21 Table 1 Underlying diseases associated with SFN Pathophysiology The peripheral nervous system is classified into different types of nerves, based on diameter, myelin sheath, and conduction velocity, see Figure 1A.7,33 Aα- and Aβ-fibers are classified as large nerve fibers and Aδ- and C-fibers are classified as small nerve fibers. Small myelinated Aδ-fibers show faster conduction velocities (4-36 m/s)34,35 compared to unmyelinated C-fibers (0.4-2.8 m/s),35–37 due to larger diameter and myelin.38 SFN is described as dysfunction of the small nerve fibers. The exact pathophysiology of isolated SFN is unknown. However, since demyelinating processes do not solely affect small nerve fibers, it is unlikely that this would be the underlying pathogenesis. Distal axonal loss or perhaps extraordinary neuronal degeneration are therefore more likely to be the underlying cause of SFN.3 Five decades ago, four stages of neuropathy pathology in unmyelinated nerve fibers were defined.39 1) Mild proliferation: This stage is characterized by merely an increase in number of isolated, small Schwann cell projections. As consequence, these Schwann cells show a more irregular shape. 2) Fiber loss: in a more advanced stage, a decreased amount of fibers in combination with increased amount of empty Schwann cells are established. 3) Regeneration: Subsequently, regeneration of unmyelinated fibers associated with signs of fiber loss have been identified. An increment can be noted from the total number of unmyelinated fibers as well as small fibers with a diameter below 0.8 µm and empty Schwann cell sub-units. 4) Advanced regeneration: Finally, the amount of empty Schwann cells will return to a normal level. During this stage, only an increase of small nerve fibers with a diameter below 0.8 µm, and of small isolated projection of Schwann cells can be distinguished.39 Patients with diabetic-mediated SFN might show a different pathophysiology compared with other underlying etiologies. For example, in diabetic patients, axon swelling seen in skin biopsies can predict progression of distal SFN to proximal large fiber or polyneuropathy.40–42 Conversely, recent research which included no diabetic patients, claims that SFN is a stable disorder and rarely progresses.43 Although symptoms typically are length-dependent, resulting in symptoms in Associated diseases of small fiber neuropathy5,9 Idiopathic Hereditary Fabry’s disease10 Mutation in sodium channels11 Wilsons disease12 Familial amyloidosis13 Metabolic Diabetes mellitus14 Impaired glucose intolerance15 Vitamin B12 deficiency16 Copper deficiency17 Abnormal thyroid function18 Infectious HIV19 Lyme20 Hepatitis C21 Toxic Alcohol22 Chemotherapy23 Neurotoxic drugs24 Vaccine-associated21,25 Immune-mediated Fibromyalgia26 Monoclonal gammopathy27 Ehlers-Danlos28 Sarcoidosis29 Rheumatic diseases (undifferentiated connective tissue disorders, rheumatoid arthritis, psoriasic arthropathy)24 Sjögren syndrome30 Primary systemic amyloidosis27 Acute inflammatory small fiber neuropathy24 Lupus31 Connective tissue disease24 Chronic inflammatory demyelinating polyneuropathy32 2 23 2
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