157 Directions for future research Based on the results described in this thesis, this paragraph will provide suggestions for future research. These suggestions relate to the diagnostic methods IENFD and 123I-MIBG scintigraphy, and treatment strategies for cardiac autonomic dysfunction and SFN. First, it might be interesting to identify the relation between Aδ-fibers and C-fibers in the process of SFN. For example, in our study cohort the only method including combined assessment of Aδ-fiber and C-fiber function, TTT, was the only method able to identify sarcoidosis-associated SFN. Autonomic function tests, corneal and intraepidermal nerve fiber density based on C-fibers were not able to identify sarcoidosis-associated SFN in our cohort. This might suggest that Aδ-fibers are more vulnerable for sensory dysfunction. Therefore, it would be interesting to identify whether Aδ-fiber dysfunction measured with TTT correlates with Aδ-fiber degeneration in skin biopsies. Labeling myelin in addition to PGP9.5 staining could introduce the new interesting parameter: intraepidermal Aδ/Cfiber ratio. Although this thesis showed no benefit of 10 µm skin biopsy sections, the search for improvement of this method should be continued. An interesting upcoming method that could improve the sensitivity of IENFD involves three-dimensional imaging with optical tissue clearing technique. This technique enables nerve structure quantification without the limits of tissue section thickness.44,45 Fiber length per unit volume was suggested to be a new alternative parameter for small nerve fiber quantification. Moreover, reduced nerve/mm3 was already established in pruritic atopic dermatitis and psoriasis skin.46 According to these studies, tissue clearance are widely applicable, rapid and low cost.44 This improves the determination of nerve fiber density because nerve fragments generated from sectioning are currently not counted according to the guidelines. Moreover, small fiber quantification cannot fully account for the actual extent of nerve innervation, because a short nerve with extensive secondary branching traversing the basal membrane is counted together as a single nerve.3 The SFNPQ specifically assessed pain in the skin, muscles and joints. It would be interesting to assess the association between specific diagnostic methods and corresponding symptoms. For example, before the diagnostic criteria were introduced in 2008, sudomotor function tests were considered as one of the most reliable diagnostic methods, up to 80% of SFN was established based on sudomotor assessment.47 However, this thesis found no association between Sudoscan (ESC) and SFN (SFNSL) (see Appendix 1, Figure 2). Although Sudoscan was associated with SFN in other studies, it was not investigated whether symptoms of hyper-, hypo- or anhidrosis were required for reaching abnormal test results.48,49 We hypothesize that phenotyping based on patient-reported outcome measures could help selecting adequate diagnostic methods.50 It would be interesting to know whether these symptoms are associated with abnormal test results of the corresponding domain. Given the fact that current guidelines for cardiac sarcoidosis do not make any recommendations regarding a diagnostic trajectory for cardiac autonomic dysfunction, we hypothesize that this specific problem is underdiagnosed in patients with sarcoidosis.26 Our study based on retrospective data showed that less than 5% of patients referred for assessment of cardiac involvement underwent an 123I-MIBG scintigraphy as diagnostic tool for cardiac autonomic dysfunction. Of this group, 43% were eventually diagnosed with cardiac autonomic dysfunction, further strengthening our hypothesis that autonomic dysfunction is underdiagnosed in patients with sarcoidosis. Based on our results, it could be useful to study the prevalence of cardiac autonomic dysfunction in a larger cohort of sarcoidosis patients referred for cardiac screening. Moreover, guidelines for treatment of cardiac autonomic dysfunction are lacking. Regarding the high estimated prevalence of SFN in patients with sarcoidosis, our data suggest that autonomic dysfunction 10 164 10
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