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

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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Corneal confocal microscopy detects small fibre neurodegeneration in Parkinson's disease using automated analysis

Scientific Reports ◽

10.1038/s41598-020-76768-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sze Hway Lim ◽

Maryam Ferdousi ◽

Alise Kalteniece ◽

Lewis Kass-Iliyya ◽

Ioannis N. Petropoulos ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Confocal Microscopy ◽

Nerve Fibre ◽

Fibre Length ◽

Mean Difference ◽

Nerve Branch ◽

Corneal Confocal Microscopy ◽

Corneal Nerve ◽

Branch Density

AbstractWe studied the utility of corneal confocal microscopy (CCM) in detecting a reduction in corneal nerve parameters in a large cohort of patients with Parkinson’s disease (PD) compared to controls using a fully automated potentially scalable method of analysis. We also assessed if CCM parameters are related to the severity and sub-type of PD. 98 participants with PD and 26 healthy controls underwent CCM with automated corneal nerve quantification, MDS-UPDRS III, Hoehn and Yahr scale, Montreal Cognitive Assessment, Parkinson’s Disease Questionnaire-39 and PD subtype assessment. Corneal nerve fibre density (mean difference: − 5.00 no/mm2, 95% confidence interval (CI) [− 7.89, − 2.12], p = 0.001), corneal nerve branch density (mean difference: − 10.71 no/mm2, 95% CI [− 16.93, − 4.48], p = 0.003), corneal total branch density (mean difference: − 14.75 no/mm2, 95% CI [− 23.58, − 5.92], p = 0.002), and corneal nerve fibre length (mean difference: − 2.57 mm/mm2, 95% CI [− 4.02, − 1.12], p = 0.001) were significantly lower in PD participants compared to controls. There was no correlation between corneal nerve parameters and duration, severity or subtype of PD, cognitive function or quality of life. CCM with automated corneal nerve analysis identifies nerve fibre damage and may act as a biomarker for neurodegeneration in PD.

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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 confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2021-319450 ◽

2021 ◽

pp. bjophthalmol-2021-319450

Author(s):

Gulfidan Bitirgen ◽

Celalettin Korkmaz ◽

Adil Zamani ◽

Ahmet Ozkagnici ◽

Nazmi Zengin ◽

...

Keyword(s):

Confocal Microscopy ◽

Nerve Fibre ◽

Fibre Length ◽

Neurological Symptoms ◽

University Hospital ◽

Nerve Branch ◽

Cross Sectional ◽

Corneal Confocal Microscopy ◽

Corneal Nerve ◽

Fibre Loss

Background/AimsLong COVID is characterised by a range of potentially debilitating symptoms which develop in at least 10% of people who have recovered from acute SARS-CoV-2 infection. This study has quantified corneal sub-basal nerve plexus morphology and dendritic cell (DC) density in patients with and without long COVID.MethodsForty subjects who had recovered from COVID-19 and 30 control participants were included in this cross-sectional comparative study undertaken at a university hospital. All patients underwent assessment with the National Institute for Health and Care Excellence (NICE) long COVID, Douleur Neuropathique 4 (DN4) and Fibromyalgia questionnaires, and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), corneal nerve fibre length (CNFL), and total, mature and immature DC density.ResultsThe mean time after the diagnosis of COVID-19 was 3.7±1.5 months. Patients with neurological symptoms 4 weeks after acute COVID-19 had a lower CNFD (p=0.032), CNBD (p=0.020), and CNFL (p=0.012), and increased DC density (p=0.046) compared with controls, while patients without neurological symptoms had comparable corneal nerve parameters, but increased DC density (p=0.003). There were significant correlations between the total score on the NICE long COVID questionnaire at 4 and 12 weeks with CNFD (ρ=−0.436; p=0.005, ρ=−0.387; p=0.038, respectively) and CNFL (ρ=−0.404; p=0.010, ρ=−0.412; p=0.026, respectively).ConclusionCorneal confocal microscopy identifies corneal small nerve fibre loss and increased DCs in patients with long COVID, especially those with neurological symptoms. CCM could be used to objectively identify patients with long COVID.

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

Scientific Reports ◽

10.1038/s41598-021-97567-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Po-Ying Wu ◽

Jo-Hsuan Wu ◽

Yi-Ting Hsieh ◽

Lin Chih-Chieh Chen ◽

Ting Cheng ◽

...

Keyword(s):

Nerve Fiber ◽

Correlation Coefficient ◽

Intraclass Correlation ◽

Fiber Density ◽

Nerve Branch ◽

Observer Reliability ◽

Automated Method ◽

Corneal Nerve ◽

Branch Density

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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Corneal nerve loss as a surrogate marker for poor pial collaterals in patients with acute ischemic stroke

Scientific Reports ◽

10.1038/s41598-021-99131-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Adnan Khan ◽

Ajay Menon ◽

Naveed Akhtar ◽

Saadat Kamran ◽

Ahmad Muhammad ◽

...

Keyword(s):

Ischemic Stroke ◽

Endothelial Cell ◽

Acute Ischemic Stroke ◽

Nerve Fibre ◽

Fibre Length ◽

Surrogate Marker ◽

Nerve Branch ◽

Cell Parameters ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

AbstractIn patients with acute ischemic stroke, pial collaterals play a key role in limiting neurological disability by maintaining blood flow to ischemic penumbra. We hypothesized that patient with poor pial collaterals will have greater corneal nerve and endothelial cell abnormalities. In a cross-sectional study, 35 patients with acute ischemic stroke secondary to middle cerebral artery (MCA) occlusion with poor (n = 12) and moderate-good (n = 23) pial collaterals and 35 healthy controls underwent corneal confocal microscopy and quantification of corneal nerve and endothelial cell morphology. In patients with MCA stroke, corneal nerve fibre length (CNFL) (P < 0.001), corneal nerve fibre density (CNFD) (P = 0.025) and corneal nerve branch density (CNBD) (P = 0.002) were lower compared to controls. Age, BMI, cholesterol, triglycerides, HDL, LDL, systolic blood pressure, NIHSS and endothelial cell parameters did not differ but mRS was higher (p = 0.023) and CNFL (p = 0.026) and CNBD (p = 0.044) were lower in patients with poor compared to moderate-good collaterals. CNFL and CNBD distinguished subjects with poor from moderate-good pial collaterals with an AUC of 72% (95% CI 53–92%) and 71% (95% CI 53–90%), respectively. Corneal nerve loss is greater in patients with poor compared to moderate-good pial collaterals and may act as a surrogate marker for pial collateral status in patients with ischemic stroke.

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The Reference Distribution of Annual Change in Corneal Nerve Fibre Length in Diabetes

Canadian Journal of Diabetes ◽

10.1016/j.jcjd.2018.08.029 ◽

2018 ◽

Vol 42 (5) ◽

pp. S10

Author(s):

Evan Jh Lewis ◽

Mitra Tavakoli ◽

Leif E. Lovblom ◽

Elise M. Halpern ◽

Maria Jeziorska ◽

...

Keyword(s):

Nerve Fibre ◽

Fibre Length ◽

Annual Change ◽

Reference Distribution ◽

Corneal Nerve

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In Vivo Confocal Microscopy Evaluation in Patients with Keratoconus

Journal of Clinical Medicine ◽

10.3390/jcm11020393 ◽

2022 ◽

Vol 11 (2) ◽

pp. 393

Author(s):

Alvin Wei Jun Teo ◽

Hassan Mansoor ◽

Nigel Sim ◽

Molly Tzu-Yu Lin ◽

Yu-Chi Liu

Keyword(s):

Confocal Microscopy ◽

Nerve Regeneration ◽

Nerve Fibre ◽

Ex Vivo ◽

Fibre Length ◽

In Vivo Confocal Microscopy ◽

Corneal Sensitivity ◽

Mechanical Removal ◽

Cellular Changes

Keratoconus is the most common primary corneal ectasia characterized by progressive focal thinning. Patients experience increased irregular astigmatism, decreased visual acuity and corneal sensitivity. Corneal collagen crosslinking (CXL), a minimally invasive procedure, is effective in halting disease progression. Historically, keratoconus research was confined to ex vivo settings. In vivo confocal microscopy (IVCM) has been used to examine the corneal microstructure clinically. In this review, we discuss keratoconus cellular changes evaluated by IVCM before and after CXL. Cellular changes before CXL include decreased keratocyte and nerve densities, disorganized subbasal nerves with thickening, increased nerve tortuosity and shortened nerve fibre length. Repopulation of keratocytes occurs up to 1 year post procedure. IVCM also correlates corneal nerve status to functional corneal sensitivity. Immediately after CXL, there is reduced nerve density and keratocyte absence due to mechanical removal of the epithelium and CXL effect. Nerve regeneration begins after 1 month, with nerve fibre densities recovering to pre-operative levels between 6 months to 1 year and remains stable up to 5 years. Nerves remain tortuous and nerve densities are reduced. Corneal sensitivity is reduced immediately postoperatively but recovers with nerve regeneration. Our article provides comprehensive review on the use of IVCM imaging in keratoconus patients.

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Reduced corneal nerve fibre length in prediabetes and type 2 diabetes: The Maastricht Study

Acta Ophthalmologica ◽

10.1111/aos.14359 ◽

2020 ◽

Vol 98 (5) ◽

pp. 485-491 ◽

Cited By ~ 1

Author(s):

Eline E.B. De Clerck ◽

Jan S.A.G. Schouten ◽

Tos T.J.M. Berendschot ◽

Renée S. Koolschijn ◽

Rudy M.M.A. Nuijts ◽

...

Keyword(s):

Type 2 Diabetes ◽

Nerve Fibre ◽

Fibre Length ◽

Corneal Nerve

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A novel investigation method for axonal damage in neuromyelitis optica spectrum disorder: In vivo corneal confocal microscopy

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217321998060 ◽

2021 ◽

Vol 7 (1) ◽

pp. 205521732199806

Author(s):

Ayşe Altıntaş ◽

Ayse Yildiz-Tas ◽

Sezen Yilmaz ◽

Betul N Bayraktutar ◽

Melis Cansu Comert ◽

...

Keyword(s):

Confocal Microscopy ◽

Nerve Fibre ◽

Disease Severity ◽

Neuromyelitis Optica ◽

Spectrum Disorder ◽

Neuromyelitis Optica Spectrum Disorder ◽

Rnfl Thickness ◽

Corneal Confocal Microscopy ◽

Corneal Nerve

Background Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disorder that damages optic nerves, brainstem, and spinal cord. In vivo corneal confocal microscopy (IVCM) is a noninvasive technique that provides corneal images with dendritic cells (DCs) and corneal subbasal nerve plexus (SBP), which arises from the trigeminal nerve. Objective We investigated corneal SBP changes in NMOSD and proposed IVCM as a potential new disease severity biomarker for NMOSD. Methods Seventeen age-sex matched NMOSD patients and 19 healthy participants underwent complete neurologic and ophthalmologic examinations. The duration of disease, first symptom, presence of optic neuritis attack, antibody status, Expanded Disability Status Scale(EDSS) score and disease severity score(DSS) were recorded. Retinal nerve fibre layer (RNFL) thickness was measured with optical coherence tomography, and corneal SBP images were taken with IVCM. Results NMOSD patients had significantly reduced corneal nerve fibre lenght-density and corneal nerve branch lenght-density compared with controls, while DC density was increased. NMOSD patients also showed significantly reduced RNFL thickness compared with controls. EDSS,DSS levels were inversely correlated with IVCM parameters. Conclusion We observed significant corneal nerve fibre loss in NMOSD patients in relation to disease severity. IVCM can be a candidate noninvasive imaging method for axonal damage assessment in NMOSD that warrants further investigation.

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