Longitudinal Assessment of Small Fiber Neuropathy Evidence of a Non-Length-Dependent Distal Axonopathy

IMPORTANCE Few data are available on the natural history of small fiber neuropathy (SNF). Peripheral neuropathy typically follows a length-dependent pattern, leading us to hypothesize that patients with SFN would lose intraepidermal nerve fibers at the distal leg more quickly than at more proximal thigh sites. OBJECTIVE To compare the longitudinal rate and pattern of intraepidermal nerve fiber density (IENFD) change in idiopathic SFN (iSFN), impaired glucose tolerance-associated SFN (IGT-SFN), and diabetes mellitus-associated SFN (DM-SFN). DESIGN, SETTING, AND PARTICIPANTS In this longitudinal, case-control study, patients diagnosed as having SFN from January 1, 2002, through December 31, 2010, and age-and sex-matched controls underwent additional evaluation at tertiary outpatient neurology clinics. Participants and healthy controls were evaluated twice separated by at least 2 years. Participants underwent standardized examinations, nerve conduction, and skin biopsy at 3 sites along the leg. A linear mixed-effects model was used to compare rates of IENFD decrease between cause and biopsy site. MAIN OUTCOMES AND MEASURES We compared the rate of IENFD loss over time in subjects with iSFN, IGT-SFN and DM-SFN as well as the spatiotemporal pattern of IENF loss at different rostal-caudal sites along the leg. RESULTS Fifty-two participants (25 with iSFN, 13 with IGT-SFN, and 14 with DM-SFN) and 10 healthy controls were evaluated. Mean (SD) ages were 50.9 (12.9), 63.1 (10.4), and 61.6 (11.6) years for the iSFN, IGT-SFN, and DM-SFN groups, respectively. There were 12, 7, and 8 female patients and 13, 6, and 6 male patients in the iSFN, IGT-SFN, and DM-SFN groups, respectively. The mean follow-up time was 24.2, 26.7, and 38.8 months for those with iSFN, IGT-SFN, and DM-SFN, respectively, and 32 months for healthy controls. At baseline, mean (SE) for distal leg IENFD (6.48 [1.06]) was lower than distal thigh (13.32 [1.08]) and proximal thigh IENFD (19.98 [1.07]) (P = .001). In addition, IENFD was significantly lower in patients with DM-SFN and IGT-SFN compared with iSFN at all biopsy sites (P = .001). All 3 neuropathy groups had significant IENFD decrease at follow-up at all 3 sites (P =.002), whereas there was no change in the control group. The mean yearly rates of IENFD change over time at the distal leg, distal thigh, and proximal thigh irrespective of cause are -1.42, -1.59, and -2.8 fibers per millimeter, respectively. The mean slopes of IENFD change over time by cause regardless of biopsy site are -0.179, -0.164, and -0.198 for iSFN, IGT-SFN, and DM-SFN, respectively. No difference was found between SFN groups in the rate of decrease. The rate of IENFD decrease was similar at all 3 biopsy sites. CONCLUSIONS AND RELEVANCE Similar rates of IENFD decrease irrespective of cause were observed. Epidermal nerve fibers were lost at similar rates in proximal and distal sites, suggesting that SFN is a non-length-dependent terminal axonopathy.