Opportunities afforded by the study of unmyelinated nerves in skin and other organs

Neurological practice is mainly focused on signs and symptoms of disorders that involve functions governed by myelinated nerves. Functions controlled by unmyelinated nerve fibers have necessarily remained in the background because of the inability to consistently stain, image, or construct clinically applicable neurophysiological tests of these nerves. The situation has changed with the introduction of immunohistochemical methods and confocal microscopy into clinical medicine, as these provide clear images of thin unmyelinated nerves in most organs. One obvious sign of change is the increasing number of reports from several laboratories of the pathological alterations of cutaneous nerves in skin biopsies from patients with a variety of clinical conditions. This study reviews recent methods to stain and image unmyelinated nerves as well as the use of these methods for diagnosing peripheral neuropathy, for experimental studies of denervation and reinnervation in human subjects, and for demonstrating the vast array of unmyelinated nerves in internal organs. The new ability to examine the great variety of nerves in different organs opens opportunities and creates challenges and responsibilities for neurologists and neuroscientists.