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Original Investigation |

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

Mohammad A. Khoshnoodi, MD1; Shaun Truelove, BA2; Ahmet Burakgazi, MD3; Ahmet Hoke, MD, PhD1; Andrew L. Mammen, MD, PhD1,4; Michael Polydefkis, MD, MHS1
[+] Author Affiliations
1Department of Neurology, Johns Hopkins University, Baltimore, Maryland
2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
3Neuroscience Section, Department of Medicine, Virginia Tech Carilion School of Medicine, Roanoke
4Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland
JAMA Neurol. 2016;73(6):684-690. doi:10.1001/jamaneurol.2016.0057.
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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.

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Figure 1.
Change in Intraepidermal Nerve Fiber Density (IENFD) Over Time

Comparison of mean IENFD at baseline and follow-up across biopsy sites. IENFD was observed to decrease more in the distal leg compared with the proximal thigh and more in patients with diabetes mellitus–associated small fiber neuropathy (DM-SFN) and impaired glucose tolerance–associated small fiber neuropathy (IGT-SFN) than in patients with idiopathic small fiber neuropathy (iSFN). Over time, there was a similar decrease in IENFD in the distal and proximal sites of biopsy with similar rates among patients with DM-SFN, IGT-SFM, and iSFN. Error bars indicate 95% CIs.

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Figure 2.
Reduction of Intraepidermal Nerve Fiber Density (IENFD) in 3 Sites of Skin Biopsy

A, The rate of reduction in IENFD is calculated by subtracting the density in the follow-up biopsy from the density in the initial biopsy and is grouped per cause and color-coded for biopsy site. B, Rate of IENFD reduction per year. Both measures indicate that the reduction in fiber density happens in the proximal and distal sites with similar rates regardless of the cause. Error bars indicate ± 2 SDs. DM-SFN indicates diabetes mellitus–associated small fiber neuropathy; IGT-SFN, impaired glucose tolerance–associated small fiber neuropathy; and iSFN, idiopathic small fiber neuropathy.

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Figure 3.
Length-Dependent Pattern of Axon Loss vs Non–Length-Dependent Distal Axonopathy

Left, Length-dependent pattern of axon loss where the most caudal projection of the longer axons are preferentially lost while more proximal sites remain constant. Right, Pattern observed in the study participants where distal projections of axons were lost at equal rates irrespective of rostral and caudal location along the leg. Gray fibers represent nerve fiber branches that have degenerated, whereas black nerve fibers are healthy. The flow of sand through the hourglasses depicts the rate of epidermal nerve fiber loss at each site. Blue dots indicate the locations of biopsy sites.

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