Assessment of dynamic corneal nerve changes using static landmarks by <i>in vivo</i> large-area confocal microscopy—a longitudinal proof-of-concept study

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Abstract

Background

The purpose of the present proof-of-concept study was to use large-area in vivo confocal laser scanning microscopy (CLSM) mosaics to determine the migration rates of nerve branching points in the human corneal subbasal nerve plexus (SNP).

Methods

Three healthy individuals were examined roughly weekly over a total period of six weeks by large-area in vivo confocal microscopy of the central cornea. An in-house developed prototype system for guided eye movement with an acquisition time of 40 s was used to image and generate large-area mosaics of the SNP. Kobayashi-structures and nerve entry points (EPs) were used as fixed structures to enable precise mosaic registration over time. The migration rate of 10 prominent nerve fiber branching points per participant was tracked and quantified over the longitudinal period.

Results

Total investigation times of 10 minutes maximum per participant were used to generate mosaic images with an average size of 3.61 mm ² (range: 3.18–4.42 mm ²). Overall mean branching point migration rates of (46.4±14.3), (48.8±15.5), and (50.9±13.9) µm/week were found for the three participants with no statistically significant difference. Longitudinal analyses of nerve branching point migration over time revealed significant time-dependent changes in migration rate only in participant 3 between the last two measurements [(63.7±12.3) and (43.0±12.5) µm/week, P<0.01]. Considering individual branching point dynamics, significant differences in nerve migration rate from the mean were only found in a few exceptions.

Conclusions

The results of this proof-of-concept study have demonstrated the feasibility of using in vivo confocal microscopy to study the migration rates of corneal subbasal nerves within large areas of the central human cornea (>1 mm ²). The ability to monitor dynamic changes in the SNP opens a window to future studies of corneal nerve health and regenerative capacity in a number of systemic and ocular diseases. Since corneal nerves are considered part of the peripheral nervous system, this technique could also offer an objective diagnostic tool and biomarker for disease- or treatment-induced neuropathic changes.

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Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy

Maryam Ferdousi, Shazli Azmi, Ioannis Petropoulos … (2015)

There are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration.

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Use of Corneal Confocal Microscopy to Detect Corneal Nerve Loss and Increased Dendritic Cells in Patients With Multiple Sclerosis

Ahmet Ozkagnici, Rayaz A. Malik, Gulfidan Bitirgen … (2017)

Question Can in vivo confocal microscopy detect axonal loss in patients with multiple sclerosis? Findings In this cross-sectional comparative study of 57 patients with multiple sclerosis and 30 healthy individuals, in vivo corneal confocal microscopy demonstrated reduced corneal nerve measures and increased dendritic cell density in patients with multiple sclerosis. Meaning Corneal confocal microscopy may be used as an imaging biomarker for identifying axonal loss in patients with multiple sclerosis. Importance Multiple sclerosis (MS) is characterized by demyelination, axonal degeneration, and inflammation. Corneal confocal microscopy has been used to identify axonal degeneration in several peripheral neuropathies. Objective To assess corneal subbasal nerve plexus morphologic features, corneal dendritic cell (DC) density, and peripapillary retinal nerve fiber layer (RNFL) thickness in patients with MS. Design, Setting, and Participants This single-center, cross-sectional comparative study was conducted at a tertiary referral university hospital between May 27, 2016, and January 30, 2017. Fifty-seven consecutive patients with relapsing-remitting MS and 30 healthy, age-matched control participants were enrolled in the study. Corneal subbasal nerve plexus measures and DC density were quantified in images acquired with the laser scanning in vivo corneal confocal microscope, and peripapillary RNFL thickness was measured with spectral-domain optical coherence tomography. Main Outcomes and Measures Corneal nerve fiber density, nerve branch density, nerve fiber length, DC density, peripapillary RNFL thickness, and association with the severity of neurologic disability as assessed by the Kurtzke Expanded Disability Status Scale (score range, 0-10; higher scores indicate greater disability) and Multiple Sclerosis Severity Score (score range, 0.01-9.99; higher scores indicate greater severity). Results Of the 57 participants with MS, 42 (74%) were female and the mean (SD) age was 35.4 (8.9) years; of the 30 healthy controls, 19 (63%) were female and the mean (SD) age was 34.8 (10.2) years. Corneal nerve fiber density (mean [SE] difference, −6.78 [2.14] fibers/mm 2 ; 95% CI, −11.04 to −2.52; P = .002), nerve branch density (mean [SE] difference, −17.94 [5.45] branches/mm 2 ; 95% CI, −28.77 to −7.10; P = .001), nerve fiber length (mean [SE] difference, −3.03 [0.89] mm/mm 2 ; 95% CI, −4.81 to −1.25; P = .001), and the mean peripapillary RNFL thickness (mean [SE] difference, −17.06 [3.14] μm; 95% CI, −23.29 to −10.82; P < .001) were reduced in patients with MS compared with healthy controls. The DC density was increased (median [interquartile range], 27.7 [12.4-66.8] vs 17.3 [0-28.2] cells/mm 2 ; P = .03), independent of a patient’s history of optic neuritis. Nerve fiber density and RNFL thickness showed inverse associations with the Expanded Disability Status Scale (ρ = −0.295; P = .03 for nerve fiber density and ρ = −0.374; P = .004 for RNFL thickness) and the Multiple Sclerosis Severity Score ( R = −0.354; P = .007 for nerve fiber density and R = −0.283; P = .03 for RNFL thickness), whereas other study measures did not. Conclusions and Relevance These data suggest that corneal confocal microscopy demonstrates axonal loss and increased DC density in patients with MS. Additional longitudinal studies are needed to confirm the use of corneal confocal microscopy as an imaging biomarker in patients with MS. This cross-sectional study examines the use of in vivo corneal confocal microscopy to identify axonal degeneration in patients with multiple sclerosis.

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Neurophysiological, nerve imaging and other techniques to assess chemotherapy-induced peripheral neurotoxicity in the clinical and research settings.

Andreas Argyriou, Susanna Park, Badrul Islam … (2019)

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting side effect of several anticancer medications. CIPN may involve multiple areas of the peripheral nervous system from the autonomic and dorsal root ganglia (DRG) to the axon and any peripheral nerve fibre type. Large diameter sensory myelinated (Aβ) fibres are more frequently involved, but motor, small myelinated (Aδ), unmyelinated (C) or autonomic fibres may also be affected. Here, we review the current evidence on techniques for the CIPN assessment in the clinical and experimental settings. Nerve conduction studies (NCS) may be used at the subclinical and early CIPN stage, to assess the extent of large nerve fibre damage and to monitor long-term outcomes, with the sural or dorsal sural nerve as the most informative. The quantitative sensory neurological examination provides valuable data alongside NCS. Quantitative sensory testing and nerve excitability studies add information regarding pathophysiology. Nerve MRI and ultrasound may provide information on enlarged nerve, increased nerve signal intensity and DRG or spinal cord changes. Skin biopsy, corneal confocal microscopy, laser-evoked potentials, contact heat-related potentials and microneurography may reveal the extent of damage to small unmyelinated nerve fibres that go undetected by NCS. The information on the role of these latter techniques is preliminary. Hence, the use of multimodal testing is recommended as the optimal CIPN assessment strategy, employing objective NCS and other specialised techniques together with subjective patient-reported outcome measures.

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Author and article information

Journal

Journal ID (nlm-ta): Quant Imaging Med Surg

Journal ID (iso-abbrev): Quant Imaging Med Surg

Journal ID (publisher-id): QIMS

Title: Quantitative Imaging in Medicine and Surgery

Publisher: AME Publishing Company

ISSN (Print): 2223-4292

ISSN (Electronic): 2223-4306

Publication date (Print and electronic): October 2022

Publication date (Print): October 2022

Volume: 12

Issue: 10

Pages: 4734-4746

Affiliations

[1 ]deptDepartment of Ophthalmology , Rostock University Medical Center , Rostock, Germany;

[2 ]deptDepartment of Obstetrics and Gynecology , University of Rostock , Rostock, Germany;

[3 ]deptDepartment Life, Light & Matter , University of Rostock , Rostock, Germany;

[4 ]Department of Anatomy Cell Biology & Physiology, Indiana University School of Medicine-Northwest, Gary , USA;

[5 ]deptInstitute for Automation and Applied Informatics , Karlsruhe Institute of Technology (KIT) , Karlsruhe, Germany

Author notes

Contributions: (I) Conception and design: A Stachs, O Stachs, S Bohn; (II) Administrative support: N Stache, KA Sterenczak, CF Marfurt, A Stachs, RF Guthoff; (III) Provision of study materials or patients: N Stache, KA Sterenczak, K Sperlich, A Stachs, O Stachs, S Bohn; (IV) Collection and assembly of data: N Stache, KA Sterenczak, K Sperlich, S Allgeier, B Köhler, R Mikut, A Bartschat, KM Reichert, S Bohn; (V) Data analysis and interpretation of data: N Stache, KA Sterenczak, CF Marfurt, O Stachs, S Bohn; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

[#]

These authors contributed equally to this work.

Correspondence to: Sebastian Bohn. Department of Ophthalmology, Rostock University Medical Center, Doberaner Straße 140, D-18057 Rostock, Germany. Email: sebastian.bohn@ 123456uni-rostock.de .

Article

Publisher ID: qims-12-10-4734

DOI: 10.21037/qims-22-15

PMC ID: 9511428

PubMed ID: 36185050

SO-VID: a834114b-eadf-46ec-b928-3bd7870fe0e2

License:

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

Assessment of dynamic corneal nerve changes using static landmarks by in vivo large-area confocal microscopy—a longitudinal proof-of-concept study

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Abstract

Background

Methods

Results

Conclusions

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Most cited references 36

Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy

Use of Corneal Confocal Microscopy to Detect Corneal Nerve Loss and Increased Dendritic Cells in Patients With Multiple Sclerosis

Neurophysiological, nerve imaging and other techniques to assess chemotherapy-induced peripheral neurotoxicity in the clinical and research settings.

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