Could many people diagnosed with FM or ME/CFS really have small nerve fiber polyneuropathy?

Chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) produce so many symptoms that diagnosing them can be difficult for uninformed doctors. While we know that small fiber polyneuropathy (SFPN) (or small fiber neuropathy (SFN) commonly occurs in both these diseases, what I didn’t realize until I read the two articles below was that some researchers believe that SFPN by itself could conceivably produce all the symptoms associated with ME/CFS and FM. That’s a new conception of SFPN which is not embraced by most neurologists.

It brought up the question, though: if you have ME/CFS or FM and SFPN – might you really have SFPN?

Mystery Illness

“I was increasingly faint and dizzy, with my heart racing whenever I changed position or had a shower; and I was experiencing a fatigue and bone-pain so profound that every few hours I needed to stop whatever I was doing and lie down on the floor. The exhaustion, which feels like the start of the flu, was particularly severe a day or two after I exercised.” Eric Schwable

First Eric Schwable thought he had the flu but then came some weird symptoms: cold feet, burning legs, heavy, cement feeling legs, painful electric shock feelings, vertigo problems with sleep, heart racing when he stood up, or had a shower. There was the immense fatigue, the “bone-pain” and … the post-exertional malaise.

For many of us his diagnosis seems clear – he has chronic fatigue syndrome (ME/CFS) and/or fibromyalgia. Schwable put off seeing a doctor as long as he could but when he did see a doctor, that doctor immediately referred him to a cardiologist, a vascular specialist and a neurologist.

It turned out the doctor got the order wrong. The first two specialists didn’t uncover anything but the neurologist knew right off what he had: after a positive skin biopsy test, he was diagnosed with small fiber neuropathy (SFN).

As Schwable explained in his Washington Post piece, “Pains, chills, fatigue, vomiting and vertigo plague me. Small fiber neuropathy causes it all“,  small nerve fiber problems can affect our circulation, breathing, digestion, and immune and glandular functions. Because they transmit sensory impulses, they can produce bizarre sensory issues.

Schwable was lucky – his neurologist was able to quickly match his wide variety of symptoms to SFN and quickly get him tested. Schwable is not well, but he’s found two drugs (pyridostigmine bromide (Mestinon) and gabapentin) that have helped.

Two Decades

“Pain is as ingrained in me as my oldest memories or my closest friends.” Jenna Birch

Jenna Birch was not so lucky. Even though the standard test is a simple one (a skin biopsy), most doctors and even most neurologists don’t know about it. Large fiber neuropathy, they know, but small fiber neuropathy, generally not.  It took Birch almost two decades to find out what she had.

In “Before She Was Diagnosed With Small Fiber Polyneuropathy, Doctors Misdiagnosed This Woman’s Pain for 18 Years“, Birch described the strange “growing pains”, the “dynamite headaches”, the problems with bladder control and diarrhea, the rashes, the full body pain she experienced during childhood, adolescence and into adulthood.

She also described the countless doctors and ER visits. She was eventually diagnosed with fibromyalgia, irritable bowel syndrome, interstitial cystitis, and premenstrual dysmorphic disorder.

Not Fibromyalgia – Small Fiber Polyneuropathy…

Then she met Dr. Anne Oaklander – the MD, PhD who’d uncovered the small nerve fiber problems in FM. Oaklander asserted that fibromyalgia was a label – not a diagnosis. What Birch really had was small fiber polyneuropathy. That made sense to Birch, who was never all that happy with her other diagnoses.

“I never felt settled in my fibromyalgia diagnosis. I have consistently had to keep my eyes and ears open for potential conditions that fit my symptoms, and then bring them to my doctors.”  Jenna Birch

Given the ubiquity of the small nerve fibers in the body, Oaklander believes damage to them to could cause just about any symptom found in FM.

  • Pain – damaged small nerve fibers that transmit pain sensations could be producing the pain sensitization seen in FM.
  • Gut Issues – damaged small nerve fibers in the gut could be impairing gut motility, causing constipation, diarrhea, gut flora problems.
  • Fatigue – damaged small nerve fibers lining the blood vessels could be producing something called “neurogenic myovasculopathy”, which appears to refer to a nervous system disease causing problems with the blood vessels in the muscles.
  • Inflammation – damaged small nerve fibers that regulate and are regulated by the immune system could be producing inflammation.
  • Brainfog/Fibrofog – damaged small nerve fibers that extend into the brain could be affecting cognition.

Oaklander is convinced that a substantial portion of FM patients are misdiagnosed SFPN patients. In 2018, Oaklander asserted that fibromyalgia had “no known biomedical cause” until the SFPN was found.  It’s not clear what Oaklander thinks about the 50% or so of FM patients without SFPN, but she’s pretty clear about what FM patients with SFPN have – they have a neurological disorder affecting their small nerves.

“Based on this definition, patients with FMS with subsequent diagnoses of SFPN (the SFPN+ group in our study) are instantly no longer considered to have FMS, per definition.” Lodahl and Oaklander

In a recent review paper, “Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review“, in The Journal of the American Medical Association (JAMA), Oaklander stated:

“A recent meta-analysis concluded that small-fiber neuropathy underlies 49% of illnesses labeled as fibromyalgia.”

Fibromyalgia, ME/CFS or Small Fiber Polyneuropathy?

Given the overlap in symptoms between the three diseases, one has to ask which diagnosis explains the most? SFPN is appealing because it has an identified cause – damage to the small nerve fibers – which can produce manifold symptoms, depending on where the SNFs are found.

Since small nerve fibers are found throughout the body – but are usually tested with a skin biopsy – is it possible that some people with nerve damage in other areas are not being properly diagnosed?  Given the ubiquity of the small nerve fibers in the body, are the multiple diagnoses that so many get a sign that one might suffering from undiagnosed SFN?

Different Symptoms?

If the SFPN is different from fibromyalgia, it should generate different symptoms. Using a 33-item symptom checklist called  Mass General Hospital Small-fiber Symptom Survey (MGH-SSS), as well as some other symptom assessments (Composite Autonomic Symptom Score-31, Short-Form Health Survey-36, and Short-Form McGill Pain Questionnaires), Oaklander compared FM patients with SFPN and without it. (The MGH-SSS survey assesses symptoms that could occur as a result of nerve damage in five different component parts of the body – gastrointestinal, somatosensory, miscellaneous, vascular, and neurological).


Fluorescent immunohistochemistry with confocal microscopy. The nerve axons or endings are in green. Healthy controls on the left, people with small nerve loss on the right. (From Scientific Advances in and Clinical Approaches
to Small-Fiber Polyneuropathy
A Review – JAMA)

Some differences were found, but overlapping symptoms were the main theme. FM patients with and without SFPN had similar pain levels. Only one of the five components of the Small Nerve Fiber Symptom Survey stood out in the SFPN patients: the vascular component. It included the following symptoms: “Skin with unusual color or changes in color,” ”Less hair growth on lower legs or feet,” “Changed pattern of sweating on body,” “Swelling in hands or feet,” and “Skin that itches for no reason.” One other symptom – tingling sensations – was increased in FM patients with SFPN as well.

When the researchers flipped the experiment around and tried to predict which patient fit in which disease category, they found that using symptoms to diagnose patients provided only a “fair predictive value”.

The authors acknowledged that the results could have been confounded because some people with SFPN may have had negative skin biopsies and autonomic testing results: i.e. they could have had undiagnosed SFPN. (One punch skin biopsy would hardly seem to be a comprehensive test of a small fiber problem that might be able to affect everything from the vascular system to the gut to the skin.)

So, while a few symptoms of SFPN may be somewhat predictive, the study found that most of the symptoms in FM and SFPN appear to be very similar. Acknowledging that the study size was small – and that its results were preliminary – a couple of possibilities arise:

  • Two Separate Diseases – SFPN and fibromyalgia are two separate diseases which just happen to produce a very similar symptom presentation.
  • FM is SFPN – Perhaps because we’re not testing for SFPN in some of the places it’s found – such as the gut or vascular system – the current tests for SFPN (skin biopsies, autonomic nervous system tests) miss a lot of SFPN; i.e. FM is SFPN – and we just don’t know that yet.
  • SFPN isn’t really a big deal in FM. Clauw has proposed that it’s a kind of add-on issue that isn’t contributing much to the symptoms that FM patient have. Instead, upregulated pain producing pathways in the central nervous system (central sensitization) are producing the vast majority of symptoms in FM. Given that, it made sense that FM patients with and without SFPN would have mostly similar symptoms. Clauw has suggested that central sensitization may be actually causing SFPN in FM.

Is the Brain Causing the Small Fiber Neuropathy in Fibromyalgia (and ME/CFS?)

The Gist

  • Small fiber polyneuropathy (SFPN) refers to damaged or missing small nerve fibers that relay sensory and/or autonomic signals.
  • These small nerves are long, mostly unmyelinated, fragile nerves that can be easily disturbed.
  • Most descriptions of SFPN describe symptoms like tingling, numbness, electric shocks and pain.
  • Dr. Anne Oaklander, though, believes SFPN could be producing just about every symptom found in FM and ME/CFS.  She believes that only about 10% of SFPN cases may be diagnosed.
  • Another study found that people with SFPN in the skin always tended to have SFPN in the nerves surrounding the blood vessels. The nerve problems around the blood vessels could be impeding blood flows to the muscles – causing the muscle and fatigue problems after exertion.
  • Some people who did not have SFPN in their skin did have nerve fiber losses around their blood vessels. That indicated that skin biopsies may miss some people with small nerve fiber problems elsewhere in their body.
  • The good news is that if the small nerve fibers are damaged, they can grow back. Dr. Oaklander suspects inflammation is the cause behind the SFPN in FM. Treatment options are limited and need more study but steroids or IVIG can help. Because steroids are cost-effective and may be helpful, Oaklander strongly recommends more studies of steroids.

Review Article

In a recent Journal of the American Medical Association review article “Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy A Review” , Oaklander and Nolano asserted SFPN is much more common that we think. They believe only 10% of SFPN cases have diagnosed.

The small nerve fibers that are affected in SFPN, it turns out, are very thin, are spread out over long distances, and most are not myelinated; in short – they’re very fragile – and can be injured in a number of ways.

Many conditions can damage them: pathogens, diabetes, autoimmunity (particularly Sjogren’s Syndrome), alcohol abuse, chemotherapy, antiretroviral HIV drugs, colchicine, vitamin B6, metronidazole, nitrofurantoin, fluoroquinolones, and arsenic, Ehlers-Danlos syndrome, ion channelopathies…

Nature appears to have compensated for the small nerves fragility, though, by giving them a unique nerve superpower: given the right conditions, they can regrow.

They’re involved in a number of systems implicated in FM and ME/CFS:  the somatosensory (sensory), motor (movement), and autonomic (fight/flight/rest/digest) systems and they also help regulate the immune system. Their purpose – monitoring the internal and external environments for danger and responding with sensations such as pain which trigger both “conscious and involuntary evasive maneuvers” – sounds like a process, which if it went awry, could set one’s systems on edge in a very FM and ME/CFS-like way.

Their ubiquity suggests SFN as the potential to produce a wide variety of symptoms. Note, though, that the classic descriptions of SFN mention only a few symptoms (pins-and-needles, pricks, tingling and numbness, burning pain, coldness and electric shock-like, brief, painful sensations.)

In what would constitute a kind of paradigm shift for this field, Oaklander and Nalono assert, though, that SFPN can also cause deep aching, fatigue, post-exertional malaise, heart racing (postural orthostatic tachycardia syndrome (POTS)), and the gut and sweating issues that many of us are familiar with. They also believe that doctors also get hoodwinked by believing that SFPN is associated with stocking-and-glove presentation (symptoms first appear in the feet and hands) – which is not always the case in FM.

The authors propose that damaged small nerve fibers leading to the spinal cord could be producing the chronic, long-term “potentiation” of pain signals (that process begins in the spinal cord)  which results in pain amplification in FM. Pointing to a Sjogren’s Syndrome study, they proposed that SFPN could even be causing cognitive problems found in ME/CFS/FM.

SFPN in the Blood Vessels = ME/CFS?

Oaklander, and David Systrom believe small fiber neuropathy may be producing something called “neuropathic microvasculopathy” in chronic fatigue syndrome (ME/CFS) and fibromyalgia. This occurs when small fiber loss in the shunts (the arteriovenous anastomosis) between the arteries and the veins in the skeletal muscles results in the blood bypassing the capillaries (and the working muscles) and going straight into the venules. In other words, the exercising muscles get little blood, while most of it goes straight into the veins where it is returned to the heart.

One wonders if a study, four years ago, with the engaging title, “Myovascular Innervation”: Axon Loss in Small Fiber Neuropathies“, may someday be described as a seminal paper. The authors speculated that damage to small nerves surrounding the blood vessels was also present in FM patients with SFPN, and produced the first study to demonstrate that.

Arteries, arterioles and capillaries. Could small nerve loss near the blood vessels be stopping blood from getting to the muscles?

They found that reduced levels of the small nerves around the blood vessels (myovascular degeneration) were correlated with reduced small nerve levels in the skin: i.e. the small nerve loss in the FM patients extended from the skin to their blood vessels.

This suggested that Oaklander, Systrom and others were right when they suggested that the small nerve fiber loss seen in FM and ME/CFS is likely present in other parts of the body. Depending on where the small nerve fiber loss is, of course, opens the door to production of many different symptoms.

Perhaps just as importantly, the study found also that some FM patients with reduced levels of small nerves around their blood vessels had normal small nerve levels in their skin. That suggests that the skin biopsy results – which most doctors rely on –  are not necessarily indicative of what’s happening elsewhere in your body: even if you have a negative skin biopsy, your small nerves could be getting whacked somewhere else in your body.

This, of course, suggests that the 50% or so of FM with documented SFPN might be an undercount. This was just a small preliminary study but it suggested that more people with FM may have SFPN than we suspect.

Patients with small nerve loss around their blood vessels – but not in their skin – tended to experience muscle pain, stiffness, or cramps – which were worsened by activity (post-exertional malaise) and autonomic symptoms. Symptoms like numbness or sensory loss, on the other hand, were rarely found.

Unfortunately, this small study has not yet been followed up on, and needs validation, but the interest in SFPN in heating up. Two recent papers highlighted the role that SFPN may play in ME/CFS and/or POTS and other diseases.  (Blogs on those are coming up.) Time will tell how far the SFPN saga in ME/CFS, FM, POTS, etc. plays out.

Diagnosis and Treatment

Oaklander and Nolano reported that several symptom assessment tools are available including the SFN specific Rasch-built overall disability scale, the Small-Fiber Symptom Survey, the Utah Early Neuropathy Scale, and most prominently, the Massachusetts General Neuropathy Exam Tool (MAGNET).

Small fiber polyneuropathy is usually diagnosed using an easy-to-access 3mm skin biopsy. The authors report, though, that the field is still evolving and that the norms to assess SFN that many laboratories use are not representative, and may lead to false negatives. Sampling error (i.e. one biopsy may not be enough) is another issue.

The quantitative autonomic function testing regimen developed at the Mayo Clinic can help, but is available at few hospitals. In vivo corneal confocal microscopy, which visualizes the small nerve innervation of the cornea, is noninvasive – and appears to be a good bet – if you can find a doctor who can do it.

Eye-Opening Finding: Small Fiber Neuropathy Found in Fibromyalgia Patients Eyes

Immunotherapy – corticosteriods or IVIG – appears to be providing the best solutions, but larger trials are needed. Oaklander’s retrospective IVIG study was pretty darn successful with 75% of patients with SFPN getting relief.

Small Nerves – Big, Big Problem? Drug Trial Points Finger at Autoimmunity in Fibromyalgia and ME/CFS

From Neuropathy Commons



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