Table 4.

Studies conducting a biopsy for SFN assessment.

Author	Test	Site	Relevant Outcomes	SFN Implication Comments
Lauria et al., 2005 [16]	Biopsy	Lateral aspect of the anterior two-thirds of the tongue	Significantly lower density of epithelial and sub-papillary nerve fibers (40%) in BMS patients compared to controls Diffuse morphological changes in epithelial and sub-papillary nerve fibers	Trigeminal small fiber sensory neuropathy The morphological changes suggest axonal degeneration.
Yilmaz et al., 2007 [17]	Biopsy	Tongue	Significantly reduced nerve fibers penetrating the epithelium in BMS patients Significantly increased TRPV1-positive fibers and NGF fibers in BMS patients Significant correlation between the baseline pain score and TRPV1 and NGF fibers, a trend toward increases of Nav1.8 fibers	increased NGF levels Up-regulation of TRPV1 and Nav1.8 nociceptor fibers suggest SFN
Beneng et al., 2010 [47]	Biopsy	Tongue (dorsal lingual mucosa, lateral to the midline in the anterior third)	Significantly increased P2X3 positive fibers in BMS patients Reduced neurofilament-staining fibers in BMS patients	P2X3 receptors are expressed predominantly in small sensory neurons, which implies that the involvement of these receptors in BMS could be part of the neuropathic pain mechanism, corroborating the presence of SFN
Beneng et al., 2010 [48]	Biopsy	Right or left dorsal lingual mucosa lateral to the midline in the anterior third of the tongue	Increased visual intensity scores for Nav1.7 in the sub-mucosal layers of the tongue, although this increase was not statistically significant between BMS and control	The increased expression of Nav1.7 could contribute to the heightened pain sensitivity and the burning sensations suggesting SFN
Penza et al., 2010 [50]	Biopsy	Anterolateral aspect of the tongue, close to the tip	Significant decrease in the density of nerve fibers in the tongue mucosa of BMS patients	This finding further strengthens the hypothesis of SFN
Borsani et al., 2014 [53]	Biopsy	Anterolateral aspect of the tongue close to the tip	Increased expression of TRPV1 throughout the full thickness of the epithelium in BMS patients	The overexpression of TRPV1 contributes to alteration of nerve fiber activity and to the burning pain characteristic of BMS. This again points towards SFN
Puhakka et al., 2016 [40]	Biopsy	Dorsal mucosa of the anterior third of the tongue	Significant decrease in intraepithelial nerve fiber density in BMS patients compared to controls Although the nerve fiber density was also lower in BMS patients compared to diabetic cadaver controls, this difference did not reach statistical significance.	This finding suggests that BMS is associated with pure peripheral small fiber damage, characteristic of SFN
Domaneschi et al., 2023 [46]	Biopsy	Tongue dorsum	Not statistically significant overexpression in Nav1.7 mRNA (3.13-fold change) Slight underexpression of Nav1.9 mRNA (0.45-fold change) Absence of detectable Nav1.8 expression	The lack of statistically significant differences in Nav1.7 expression might suggest that while this channel plays a role in the sensory processing abnormalities seen in BMS, it may not be the dominant factor in all patients Reduced expression of Nav1.9 might contribute to the altered pain perception and heightened sensitivity. This suggests that the nociceptive pathways in BMS might be dysregulated, leading to both hyposensitivity and hypersensitivity to sensory stimuli, characteristic of SFN.

Abbreviations: BMS: burning mouth syndrome; SFN: small fiber neuropathy; TRPV1: Transient Receptor Potential Vanilloid 1; NGF: Nerve Growth Factor; Nav1.7: sodium channel Nav1.7; Nav1.8: sodium channel Nav1.8; Nav1.9: sodium channel Nav1.9.