28 Figure 4 Overview of neuropathy questionnaires, divided into screening questionnaires, assessment questionnaires, specific small fiber questionnaires, and pain intensity questionnaires. Quantification of small nerve fiber density Skin biopsy Protein gene product 9.5 (PGP 9.5) is present in all axons and can be detected with the use of PGP 9.5 antibody. Dermal somatic cholinergic Aδ and C nerve fibers can be quantified after staining, with the use of microscopy. Morphological changes include swelling, weaker immunoreactivity and change in branching.50 It is suggested that nerve swelling and excessive proximal branching may be a manifestation of the denervation-reinnervation process in the beginning of the neuropathic process.74 Most frequently reported pathology in SFN is decreased IENFD. All those changes are also seen in healthy subjects, but to a lower extent.3,75 Sweat gland nerve fiber density Sweat glands are innervated by cholinergic sympathetic post-ganglionic C-fibers. Since these fibers are peripheral, are long, thin and have no myelin, they are prone to nerve damage in many neuropathies. Deteriorated sudomotor function shows to be a reliable predictor for SFN.76,77 Sweat gland nerve fiber density (SGNFD) decreases and sweat gland atrophy appears in SFN.78,79 SGNFD can be determined with the same biopsy diameter and staining used for IENFD, but requires thicker skin biopsy. Although data confirm validity of assessing SGNFD.78,79 it is labor intensive (requiring 30-40 hours to evaluate a single biopsy) and not suitable for routine use in clinical settings.79 Corneal confocal microscopy The cornea is highly innervated by Aδ and C nerve fibers and contains up to 300-400 times more small nerve fibers compared to the skin.80 Therefore the cornea seems to be the ultimate location for distal SFN to proliferate. Corneal confocal microscopy (CCM) gives the unique possibility to quantify the NFD of the cornea in vivo. A correlation between corneal NFD and IENFD has been confirmed. CCM is able to determine the nerve fiber length (NFL), nerve fiber branching (NFB) and tortuosity.81,82 Some major advantages are its non-invasiveness, its time-efficiency, its high reproducibility and its allowance for 2 30 2
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