96 Although research has been conducted over the past 20 years to support its clinical use, CCM is still primarily used for research purposes only. Many hurdles have already been overcome in translating this technique from research to clinical use. For example, normative values are available12 and a detailed protocol can be used for accurate quantification of peripheral neuropathy.13 In addition, a solid body of literature is currently available to support the utility of CCM in neurodegenerative diseases.14 The cornea harbors a high nerve fiber density, up to 400 times higher compared to IENFD.15 Morphologic changes of the subbasal nerve plexus, such as the beading, length, branching and tortuosity of the nerve fiber are related to the presence of small fiber neuropathy.11,16 There are several quantification methods available to analyze corneal nerve fibers17 ranging from manual analysis18, semi-automatic analysis19 and automatic analysis.20,21 Parameters such as corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD) and nerve fiber area (NFA) can be identified using these techniques. However, guidelines on which analysis system should be used are lacking, as well as data on comparison of these different programs. CNFD counts the number of main nerves in the image (no./mm2), CNBD counts the number of branches (no./mm2) and CNFL counts the total length of both main nerves and branches (mm/mm2). Compared to CNFL, NFA is defined by the sum of total length of both main nerves and branches and the variation in the width (µm2/mm2) of nerve the fibers. As a result, NFA shows a nonlinear relation with CNFL and provides additional information when the structure but not the length of the small fibers changes. In the early stage of small fiber neuropathy, nerves tend to swell, while nerve degeneration can be observed in a more advanced stage of SFN. We illustrated this process in Figure 1, which was based on the study describing this nerve pathology.6 Based on the fact that in the early phase of SFN development nerve fiber length remains stable (Fig 1), it is suggested that the use of NFA increases the sensitivity for diagnosing SFN.21 To date, no study has examined the correlation between NFA FIJI and ACCMetrics NFA. In patients with and without diabetes, there is good agreement between manual, semi-automatic and automatic analysis of CNFL.22 Figure 3 A schematic presentation of a small nerve fiber in different stages in the epidermis. A healthy nerve has a small diameter. The small nerve swells at an early pathological stage before degenerating and can be recognized as SFN with decreased nerve fiber density. Advanced degeneration results severely decreased intraepidermal nerve fiber density. After degeneration, sprouting results in new nerve structures. The graph below shows a schematic progression of NFA and CNFL during the stages of healthy nerve, nerve swelling and nerve degeneration. NFA can detect nerve swelling in the early stage of SFN by measuring an increasing number of pixels in the nerve structures. CNFL will measure a decreased number of pixels when nerve degeneration appears. Looking at the different etiopathogenesis of diabetes and sarcoidosis, it remains to be seen whether the results found in patients with diabetes can be extrapolated to patients with sarcoidosis.23 For 6 101 6
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