153 sympathetic cholinergic function (Sudoscan and water immersion skin wrinkling (WISW)) and one assessed sympathetic adrenergic function (blood pressure variability), which were all unmyelinated Cfibers. To summarize, TTT was the only method assessing Aδ-fibers as well as unmyelinated C-fibers. Furthermore, it showed to be more sensitive than other methods, and Aδ-fiber cold receptors showed the most abnormalities. Therefore, our hypothesis that small myelinated Aδ-fibers are more vulnerable for SFN remains standing. Another interesting finding of this thesis is that CNFD and 10 µm IENFD both assessed nerve fiber density but showed no correlation with each other (see Appendix 1, Figure 2). This suggests that structural assessment of nerve fiber density could vary between measuring sites (cornea, skin). This might be due to difference in measuring site, as IENFD is known to be measured more distally compared with CNFD measurements, or in-vivo vs. ex-vivo methods.21 Furthermore, eyes are immune privileged22 which may result into a different reaction of small nerve fibers on systemic inflammation. Finally, the correlation between CCM parameters and IENFD showed to be lower for patients with sarcoidosis compared to patients with metabolic diseases, which might explain the lack of correlation in our cohort.15 Although CCM parameters showed no differences between sarcoidosis patients with and without SFN, and healthy controls (see Appendix 1, Table 1), and the strong correlation between CNFD and SFNSL23 could not be reproduced in our population (see Appendix 1, Figure 2), it still may be an elegant technique to monitor small fiber morphology over time in individual patients because it is rapid and noninvasive. Especially in case of monitoring during and after therapy, CCM may be of benefit. Studies have already shown that an increase in small fiber density can be detected using CCM , after treatment with ARA-290, an erythropoietin-derived peptide that interacts with the innate repair receptor that mediates tissue protection.24,25 In future studies regarding treatment of SFN, we believe that the assessment of morphological changes of small nerve fibers might be useful to learn more about the complex pathophysiology of SFN. Diagnosing cardiac autonomic dysfunction Current guidelines for diagnosis and management of cardiac sarcoidosis do not make any recommendations regarding a diagnostic trajectory for cardiac autonomic dysfunction.26 Our study based on retrospective data showed that in our center at present, less than 5% of patients referred for assessment of cardiac sarcoid involvement underwent an 123I-MIBG scintigraphy as diagnostic tool for cardiac autonomic dysfunction. Of this group, 43% were eventually diagnosed with cardiac autonomic dysfunction, based on abnormal 123I-MIBG uptake or washout. In conclusion, increased awareness is needed to prevent underdiagnosing cardiac autonomic dysfunction in patients with sarcoidosis, both with and without cardiac sarcoid involvement or SFN. Symptoms Recognizing symptoms accurately is crucial for diagnosis and effective treatment of sarcoidosisassociated SFN, as it ensures suitable intervention and eventually may lead to improved health-related quality of life (HRQL). For example, failing to recognize a concurrent diagnosis of RLS in patients with sarcoidosis and SFN, might withhold these patients from receiving appropriate treatment for RLS. Thus, clinicians should be aware of the prevalence and severity, as well as the associations between fatigue, pain, RLS and cognitive impairment in these patients. It is crucial to not only assess pain but also consider other symptoms that can adversely affect the quality of life of patients with sarcoidosis. Although many of these symptoms cannot currently adequately treated, some, such as pain and RLS, may be managed effectively. Acknowledging and addressing these distressing symptoms is of utmost importance for improving patient care. 10 160 10
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