The Missing Body

“It’s commonly claimed that, despite its severity and widespread nature, FM has not been associated with an identifiable peripheral-tissue lesion” Authors

Man's Head abstract

Fibromyalgia has come mostly to be thought as a ‘brain disorder’ but recent studies are putting focus back on the body

The ‘word’ on Fibromyalgia, which was originally proposed to be a disorder of the muscles, has been that it’s a disorder of the central nervous system. Studies have found that both the pain-producing and the pain-inhibiting sides of the central nervous system in Fibromyalgia are clearly dysregulated. These are important findings, but they’re not the whole story. You wouldn’t know that from overviews of the disorder on the web where the central nervous system paradigm dominates.

Some have speculated that lower levels of a brain neurotransmitter called serotonin leads to lowered pain thresholds or an increased sensitivity to pain. Serotonin is associated with a calming, anxiety-reducing reaction. The lowered pain thresholds in fibromyalgia patients may be caused by the reduced effectiveness of the body’s natural endorphin painkillers and the increased presence of a chemical called “substance P”. Web MD

Even the National Fibromyalgia Association makes no mention of the peripheral nervous system (although it does mention cytokines) in its overview of causes

The FM patient experiences pain amplification due to abnormal sensory processing in the central nervous system. An increasing number of scientific studies now show multiple physiological abnormalities … including: increased levels of substance P in the spinal cord, low levels of blood flow to the thalamus region of the brain, HPA axis hypofunction, low levels of serotonin and tryptophan and abnormalities in cytokine function.

The Body is Back

The evidence has been mounting over time, but over the past year it’s become clear that Fibromyalgia is not a brain or a body disorder: it’s both. Recent studies have found immune, autonomic nervous system, and muscle issues in FM. With this fourth study in the past year showing substantial damage occurring in the peripheral nervous systems, the body is back in the FM spotlight big time.

With small nerve fiber problems showing up consistently in Fibromyalgia, the body is back in the spotlight

The next big question is going to be what is the chicken and what is the egg in FM. The authors of this paper are clear that they believe nerve problems in the body are the egg.

Arthritis Rheumatol. 2014 Apr 9. doi: 10.1002/art.38662. [Epub ahead of print]Evidence of abnormal epidermal nerve fiber density in fibromyalgia: Clinical and immunologic implications.

The lead author in this study, Dr. Xavier J. Caro, reported finding large-fiber neuropathy in FM patients in 2008 and was the first to report small nerve fiber problems in FM. His work with large fiber neuropathy was curtailed by the invasive, painful and costly nature of the testing, but then he turned to looking at small fiber neuropathy (SFN)’

In the study, Dr. Caro and Dr. Earl Winter state their interest in the peripheral (body’s) nervous system (as opposed to the nervous system in the brain) is really quite simple. When people with FM describe their symptoms they’re describing neuropathic or nerve problems. They note that the ‘language’ of FM can seem fantastic to the uninitiated but clearly indicate that problems with the nerves are present. Terms like ‘burning’, ‘stabbing’, ‘pins and needles’, ‘hot’, even just ‘miserable’ all describe nerve problems.

For myself the hot, burning sensations I get after too much exercise are rarely found on symptom checklists. I don’t think they’ve been used as diagnostic by any physicians I’ve seen, yet for me they are a major symptom and a major part of post-exertional malaise. They are also nerve symptoms.

Nerve symptoms are very common in FM. Caro and Winter note that over 75% of their FM patients use nerve symptoms to describe their disorder, but only about 20% of rheumatoid arthritis patients do,  and other studies have found even higher rates of neuropathic language in FM. In fact, people with FM use much the same language to describe their symptoms, as do diabetics who have peripheral neuropathy.

The Study

Between 2007 and 2011 Caro collected skin biopsies from about 40 FM patients and 40 healthy controls and examine their blood for immune factors. The results make up this present study.

A screen for an array of autoimmune and sensory disorders ultimately eliminated over 20% of the initial pool of FM patients due to the presence of diabetes, autoimmune disorders, hepatitis, etc.


“We … report a surprisingly high prevalence of diminished ENFD (epidermal nerve fiber density) in FM” Authors

fishnet stockings

All people with Fibromyalgia had a ‘stocking distribution’ pattern in which nerve losses were worse the further ‘south’ one went

This was an older group of FM patients (mean age 60), every single one of which had some diminished sensory perception in their lower extremities. They also had significantly decreased nerve fiber density in their feet and thighs (p = 0.0002) – a sign that their peripheral nerves had been damaged – compared to the controls. In what’s called a ‘stocking distribution’, the further down the legs they tested the more damage they found – a pattern that is often found in small fiber neuropathy.

Fourteen of 40 FM subjects had evidence of hypercholesterolemia, and 11 had hypertriglyceridemia.

The fact that pain levels were not significantly associated with nerve fiber loss suggested that the pain in FM was not solely due to that loss.

Given their past findings of large fiber neuropathy in FM, they assume the FM patients with SFN also have large fiber involvement as well.

Immune System

“We consider it likely that an immunopathogenic mechanism is at work” Authors

The lead author in this study, Xavier J. Caro MD, is a rheumatologist and has quite a history in studying and treating FM. Thirty years ago he reported finding IgG at the dermal/epidermal junction in FM patients, and in 1989 he proposed that FM was in part an immune disorder. In this study he and his co-investigator, Earl F. Winter PhD, noted a variety of abnormal nervous system and immune findings associated with the skin in FM patients, with most of those abnormalities dating back to the late 1980s.


The skin provides a window into sensory and autonomic nerve functioning in FM

More recent studies have found evidence of increased mast cell activation, changes in collagen structure, and increased cytokine levels in the skin. In 2013 Caro published a chapter in a rheumatology textbook where he called Fibromyalgia a ‘neuroimmune’ disorder (“Fibromyalgia: Evaluation and therapy of a neuroimmune disorder”). One has the feeling he’s been looking forward to having this discussion for a long time.

In this study, low nerve densities were significantly correlated with increased IL-2R levels. Il-2R activates T-cells and macrophages, and high levels have been associated with autoimmune disorders including multiple sclerosis.

They noted, as have others, that intravenous immunoglobulin (IVIG) does help some people with Fibromyalgia. (In Dr. Sivieri’s experience, small fiber neuropathy in FM is associated with IgG subclass deficiencies, particularly in the IgG subclass. IgG’s or immunoglobulins refer to antibodies produced by B-cells.)

Pointing a finger straight at the immune system, the authors suggested that a ‘cytokine-related’ lesion (i.e., small fiber loss) would not be unexpected and noted that IL-2R administration in cancer patients can produce an FM-like state.
(Discovery of cytokine-induced small fiber neuropathy might be a good thing because it presents the possibility of producing a drug to block IL2-R.)


Why the pain if the nerve fibers – the source of the pain – have been destroyed? Because they haven’t been completely destroyed and those that are still left are understandably upset (hyperexcitable) and they’re also communicating that upset to the secondary nerve fibers that are intact around them.

‘Central’ Sensitivity Not So Central?

The authors clearly have not been taken with the central sensitivity paradigm that’s held sway for past decade or so in FM. They bluntly stated that the two CNS factors primarily blamed for FM, wind-up and central sensitization (CS), are likely to be secondary rather than primary. They went so far as to state that there is “no credible scientific or clinical evidence that reducing, or even eliminating, CS down-regulates pathological peripheral pain input at all.”

They’re not saying that medications that reduce factors associated with central sensitization don’t work; they may reduce pain, but they play no role in reducing pain inputs from the periphery.


Dr. Caro successfully uses immune modulators to treat Fibromyalgia/ME/CFS

In the past it’s been thought that small pain inputs from the periphery or body in FM get jacked up by a process of central sensitization. These authors believe the pain inputs from the body – from the damaged nerves they and others are finding – are pathological.

If central sensitization was responsible for the pain coming in from the periphery, then diminishing it should result in reduced pain coming in from the body. But they see no evidence of that.

Instead, they provide hope that the going after the problems in the peripheral nerves can eliminate the ‘dysfunctional’ nature of the body pain in FM, and that treating the nerve problems lends itself ‘very well’ to ‘everyday clinical management’ of FM.  In response to an email Dr. Caro stated that the treatment of FM is complex and that  no two cases are alike but that in the main most Fibromyalgia patients require ‘immune modulators’ – an amazing statement given the current focus on the brain in FM.


In another study Caro reported that immunoglobulins were effective at times in FM

But with small nerve fiber damage showing up, and studies proposing that an immune signature has been found,  and with Dr. Pridgen reporting  ‘impressive results’ from his antiviral trial, perhaps an approach using immune modulators in Fibromyalgia isn’t so amazing after all.

Dr. Caro has written a chapter on evaluating Fibromyalgia patients  and is planning to write a chapter on FM treatment. A  study on immune deficiency  in FM has been completed as well and will be released at a National Arthritis Conference in the fall.

If you’re thinking all this applies to FM and not to Chronic Fatigue Syndrome think again. Dr. Caro stated that he doesn’t really differentiate between the two.

Two more things: The authors don’t talk about the autonomic issues arising from small fiber neuropathy, but they do note that autonomic nerve fibers are involved. Nor do they talk about the effect of SFN on exercise. We don’t know how far the neuropathy in FM and presumably ME/CFS extends, but a loss of nerve density in the muscles would reduce muscle activation as well.

When one person with SFN noted how her muscles kept locking up the day after exercise, her neurologist explained that most muscles have several sets of nerves feeding them. When one set of nerves is ‘used up’ during exercise, the others kick in (and activate more parts of the muscles). If’s you’ve only got one set of nerve fibers left, if you keep sending messages down that nerve the muscles will just lock up. Symptomatically that sounds a lot like the muscle stiffness that I experience after exercise.

Check out other small fiber neuropathy posts


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