Dysimmune small fiber neuropathies

Abstract Small-fiber polyneuropathy (SFN) consists of exclusive or preferential damage to very thin A-delta and thinner sensory and autonomic/trophic C-fibers, the most vulnerable axons. Lack of myelination and a high axolemma/axoplasm ratio leave their distal neurites most likely to malfunction and degenerate in suboptimal conditions. SFN’s cardinal symptoms—symmetric neuropathic pain and itch, postexertional fatigue, postural orthostasis, and postprandial gastrointestinal distress—are so nonspecific that confirmation with PGP9.5-immunolabeled skin biopsies is recommended for uncertain cases. Sensory symptoms reflect excess axonal firing plus deafferentation of central inhibitory circuits. Internal symptoms also reflect premature hypoxia and impaired cardiac return from malfunctioning sympathomotor blood-vessel regulation. With half of fibromyalgia patients having evidence of SFN, it could be the most common peripheral neuropathy, but currently, SFN symptoms are often managed palliatively leaving the SFN undiagnosed and untreated, particularly in children. Among the many patients without diabetes or evidence cause (initially idiopathic SFN/iiSFN), dysimmunity is increasingly implicated. Almost all nonlength-dependent iiSFN (sensory and/or autonomic ganglionitis/neuronitis) is autoantibody-mediated, with Sjogren’s syndrome most common. B-cells also appear involved in acute, Guillain-Barre-like and chronic length-dependent iiSFN, akin to chronic inflammatory demyelinating polyneuropathy. A large series documents elevated prevalences of immune markers, and a passive-transfer experiment reproduced iiSFN behaviorally and pathologically in mice injected with patient sera. A small case series documents the responsiveness of apparently dysimmune SFN to corticosteroids, with four larger series reporting efficacy of intravenous immunoglobulins (IVIg). For immune-mediated SFN, pain management alone is only marginally effective, and it permits damage to continue, risking disability and medication dependence. In contrast, immunomodulation not only can improve symptoms, but also reduce medication use and encourage small-fiber regrowth and recovery. When SFN is arrested, the prognosis is good for restoring life quality and trajectory, particularly in young and otherwise healthy patients. Hence, the need to improve the diagnosis and treatment of dysimmune SFN.