149 Summary, general discussion & directions for future research The aim of this thesis is to gain more insight in SFN that is associated with sarcoidosis. The pathophysiology of sarcoidosis-associated SFN and autonomic dysfunction remains unknown, no gold standard is available for diagnosis, the proposed diagnostic criteria are challenging and no specific therapy is available. Therefore, diagnosis, symptoms, measurement of patient-reported outcomes and treatment of SFN and cardiac autonomic dysfunction in sarcoidosis patients were subject of study. Summary Before discussing the results of this thesis, the main findings will be presented first. Chapter 3 highlighted the high prevalence of fatigue, restless legs syndrome (RLS), pain and cognitive impairment in patients with sarcoidosis-associated SFN compared with patients with sarcoidosis without SFN. Additionally, the correlation between these non-organ specific symptoms were established. The prevalence of each symptom was significantly higher in patients with sarcoidosis compared to healthy controls and was even higher in patients with sarcoidosis and SFN. In addition, these symptoms showed a moderate to strong correlation with each other. In conclusion, patients with sarcoidosis and SFN experience higher disease burden. Chapter 4 investigated the prevalence of patient reported pain in the skin, muscles, and joints with the new SFN phenotyping questionnaire (SFNPQ). A distinction was made between pain in the head, thorax, arms, hands, back/abdomen, legs, and feet. Cutaneous symptoms in the feet and muscular symptoms in the legs showed the highest prevalence in sarcoidosis-associated SFN (67% and 77% respectively). Joints symptoms were highly prevalent in patients with sarcoidosis, both with and without SFN. Finally, the SFNPQ was able to discriminate characteristics and anatomical origins of SFNrelated symptoms, which adds value for future research as well as for clinical purposes. Chapter 5 describes the diagnostic performance of thermal threshold testing (TTT). Strengths and limitations of this method were evaluated and a proposal was made to select the best parameters and measuring sites. Diagnostic accuracy for multiple combinations of parameters and measuring sites revealed that all parameters except for the method of levels, measured at both feet showed the best diagnostic accuracy. Moreover, a cutoff value of at least 2 abnormalities was required for optimal diagnostic accuracy. Subsequently, this raised awareness about the definition of abnormal TTT and its relation with the number of measuring sites in combination with parameter selection. As a result, a new parameter was proposed based on the number of abnormalities measured with TTT (TTT NOAs). Chapter 6 compared multiple analysis methods to assess corneal nerve fiber length (CNFL) from corneal confocal microscopy (CCM) images. CNFL was compared between healthy controls, sarcoidosis patients without SFN and sarcoidosis patients with established SFN. No decreased CNFL or corneal nerve fiber area (CNFA) could be established in sarcoidosis patients with SFN. Therefore, CCM could not add value to diagnosing sarcoidosis-associated SFN. A good correlation could be established for manual, semi-automatic and automatic analysis of CNFL and CNFA between CCMetrics, ACCMetrics and NFA FIJI. Consequently, future studies can use automatic programs to reduce labor intesity. Chapter 7 identifies non-length-dependent, length-dependent, intermittent or continuous SFN symptoms with the new SFN phenotyping questionnaire (SFNPQ) in patients with sarcoidosis, based on Appendix 2 – Figure 1. Additionally, the association between phenotype and different diagnostic modalities was investigated. While it has been suggested that immune mediated SFN would present more often non-length-dependent, this chapter revealed no significant difference between length10 156 10
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