9 Until now, SFN has generally been assessed by skin biopsy and QST, following diagnostic criteria.17 Currently, however, up to 25 methods have been developed to assess specific small nerve fiber functions. This paragraph will be limited to those used during our prospective studies. The other methods are described in Chapter 2. Skin biopsy Decreased IENFD, as mentioned in the diagnostic criteria, can be established through skin biopsy. Assessment of IENFD is recommended using a manual staining technique with 50 µm of skin biopsy slides, which is available only in specialized centers due to the need for adequate training and its laborintensive nature.18 Due to the lack of automatic staining protocols for assessing IENFD, this specific method for diagnosing SFN is unavailable in most hospitals in the Netherlands. Another limitation of IENFD is the low sensitivity, between 28-38%,19–21 for diagnosing SFN in patients with sarcoidosis. Thermal threshold testing QST assesses both small and large nerve fibers.22 Since performing the full test is time-consuming, a subset of parameters has been selected to specifically assess small nerve fiber function through thermal threshold testing (TTT).23–25 Additionally, nerve conduction studies are recommended to assess large nerve fibers.26 TTT measures the cold detection threshold (CDT), warm detection threshold (WDT), thermal sensory limen (TSL), paroxysmal heat sensation (PHS), cold pain threshold (CPT) and heat pain threshold (HPT). CDT and WDT can be measured using the method of limits (MLi) and the method of levels (MLe). The MLi is time-dependent and requires the participant to respond as soon as they feel a change in temperature. MLe applies standardized temperature changes and requires feedback with a yes or no button to determine whether the next stimulus is higher (after “no”) or lower (after “yes”). No clear agreement has been reached on the superiority of either method, and results are conflicting.17,25 For example, the German Research Network on Neuropathic Pain (DFNS) protocol,27 the most widely recognized and standardized protocol for QST procedures, recommends the MLi. In contrast, the Besta criteria, the most widely recognized and standardized diagnostic criteria for SFN, recommend the MLe.17 Known disadvantages of the MLe are high time consumption and desensitization due to the numerous repeated measurements.28 Corneal Confocal Microscopy Corneal confocal microscopy (CCM) has been explored as a novel and minimally invasive alternative method to detect SFN.29,30 CCM generates in vivo images of the corneal subbasal nerve plexus with resolutions comparable to ex vivo histochemical methods.31 The cornea harbors a high nerve fiber density, up to 400 times higher compared with skin.32 Morphologic changes in the subbasal nerve plexus such as nerve fiber beading, length, branching, and tortuosity, are related to the presence of small fiber neuropathy.31,33 Multiple different quantification methods are available to analyze corneal nerve fibers,34 varying from manual analysis35 to semi-automatic analysis36 and automatic analysis.37,38 In patients with and without diabetes, good agreement is found between manual, semi-automatic, and automatic analysis of corneal nerve fiber length (CNFL).39 Parameters such as corneal nerve fiber density (CNFD), CNFL, corneal nerve branch density (CNBD) and nerve fiber area (NFA) can be identified with these techniques. 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 of nerve fiber width (µm2/mm2). Consequently, NFA has a nonlinear relation with CNFL and provides additional information when the structure, but not the length of the small fibers change. In the early stage of small fiber neuropathy nerves tend to swell, whereas degeneration of nerves can be observed in more advanced stages of SFN (see Figure 1A).40 Based on the fact that nerve fiber 1 10 1
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