60 Among healthy controls, an elevated QFC-score was measured in one individual (5%). Although, pain and RLS were fully absent in healthy controls, fatigue and cognitive failure were present. The difference between those symptoms is that CFQ and fatigue measure subjective mental status while pain and RLS are more physically orientated. Cognitive functioning is a complex process and can be influenced by many factors. For example circadian typology, wakefulness, mood, stress, environment, activity, age, hormonal state and time of the day show respectively increased risk of cognitive failures.33 These results show that it is important to realize that healthy people also sometimes experience fatigue and reduced cognitive functioning. There is a huge clinical unmet need regarding better treatment options for these symptoms negatively impacting quality of life in patients with sarcoidosis. For example, overlooking a concomitant diagnosis of RLS in patients with sarcoidosis with SFN, might withhold these patients from accurate therapy for RLS. Current treatment of painful SFN mainly consists of pregabalin and gabapentin, which could also be beneficial in treatment of RLS, but pharmacological RLS therapy options are more extensive, with apart from alpha2-delta calcium channel ligands, also dopamine (agonist) or (low-potency) opioids. 31 In addition, it is important to state that antidepressants, which are frequently used in treatment of SFN, may induce or worsen pre-existing RLS.34 In addition to pharmacotherapeutic treatment, life style interventions regarding RLS have been studies. For instance, focus on mental alerting and trial of abstinence from caffeine and alcohol could be beneficial in some patients.31 Moreover, exercises, acupuncture pneumatic compression devices and near-infrared light showed significant effects on reducing RLS symptoms.35 Whole-body cryotherapy, transcutaneous stimulation and repetitive transcranial stimulation shows short-term positive effects on RLS. Lastly, general assessment for RLS also includes examination for iron deficiency, other sleeping disorders or medication which can induce RLS. When all symptoms in the legs are assumed to be due to SFN instead of RLS, there would be no attention for an appropriate RLS analysis. Specific medication for treatment of fatigue in sarcoidosis is lacking. Nevertheless some small RCTs suggest that neurostimulants, such as methylphenidate and armodafinil,36,37 or steroids such as dexamethasone,38 could have the potential to improve sarcoidosis-associated fatigue. More recently, interest in non-pharmacological therapy options for fatigue in sarcoidosis is growing. A recent study in patients with sarcoidosis showed improvements in fatigue after a 12-week online mindfulnessbased cognitive therapy.39 A limitation of our study was the subjective nature of questionnaires. The results of questionnaires are patient reported, providing an adequate impression of subjective fatigue, pain, RLS symptoms and cognitive impairment. No quantitative methods for assessment of fatigue, pain and cognition are available. Diagnostic criteria for RLS do not rely on a diagnostic test,40 however, polysomnography could be a method to quantify periodic limb movements during sleep.15 In general, objective clinical parameters correlate poorly with the patients’ subjective sense of well-being.22 For example, subjective cognitive impairment can be influenced by the discrepancy between everyday memory functioning and memory demands.9 However, the subjects’ sense of well-being may influence the QoL,2 which justifies the importance of rather subjective results gathered with questionnaires. Another limitation is the lack of diagnosing SFN with skin biopsy and/or quantitative sensory testing (QST) according to the current diagnostic criteria for SFN.20,41,42 However, given the low sensitivity of skin biopsy, the subjective outcome of QST and the fact that in clinical practice many patients suffer from SFN-associated complaints, we chose to study patients with a diagnosis of probable SFN instead of established SFN. The strength of this study is a clear comparison of multiple non-organ related consequences of sarcoidosis, such as fatigue, pain, RLS, SFN and cognitive impairment in sarcoidosis patients, which are 3 63 3
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