Thesis

10 length remains stable in the early stage of SFN, it is suggested that using NFA increases diagnostic sensitivity for SFN.38 Although research has been conducted over the past 20 years to support its clinical use, CCM is still primarily used for research purposes. CCM was explored in this thesis due to its benefits over skin biopsy and its potential as a diagnostic method for SFN in the future. Autonomic function testing Besides IENFD, TTT and CCM, multiple other tests have been developed to assess small fiber autonomic dysfunction, including Sudoscan,41 blood pressure variability (BPV)42 and heart rate (HR)43 after postural change, and water immersion skin wrinkling (WISW).44 Sudoscan measures the electrochemical skin conductance, enabling the detection of hypo- or hyperhidrosis in patients with SFN. BPV and HR after postural change can detect orthostatic hypotension caused by autonomic dysfunction. Sympathetic nerve dysfunction prevents vasoconstriction, resulting in absent skin wrinkling after exposure to warm water. Currently, the prevalence of SFN is likely underestimated due to lack of a gold standard and limited awareness among clinical physicians.45,46 Improving diagnostic methods is crucial to enhance the recognition of SFN symptoms, deepen insights into its pathophysiology, and facilitate future drug trials. Symptoms Because a gold standard for diagnosing SFN is still lacking, it is important to evaluate the symptoms associated with SFN. This section describes a selection of SFN-associated symptoms and their relation to various small nerve fiber functions. The potential symptoms are numerous and often significantly impacts quality of life.47 More general and nonspecific SFN-related symptoms include fatigue, cognitive impairment, widespread musculoskeletal pain, headache, and temporomandibular malfunction.46,48 Sensory dysfunction result in symptoms of neuropathic pain, burning sensations, or itching.6,16,46 Autonomic dysfunction results in sweating abnormalities, cardiovascular dysfunction, gastrointestinal dysfunction, urogenital dysfunction, or other autonomic functions.4,46 Table 2 summarizes some of the best-known SFN-related symptoms. Table 2 Symptoms related to small fiber neuropathy General Symptoms Sensory disturbances Autonomic dysfunction Fatigue Neuropathic pain Skin changes Cognitive disturbances Burning sensations Sweating abnormalities Widespread musculoskeletal pain Numbness Dry eyes Headache Tingling Dry mouth Itching Gastrointestinal dysmotility Frostbite-like sensations Orthostasis Bedsheet intolerance Palpitations or arrhythmias Stocking-glove / random / migratory and/or intermittent Bowel or bladder changes Sexual dysfunction SFN pathophysiology and phenotypes SFN is associated with a wide variety of diseases as underlying mechanisms, but can also present as idiopathic.46,49 Although the pathogenesis of SFN remains unknown, the possible underlying disease seems to influence its presentation. For example, in patients with diabetes mellitus (DM) typical length-dependent symptoms are described. Moreover, studies confirm that distal axonal loss, measured in skin biopsies, predicts the progression of distal SFN to proximal large fiber neuropathy.13 In contrast, studies examining patients with diseases other than DM reveal that SFN rarely progresses 1 11 1

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