95 Abstract Introduction: No guidelines are available on the preferred method for analyzing corneal confocal microscopy (CCM) data. Manual, semi-automatic and automatic analyzes are all currently in use. The purpose of the present study was threefold. First, we aimed to investigate the different methods for CCM analysis in patients with and without small fiber neuropathy (SFN). Second, to determine the correlation of different methods for measuring corneal nerve fiber length (CNFL) and nerve fiber area (NFA). Finally, we investigated the added value of automatic NFA analysis. Methods: We included 20 healthy controls and 80 sarcoidosis patients, 31 with established SFN and 49 without SFN. The CNFL was measured using CCMetrics, ACCMetrics and NeuronJ. NFA was measured with NFA FIJI and ACCMetrics NFA. Results: CNFL and NFA could not distinguish sarcoidosis with and without SFN or healthy controls. CCMetrics, NeuronJ and ACCMetrics CNFL highly correlated. Also, NFA FIJI and ACCMetrics NFA highly correlated. Reproducing a nonlinear formula between CNFL and NFA confirmed the quadratic relationship between NFA FIJI and ACCMetrics CNFL. CCMetrics and NeuronJ instead showed a square root relationship and appear to be less comparable due to differences between automatic and manual techniques. Conclusions: ACCMetrics can be used for fully automatic analysis of CCM images to optimize efficiency. However, CNFL and NFA do not appear to have a discriminatory value for SFN in sarcoidosis. Further research is needed to determine the added value and normative values of NFA in CCM analysis. Translational Relevance: Our study improves the knowledge about CCM software and pathophysiology of SFN. Introduction Sarcoidosis is a systemic inflammatory disease of unknown cause, primarily affecting intrathoracic lymph nodes, lungs and skin.1 Small fiber neuropathy (SFN) is the result of damaged small myelinated (Aδ-fibers) and unmyelinated (C-fibers) nerve fibers. It is estimated that between 40-86% of patients with sarcoidosis suffer from SFN related symptoms.2,3 There is no gold standard available for the diagnosis of SFN, but the Neurodiab criteria4 are currently the best described criteria. These criteria are based on a large group of patients with diabetes and define three levels of diagnostic certainty. For a diagnosis of possible SFN, symptoms and/or signs of neuropathic sensory symptoms should be present. A diagnosis of probable SFN additionally includes normal nerve conduction studies. To diagnose definite SFN, decreased intra-epidermal nerve fiber density (IENFD) and/or abnormal quantitative sensory testing (QST) is also required.4 A more recent reappraisal and validation study increased the reliability of the diagnosis by stating that at least two clinical signs should be present.5 A very complex and time-consuming protocol has been proposed to determine the IENFD.6,7 QST shows varying reliability due to the lack of standardized data.8 Therefore, corneal confocal microscopy (CCM) has been investigated to detect small fiber neuropathy (SFN) as a novel and minimally invasive alternative.9,10 CCM generates in vivo images of the corneal subbasal nerve plexus with resolutions comparable to ex vivo histochemical methods.11 6 100 6
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