7 General introduction Sarcoidosis is a granulomatous, multisystem disorder of unknown cause, mainly affecting the lungs and lymph nodes.1 Small fiber neuropathy (SFN) is a significant problem in sarcoidosis patients, with an estimated prevalence between 40-86%.2,3 This thesis focuses on SFN and cardiac autonomic dysfunction that is associated with sarcoidosis. Diagnosis, symptoms, measurement of patientreported outcomes and treatment of SFN and cardiac autonomic dysfunction in sarcoidosis patients will be subject of study. In this chapter, these topics will be explained, after first introducing the different types of fibers of the nervous system and stages of neuropathy. Neurophysiology and neuropathology of small nerve fibers SFN can affect small sensory fibers, autonomic fibers or both, resulting in sensory changes, autonomic dysfunction, or combined symptoms.4 The peripheral nervous system is classified into different types of nerves based on diameter, myelin sheet, and conduction velocity, as depicted in Figure 1A.5,6 Aα- and Aβ-fibers are classified as large nerve fibers, while Aδ- and C-fibers are classified as small nerve fibers. SFN is caused by damaged sensory and/or autonomic Aδ- and C-fibers. Small myelinated Aδfibers are characterized by faster conduction velocities (4-36 m/s)7,8 compared to unmyelinated Cfibers (0.4-2.8 m/s),8–10 due to larger diameter and myelin.11 Due to the difference in conduction velocity, Aδ-fibers are responsible for the sharp, pricking or “first” pain response, and C-fibers for the burning or “second” pain response, as shown in Figure 1B.5 Aδ-fibers that respond to heat are divided into type I and II A mechano-heat (AMH) units. AMH type I fibers are responsible for first pain sensation of mechanical stimuli, and AMH type II fibers are involved in first pain sensation of heat pain stimuli.5,11 C-fibers can be polymodal, responsive to noxious, thermal and mechanical stimuli. Additionally, they may respond to a specific stimulus, multiple stimuli or non-specific stimuli.12 Figure 1 A) Overview of nerve fiber sizes, conduction velocities and other characteristics. Aα and Aβ fibers are large and myelinated nerve fibers, Aδ nerve fibers are small myelinated nerve fibers, and C-fibers are small unmyelinated nerve fibers. B) Corresponding pain response. Large nerve fibers show a fast response with high amplitude. The smaller the nerve fiber, the lower the amplitude and the slower conduction velocities. 1 8 1
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