Identification of presumed corneal neuromas and microneuromas using laser-scanning in vivo confocal microscopy: a systematic review

Abstract

Background/aimsThis systematic review critically evaluated peer-reviewed publications describing morphological features consistent with, or using terms related to, a ‘neuroma’ or ‘microneuroma’ in the human cornea using laser-scanning in vivo confocal microscopy (IVCM).MethodsThe review was prospectively registered on PROSPERO (CRD42020160038). Comprehensive literature searches were performed in Ovid MEDLINE, Ovid Embase and the Cochrane Library in November 2019. The review included primary research studies and reviews that described laser-scanning IVCM for examining human corneal nerves. Papers had to include at least one of a pre-specified set of keyword stems, broadly related to neuromas and microneuromas, to describe a corneal nerve feature.ResultsTwenty-five papers (20 original studies; 5 reviews) were eligible. Three original studies evaluated corneal nerve features in healthy eyes. Most papers assessed corneal nerves in ocular and systemic conditions; seven studies did not include a control/comparator group. There was overlap in terminology used to describe nerve features in healthy and diseased corneas (eg, bulb-like/bulbous, penetration, end/s/ing). Inspection of IVCM images within the papers revealed that features termed ‘neuromas’ and ‘microneuromas’ could potentially be physiological corneal stromal-epithelial nerve penetration sites. We identified inconsistent definitions for terms, and limitations in IVCM image acquisition, sampling and/or reporting that may introduce bias and lead to inaccurate representation of physiological nerve characteristics as pathological.ConclusionThese findings identify a need for consistent nomenclature and definitions, and rigorous IVCM scanning and analysis protocols to clarify the prevalence of physiological, as opposed to pathological, corneal nerve features.

Corneal Nerve Abnormalities in Painful Dry Eye Disease Patients

“…Although microneuromas do bear witness of corneal nerve abnormalities [27,36], the latter seem insufficient to produce neuropathic pain. Therefore, from a diagnostic standpoint, the mere presence of microneuromas seems insufficient to suggest corneal neuropathic alterations.…”

“…(3) number, area, and perimeter of microneuromas (Figure 3); microneuromas were defined as nerve abnormalities that present as irregularly shaped, hyperreflective, terminal enlargements of subbasal nerve endings, according to the relevant literature [27,31] (median (range): 77 images/patient).…”

“…The morphological study of the corneal nerves was analyzed by the following parameters: (1) nerve tortuosity classified in four grades according to an ad hoc tortuosity scale (Figure 2) (median (range): 77 ) images/patient); (2) density of nerves (μm/mm 2 ) was calculated using only images with clear uninterrupted visualization of the corneal nerves and less than 20% overlap between slices, to avoid any miscounts (median (range):11 (5-31) representative images/patient). These images were analyzed using the NeuronJ plugin in ImageJ; (3) number, area, and perimeter of microneuromas (Figure 3); microneuromas were defined as nerve abnormalities that present as irregularly shaped, hyperreflective, terminal enlargements of subbasal nerve endings, according to the relevant literature [27,31] (median (range): 77 images/patient).…”

“…IVCM has been used to image subbasal nerve attributes in various ocular surface diseases, including DED [24][25][26]. IVCM has identified subbasal nerve alterations such as reduced nerve density, increased tortuosity, reflectivity, and presence of microneuromas [27][28][29][30]. Although it has recently been suggested that the visualization of microneuromas in IVCM could represent an objective biomarker for the diagnosis of NCP [31], there are scarce data regarding the IVCM-assessed ultrastructural characteristics of corneal nerves and microneuromas in patients with DED-related NCP.…”

Defining an Optimal Sample Size for Corneal Epithelial Immune Cell Analysis Using in vivo Confocal Microscopy Images

“…Previous corneal IVCM studies have used a variety of sample sizes, including quantifications from three ( 9 , 15 , 19 – 22 ), five ( 6 ), eight ( 23 ), or twelve ( 24 ) non-overlapping images, to derive an estimate of central corneal epithelial IC density for a single participant. Using a larger sample would be expected to yield a more accurate estimate, as a larger portion of the corneal region is directly quantified; the trade-off is that more time and effort is required for the image acquisition, selection and analysis ( 25 ). Using randomly selected images, rather than images selected by an observer, would be expected to reduce biases in image selection.…”