20 Abstract Small fiber neuropathy (SFN) is a disorder of the small myelinated Aδ-fibers and unmyelinated Cfibers.1,2 SFN might affect small sensory fibers, autonomic fibers or both, resulting in sensory changes, autonomic dysfunction, or combined symptoms.3 As a consequence, the symptoms are potentially numerous and have a large impact on quality of life.4 Since diagnostic methods for SFN are numerous and its pathophysiology complex, this extensive review focuses on categorizing all aspects of SFN as disease and its diagnosis. In this review, sensitivity in combination with specificity of different diagnostic methods are described using the areas under the curve. In the end, a diagnostic workflow is suggested based on different phenotypes of SFN. Introduction Etiology Small fiber neuropathy (SFN) is a disorder of the small myelinated Aδ-fibers and unmyelinated Cfibers.1 Incidence and prevalence are estimated to be 12/100,000 and 53/100,000, respectively, and are expected to rise with increasing awareness of SFN worldwide.2 SFN can affect either small sensory fibers, autonomic fibers, or both, resulting in sensory changes, autonomic dysfunction or combined symptoms.3 As a consequence, the potential symptoms are numerous and show a large impact on quality of life.4 General symptoms are fatigue, cognitive disturbances, widespread musculoskeletal pain, headache and temporomandibular disorder.5,6 Somatic small nerve fibers transmit information about temperature, pain and itch.5,7,8 The autonomic small nerve fibers are responsible for thermoregulatory, sudomotor, cardiovascular, gastrointestinal, urogenital and other autonomic functions.3,5 SFN is associated with a great variety of diseases as underlying mechanisms but can also present idiopathic.1 Table 1 shows an overview of some underlying disorders.1,5 Common nerve conduction tests only assess large myelinated nerve fibers. As a consequence, SFN is difficult to diagnose following the regular procedures.7,8 Currently, the prevalence of SFN is probably highly underestimated due to lack of a gold standard and awareness among clinical physicians.5 Improving diagnostic methods is important to improve recognition of symptoms in SFN patients, it can improve insight of pathophysiology and will facilitate future drug trials. 2 22 2
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