37 pain” and “small fiber mediated autonomic dysfunction”, has been proposed8. Although symptoms may overlap between different phenotypes, SFN patients may differ from each other and require different therapies. For example, sodium-channel blockers are only effective in patients with proven sodium-channel mutations.8 Figure 6 shows a roadmap proposing sufficient diagnostic methods, based on different phenotypes. Only methods currently available for routine use are suggested (i.e. level 1-3). Table 4 Level of applicability and limitations for each method. Method Limitations Level of applicability Quantification of small nerve fiber density Skin biopsy (IENFD) Thickness of tissue sections not applicable for routine diagnostics Fluorescence microscopy less available Counting IENF number per epidermal length in light microscopy cannot easily be standardized without computer-assisted image analysis 144 Morphological changes also appear in healthy subjects75 Morphological changes may occur without decreased IENFD145 Decreased IENFD is not correlated with pain intensity in all cases146 Normal IENFD + morphological changes may appear in an early stage of SFN and show decreased IENFD after repeated biopsy75 May be unclear in patchy diseases18,147 The pattern of symmetric, non-length dependent neuropathic pain with face and trunk involvement suggests a selective disorder of dorsal ganglia cells sub serving small nerve fibers.148 Training required149 Level 3 Sweat Gland Nerve Fiber Density (SGNFD) Complex 3D structure No standardized and validated method available149 Limited depth of view Biopsy thickness of 50 µm Labor intensive (30-40 hours only for staining) Not applicable for routine use76 Level 4 Corneal Confocal Microscopy (CCM) Limited availability Not yet approved by the FDA for clinical use84 Level 4 Sensory function tests Quantitative Sensory Testing (QST) Great inter-observer variability Lack of world-wide standardization90 Test results may be influenced by patients (lack of) motivation Level 2 2 39 2
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