8 A healthy nerve has a small diameter and normal nerve fiber length. In SFN, several stages are defined. In an early pathological stage, the small nerve swells, increasing the nerve fiber area (NFA) while keeping the nerve fiber length (NFL) and density (NFD) within normal ranges.13 Advanced degeneration results in a severely decreased intraepidermal nerve fiber density (IENFD). After degeneration, sprouting results in new nerve structures, see Figure 2A. Figure 2B shows a schematic course of NFA and NFL during the stages of a healthy nerve, nerve swelling and nerve degeneration. Nerve degeneration might be followed by regeneration due to nerve sprouting, as illustrated in Figure 2.14 Figure 2 A) Several stages of small nerve fiber neuropathy in the epidermis. B) Change of nerve fiber area and nerve fiber length during different stages of SFN. Diagnosis The lack of a gold standard makes diagnosing SFN challenging in daily clinical practice.15 Common nerve conduction tests assess only large myelinated nerve fibers, providing no information on small fiber function.6,16 Furthermore, the heterogeneous presentation of SFN requires multimodal testing. Diagnostic criteria suggest diagnosis based on different levels of certainty. A diagnosis of possible SFN can be made if symptoms (explained in the next paragraph) are present and at least two clinical signs of SFN, such as pinprick, thermal sensory loss, allodynia or hyperalgesia. A diagnosis of probable SFN can be made when symptoms, at least 2 clinical signs and normal nerve conduction studies are present. Finally, a diagnosis of definite SFN can be established if symptoms, at least 2 clinical signs, normal nerve conduction studies and abnormal quantitative sensory testing (QST) or decreased IENFD are present, as shown in Table 1.17 Table 1 Diagnostic criteria for small fiber neuropathy according to the Besta criteria Diagnosis Criteria Possible SFN Symptoms ≥2 clinical signs Probable SFN Symptoms ≥2 clinical signs Normal nerve conduction studies Definite SFN Symptoms ≥2 clinical signs Normal nerve conduction studies Abnormal QST or Decreased IENFD SFN = small fiber neuropathy; QST = quantitative sensory testing; IENFD = intra-epidermal nerve fiber density 1 9 1
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