Axonal swellings, defined as focal enlargements greater than two times the width of the axon, and complex branching patterns with fibers traversing parallel to the skin surface may be a predegenerative finding
Multiple conditions have been associated with non-length-dependent painful sensory neuropathies, including but not limited to diabetes, impaired glucose tolerance, Sjögren syndrome, hepatitis C, and celiac disease .
small fiber ganglionopathy of various etiologies who had painful non-length-dependent sensory symptoms, skin biopsy was abnormal in 14 of 17 cases .
Corneal confocal microscopy is a promising noninvasive method for directly measuring nerve fiber density in the cornea, but it is not widely available [37,38].
Sympathetic skin response is very insensitive for the diagnosis of small fiber neuropathy [39,40]. Quantitative sensory testing for heat, pain, or cold detection thresholds is sensitive, but subjects with psychogenic sensory complaints may have convincing abnormalities .
Electrochemical skin conductance is incompletely validated and not widely available .
Tests of sudomotor function, particularly the quantitative sudomotor axonal reflex test, are sensitive and specific , but have lower reproducibility compared with quantitative sensory testing  and require special equipment and expertise .
By contrast, skin biopsy has a very high diagnostic accuracy, with positive and negative predictive values of greater than 90 percent .Skin biopsy typically does not allow for differentiation of different causes of small fiber neuropathy. Reduced fiber density has been documented in a variety of neuropathies, including metabolic, infectious, inflammatory, environmental, hereditary, nutritional, and idiopathic neuropathies [10,46-54].
If amyloidosis is suspected, biopsy sections may be stained with Congo red to detect amyloid deposits .
In patients with foot pain and possible neuropathy, a skin biopsy with normal fiber density and morphology should prompt a careful search for a central nervous system or orthopedic problem.
In a prospective series of 117 subjects with foot pain and suspected neuropathy, normal nerve conduction studies and skin biopsy results were noted in 13 patients (11 percent) . In this group, two were ultimately diagnosed with multiple sclerosis.
●Skin biopsy :
relatively benign procedure.
3 mm punch to obtain skin tissue.
does not require a suture, and the biopsy site heals over several weeks.
risks: local bleeding and infection.
very well tolerated and may be repeated multiple times in order to follow neuropathy progression.
The biopsy site depends on specific indication. After fixation, the biopsy is sectioned and stained with antiprotein gene product 9.5 antibody (PGP 9.5), which avidly stains all axons.
Traditional measures of neuropathy severity are insensitive to small fiber injury. Skin biopsy provides a unique and powerful tool to visualize and assess small nociceptive fibers in a reproducible and validated manner. Thus, the most frequent clinical indication for skin biopsy in neuromuscular disease is for the diagnosis of patients with suspected small fiber sensory neuropathy. Skin biopsy may also be useful for the evaluation of patients with suspected non-length-dependent painful gangliopathy, postherpetic neuralgia, meralgia paresthetica, or anhidrosis (to document the status of sweat gland innervation)