Ueceyler Nurcan SFN

Uceyler has published seven papers on SFN in fibromyalgia.

Some studies a field waits for – and this is one. The past nerve fiber studies in fibromyalgia (FM) have tended to be small and use different methods and criteria – making it difficult to be clear about the extent of the problem. When a field gets to a certain point, though, funding becomes available for bigger studies. It’s now very clear that the small fiber neuropathy (SFN) in FM is real – and that means it’s time for bigger and more complex studies.

That the first big study is coming out of Nurcan Uceyler’s Neuroscience lab at the University of Wuerzburg, Germany is no surprise. A leader in the field, Uceyler’s interest in small fiber neuropathy dates back to 2010.  Her first fibromyalgia SFN paper showed up in 2013: since then she’s published no less than 7 papers, including three this year. Plus, she has a long history of fibromyalgia research to boot – having published no less than 20 other FM studies in the past 16 years.

The Study

Seeking to get some clarity, Uceyler threw the kitchen sink at the 117 women with fibromyalgia in the “Reduction of skin innervation is associated with a severe fibromyalgia phenotype” study. They got questionnaires, a neurological examination and no less than five small nerve fiber tests including skin punch biopsy (in two places), corneal confocal, microscopy, microneurography, and quantitative sensory testing (which examined C-tactile afferents, and pain-related evoked potentials). This is the first time I know of that the same patients received both skin biopsies and corneal examinations.

They also did most of the above to a group of people with major depression and widespread chronic pain – who, demonstrating that there’s more than one way to produce widespread pain – exhibited very similar pain symptoms to the FM patients.


The Types of  Pain in Fibromyalgia and Depression with Chronic Widespread Pain

  • Pressing – 40%
  • Burning – 38%
  • Stabbing – 25%
  • Muscle soreness – 25%
People with Major Depressive Disorder and Widespread Pain
  • Pressing – 73%
  • Burning – 55%
  • Stabbing – 36%

Small Nerve Fiber Density


Looking at the prevalence of nerve fibers in the lower leg and thigh, four distinct groups of SFN were found in FM:

  • 37% had normal small fiber levels
  • 17% had reduced lower leg small fiber levels
  • 31% had reduced thigh small fiber levels
  • 15% had both reduced lower leg and thigh levels

Depression with Chronic Widespread Pain

The only small fiber neuropathy found was in one patient in one place (thigh).

SFN, then, is not associated with major depression and chronic widespread pain. That’s an interesting finding, given that many of the pain and mood pathways in the brain intersect. Despite the high incidence of depression in FM, however, some different processes are clearly at work. (The study excluded “severe psychiatric illnesses” which required attention by a physician.)

The Eyes

Small nerve fiber levels were significantly reduced in the eyes of FM patients relative to healthy controls. The small fiber levels in the eyes of people with major depressive disorder and widespread pain were, again, similar to those in the healthy controls.

The Strangeness of Fibromyalgia: sensitivity to warmth, cold, touch and pressure

The study involved numerous assessments of sensitivities to different stimuli. Interestingly the sensitivity to heat, touch, and hyposensitivity to warmth (WDT; p<0.01), tactile (MDT; p<0.001), and “painful punctate mechanical stimuli” was reduced in the FM patients, while the sensitivity to cold, and, in particular, mechanical stimulation and blunt pressure, was increased in the FM patients.

The thermal finding highlighted how different the SFN in FM is; small fiber neuropathy in other diseases is usually associated with increased heat sensitivity – but the FM patients demonstrated decreased sensitivity to heat stimuli. It’s not clear why this is.

small nerve fiber loss cornea

The authors seemed surprised to see small nerve fiber loss in the eyes.

The authors were also at something of a loss to explain the increased sensitivity to “mechanical stimuli” found in FM, an issue that is usually associated with large nerve issues – which this study did not find. Stretching a bit for an answer, they suggested that problems with the small nerves (c-tactile nerves) that detect light touches (and play a role in allodynia) might play a role.

The authors also had difficulty explaining the nerve loss and reduced nerve lengths found in the cornea of the eyes, as the eyes are not a place they would expect to find that. The eye issue might bring up the question of just how widespread the small nerve loss is in fibromyalgia. Thus far, it’s only been tested in the skin and eyes, but some researchers, including these, believe it might be much more widespread.

The A-delta nerve fibers that transmit heat and pain signals to the brain were found to have reduced excitability. That indicated that the SFN problem in FM goes beyond just losing fibers – the ones that remain have been damaged as well.

The Widespread Nerve Loss Group

The larger FM group – the one with small nerve fiber loss in just their lower legs or thighs – did not experience significantly increased pain, reduced functionality, etc. relative to the FM patients without nerve loss.

The 15% of the cohort with more widespread nerve fiber loss, however, did – in spades.  Clauw and others have long proposed that SFN is kind of an epiphenomena, a not particularly important problem in FM which has little effect on pain. The results from this large study suggests, though, that once the small fiber nerve loss really gets going, it’s associated with dramatically increased pain levels, reduced functionality, etc.

The FM patients with the most widespread small fiber loss (in their lower legs, thighs and eyes) were in significantly more pain that FM patients without small fiber loss. They reported higher levels of pain in several areas of their body, more widespread pain, different kinds of pain (stabbing pains associated with pins and needles), plus they had higher pain intensity overall. Also, the questionnaires indicated that this group reported greater impairment and disability, had more severe symptoms overall (Fibromyalgia Impact Quotient), and were more anxious.

hyperexcitable nerves FM

The authors suggested that hyperexcitable nerves may precede small fiber pathology in FM.

Why might this group be so much worse off? The authors suggested that the missing nerve fibers might have been alleviating pain. The damaged nerve fibers that remain might be more susceptible to triggering by pain mediators near them. They also believe that distinct nerve fibers such as the c-tactile nerve fibers are being targeted in FM.

But what about the third or so of FM patients without any evidence of small fiber neuropathy? If widespread SFN is associated with significantly increased pain, what is going on with this group and their intact nerve fibers but still considerable pain? The authors raised the possibility that their nerves may be intact but are not operating normally. The FM group as a whole, after all, demonstrated considerable amounts of abnormal nerve functioning. The authors suggested that small nerve hyperexcitability in the normal small nerve fiber group could precede the small nerve pathology found in the rest of the group.

Thigh Biopsy Preferred

If you’ve had a negative foot or lower leg biopsy, don’t think that SFN has been ruled out. The study suggests that if you’re going to have a biopsy done – the thigh, with almost half (46%) of the FM patients testing positive there – is probably the place to have the biopsy. (Thirty-two percent were positive for the lower leg.) Unfortunately, I couldn’t access the supplemental tables and wasn’t able to determine how many patients had small fiber losses in their eyes.

Meta-Review of Small Nerve Fiber Pathology in Fibromyalgia

You know you’re getting somewhere when meta-reviews start popping up. The review focused on the prevalence of small fiber pathology – not neuropathy – that is present in FM. This is because it’s becoming more and more clear that the small fiber problems in fibromyalgia (and therefore probably ME/CFS) are distinct from those found in other diseases.

small nerve fiber loss fibromyalgia blood vessels

For the first time I’m aware of, the authors suggested that small fiber loss may be affecting the blood vessels contributing to exercise intolerance.

The small nerve fibers are not just disappearing in the skin of FM patients, but the ones that remain are being altered as well: they are smaller and appear to be functioning differently.  The review upped the likely prevalence of small fiber pathology (SFP) in fibromyalgia up to almost 50% (49%).

The authors tackled the origin question: whether the SFP found in FM is part and parcel of the central sensitization present in the brain or whether it’s coming from some process occurring in the body – an important question as the treatment options are completely different.  Noting that the “painful neuropathies” most doctors are familiar with are clearly caused by the body, the authors were not able to come to a conclusion regarding the source of the SFP in FM.

They seemed to tip their hats towards the body, though, when they reported that the small fiber pathology found in FM could be affecting the small blood vessels and could help explain the problems with muscle perfusion, exercise intolerance, the deep muscle pain sometimes felt, and even the brain fog. Those are very interesting ideas, given the possibility of small blood vessel problems in FM and ME/CFS, the presence of myofascial problems, and even possibly the connective tissue problems found by Peter Rowe. Given the increased exercise problems seen in ME/CFS, it’s going to be very interesting to see if the small nerve fiber pathology is even worse there.

More Mysteries

Much remains to be learned about the role the peripheral nerves play in FM and ME/CFS. Several years ago, Dr. Rice found a veritable explosion of small nerves not in the skin but in the hands of FM patients, which he thinks could affect blood flows to the muscles, exercise, etc. Dr. Martinez-Lavin believes the small nerve fiber problems indicate FM is a dysautonomia-associated nerve disorder.

Hands Up! A Key to the Fatigue, Sleep and Pain in Fibromyalgia Found?

  • Coming Up – the autonomic nervous system connection (?) and potential treatments


“Our findings underscore the importance of the peripheral nervous system for FMS symptoms” The authors

In conclusion, the biggest and most complete SNP study done yet in FM found that unusual small nerve problems and stimuli responses are commonly found and significantly upped the prevalence of small nerve fiber pathology to 63%.  Plus, the study indicated that small fiber pathology may not be, as has been suggested, a mostly benign problem. More widespread small nerve pathology was associated with increased pain, disability, functionality, etc.

SFN was not associated with glucose problems in FM and is not found in depressed patients with chronic widespread pain.

A meta-review boosted the prevalence of small nerve fiber pathology in FM up to almost 50% and opened a new window of possibility with the suggestion that the small nerve problems could also help explain the muscle perfusion problems, exercise intolerance and even the brain fog found in FM. That appears to suggest that the small nerve problems may extend far beyond the eyes and skin in FM, and this may apply to ME/CFS as well.

Small Fiber Neuropathy (SFN) Fibromyalgia and ME/CFS Resource Page





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