In small fiber neuropathy (SFN), the degeneration of thinly myelinated and unmyelinated sensory axons is associated with symptoms such as pain, tingling, and numbness. In diagnosing the condition, clinicians often rely on a snapshot of nerve fiber loss by measuring the density of fibers within the skin at a single point in time. However, some patients with clear symptoms of SFN can nonetheless have normal quantities of epidermal nerve fibers, suggesting that additional diagnostic measures are needed.

Now, a small longitudinal study led by Michael Polydefkis, Johns Hopkins University, Baltimore, US, points to the rate of epidermal nerve fiber loss as one such potential measure. In contrast to healthy participants who had stable levels of epidermal nerve fibers in the two to three years from their initial evaluation, patients with diverse causes of SFN all showed similar reductions in fiber density over time. The researchers also detected similar rates of fiber loss along different sites of the leg, a surprising finding since symptoms of SFN usually begin at the feet and work their way upwards.

“This paper suggests a new variable to track from neurodiagnostic skin biopsies—the change in epidermal innervation density over time,” wrote Anne Louise Oaklander, Massachusetts General Hospital and Harvard Medical School, Boston, US, in an email to PRF. “Maybe in the future we’ll be able to factor this ‘delta’ into our determinations of who does or does not have polyneuropathy, particularly in the early stages when the nerve fiber counts might still be in the normal range, but dropping,” she added.

The results were published online April 11 in JAMA Neurology.

Losing nerve fibers over time

It is well known that nerve fibers innervating the skin retract in SFN, and yet few studies have taken a close look at the progression of such fiber loss (Lauria et al., 2003; Gibbons et al., 2006). “One motivation [for the current study] was to define the natural history of this process,” Polydefkis told PRF. The authors were also interested in whether there are differences among patients with different causes of SFN, including those with idiopathic SFN, impaired glucose tolerance-associated SFN, and diabetes-associated SFN. “We expected that people with diabetes-associated SFN would progress more quickly,” said Polydefkis.

To track nerve fiber density over time, lead author Mohammad Khoshnoodi and colleagues examined the density of intraepidermal fibers in skin biopsies taken from three areas along the leg—the distal leg, the distal thigh, and the proximal thigh. For healthy participants and each group of SFN patients, the authors measured the change in fiber density in the epidermal regions by comparing values from an initial visit to a follow-up at least two years after the first examination. The proportions of men and women, as well as their average age, were the same between the different groups, with a total of 52 participants with SFN, and 10 healthy controls.

The authors found that across the different groups of SFN patients, all three sites along the leg had similar reductions in fiber density, unlike healthy participants whose densities remained stable. Contrary to what the authors predicted, though, the three groups of SFN patients did not differ from one another in the rate of fiber loss, although those with diabetes- and impaired glucose tolerance-associated SFN had lower densities than idiopathic SFN patients at baseline.

These findings suggest that in SFN, there is a slowly progressive loss of epidermal nerve fibers over time, supporting similar results from studies carried out by Polydefkis and others (Lauria et al., 2003; Gibbons et al., 2006), and that the patterns of this loss are similar in patients with different causes of SFN. Based on these results, the rate of nerve fiber loss could potentially be used as another diagnostic measure of SFN.

Are the longest axons the first to go?

The symptoms observed in SFN typically follow a length-dependent pattern, beginning in areas of the body innervated by the longest axons. Researchers think that the loss of epidermal nerve fibers mirrors this pattern. Indeed, the authors found that fiber density in the distal leg was lower than in the distal or proximal thigh in SFN patients at baseline. However, when they examined changes in fiber density over time, they unexpectedly found no differences among the three areas. “In my opinion, this shows us that SFN might be a more diffuse process than we thought previously,” wrote Khoshnoodi in an email to PRF.

Yet, in an accompanying editorial, John Kissel, Ohio State University Wexner Medical Center, Columbus, US, and Gordon Smith, University of Utah School of Medicine, Salt Lake City, US, raise concerns about the absolute values of epidermal nerve fiber density observed in the study, as well as the magnitude of nerve fiber loss. They write that both measures are surprisingly high, relative to findings from other studies, and that if nerve fiber loss continued at the rate seen in the current work, nerve fibers would ultimately disappear in distal and proximal areas of the body, which is inconsistent with clinical findings.

“Epidermal fibers are absent distally in a significantly few patients with neuropathy, but they are only rarely absent proximally,” they wrote. “This observation strongly suggests that the cohort in this sample is indeed different from others reported or that the long-term temporal profile of [intraepidermal nerve fiber density] decrease must be different proximally, calling into question the central conclusion that SFN may not be length dependent.”

Polydefkis, however, said that SFN may appear length-dependent because of a pre-existing difference between the distal and proximal portions of the body. That is, the distal leg is known to have fewer fibers than the proximal thigh in healthy individuals, perhaps explaining why SFN patients in the study had lower fiber counts in the distal leg than the proximal thigh at baseline, and why symptoms often arise in areas with the longest axons. “If you start out with fewer fibers distally, and you lose fibers at a constant rate, you’ll theoretically become symptomatic soonest at the distal site,” he said.

Finally, with regard to pain, Oaklander emphasized that pain in SFN is not a direct result of intraepidermal fiber loss. “It’s a biomarker for other abnormalities in the nociceptive pathways,” she wrote, pointing to evidence implicating central nervous system (CNS) neurons as the primary culprits. “Second- and third-order neurons in the CNS may be affected by the loss of some of their primary afferent input to fire excessively.”

Matthew Soleiman is a neuroscientist-turned-science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman