120 dependent pain (n=48, p=0.02, Mann-Whitney U tested). Dotted line represents cutoff value of TTT NOAs as established in chapter 5. Abbreviations: LD int = intermittent length-dependent pain; LD con = continuous length-dependent pain; NLD int = intermittent non-length-dependent pain; NLD con = continuous non-length-dependent pain; SFNSL = small fiber neuropathy screening list; TTT NOAs = thermal threshold testing number of abnormalities; IENFD = intraepidermal nerve fiber density; CNFD = corneal nerve fiber density; CNFL = corneal nerve fiber length; CNBD = corneal nerve branch density; ESC = electrochemical skin conductance; WISW = water immersion skin wrinkling. Discussion This study describes patient-reported outcomes in SFN-associated pain in a cohort of patients with sarcoidosis and probable SFN. SFN-associated pain in our cohort of patients with sarcoidosis was reported both to be length-dependent and non-length-dependent phenotype. The most important and novel finding of our study is that TTT in patients with SSFN was only associated with continuous length-dependent pain. Sarcoidosis is an immune-mediated inflammatory disease with unknown cause. SFN-related pain in our cohort with sarcoidosis patients was reported both length-dependent and non-length-dependent. This contradicts previous results that claim more often non-length-dependent symptoms.11,33 However, SFN-related symptoms are more often non-length-dependent and patchy in patients with immune-mediated disorders, than in patients with metabolic diseases such as diabetes mellitus, who manifest mainly with length-dependent symptoms.10,11 A possible explanation is that glucose dysmetabolism probably affects distal nerve axons in the form of a “dying-back” process, and that immune-mediated diseases mainly affect sensory neurons in a more random process.11 Furthermore, there may be a link between immune-mediated diseases and inflammatory dorsal root ganglionitis, which affects the small sensory neurons of the dorsal root ganglia.34 Commonly used and well established diagnostic criteria for SFN include IENFD and TTT.27 Because both methods are performed on distal parts of the extremities, it remains to be seen whether these tests are most suitable for SSFN, which based on our results is non-length-dependent in more than 40% of patients with sarcoidosis. CCM can be used to determine CNFD of the sensory terminals of the trigeminal nerve in the cornea. Because the trigeminal nerve is a short nerve, it has been suggested that decreased CNFD could be informative in patients with non-length-dependent SFN. We found no difference between CNFD in SSFN patients with a length-dependent or non-length-dependent phenotype. Other diagnostic tests, such as Sudoscan and WISW, also failed to distinguish between length-dependent and non-length-dependent phenotypes. Because patient-reported pain in probable SSFN has never been classified as continuous or intermittent, we addressed this issue. Interestingly, we found a difference in TTT results when we assessed phenotypes based on length-dependent, non-length-dependent, continuous and intermittent pain. Patients with continuous length-dependent pain showed significantly more TTT NOAs than patients without continuous length-dependent pain. This indicates that TTT is likely prone to give false-negative results in patients with intermittent length-dependent or non-length-dependent pain. It is important to note that TTT alone is not solely sensitive for SFN. For example, abnormal TTT measurements can be found in patients with central nervous system disorders35 and dependent on the patient cooperation.36 To minimize these influences, we used strict exclusion criteria to ensure a normal central nervous system and normal large nerve fibers. As applicable to other neurophysiologic tests, TTT should always be interpreted in light of the patient’s clinical presentation. Therefore, identifying phenotypes of SFN could help interpret the combination of clinical presentation and TTT results. 7 126 7
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