We’re going to take a deeper look at the oh so interesting field of small fiber neuropathy fibromyalgia (FM). A debate is raging over how big of a role SFN plays in FM. The central sensitization guys are saying probably “not much” while the immune oriented doctors/researchers believe the findings are telling us something new – and key – about fibromyalgia.

  • Small fiber pathology—a culprit for many painful disorders? Nurcan Uceyler*2015 International Association for the Study of Pain n157 (2016) S60–S66.
  • The Role and Importance of Small Fiber Neuropathy in Fibromyalgia Pain. Xavier J. Caro1 & Earl F. Winter. Curr Pain Headache Rep (2015) 19: 55
  • What is the meaning of “small fiber neuropathy” in fibromyalgia? Daniel J. Clauw. International Association for the Study of Pain n157 (2016) November 2015·Volume 156·Number 11

They believe FM is not simply a central nervous system disorder. With studies showing damage to small nerve fibers in the skin in multiple places, they’re arguing that something systemic is causing nerve problems in many FM patients, and that something is probably the immune system.

First, let’s look at what nerve fibers are being affected and how they are being effected.

Those Small Nerve Fibers

Small nerve fibers are tiny, thinly myelinated or unmyelinated nerve fibers that convey sensory information such as touch, heat/cold and pain to the brain or regulate autonomic activities like blood pressure and sweating. These fibers generally stretch from an organ located just outside the spine called the dorsal root ganglia to the skin.

small fiber neuropathy fibromyalgia

The first problem discovered in FM was fewer nerve fibers than usual in the skin. (The dark lines are the nerve fibers).

The problem that’s showing up is a reduced density of nerve fibers in the skin. Healthy people tend to have ten or more nerve fibers per ml of their skin. People with SFN have seven or less and some just less than three. Something is causing these small nerve fibers to disappear.

Since the density or number of pain sensing nerve fibers is reduced it’s not clear why many people with SFN experience increased pain instead of less pain. Several possibilities do exist, however.

Pain inhibiting nerve fibers could be selectively reduced leaving pain sensing nerve fibers more active, or the remaining nerve fibers could be more sensitive to inflammatory cytokines. It’s also possible that the sodium channels that transmit pain signals in the remaining nerve fibers could be hyperactive.

At least two types of small nerve fibers (A-delta and C-nerve fiber) with several subclasses (peptidergic, cholinergic, and adrenergic) are found. The work has not to my knowledge been done to determine if certain subclasses are effected in FM or if all of them are.

There is no doubt that central sensitization – the major finding in FM so far – plays a major role in FM. Central sensitization refers to a pathological magnification of pain signals by the central nervous system. The chicken and egg question facing the field now, however, is how to explain how nerve issues in the body cropped up in what has been assumed to be a central nervous system disorder.

A Central Sensitization Disorder?

“…this finding should be treated much like a herniated disc on magnetic resonance imaging, when accompanied by the appropriate findings on history and physical it may very well be responsible for pain, but it is also very often an incidental finding.” Daniel Clauw

Daniel Clauw is a major player in the fibromyalgia world. He deserves much thanks for his years of work to get FM accepted as a real illness. Clauw is an SFN skeptic and he’s not alone. Not long ago he provided an overview of FM which didn’t so much as mention SFN. Recently he provided a commentary on the role SFN plays in FM.

He pointed out that small fiber neuropathy has been found in most of the chronic pain conditions it’s been looked for in, and in conditions such as postural tachycardia syndrome (POTS) that are not associated with pain.

central nervous system fibromyalgia

Clauw believes fibromyalgia is overwhelmingly as central nervous system disorder. He could be right.

Because damage to the periphery; i.e. the body often does not correlate with the amount of pain a person is in Clauw largely discounts the idea that SFN is the cause of, or is contributing to FM. The pain in FM, he believes, is largely a function of central nervous system dysfunction.

He rightly asks how damage to the nerves in the skin could account for the deeper feelings of pain or for the fatigue, sleep, cognitive and mood symptoms FM patients typically experience. These appear to be central nervous system type symptoms.

But Clauw also suggests the central nervous and peripheral nervous system problems could be linked; both could reflect hyperactive nervous systems, he believes.

At the end of his commentary, however, Clauw asserts that for now, at least, the SFN findings in FM are most likely to be “incidental”.

A Small Fiber Neuropathy / Immune Disorder?

Many of the considerations put forth within this article imply that we are entering an exciting era of shifting paradigms in this enigmatic disorder. Caro and Winter

Caro and Winter, two doctors who have treated FM patients for decades, provide another viewpoint. They point out that many of the therapies used in FM (pregabalin, gabapentin, and the tricyclic antidepressants) may actually be treating the SFN problems found in the disease.

central nervous system fibromyalgia

Caro and Winter believe the immune system may be causing both the SFN and the central nervous system problems in FM

They note that there’s nothing incidental about a consistent loss of nerve fibers in the skin and now the corneas of FM patients. While Clauw questions whether the pain in FM is similar to that in people with SFN, Caro and Winter point out that the language FM patients often use to describe their pain (hot, burning, pins and needles, knife-like, unbearable, miserable) is very much the language of people with small fiber neuropathy.

They propose that the peripheral nerve issues in FM may, in fact, be worse, than currently thought. Besides the reduction in density of small nerve fibers in FM, Caro and Winter point to studies using techniques like quantitative sensory testing, sudomotor axon reflex testing, and microneurographic recordings which have found other problems with the peripheral nerves in FM. Their own findings of abnormalities to vibration, sensation and muscle weakness, indicate a “mixed fiber neuropathy” (MFN) consisting of both small and large fiber neuropathies may be present in many patients.

In fact, Caro and Winter reported they expect to publish a paper soon indicating that large fiber neuropathy is often found in their fibromyalgia patients as well.

New Diagnostic Criteria For Fibromyalgia?

The Wartenburg pinwheel

The Wartenburg pinwheel

They propose that clinicians should routinely examine FM patients for signs of nerve injury using the Wartenburg pinwheel and a 128-Hz tuning fork in their lower extremities. They report that almost 90% of their patients exhibit a “stocking distribution” which increased nerve problems the further one goes out from the trunk (i.e. in the feet and hands).

Caro and Winter have gone so far as to use SFN findings to diagnose and subset their patients. They describe three subsets of FM patients they’ve found.

FM Patients with Normal Nerve Fiber Densities

They believe that FM patients with normal nerve densities often have another, hidden disease such as rheumatoid arthritis or osteoarthritis. They pointed to the case of a 21 year old college student with FM whose pain responded to Cymbalta but not to Neurontin or Lyrica. (The lack of response to Neurontin/Lyrica was apparently something of a clue that SFN may not have been present.)

The normal nerve fiber levels in her skin biopsy prompted them to look for a pain generator other than SFN. Tests indicated she had elevated C-reactive protein levels (but normal sedimentation rate, rheumatoid factor, CCP-IgG, and antinuclear antibodies). With her history of early morning stiffness and small joint pain they diagnosed her as having early “seronegative rheumatoid arthritis.”

She was successfully treated using a tapered regimen of steroids, hydroxychloroquine, and an immune modulating biologic drug called Orencia (abatacep).

FM Patients With Very Low Densities (< 3.0 fibers per ml) of Nerve Fibers

The belief is that FM patients with very low (< 3.0 fibers per ml) small nerve fiber densities in their skin have another condition known to produce SFN. These conditions include diabetes mellitus, untreated Vitamin B-12 deficiency, an autoimmune/connective tissue disorder (Sjogren’s, lupus, scleroderma, etc.), infection, metabolic disorder (hypothyroidism) toxins and others. The treatment protocol for these patients is to identify the undiagnosed disorder and treat it.

FM Patients With Low Densities of Nerve Fibers (< 7.0 per ml) Who Do Not Have Another Condition

Absent the identification of another disease, Caro and Winter propose that the immune system is largely driving the small and large fiber neuropathy seen in FM. Since the immune system is often implicated in tissue injuries it makes sense, they assert, to assume that it probably plays a role in the small nerve problems found as well. They report that a substantial number of their FM patients respond to immune therapies such as IVIG.

Caro and Winter end their review by asking if in some people FM presages inflammatory disorders such as rheumatoid arthritis or if it exists in a kind of limbo between better defined disorders. They suggest that the gastrointestinal microbiome would be the most likely place to look for the source of the inflammatory activities they believe may be causing FM.


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