Comparing the results of manual and automated quantitative corneal neuroanalysing modules for beginners

AbstractThis study aimed to evaluate the reliability of in vivo confocal microscopic neuroanalysis by beginners using manual and automated modules. Images of sub-basal corneal nerve plexus (SCNP) from 108 images of 18 healthy participants were analyzed by 7 beginner observers using manual (CCMetrics, [CCM]) and automated (ACCMetrics, [ACCM]) module. SCNP parameters analyzed included corneal nerve fiber density (NFD), corneal nerve branch density (NBD), corneal nerve fiber length (NFL), and tortuosity coefficient (TC). The intra-observer repeatability, inter-observer reliability, inter-module agreement, and left–right eye symmetry level of SCNP parameters were examined. All observers showed good intra-observer repeatability using CCM (intraclass correlation coefficient [ICC] > 0.60 for all), except when measuring TC. Two observers demonstrated especially excellent repeatability in analyzing NFD, NBD, and NFL using manual mode, indicating the quality of interpretation may still be observer-dependent. Among all SCNP parameters, NFL had the best inter-observer reliability (Spearman’s rank-sum correlation coefficient [SpCC] and ICC > 0.85 for the 3 original observers) and left–right symmetry level (SpCC and ICC > 0.60). In the additional analysis of inter-observer reliability using results by all 7 observers, only NFL showed good inter-observer reliability (ICC = 0.79). Compared with CCM measurements, values of ACCM measurements were significantly lower, implying a poor inter-module agreement. Our result suggested that performance of quantitative corneal neuroanalysis by beginners maybe acceptable, with NFL being the most reliable parameter, and automated method cannot fully replace manual work.

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An In Vivo Confocal Microscopic Study of Corneal Nerve Morphology in Unilateral Keratoconus

BioMed Research International ◽

10.1155/2016/5067853 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5 ◽

Cited By ~ 7

Author(s):

Natasha Kishore Pahuja ◽

Rohit Shetty ◽

Rudy M. M. A. Nuijts ◽

Aarti Agrawal ◽

Arkasubhra Ghosh ◽

...

Keyword(s):

Nerve Fiber ◽

Nerve Branch ◽

Intergroup Comparison ◽

Corneal Nerve ◽

Group 3 ◽

Group 2 ◽

Branch Density ◽

Corneal Nerve Morphology ◽

Group 1

Purpose.To study the corneal nerve morphology and its importance in unilateral keratoconus.Materials and Methods.In this prospective cross-sectional study, 33 eyes of 33 patients with keratoconus in one eye (Group 3) were compared with the other normal eye of the same patients (Group 2) and 30 eyes of healthy patients (Group 1). All patients underwent detailed ophthalmic examination followed by topography with Pentacam HR and in vivo confocal microscopy (IVCM). Five images obtained with IVCM were analyzed using an automated CCmetrics software version 1.0 for changes in subbasal plexus of nerves.Results.Intergroup comparison showed statistically significant reduction in corneal nerve fiber density (CNFD) and length (CNFL) in Group 3 as compared to Group 1 (p<0.001andp=0.001, resp.) and Group 2 (p=0.01andp=0.02, resp.). Though corneal nerve fiber length, diameter, area, width, corneal nerve branch density, and corneal total branch density were found to be higher in decentered cones, only the corneal nerve branch density (CNBD) was found to be statistically significant (p<0.01) as compared to centered cones.Conclusion.Quantitative changes in the corneal nerve morphology can be used as an imaging marker for the early diagnosis of keratoconus before the onset of refractive or topography changes.

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Corneal Nerve Loss in Patients With TIA and Acute Ischemic Stroke in Relation To Circulating Markers of Inflammation and Vascular Integrity

10.21203/rs.3.rs-301595/v2 ◽

2021 ◽

Author(s):

Adnan Khan ◽

Aijaz Parray ◽

Naveed Akhtar ◽

Abdelali Agouni ◽

Saadat Kamran ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebrovascular Disease ◽

Acute Ischemic Stroke ◽

Nerve Fiber ◽

Fiber Density ◽

Nerve Branch ◽

Vascular Integrity ◽

Markers Of Inflammation ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

Abstract Background Vascular and inflammatory mechanisms are implicated in the development of cerebrovascular disease and corneal nerve loss occurs in patients with transient ischemic attack (TIA) and acute ischemic stroke (AIS). We have assessed whether serum markers of inflammation and vascular integrity are associated with the severity of corneal nerve loss in patients with TIA and AIS. Methods Corneal confocal microscopy (CCM) was performed to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) in 105 patients with TIA or AIS and age matched control subjects (n=56). Circulating levels of IL-6, MMP-2, MMP-9, E-Selectin, P-Selectin and VEGF were quantified in patients within 48 hours of presentation with a TIA or AIS. Results CNFL (P=0.000, P=0.000), CNFD (P=0.122, P=0.000) and CNBD (P=0.002, P=0.000) were reduced in patients with TIA and AIS compared to controls, respectively with no difference between patients with AIS and TIA. The NIHSS Score (P=0.000), IL-6 (P=0.011) and E-Selectin (P=0.032) were higher in patients with AIS compared to TIA with no difference in MMP-2 (P=0.636), MMP-9 (P=0.098), P-Selectin (P=0.395) and VEGF (P=0.831). CNFL (r=0.218, P=0.026) and CNFD (r=0.230, P=0.019) correlated with IL-6 and multiple regression analysis showed a positive association of CNFL and CNFD with IL-6 (P=0.041, P=0.043). Conclusions Patients with TIA and stroke have evidence of corneal nerve loss and elevated IL6 and E-selectin levels. Larger longitudinal studies are required to determine the association between inflammatory and vascular markers and corneal nerve fiber loss in patients with cerebrovascular disease.

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Corneal nerve loss in patients with TIA and acute ischemic stroke in relation to circulating markers of inflammation and vascular integrity

10.21203/rs.3.rs-301595/v1 ◽

2021 ◽

Author(s):

Adnan Khan ◽

Aijaz Parray ◽

Naveed Akhtar ◽

Abdelali Agouni ◽

Saadat Kamran ◽

...

Keyword(s):

Ischemic Stroke ◽

Cerebrovascular Disease ◽

Acute Ischemic Stroke ◽

Nerve Fiber ◽

Fiber Density ◽

Nerve Branch ◽

Vascular Integrity ◽

Markers Of Inflammation ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

Abstract Background Vascular and inflammatory mechanisms are implicated in the development of cerebrovascular disease and corneal nerve loss occurs in patients with transient ischemic attack (TIA) and acute ischemic stroke (AIS). We have assessed whether serum markers of inflammation and vascular integrity are associated with the severity of corneal nerve loss in patients with TIA and AIS. Methods Corneal confocal microscopy (CCM) was performed to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) in 105 patients with TIA or AIS and age matched control subjects (n = 56). Circulating levels of IL-6, MMP-2, MMP-9, E-Selectin, P-Selectin and VEGF were quantified in patients within 48 hours of presentation with a TIA or AIS. Results CNFL (P = 0.000, P = 0.000), CNFD (P = 0.122, P = 0.000) and CNBD (P = 0.002, P = 0.000) were reduced in patients with TIA and AIS compared to controls, respectively with no difference between patients with AIS and TIA. The NIHSS Score (P = 0.000), IL-6 (P = 0.011) and E-Selectin (P = 0.032) were higher in patients with AIS compared to TIA with no difference in MMP-2 (P = 0.636), MMP-9 (P = 0.098), P-Selectin (P = 0.395) and VEGF (P = 0.831). CNFL (r = 0.218, P = 0.026) and CNFD (r = 0.230, P = 0.019) correlated with IL-6 and multiple regression analysis showed a positive association of CNFL and CNFD with IL-6 (P = 0.041, P = 0.043). Conclusions Patients with TIA and stroke have evidence of corneal nerve loss and elevated IL6 and E-selectin levels. Larger longitudinal studies are required to determine the association between inflammatory and vascular markers and corneal nerve fiber loss in patients with cerebrovascular disease.

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Augmented Corneal Nerve Fiber Branching in Painful Compared With Painless Diabetic Neuropathy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-01072 ◽

2019 ◽

Vol 104 (12) ◽

pp. 6220-6228

Author(s):

Sonja Püttgen ◽

Gidon J Bönhof ◽

Alexander Strom ◽

Karsten Müssig ◽

Julia Szendroedi ◽

...

Keyword(s):

Nerve Fiber ◽

Rating Scale ◽

Nerve Fibers ◽

Control Group ◽

Fiber Density ◽

Nerve Branch ◽

Perception Threshold ◽

Cross Sectional ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

AbstractContextThe factors that determine the development of diabetic sensorimotor polyneuropathy (DSPN) as a painful or painless entity are unknown.ObjectiveWe hypothesized that corneal nerve pathology could be more pronounced in painful DSPN, indicating predominant small nerve fiber damage.Design and MethodsIn this cross-sectional study, we assessed 53 patients with painful DSPN, 63 with painless DSPN, and 46 glucose-tolerant volunteers by corneal confocal microscopy (CCM), nerve conduction (NC), and quantitative sensory testing. DSPN was diagnosed according to modified Toronto Consensus criteria. A cutoff at 4 points on the 11-point rating scale was used to differentiate between painful and painless DSPN.ResultsAfter adjustment for age, sex, body mass index, and smoking, corneal nerve fiber density, corneal nerve fiber length, and corneal nerve branch density (CNBD) were reduced in both DSPN types compared with the control group (P < 0.05). Only CNBD differed between the groups; it was greater in patients with painful DSPN compared with those with painless DSPN [55.8 (SD, 29.9) vs 43.8 (SD, 28.3) branches/mm2; P < 0.05]. Several CCM measures were associated with NC and cold perception threshold in patients with painless DSPN (P < 0.05) but not those with painful DSPN.ConclusionDespite a similarly pronounced peripheral nerve dysfunction and corneal nerve fiber loss in patients with painful and painless DSPN, corneal nerve branching was enhanced in those with painful DSPN, pointing to some susceptibility of corneal nerve fibers toward regeneration in this entity, albeit possibly not to a sufficient degree.

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Validation of the Use of Automated and Manual Quantitative Analysis of Corneal Nerve Plexus Following Refractive Surgery

Diagnostics ◽

10.3390/diagnostics10070493 ◽

2020 ◽

Vol 10 (7) ◽

pp. 493 ◽

Cited By ~ 2

Author(s):

Jia Ying Chin ◽

Lily Wei Yun Yang ◽

Angel Jung Se Ji ◽

Mario Nubile ◽

Leonardo Mastropasqua ◽

...

Keyword(s):

Nerve Fibre ◽

Refractive Surgery ◽

Fibre Length ◽

Observer Agreement ◽

Nerve Branch ◽

Lenticule Extraction ◽

Manual Methods ◽

Corneal Nerve ◽

Branch Density

Following refractive surgery, the cornea is denervated and re-innervated, hence a reproducible tool to objectively quantify this change is warranted. This study aimed to determine the repeatability and reproducibility of corneal nerve quantification between automated (ACCMetrics) and manual software (CCMetrics) following refractive surgery. A total of 1007 in vivo confocal microscopy images from 20 post-small incision lenticule extraction (SMILE) or post-laser-assisted in situ keratomileusis (LASIK) patients were evaluated by two independent observers using CCMetrics for corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), and corneal nerve fibre length (CNFL). Intra-observer and inter-observer reproducibility and repeatability, as well as agreement and correlation between the measurements obtained by ACCMetrics and CCMetrics, were assessed. We found that CNFL demonstrated the best intra- and inter-observer agreement followed by CNFD (intra-class correlation coefficient (ICC) = 0.799 and 0.740, respectively for CNFL; 0.757 and 0.728 for CNFD). CNBD demonstrated poorest intra- and inter-observer ICC. There was an underestimation in ACCMetrics measurements compared to CCMetrics measurements, although the differences were not significant. Our data suggested that both automated and manual methods can be used as reliable tools for the evaluation of corneal nerve status following refractive surgery. However, the measurements obtained with different methods are not interchangeable.

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Bilateral morphometric analysis of corneal sub-basal nerve plexus in patients undergoing unilateral cataract surgery: a preliminary in vivo confocal microscopy study

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-315449 ◽

2020 ◽

pp. bjophthalmol-2019-315449 ◽

Cited By ~ 3

Author(s):

Giuseppe Giannaccare ◽

Federico Bernabei ◽

Marco Pellegrini ◽

Fabio Guaraldi ◽

Federica Turchi ◽

...

Keyword(s):

Confocal Microscopy ◽

Cataract Surgery ◽

Nerve Fibre ◽

Fibre Length ◽

Nerve Plexus ◽

In Vivo Confocal Microscopy ◽

Corneal Nerve ◽

Branch Density ◽

Unilateral Cataract

AimsTo evaluate bilateral morphometric changes of corneal sub-basal nerve plexus (CSNP) occurring after unilateral cataract surgery by in vivo confocal microscopy (IVCM) images analysed with automated software.MethodsIVCM was performed before (V0) and 1 month after surgery (V1) in both operated eyes (OEs) and unoperated eyes (UEs) of 30 patients. Thirty age and sex-matched subjects acted as controls. Corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), corneal nerve fibre length (CNFL), corneal nerve total branch density (CTBD), corneal nerve fibre area (CNFA), corneal nerve fibre width, corneal nerve fractal dimension (CNFrD) and dendritic cells density were calculated.ResultsMean CNFD, CNBD, CNFL, CTBD, CNFA and CNFrD significantly decreased at V1 versus V0 in both eyes (respectively, 15.35±7.00 vs 21.21±6.56 n/mm2 in OEs and 20.11±6.69 vs 23.20±7.26 in UEs; 13.57±12.16 vs 26.79±16.91 n/mm2 in OEs and 24.28±14.88 vs 29.76±15.25 in UEs; 9.67±3.44 mm/mm2 vs 13.49±3.42 in OEs and 12.53±3.60 vs 14.02±3.82 in UEs; 22.81±18.77 vs 42.25±24.64 n/mm2 in OEs and 38.06±20.52 vs 43.93±22.27 in UEs; 0.0040±0.0021 vs 0.0058±0.0020 mm2/mm2 in OEs and 0.0049±0.0016 vs 0.0057±0.0019 in UEs; 1.418±0.058 vs 1.470±0.037 in OEs and 1.466±0.040 vs 1.477±0.036 in UEs; always p<0.049).ConclusionPatients undergoing cataract surgery exhibit bilateral alterations of CSNP. This finding could have broad implications in the setting of sequential cataract surgery.

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Erratum to: ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density

Molecular Medicine ◽

10.2119/molmed.2013.00122.erratum ◽

2016 ◽

Vol 22 (1) ◽

pp. 674-674

Author(s):

Albert Dahan ◽

Ann Dunne ◽

Maarten Swartjes ◽

Paolo L. Proto ◽

Lara Heij ◽

...

Keyword(s):

Nerve Fiber ◽

Fiber Density ◽

Corneal Nerve ◽

Nerve Fiber Density ◽

Small Nerve

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Corneal nerve quantification predicts the severity of symptoms in sarcoidosis patients with painful neuropathy

TECHNOLOGY ◽

10.1142/s2339547813500039 ◽

2013 ◽

Vol 01 (01) ◽

pp. 20-26 ◽

Cited By ~ 6

Author(s):

M. Brines ◽

M. Swartjes ◽

M.R. Tannemaat ◽

A. Dunne ◽

M. van Velzen ◽

...

Keyword(s):

Nerve Fiber ◽

Adult Population ◽

Brief Pain Inventory ◽

The United States ◽

Fiber Density ◽

Painful Neuropathy ◽

Small Fiber ◽

Corneal Confocal Microscopy ◽

Fiber Number ◽

Corneal Nerve

Small fiber neuropathy (SFN) is a debilitating condition characterized by chronic pain as well as sensory and autonomic dysfunction. SFN is an increasingly recognized component of a large number of diseases, including sarcoidosis. Although affecting an estimated 2–3% of the adult population in the United States, it often remains undiagnosed. Skin biopsy for evaluating intra-epidermal nerve fiber density (IENFD) and more recently corneal confocal microscopy (CCM) have been used to identify small fiber damage in patients with neuropathy. We demonstrate a significant reduction in IENFD, corneal nerve fiber number and length, with no change in the number of branches in patients with painful sarcoid neuropathy. Moreover, unlike IENFD, corneal nerve fiber number and length inversely correlate with the degree to which pain interferes with activities of daily living as assessed by the Brief Pain Inventory questionnaire. CCM thus constitutes an accurate, non-invasive assessment technique to aid in the diagnosis of SFN, as well as an objective marker of symptoms in patients with painful sarcoid neuropathy.

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Corneal confocal microscopy demonstrates axonal loss in different courses of multiple sclerosis

Scientific Reports ◽

10.1038/s41598-021-01226-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ioannis N. Petropoulos ◽

Kathryn C. Fitzgerald ◽

Jonathan Oakley ◽

Georgios Ponirakis ◽

Adnan Khan ◽

...

Keyword(s):

Multiple Sclerosis ◽

Confocal Microscopy ◽

Nerve Fiber ◽

Clinically Isolated Syndrome ◽

Axonal Loss ◽

Fiber Density ◽

Corneal Confocal Microscopy ◽

Segmentation Methods ◽

Relapsing Remitting ◽

Corneal Nerve

AbstractAxonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing–remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm2, 95% CI − 18.24 to − 11.59, P < .0001), CNFL [for ACCMetrics: 19.75 ± 2.39 vs. 12.40 ± 3.30 mm/mm2, 95% CI − 8.94 to − 5.77, P < .0001; for deepNerve: 21.98 ± 2.76 vs. 14.40 ± 4.17 mm/mm2, 95% CI − 9.55 to − 5.6, P < .0001] and CNFrD [for ACCMetrics: 1.52 ± 0.02 vs. 1.45 ± 0.04, 95% CI − 0.09 to − 0.05, P < .0001; for deepNerve: 1.29 ± 0.03 vs. 1.19 ± 0.07, 95% − 0.13 to − 0.07, P < .0001]. Corneal nerve parameters were comparably reduced in different courses of MS. There was excellent reproducibility between the algorithms. Significant corneal axonal loss is detected in different courses of MS including patients with clinically isolated syndrome.

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Combining In Vivo Corneal Confocal Microscopy with Deep Learning-based Analysis Reveals Sensory Nerve Fiber Loss in Acute SIV Infection

10.1101/2020.04.19.048926 ◽

2020 ◽

Author(s):

Megan E. McCarron ◽

Rachel L. Weinberg ◽

Jessica M. Izzi ◽

Suzanne E. Queen ◽

Stuti L. Misra ◽

...

Keyword(s):

Fractal Dimension ◽

Deep Learning ◽

Confocal Microscopy ◽

Nerve Fiber ◽

Fiber Length ◽

Sensory Nerve ◽

Corneal Confocal Microscopy ◽

Siv Infection ◽

Corneal Nerve

AbstractPurposeTo characterize corneal subbasal nerve plexus morphologic features using in vivo corneal confocal microscopy (IVCM) in normal and SIV-infected macaques and to implement automated assessments using novel deep learning-based methods customized for macaque studies.MethodsIn vivo corneal confocal microscopy images were collected from both male and female age-matched specific-pathogen free rhesus and pigtailed macaques housed at the Johns Hopkins University breeding colony using the Heidelberg HRTIII with Rostock Corneal Module. We also obtained repeat IVCM images of 12 SIV-infected animals including pre-infection and 10 day post-SIV infection time-points. All IVCM images were analyzed using a novel deep convolutional neural network architecture developed specifically for macaque studies.ResultsDeep learning-based segmentation of subbasal nerves in IVCM images from macaques demonstrated that corneal nerve fiber length (CNFL) and fractal dimension measurements did not differ between species, but pigtailed macaques had significantly higher baseline corneal nerve fiber tortuosity than rhesus macaques (P = 0.005). Neither sex nor age of macaques was associated with differences in any of the assessed corneal subbasal nerve parameters. In the SIV/macaque model of HIV, acute SIV infection induced significant decreases in both corneal nerve fiber length and fractal dimension (P= 0.01 and P= 0.008 respectively).ConclusionsThe combination of IVCM and objective, robust, and rapid deep-learning analysis serves as a powerful noninvasive research and clinical tool to track sensory nerve damage, enabling early detection of neuropathy. Adapting the deep-learning analyses to human corneal nerve assessments will refine our ability to predict and monitor damage to small sensory nerve fibers in a number of clinical settings including HIV, multiple sclerosis, Parkinson’s disease, diabetes, and chemotherapeutic neurotoxicity.

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