Goldmann Tonometry and Corneal Biomechanics
Round 1
Reviewer 1 Report
The authors present a critical analysis of intraocular pressure (IOP) measured by Goldman applanation tonometry (GIOP), the gold standard technique for the measurement of intraocular pressure, compared to measurements obtained by a pressure transducer inserted in the ocular anterior chamber (TIOP). Finally, they found that evidence is crucial for the detection and prevention of glaucoma as one of the main causes of irreversible blindness worldwide.
Really this paper I find great!! I honestly don't see any glitches. I really agree with the authors in the GAT is something of the past (although there is and is ''effective'') which in addition to what the authors already refer (it is influenced by CCT, curvature and stiffening) is highly subjective and with a high interobserver variability (this is already published) and very browser dependent. I really believe that studying or standardizing IOP based on methods that correct these factors (Corvis type) should be the future.
As but to the study, it is in pig's eyes (which although they look alike, logically are not the same) and in addition it was extracted and mounted on a special device which increases the difference even more. It would be interesting although LOGICALLY very difficult to study in vivo.
Author Response
Reviewer #1: The authors present a critical analysis of intraocular pressure (IOP) measured by Goldman applanation tonometry (GIOP), the gold standard technique for the measurement of intraocular pressure, compared to measurements obtained by a pressure transducer inserted in the ocular anterior chamber (TIOP). Finally, they found that evidence is crucial for the detection and prevention of glaucoma as one of the main causes of irreversible blindness worldwide.
Really this paper I find great!! I honestly don't see any glitches. I really agree with the authors in the GAT is something of the past (although there is and is ''effective'') which in addition to what the authors already refer (it is influenced by CCT, curvature and stiffening) is highly subjective and with a high interobserver variability (this is already published) and very browser dependent. I really believe that studying or standardizing IOP based on methods that correct these factors (Corvis type) should be the future.
As but to the study, it is in pig's eyes (which although they look alike, logically are not the same) and in addition it was extracted and mounted on a special device which increases the difference even more. It would be interesting although LOGICALLY very difficult to study in vivo.
We thank the reviewer for his/her enthusiastic appreciation of our work. We added a paragraph on the limitations of our work which also mentions the fact that the study was performed in vitro and not in vivo and in pig eyes, not human eyes.
Reviewer 2 Report
Manuscript Number:applsci-1161694
Goldmann tonometry and corneal biomechanics
The authors presented an interesting study evaluating the relationship between correlations between Goldmann tonometry and corneal biomechanical properties by means of in vitro tests in enucleated pig eyes. The manuscript is with merit and the findings are worth reporting. However, before publication could be considered, the authors should revise the manuscript and address the following concerns.
- INTRODUCTION
- Lines 53-54:“Together with visual field analysis, IOP is the old standard for the diagnosis and the correct evaluation of the progression of the disease.” In addition to the evaluation of the IOP and visual field analysis, the authors should at least cite the importance of the structural evaluation of the ONH and RNFL (with corresponding references) as important aspect of glaucoma diagnosis and progression evaluation.
- DISCUSSION
- The authors should include a paragraph discussing the limitations of the study
- Additional information should be provided regarding the differences between the human and pig eyes which may have influenced the results
- More insight should be provided regarding the clinical applications of the findings in the clinical practice
- TABLES/FIGURE LEGENDS
- Abbreviation are used in the figures and tables without a corresponding explanation in the legends (i.e. Figure 3. IOP should be indicated as Intra Ocular Pressure (IOP) in the legend of the figure): please revise the legends and provide the complete explanation of the abbreviations used
Author Response
Reviewer #2: The authors presented an interesting study evaluating the relationship between correlations between Goldmann tonometry and corneal biomechanical properties by means of in vitro tests in enucleated pig eyes. The manuscript is with merit and the findings are worth reporting. However, before publication could be considered, the authors should revise the manuscript and address the following concerns.
INTRODUCTION
Lines 53-54:“Together with visual field analysis, IOP is the gold standard for the diagnosis and the correct evaluation of the progression of the disease.” In addition to the evaluation of the IOP and visual field analysis, the authors should at least cite the importance of the structural evaluation of the ONH and RNFL (with corresponding references) as important aspect of glaucoma diagnosis and progression evaluation.
R: We thank the reviewer for the comment. We added this sentence and references at lines 58-60:
Recently, useful software has been developed to analyze optical fibers at the peripapillary and macular levels using Optical Coherence Tomography (OCT) to monitor disease progression (Mihaylova 2018; Bussel 2014; Michelessi 2021).
DISCUSSION
The authors should include a paragraph discussing the limitations of the study
R: We thank the reviewer for the observation. A paragraph discussing the limitation of the study has been added accordingly in the end of Discussion:
Our study presents a few limitations. First of all, it was conducted in vitro so missing several of the in vivo factors which may affect the results. Although this is an obvious drawback, it allows to perform controlled experiments and obtain reproducible results. Tests were conducted on pig eyes which are very similar to human eyes but present some differences. In particular, pig corneas are much thicker than human corneas and they may possess different material properties relative to the human corneas. The effect of thickness on the results of the present study has already been discussed above. The interpretation of experimental data on porcine eyes (Pandolfi and Holzapfel, 2008, Pandolfi and Boschetti 2015), showed that the porcine stroma has, on the average, mechanical properties very similar to the ones of the human stroma. Tests conducted on human corneas would clearly be of great importance to confirm our results obtained on porcine corneas. Regarding the methods, we evaluated the apex displacement of corneas from 2D images, whereas a 3D strain distribution may have resulted in more precise calculations. We measured the cornea thickness after the experiments on excised strips of the tested corneas. A pachymetry used on corneas during the test would probably give more precise results. Finally, we did not investigate the correlation with the radius of curvature, R, since our pig eyes, originating from animals of the same age of the same facility, were roughly of the same dimension with very low variability in R data (see Table 3).
Additional information should be provided regarding the differences between the human and pig eyes which may have influenced the results
R: We thank the reviewer for the comment. We added this information in the paragraph discussing the limitations. In particular:
Tests were conducted on pig eyes which are very similar to human eyes but present some differences. In particular, pig corneas are much thicker than human corneas and they may possess different material properties relative to the human corneas. The effect of thickness on the results of the present study has already been discussed above. The interpretation of experimental data on porcine eyes (Pandolfi and Holzapfel, 2008, Pandolfi and Boschetti 2015), showed that the porcine stroma has, on the average, mechanical properties very similar to the ones of the human stroma. Tests conducted on human corneas would clearly be of great importance to confirm our results obtained on porcine corneas.
More insight should be provided regarding the clinical applications of the findings in the clinical practice
R: We thank the reviewer for the suggestion. We added a paragraph in the end of Discussion:
In conclusion, glaucoma is a multifactorial opticopathy with a neurodegenerative component also present at the extraocular level (Gupta et al 206, Gupta et al 2009, Zhang et al 2019). Of all the factors to be taken into consideration, at present only IOP certainly plays an important diagnostic role besides being the target for therapies to treat glaucoma. Obviously, correct measurement and assessment of IOP is essential. Goldmann tonometry has been a gold standard reference for at least 70 years, though with the improvement of technology, it is now being discussed and critically analyzed. In our study, we have clearly shown that several factors, and in particular corneal stiffness and thickness, come into play in the measurement and assessment of ocular tone, and, above all, that the Goldmann tonometer underestimated IOP values with respect to real intraocular pressure especially for softer and thinner than normal corneas. From this point of view, these data could explain, at least in part, why normotensive glaucoma are diagnosed and also why, after medical, parasurgical or surgical hypotonization, glaucomatous disease still progresses in some patients. Further clinical investigation should be carried out in presence of normal GIOP values if the cornea appears particularly thin and soft. Whereas the thickness in regularly measured by a pachymeter, at present only the ophthalmologist experience and sensitivity can detect a sub-normal corneal stiffness. The development of a novel instrument, able to measure the force required to flatten the cornea coupled with a biomechanical model would be a great step forward for measuring the real IOP.
TABLES/FIGURE LEGENDS
Abbreviation are used in the figures and tables without a corresponding explanation in the legends (i.e. Figure 3. IOP should be indicated as Intra Ocular Pressure (IOP) in the legend of the figure): please revise the legends and provide the complete explanation of the abbreviations used
R: We thank the reviewer for the observation. Figures and tables have been updated accordingly.
Reviewer 3 Report
My main concerns are related to the Introduction. Its flow is very difficult and verbose. Additionally, I suggest to clarify the points that are listed below:
1) “Glaucoma is a multifactorial optic neuropathy characterized by progressive loss of retinal ganglion cells, changes in optic disk morphology and visual field defects.” Please also specify that “neurodegeneration in glaucoma is not limited to RGCs and their axons, forming the optic nerve, but seems to affect numerous brain structures, particularly vision-related brain structures”
2) “An association between increased IOP and the loss of sight in glaucoma has been noted for many centuries, starting from observations of eye hardness for cases of not improved vision after cataract operations, till the definition of a relationship between the level of IOP and the likelihood to lose sight.” Please better specify the glaucomatous damage affects the sight (visual field alterations or scotoma up to complete blindness).
3) To date, Goldman tonometry is the gold standard for IOP evaluation. However, some authors have recently highlighted the role of twenty-four-hour contact lens sensor monitoring of aqueous humor dynamics in surgically or medically treated glaucoma patients. Unluckely, these new devises have many limitations and drawbacks, especially due to their difficult use. Please discuss these aspects in the introduction or in the discussion. Please use the following reference:
Twenty-Four-Hour Contact Lens Sensor Monitoring of Aqueous Humor Dynamics in Surgically or Medically Treated Glaucoma Patients. J Ophthalmol. 2019; 2019:9890831.
4) The treatment of glaucoma usually requires in most of cases a lifelong daily instillation of IOP-lowering eye drops or in case of a refractive phenotypes an aggressive surgical treatment. Considering the above, there is an urgent need to develop more efficacious methods for chronic IOP control. Please stress this aspect in the introduction. Please use the following references:
Safety and Efficacy of Second Ahmed Valve Implant in Refractory Glaucoma. J Clin Med. 2020 Jun 29;9(7):2039.
5) Glaucoma is the most frequent cause of irreversible blindness worldwide. Please add some epidemiological data about glaucoma in the introduction. It is usefull for the readers to have an overview about the impact of the disease. Please use the following updated reference:
Early impact of COVID-19 outbreak on eye care: Insights from EUROCOVCAT group. Eur J Ophthalmol. 2021; 31(1):5-9.
6) Unfortunately, in some glaucoma patients there is a progression of the disease, regardless of an apparently normal IOP. Please clarify that there are different subtypes of glaucoma. The “glaucoma sine-pressione” is a very well-know subtype.
7) From line 59 to line 68 please add some references.
8) In the discussion create a separate paragraph for the limitations of the study. Please also close the manuscript starting with “In conclusion,…” summarizing the main results and the future perspective of the following study.
Author Response
Reviewer #3: My main concerns are related to the Introduction. Its flow is very difficult and verbose. Additionally, I suggest to clarify the points that are listed below:
We thank the reviewer for the suggestion. We revised the introduction, rephrasing some sentences and clarifying the suggested points
1) “Glaucoma is a multifactorial optic neuropathy characterized by progressive loss of retinal ganglion cells, changes in optic disk morphology and visual field defects.” Please also specify that “neurodegeneration in glaucoma is not limited to RGCs and their axons, forming the optic nerve, but seems to affect numerous brain structures, particularly vision-related brain structures”
R: We thank the reviewer for the observation. We modified the sentence:
Glaucoma is a multifactorial optic neuropathy characterized by progressive loss of retinal ganglion cells, the neurodegeneration can also involve the neuronal pathways up to the geniculate body and occipital cortex, resulting in changes in optic disk morphology and visual field defects
2) “An association between increased IOP and the loss of sight in glaucoma has been noted for many centuries, starting from observations of eye hardness for cases of not improved vision after cataract operations, till the definition of a relationship between the level of IOP and the likelihood to lose sight.” Please better specify the glaucomatous damage affects the sight (visual field alterations or scotoma up to complete blindness).
R: We thank the reviewer for the suggestion. We modified the sentence:
An association between increased IOP and the loss of sight in glaucoma has been noted for many centuries, from observations of eye stiffness for cases of continued impaired vision following cataract surgery, through the establishment of the relationship between the IOP and loss of sight. In particular, elevated IOP increases the likelihood of visual filed alterations or scotoma and even complete blindness.
3) To date, Goldman tonometry is the gold standard for IOP evaluation. However, some authors have recently highlighted the role of twenty-four-hour contact lens sensor monitoring of aqueous humor dynamics in surgically or medically treated glaucoma patients. Unluckely, these new devises have many limitations and drawbacks, especially due to their difficult use. Please discuss these aspects in the introduction or in the discussion. Please use the following reference:
Twenty-Four-Hour Contact Lens Sensor Monitoring of Aqueous Humor Dynamics in Surgically or Medically Treated Glaucoma Patients. J Ophthalmol. 2019; 2019:9890831.
R: We thank the reviewer for the suggestion. We added a paragraph on tonometers and also cited the suggested paper.
In addition to the Goldmann applanation tonometer (GAT), which will be further discussed below, several types of tonometers are currently available, each with advantages and disadvantages (Aziz 2018). The non-contact tonometry (NCT) is influenced by tear meniscus height (TMH), as the measured IOP increases with increasing tear film, and by central corneal thickness (CCT) (Tonnu 2005, Yilmaz 2014, Seol 2019). The Ocular Response Analyzer (ORA) uses a jet of air as the applanating force to the apex of the cornea; it can measure corneal hysteresis and the corneal resistance factor and provides higher IOP measurements as compared to GAT (Knigopoulos 2008). Pneumatonometer is a portable instrument which overestimates IOP at high values and at high CCT (Tonnu 2005). The Icare HOME tonometer is a portable device, contact rebound tonometer. It also has been recently shown to overestimate IOP compared to GAT (Takagi 2017). The Dynamic Contour Tonometer (DCT) or Pascal tonometer differs from GAT having a concave tip equipped with a tiny piezoelectric sensor: it takes about a hundred measurements per second and also evaluates IOP fluctuations with systemic pressure variation; no statistically significant effect of corneal curvature, astigmatism, axial length, and age on the difference between DCT and intracameral IOP has been detected Francis2007, Bochmann 2010). A recent study has been carried out on an IOP sensor mounted on contact lens, not yet available for clinical use, that can be worn by patients for up to 24 hours, also measuring the circadian rhythm. The data show an overnight rise in IOP(Posarelli 2019). Finally, the Corvis tonometer, a rebound tonometer, able to take into account corneal biomechanical characteristics, also has been shown to measure higher IOP values compared to GAT (Hong 2013). Although observations outlined above underline that most of the tonometers on the market "overestimate" the IOP measured by the Goldmann tonometer, the Goldmann Applanation Tonometry (GAT) is internationally considered as the gold standard for IOP measurement in clinical practice without the need to deform appreciably the cornea [33,34].
4) The treatment of glaucoma usually requires in most of cases a lifelong daily instillation of IOP-lowering eye drops or in case of a refractive phenotypes an aggressive surgical treatment. Considering the above, there is an urgent need to develop more efficacious methods for chronic IOP control. Please stress this aspect in the introduction. Please use the following references:
Safety and Efficacy of Second Ahmed Valve Implant in Refractory Glaucoma. J Clin Med. 2020 Jun 29;9(7):2039.
R: We appreciate the observation. Our study is focused on measurement of IOP and not on clinical treatment of glaucoma, so we are sorry but there is no place for this reference in our paper.
5) Glaucoma is the most frequent cause of irreversible blindness worldwide. Please add some epidemiological data about glaucoma in the introduction. It is usefull for the readers to have an overview about the impact of the disease. Please use the following updated reference:
Early impact of COVID-19 outbreak on eye care: Insights from EUROCOVCAT group. Eur J Ophthalmol. 2021; 31(1):5-9.
R: We thank the reviewer for the suggestion. We included a sentence referring to epidemiology in the Introduction
Glaucoma is a multifactorial optic neuropathy characterized by progressive loss of retinal ganglion cells, the neurodegeneration can also involve the neuronal pathways up to the geniculate body and occipital cortex, resulting in changes in optic disk morphology and visual field defects [1–3]. It is the leading cause of irreversible blindness worldwide, accounting for 8% of vision loss [4,5]
6) Unfortunately, in some glaucoma patients there is a progression of the disease, regardless of an apparently normal IOP. Please clarify that there are different subtypes of glaucoma. The “glaucoma sine-pressione” is a very well-know subtype.
R: We thank the reviewer for the suggestion. We modified the sentence:
Unfortunately, in some glaucoma patients there is a progression of the disease, regardless of an apparently normal IOP, particularly in normal tension glaucoma, which is an otticopathy in which the IOP before ocular hypotonizing therapy is less than 21 mmHg, apparently normal values (Mallick 2016, Killer 2018, Messenio2016).
7) From line 59 to line 68 please add some references.
R: We thank the reviewer for the suggestion. We added three references for manometry measurement of IOP
Shim, J.; Kang, S.; Park, Y.; Kim, S.; Go, S.; Lee, E.; Seo, K. Comparative intraocular pressure measurements using three different rebound tonometers through in an ex vivo analysis and clinical trials in canine eyes. Vet. Ophthalmol. 2021, 24 Suppl 1, 186–193, doi:10.1111/vop.12771.
Elsmo, E.J.; Kiland, J.A.; Kaufman, P.L.; McLellan, G.J. Evaluation of rebound tonometry in non-human primates. Exp. Eye Res. 2011, 92, 268–273, doi:10.1016/j.exer.2011.01.013.
McCafferty, S.; Levine, J.; Schwiegerling, J.; Enikov, E.T. Goldmann and error correcting tonometry prisms compared to intracameral pressure. BMC Ophthalmol. 2018, 18, 2, doi:10.1186/s12886-017-0668-z.
8) In the discussion create a separate paragraph for the limitations of the study. Please also close the manuscript starting with “In conclusion,…” summarizing the main results and the future perspective of the following study.
R: We thank the reviewer for the suggestions. We added a paragraph with limitations and a paragraph with conclusions in the end of discussion.
Our study presents a few limitations. First of all, it was conducted in vitro so missing several of the in vivo factors which may affect the results. Although this is an obvious drawback, it allows to perform controlled experiments and obtain reproducible results. Tests were conducted on pig eyes which are very similar to human eyes but present some differences. In particular, pig corneas are much thicker than human corneas and they may possess different material properties relative to the human corneas. The effect of thickness on the results of the present study has already been discussed above. The interpretation of experimental data on porcine eyes (Pandolfi and Holzapfel, 2008, Pandolfi and Boschetti 2015), showed that the porcine stroma has, on the average, mechanical properties very similar to the ones of the human stroma. Tests conducted on human corneas would clearly be of great importance to confirm our results obtained on porcine corneas. Regarding the methods, we evaluated the apex displacement of corneas from 2D images, whereas a 3D strain distribution may have resulted in more precise calculations. We measured the cornea thickness after the experiments on excised strips of the tested corneas. A pachymetry used on corneas during the test would probably give more precise results. Finally, we did not investigate the correlation with the radius of curvature, R, since our pig eyes, originating from animals of the same age of the same facility, were roughly of the same dimension with very low variability in R data (see Table 3).
Future work will be directed to the quantification of possible correlations with the scleral stiffness, since the presence of various types of diseases can easily lead to con-siderable changes in the elasticity of the scleral tissue [73-75].
In conclusion, glaucoma is a multifactorial opticopathy with a neurodegenerative component also present at the extraocular level (Gupta et al 206, Gupta et al 2009, Zhang et al 2019). Of all the factors to be taken into consideration, at present only IOP certainly plays an important diagnostic role besides being the target for therapies to treat glaucoma. Obviously, correct measurement and assessment of IOP is essential. Goldmann tonometry has been a gold standard reference for at least 70 years, though with the improvement of technology, it is now being discussed and critically analyzed. In our study, we have clearly shown that several factors, and in particular corneal stiffness and thickness, come into play in the measurement and assessment of ocular tone, and, above all, that the Goldmann tonometer underestimated IOP values with respect to real intraocular pressure especially for softer and thinner than normal corneas. From this point of view, these data could explain, at least in part, why normotensive glaucoma are diagnosed and also why, after medical, parasurgical or surgical hypotonization, glaucomatous disease still progresses in some patients. Further clinical investigation should be carried out in presence of normal GIOP values if the cornea appears particularly thin and soft. Whereas the thickness in regularly measured by a pachymeter, at present only the ophthalmologist experience and sensitivity can detect a sub-normal corneal stiffness. The development of a novel instrument, able to measure the force required to flatten the cornea coupled with a biomechanical model would be a great step forward for measuring the real IOP.
