Burning mouth syndrome is a common disorder that frequently affects women in the 
5th-7th decade. It is characterized by persisting painful symptoms mainly 
involving the anterior two-thirds of the tongue. For several years it has been 
attributed to psychological causes. We investigated the innervation of the 
epithelium of the tongue to assess whether damage of peripheral nerve fibers 
underlies the pathogenesis of the disease. We examined 12 patients with 
clinically definite burning mouth syndrome for at least 6 months. We obtained 
superficial biopsies of the lateral aspect of the anterior two-thirds of the 
tongue from all patients and nine healthy controls. Immunohistochemical and 
confocal microscope co-localization studies were performed with cytoplasmatic, 
cytoskeletric, Schwann cell, and myelin markers for pathological changes. The 
density of epithelial nerve fibers was quantified. Patients showed a 
significantly lower density of epithelial nerve fibers than controls, with a 
trend toward correlation with the duration of symptoms. Epithelial and 
sub-papillary nerve fibers showed diffuse morphological changes reflecting 
axonal degeneration. Our study demonstrates that burning mouth syndrome is 
caused by a trigeminal small-fiber sensory neuropathy and that superficial 
biopsy of the tongue can be helpful in assessing the diagnosis. These findings 
shed light into the pathogenesis of this common disorder and could contribute to 
evaluate targeted therapies in patients.