist and vision research, Queensland University of Technology

  To the Editor,

  We appreciate the authors' interest in our study. In their letter to the editor regarding our meta-analysis[1], the authors raise an issue regarding the inclusion of the diseases in the two groups i.e. limbal stem cell deficiency (LSCD) and ocular surface disease (OSD). We adhered to the categorization of the diseases as indicated or mentioned in the publications which were included in the meta-analysis. Our literature search based on combinations of various “key-words” or “key-terms” returned results as depicted in the categorization of the diseases in the study.[2,3] LSCD being a sub-set of OSD, has signs and symptoms in common with many other conditions, hence it was important that the term “limbal stem cell deficiency” appeared in the publications for the study participants to be categorized into the LSCD group.[2,3,4]

  The lack of consideration of the severity of LSCD and OSD was unavoidable due to the limited data within the source publications. It is apparent that the severity of the disease may affect the corneal epithelial basal cell density (BCD) and nerve fibre parameters.[5,6] The lack of data is likely explained by the difficulty in imaging in the more severe disease when corneal transparency is reduced; the corneal basal cells and nerves are difficult to image using confocal microscopy when the cornea is not clear. This is an important factor which is highlighted in our study.[1] Furthermore, our analysis did not attempt to c...

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  To the Editor,

  We appreciate the authors' interest in our study. In their letter to the editor regarding our meta-analysis[1], the authors raise an issue regarding the inclusion of the diseases in the two groups i.e. limbal stem cell deficiency (LSCD) and ocular surface disease (OSD). We adhered to the categorization of the diseases as indicated or mentioned in the publications which were included in the meta-analysis. Our literature search based on combinations of various “key-words” or “key-terms” returned results as depicted in the categorization of the diseases in the study.[2,3] LSCD being a sub-set of OSD, has signs and symptoms in common with many other conditions, hence it was important that the term “limbal stem cell deficiency” appeared in the publications for the study participants to be categorized into the LSCD group.[2,3,4]

  The lack of consideration of the severity of LSCD and OSD was unavoidable due to the limited data within the source publications. It is apparent that the severity of the disease may affect the corneal epithelial basal cell density (BCD) and nerve fibre parameters.[5,6] The lack of data is likely explained by the difficulty in imaging in the more severe disease when corneal transparency is reduced; the corneal basal cells and nerves are difficult to image using confocal microscopy when the cornea is not clear. This is an important factor which is highlighted in our study.[1] Furthermore, our analysis did not attempt to correlate the BCD and corneal nerve parameters in LSCD (or OSD) based on disease severity, the analysis reported the difference in these parameters in LSCD and OSD to those participants with the normal ocular surface.

  The authors report the analysis of corneal nerve fibre length (CNFL) after removing 7 studies from the OSD group and suggest that CNFL was reduced in LSCD compared to OSD. However, removing these studies caused a significant increase in the overall heterogeneity as the I-square value increased to 88.7% as compared to 49.6% in the published report. Furthermore, due to the lack of data in the LSCD group (only 2 studies), it is difficult to draw meaningful conclusions. We addressed this issue of power and what conclusions could be confidently made in the limitation section of our paper. For BCD, after redoing the analysis as suggested by the authors, we did not find a significant difference in the weighted mean difference (WMD) between LSCD and OSD (P=0.11). In addition, the modified analysis showed increased heterogeneity where the I-square value increased to 61.9% compared to 56.1% in the published report. Hence, when statistically considered, we cannot conclude there exists a significant difference in BCD between OSD and LSCD, based on current evidence.

  Various studies have shown reduced corneal nerve parameters and BCD even in systemic diseases like diabetes.[7] Hence, central corneal BCD and nerve fibre parameters need to be used in conjunction with both the clinical presentation and any laboratory results. After considering the Clemence et al.’s suggestions, we are confident that our analysis and method for characterizing the participants remains correct.

  Meta-analysis depends on research groups spending much time and resources collecting primary data. We remain indebted to the authors of the papers we included in our analysis and again thank those that sent us missing data and responded to our queries that enabled the inclusion of their work. When more studies are completed, updated analysis and conclusions can be made on differences in BCD and corneal nerve morphology in OSD and LSCD.

  Authors: Pradipta Bhattacharya, M Phil., Katie Edwards, Ph.D., Damien Harkin, Ph.D., Katrina L Schmid, PhD.

  Financial Disclosures/ Conflict of Interest: None reported.

  REFERENCES
  1. Bhattacharya P, Edwards K, Harkin D, Schmid KL. Central corneal basal cell density and nerve parameters in ocular surface disease and limbal stem cell deficiency: a review and meta-analysis. Br J Ophthalmol 2020.
  2. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009;18;151(4):W-65.
  3. Shortt AJ, Tuft SJ, Daniels JT. Corneal stem cells in the eye clinic. Br Med Bull 2011;100:209–25.
  4. Deng SX, Borderie V, Chan CC, Dana R, Figueiredo FC, Gomes JA, Pellegrini G, Shimmura S, Kruse FE, International Limbal Stem Cell Deficiency Working Group. Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency. Cornea 2019;38(3):364-75.
  5. Chan EH, Chen L, Rao JY, Yu F, Deng SX. Limbal basal cell density decreases in limbal stem cell deficiency. Am J Ophthalmol 2015;160(4):678-84.
  6. Deng SX, Sejpal KD, Tang Q, Aldave AJ, Lee OL, Yu F. Characterization of limbal stem cell deficiency by in vivo laser scanning confocal microscopy: a microstructural approach. Arch Ophthalmol 2012;130(4):440-5.
  7. Dehghani C, Pritchard N, Edwards K, Russell AW, Malik RA, Efron N. Abnormal anterior corneal morphology in diabetes observed using in vivo laser-scanning confocal microscopy. Ocul Surface 2016;14(4):507-14.

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  Conflict of Interest:
  None declared.

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• Published on: 9 April 2020

  Letter to the Editor

  • Clemence Bonnet, Cornea fellow Stein Eye Institute, UCLA

  To the Editor,
  We read with great interest the article entitled “Central corneal basal cell density and nerve parameters in ocular surface disease and limbal stem cell deficiency: a review and meta-analysis”. In the analysis, the authors found a similar reduction of basal cell density (BCD) and corneal nerve parameters between the limbal stem cell deficiency (LSCD) group and the ocular surface disorders (OSD) group. However, several missteps in the study methods occurred.
  First, the analysis included ocular diseases that could lead to LSCD in the OSD group (eg, severe and chronic vernal and atopic keratoconjunctivitis, bullous keratopathy, and ocular graft-versus-host disease).[1] Second, acute microbial infectious keratitis, which is generally not considered as an OSD because of its distinct pathology, was included in the OSD group. Third, the severity of LSCD and OSD was not considered in the analysis. As previously demonstrated, the decrease in BCD and basal nerve density is positively correlated with LSCD severity.[2 3] Fourth, the overall sample size was very small. Lastly, no sensitivity/meta-regression analysis was done despite the significant heterogeneity in the OSD group.
  We repeated the analysis after removing 7 studies wrongly included into the OSD group (Al-Aqaba &al, Leonardi &al, Muller &al -2 reports-, Moein &al, Cavalcanti &al, Tepelus &al) and not including them in the LSCD group because of heterogeneity of the st...

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  To the Editor,
  We read with great interest the article entitled “Central corneal basal cell density and nerve parameters in ocular surface disease and limbal stem cell deficiency: a review and meta-analysis”. In the analysis, the authors found a similar reduction of basal cell density (BCD) and corneal nerve parameters between the limbal stem cell deficiency (LSCD) group and the ocular surface disorders (OSD) group. However, several missteps in the study methods occurred.
  First, the analysis included ocular diseases that could lead to LSCD in the OSD group (eg, severe and chronic vernal and atopic keratoconjunctivitis, bullous keratopathy, and ocular graft-versus-host disease).[1] Second, acute microbial infectious keratitis, which is generally not considered as an OSD because of its distinct pathology, was included in the OSD group. Third, the severity of LSCD and OSD was not considered in the analysis. As previously demonstrated, the decrease in BCD and basal nerve density is positively correlated with LSCD severity.[2 3] Fourth, the overall sample size was very small. Lastly, no sensitivity/meta-regression analysis was done despite the significant heterogeneity in the OSD group.
  We repeated the analysis after removing 7 studies wrongly included into the OSD group (Al-Aqaba &al, Leonardi &al, Muller &al -2 reports-, Moein &al, Cavalcanti &al, Tepelus &al) and not including them in the LSCD group because of heterogeneity of the study populations. We found a significant difference in the weighted mean difference of corneal nerve fiber length (P = 0.003) and a trend for a significant reduction in BCD (P = 0.06) in the LSCD group.
  Because of the significant flaws in the study methods, the results of the analysis are incorrect and the conclusions are misleading. Understanding the pathophysiology and clinical characteristics of diseases is necessary to conduct a meaningful and sound meta-analysis.

  Clemence Bonnet, MD, Tran Tu, MS, Sophie X. Deng, MD, PhD

  References
  1. Deng SX, Borderie V, Chan CC, et al. Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. Cornea 2019;38(3):364-75 doi: 10.1097/ICO.0000000000001820[published Online First: Epub Date]|.
  2. Chan EH, Chen L, Rao JY, Yu F, Deng SX. Limbal Basal Cell Density Decreases in Limbal Stem Cell Deficiency. Am J Ophthalmol 2015;160(4):678-84 e4 doi: 10.1016/j.ajo.2015.06.026[published Online First: Epub Date]|.
  3. Chuephanich P, Supiyaphun C, Aravena C, Bozkurt TK, Yu F, Deng SX. Characterization of the Corneal Subbasal Nerve Plexus in Limbal Stem Cell Deficiency. Cornea 2017;36(3):347-52 doi: 10.1097/ICO.0000000000001092[published Online First: Epub Date]|.

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  Conflict of Interest:
  None

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