155 important difference but did not reach statistical significance.38 The retrospective design and the absence of standardized SFN diagnostic criteria may have skewed the population toward a nonresponding cohort. Additionally, ARA290, an erythropoietin derivative with tissue-protective and healing properties, demonstrated positive effects on both pain-related and non-pain-related symptoms in sarcoidosis patients.25 Given that ARA290 can reduce inflammation via innate immune receptors, this suggests a potential link between sarcoidosis-related inflammation and SFN symptoms. Therefore, investigating the effects of anti-inflammatory treatments on SFN in a prospective study remains a compelling avenue for further research. Next to SFN, guidelines for treatment of cardiac autonomic dysfunction are also lacking. Based on retrospective data, this thesis found that 88% of patients with sarcoidosis-associated cardiac autonomic dysfunction and carvedilol treatment experienced relieve of cardiac symptoms. However, 50% of patients experienced side effects. Consequently, only one-third successfully continued treatment after 3 months. Limitations One of the most important bottlenecks of this thesis was the lack of IENFD according to the EFNS guidelines to define patients with SFN.3 As alternative, we used “probable SFN” according to the diagnostic criteria2 to define our population of SFN patients. We believe this method is valid because no actual gold standard for diagnosing SFN is available and IENFD is currently a surrogate gold standard.39 In case no gold standard is available, an alternative method to test the amount of agreement between index test and the reference standard can be applied. “Validate index test results” is a method which abandons the test accuracy paradigm and relates to other relevant clinical characteristics.40 “Probable SFN” was based on symptoms, clinical signs and negative EMG test results which fits the requirement for relevant clinical characteristics. To apply this method, strict inclusion criteria were applied resulting into a well-defined study population. Patients with symptoms and clinical signs of SFN also showed significantly higher SFNSL-score, underlining the strict patient selection. Proposal: new diagnostic workflow Although in recent years multiple studies revealed a low sensitivity of IENFD in the diagnosis of SFN, it remains a key component of the diagnostic criteria for SFN. More recently, consistent with the findings presented in this thesis, it has been shown that in majority of patients diagnosed with SFN, the diagnosis could be established based on abnormal TTT rather than abnormal IENFD.9 The pathophysiology of SFN is very complex and too little understood to design one diagnostic method as gold standard for diagnosis.39 Moreover, the heterogeneity of the disorder is possibly the main limitation for having an individual gold standard. Consequently, multimodal testing would probably remain the best alternative.41,42 Therefore, we suggest a more accessible and clinical applicable approach for diagnosing SFN using IENFD only if TTT is normal in patients suspected of having SFN, (Figure 1). 10 162 10
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