150 dependent and non-length-dependent symptoms in patients with sarcoidosis-associated SFN. Furthermore, length-dependent continuous pain was the only phenotype, and TTT NOAs at the feet was the only diagnostic parameter showing an association with this phenotype. This suggested higher diagnostic yield for TTT in patients with continuous length-dependent pain. The fact that none of the other diagnostic methods showed an association with one of the phenotypes, should create awareness for possible false negative results in patients with intermittent and non-length-dependent pain. New research should be conducted to understand the differences in pathophysiologic mechanisms between intermittent and continuous pain. The development of new and more accurate diagnostic methods may be in reach in the future. Chapter 8 investigated the effects of treating the inflammatory activity in patients with sarcoidosis on the symptoms associated with SFN. In this study the effects of infliximab on sarcoidosis activity and small fiber neuropathy associated symptoms were assessed. Patients with sarcoidosis, at least 3 months on infliximab therapy and high scores on the small fiber neuropathy screening list (SFNSL) were investigated. After 3 months of therapy with infliximab, the inflammation of sarcoidosis significantly decreased, as measured by SUVmax on FDG-PET and biomarkers such as sIL-2R and ACE. However, the SFNSL revealed no significant improvement. Therefore, no association could be established between inflammatory markers and SFN-related symptoms based on the SFNSL in sarcoidosis patients. Chapter 9 described the added value of [123I]-meta-iodobenzylguadine (MIBG) scintigraphy in assessing cardiac autonomic dysfunction. Additional diagnostics for cardiac autonomic dysfunction may be particularly valuable in patients with cardiac symptoms where cardiac sarcoidosis has been excluded, as well as in patients with cardiac sarcoidosis who experience therapy-resistant cardiac complaints. In our cohort of sarcoidosis patients who underwent [123I]-MIBG scintigraphy between 2017 and 2024, 44% showed abnormalities on the scan. These findings suggest that [123I]-MIBG scintigraphy can provide further insight into otherwise unexplained symptoms. A more detailed assessment of cardiac autonomic dysfunction in sarcoidosis patients may contribute to a more personalized treatment approach. General discussion The discussion section of this thesis delves into the implications of the findings on SFN and cardiac autonomic dysfunction in sarcoidosis patients. It describes the challenges in diagnosing these conditions, given the often-overlapping and nonspecific symptoms. It assesses the efficacy of various diagnostic tools and patient-reported outcome measures. Furthermore, this section explores the clinical significance of the relationship between SFN, cardiac autonomic dysfunction and sarcoidosis, particularly in terms of patients’ prognosis and quality of life. Treatment strategies are also critically analyzed, highlighting the need for more tailored approaches. Ultimately, the discussion aims to provide a nuanced understanding of how these findings can inform and improve clinical practice and patient care. Diagnosis Current diagnostic criteria remain very challenging due to conflicting TTT protocols1,2 and a highly complex and labor intensive protocol for intraepidermal nerve fiber density (IENFD) staining.3 Moreover, sensitivity of IENFD in patients with sarcoidosis-associated SFN is rather low, between 2838%.4–6 Therefore, this thesis suggests an optimized diagnostic work-flow for SFN by evaluating a simplified IENFD protocol, recommends how to optimize the TTT protocol and implement corneal confocal microscopy (CCM) parameters as easier and faster alternative for IENFD. 10 157 10
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