Small fiber neuropathy: is skin biopsy the holy grail?

Small fiber neuropathy (SFN) is characterized by negative sensory symptoms (thermal and pinprick hypoesthesia) reflecting peripheral deafferentation and positive sensory symptoms and signs (burning pain, allodynia, hyperalgesia), which often dominate the clinical picture. In patients with pure SFN, clinical and neurophysiologic investigation do not show involvement of large myelinated nerve fiber making the diagnosis of SFN challenging in clinical practice. Over the last 15 years, skin biopsy has emerged as a novel tool that readily permits morphometric and qualitative evaluation of somatic and autonomic small nerve fibers. This technique has overcome the limitations of routine neurophysiologic tests to detect the damage of small nerve fibers. The recent availability of normative reference values allowed clinicians to reliably define the diagnosis of SFN in individual patients. This paper reviews usefulness and limitations of skin biopsy and the relationship between degeneration and regeneration of small nerve fibers in patients with diabetes and metabolic syndrome.