152 Table 1 Overview of small nerve fiber receptors, their corresponding nerve type, modality and TTT parameters. TTT = thermal threshold testing; AMH = A Mechano-Heat unit; CDT = cold detection threshold; TSL = thermal sensory limen; PHS = paroxysmal heat sensation; WDT = warm detection threshold; HPT = heat pain threshold; CPT = cold pain threshold. Corneal confocal microscopy: a novel method Corneal confocal microscopy (CCM) has been explored as a novel and minimal invasive alternative method12,13 to measure nerve fiber density. However, our cohort showed no decreased corneal nerve fiber density (CNFD) in patients with sarcoidosis-associated SFN. Corneal nerve fibers change in a complex way as function of SFN severity, which could explain the limited diagnostic accuracy of CNFD in our cohort. In addition, C-fibers are below the resolution of CCM.14,15 Therefore, CCM images contain subbasal nerve fiber bundles surrounded by a Schwann cell sheath. These bundles contain up to 30 individual nerve fibers in healthy individuals.16 Consequently, if a nerve fiber inside a trunk degenerates, it will probably not be detected with CCM. The width of corneal nerves varies depending on the number of fibers within a nerve bundle. Moreover, bundles branch to a variable degree and exhibit beading depending on mitochondrial accumulation with variable spacing and size.16 This variation may reduce the diagnostic accuracy. Evaluating the diagnostic approaches for SFN This section provides a detailed evaluation of the diagnostic approaches utilized in this thesis, including IENFD, TTT, CCM, Sudoscan, water immersion skin wrinkling (WISW), and blood pressure variability. According to Appendix 1 – Table 1, only TTT NOAs were able to diagnose SFN in our cohort of patients with sarcoidosis. This part of the discussion particularly focuses on explaining this result, highlighting the unique strengths of TTT NOAs compared to the other diagnostic tools. Our cohort sarcoidosis patients with SFN showed abnormal cold detection threshold (CDT) in 42% and warm detection threshold (WDT) in 23% of participants, see Chapter 5.11 According to Table 1, CDT tests the small myelinated Aδ-fibers, while WDT tests the unmyelinated C-fibers. Therefore, we hypothesize that small myelinated Aδ-fibers, especially the cold receptors, are more vulnerable to sarcoidosis-associated SFN. In order to investigate this hypothesis, it is important to clarify the relationship between the other investigated diagnostic methods, Aδ-fibers and C-fibers. First, we wanted to know which nerve fibers are stained and counted with IENFD according to the EFNS guidelines. Cutaneous Aδ-fiber size ranges between 1-5 µm and C-fibers between 0.2-2 µm.17 Axonal swelling predicts degeneration of epidermal nerve fibers.18,19 Nerve size below 1.5 µm was used as cutoff for healthy nerve fibers, which could include myelinated Aδ-fibers as well as unmyelinated C-fibers.19 However, the IENFD protocol only stains somatic C-fibers.19 Next, we investigated which nerve fibers were measured with CCM and the autonomic nerve fiber tests (Sudoscan, WISW and blood pressure variability). The cornea is almost entirely innervated by unmyelinated C-fibers14,15 and only C-fibers contribute to postganglionic autonomic function.20 In this thesis, three different tests were used to assess autonomic dysfunction, two of which assessed Receptor type Fiber group Modality TTT Parameter Thermal receptors Cold receptors Warm receptors Heat nociceptors Cold nociceptor Aδ C Aδ (AMH II (45°C)) C Temperature Skin cooling (250C) Skin warming (410C) Hot temperatures (>450C) Cold temperatures (<50C) CDT/TSL/PHS WDT/TSL/PHS HPT CPT 10 159 10
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