41 Discussion In order to present an overview of the AUC values, all available diagnostic methods are included. However, due to the large amount of methods, no subdivision is made for multiple parameters within one method. For example, TTT and CCM measurements both result into 4 different outcome measures. Each test shows different sensitivity and specificity values. In order to show an overview of all methods as complete as possible, no studies are excluded based on sample size. For many techniques, sensitivity and specificity are only calculated based on small sample sizes. Since the available methods to test for SFN are so numerous, it would add little information if sensitivity and specificity were only included for a few methods, based on large samples sizes. As a consequence, these values are less reliable, compared to studies with large sample size. In addition, positive and negative predictive values are not presented due to limited data. SFN is associated with many different underlying etiologies. Since pathophysiology and cause are unknown, SFN etiology may differ between different populations. In case of different etiologies, some methods can be more or less sensitive for specific phenotypes. Sensitivity and specificity depends on the amount of patients with SFN included in the study. When fewer patients with SFN are included in the study, sensitivity and specificity are less reliable compared to studies including a large amount of SFN patients. No criteria are used to exclude studies with lower number of SFN patients compared to control groups. Clinical applicability levels are designed for this review, based on the Dutch healthcare system. A level is ascribed based on research papers and reviews, which describe the limitations of a technique and whether it is used for research or clinical use. In case of clinical use, an estimation is made about how simple the method can be implemented. Labor intensity, expenses and the required size of research room are amongst other factors which influence the clinical applicability levels. The diagnostic workflow presented in Figure 6, is based on the results of extensive literature research. It has not yet been validated and consensus for a definite SFN diagnosis, is still lacking. Conclusion Diagnosing SFN remains a challenge. While small fibers have a wide range of functions, current diagnostic tools only focus on specific areas. Therefore, SFN in areas outside of the diagnostic test range might be missed. Moreover, tools focusing on different areas do not correlate with each other. A reliable test that examines all parts of the small fiber system has yet to be developed. In the absence of a true gold standard, the most reliable diagnosis of SFN in daily clinical practice is made using a combination of tests based on structural and sensory function tests of the small fiber nerves. Ideally, Na-channel mutation research and autonomic tests should be added to also test all phenotypes of SFN. A diagnostic work-flow based on phenotypes is suggested. Given the magnitude of the clinical problem further research is necessary in order to obtain a simple, reliable and non-invasive technique to assess SFN. 2 43 2
RkJQdWJsaXNoZXIy MjY0ODMw