Nerve Fiber Loss in Small-Fiber Neuropathy: It’s Not Just How Much, But How Fast

A recent study shows that looking at the change of nerve fiber density over time can help diagnosis. Image: Healthy small nerve fibers (left); amaged small nerve fibers (right). Credit: Michael Polydefkis.

A recent study shows that looking at the change of nerve fiber density over time can help diagnosis. Image: Healthy small nerve fibers (left); damaged small nerve fibers (right). Credit: Michael Polydefkis.

If you ask someone with small-fiber neuropathy (SFN) what they feel in their feet, they may say pain, tingling, or numbness—symptoms that develop as nerve fibers degrade. When diagnosing SFN, it is routine for physicians to measure the number of nerve fibers in a patch of skin at a single point in time. However, some patients with clear symptoms of SFN can nonetheless have normal quantities of nerve fibers, suggesting that doctors need additional ways to help them make a diagnosis.

Now, a small study published recently in June, in the journal JAMA Neurology, builds the case that measuring the change in nerve fiber density over time, rather than only taking a snapshot at one single moment, could serve as an additional way to determine who has SFN.

How does small fiber neuropathy evolve over time?
Knowing that nerve fibers retract from the skin in SFN, the study authors sought to find out how this loss of fibers progresses. “One motivation [for the current study] was to define the natural history of this process,” says researcher and neurologist Michael Polydefkis, Johns Hopkins University, Baltimore, US, who led the study.

To this end, lead author Mohammad Khoshnoodi and colleagues measured the density of nerve fibers in skin biopsies from patients with SFN, and from healthy volunteers used as controls, at an initial evaluation. They did the same two to three years later at a follow-up visit, and compared the results to the first assessment.

Because symptoms of SFN commonly start in the feet and work their way upwards, the researchers were also interested in the pattern of fiber loss across different areas of the body. As a result, they took skin biopsies from three spots along the leg at varying lengths from the foot; the areas closest to the foot are known to have the longest nerve fibers.

Though study patients had SFN from different causes–either SFN associated with diabetes, SFN associated with pre-diabetes (the precursor stage to diabetes), or SFN without a known cause—they all showed similar decreases over time in the density of nerve fibers, compared to healthy volunteers who showed no such changes. This suggests that those with SFN lose nerve fibers in the skin gradually over time. Interestingly, the rate of nerve fiber loss did not differ at the three spots along the leg where the researchers made their measurements.

The new work, which confirms similar results from smaller, previously published studies, points to the change in the density of nerve fibers over time as a new variable to track in diagnosing SFN, says Anne Louise Oaklander, a pain researcher and SFN expert at Massachusetts General Hospital and Harvard Medical School, who was not involved in the study.

Are longer fibers more susceptible?
The lack of differences in the rate of nerve fiber loss between the different areas along the length of the leg was unexpected, says Polydefkis, given the prevailing view that SFN affects the longest nerve fibers first. “In my opinion, this shows us that SFN might be a more diffuse process than we thought previously,” writes Khoshnoodi in an email to RELIEF.

But others remain skeptical about that conclusion. 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, write that the density of nerve fibers, as well as how quickly the fibers were lost, were surprisingly high in the SFN patients, compared to past reports. If patients continued to lose fibers at the rate seen in the study, some areas higher up on the leg would eventually become devoid of fibers, something that is rarely seen. Thus the population examined in the study may not be representative of most SFN patients.

On the other hand, while it is true that SFN patients first report symptoms in the feet, Polydefkis says that this pattern may simply reflect that different areas of the body have different numbers of nerve fibers to start out with. That is, in healthy people, the thigh contains 30 percent more fibers than areas further down the leg. In SFN patients, perhaps it is not surprising that the fibers furthest down the leg appear to get hit the hardest, if there aren’t as many of those fibers in that area to begin with.

Regardless, the current results hold promise to help doctors improve how they diagnose SFN. —Matthew Soleiman

To read about the research in more detail, see the related Pain Research Forum news story here.

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