24 Figure 2 Complete overview of the nervous system, showing anatomical differences between the somatic and autonomic system and differences in nerve anatomy and use of neurotransmitters. In addition, all diagnostic methods are presented at their corresponding measuring area. Different font styles are used to discriminate between methods based on NFD (bold), small nerve fiber function (italic) and imaging (normal). Moreover, for some functional tests, an additional mark is established to discriminate between tests based on thermal and/or mechanical nociceptors. Abbreviations: EPs, evoked potentials; fMRI, functional magnetic resonance imaging; TST, thermoregulatory sweat testing; US, ultrasound; CCM, corneal confocal microscopy; IENFD, intra-epidermal nerve fiber density; QST, quantitative sensory testing; TTT, temperature threshold testing; HR, heartrate; EMG, electromyography; MIBG, 123I-meta-iodobenzylguadine; QPART, quantitative pilomotor axon-reflex test; BP, blood pressure; SGNFD, sweat gland nerve fiber density; LDIflare, laser Doppler imaging flare; QSART, quantitative sudomotor axon reflex test; QDIRT, quantitative direct and indirect reflex test; SSR, sympathetic skin response. Diagnostic methods Various methods have been described to diagnose SFN. Diagnostic methods can be categorized into questionnaires, genetic analysis, quantification of small nerve fiber density (NFD), sensory function tests, autonomic function tests and imaging techniques to quantify small nerve fibers.48 Questionnaires are rather subjective and imaging techniques are still in the early stages of assessing their diagnostic utility for SFN. Quantification of small sensory nerve fibers through NFD measurements, as well as functional assessments of sensory and autonomic small nerve fibers, have been frequently studied and compared. It is important to keep in mind that NFD or functional outcomes are very different measures for SFN.49 Diagnosing SFN remains challenging and a gold standard is not yet available. The presence of at least two abnormal findings at clinical, QST and skin biopsy examination have been suggested as best diagnostic criteria for SFN.24,50 However, there remains some controversy on this suggestion.51 Moreover, the clinical utility of skin biopsy is limited by labor intensity, availability in few centers, high costs and impracticality for longitudinal studies. Therefore, another research group suggests the presence of at least two abnormal findings at clinical, QST and Quantitative Sudomotor Axon-Reflex Test (QSART) examinations for a definite diagnosis.52 2 26 2
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