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.
Results
The Types of Pain in Fibromyalgia and Depression with Chronic Widespread Pain
Fibromyalgia
- 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
Fibromyalgia
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.
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.
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.
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.
- Coming Up – the autonomic nervous system connection (?) and potential treatments
Conclusion
“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.
If small fiber neuropathy or any small fiber pathology does happen to be diagnosed is there any treatment for it?
Yes there are quite a few possible treatments including IVIG. They and emerging treatment options will be covered in an upcoming blog. The good news with regard to small nerve fibers is that they can grow back (!)
I wished I lived in an other country instead of belgium, her for fm and me/cfs it is still GET and CBT and no specialist or homephysician (am bedbound) who would try the medications I read about that helped people. it is so sad, rotting in my bed as hell. and the specialists and docters are even not aware of what happens, is treatable in other countrys. they do not care. just a 10 minite video from dr kaufman is to much to see for them. I am declining and declining, more then 3 decades ill. to ill to even talk about it to homephysicians, go to specialists who only say get and cbt, no treatment for me. even not symptom treatment for sleep, pain, etc I feel as if I have no chance at all here …
Great reporting! Thank you, Cort!
Cort, about small nerves growing back, does this always happen though if the autoimmune process is stopped? I’m afraid not!?
I got IVIG which helped my POTS and SFN a lot, but short lasting, need it often, but also super large doses of Vitamin D help it immediately. I know because i start sitting more and usually i never do because POTS… i avoid sitting… next day of large vit D dose i started to sit and get ‘different’ feeling in my feet… it recovers something for sure… and well,, severeal studies for diabetic SFN show vit D universally reverses it. and diabetic SFN is also considered likely autoimmune.
worth trying who cant get IVIG.
Interesting Petr. All I know is that they can grow back.
Btw I read your mom has Sjogrens, turns out my ME is in fact neuro-Sjogrens, without sicca. It is very often as you know, you should check it.
I’ts crazy hard to diagnose neuroSjogrens.
I have POTS 20 Yrs and even now i dont have sicca and my biopsy is borderline, also SSA antibody borderline. It’s just neuro-sjogrens, sicca develops very slowly.
I had one ME friend housebound 5 yrs, turns out he has Sjogrens all this time too… it’s not ME.
he also doesnt have sicca, his SSA was positive but nobody payed attention. I made him do biopsy and was positive.
Severe SFN nerve loss, fatigue.. 99% neuro symptoms, just like in me
i wonder are there at least 20-30% of ME people who in fact have Sjogrens!
I wouldn’t be surprised! It seems to be rampant in POTS.
That is a tricky disease to diagnose! I didn’t know about neuro-Sjogrens, though.
Hi, Cort – I have severe SFPN. Biopsied (finally) this year. No reflexes anymore. But debilitating pain. I know I have read the peripheral nerves can recover. Damage is not permanent….but my neurologist and rheumatologist both say there is nothing they can do for me. I have tried to get doctors to order IVIgG but so far, no one will, although my I.S. is terrible. My IgG is consistently down in the 400s. My killer cells are at 3. I am not aware of any alternative treatment. Can you help? Thanks!!!
“…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…”
How are we sure that the direction of the progression of the condition is
1) small fibre nerve loss leading to 2) increased pain
Versus 1) increased pain leading to 2) small fibre nerve loss
I find the second hypothesis more credible. Researchers should be looking for real biochemical causes of pain that perhaps aren’t sufficiently understood yet, which pain leads to nervous system overload and self-destruction. Starlanyl cites studies where biopsies found a very high level of various toxins in the adhesions in fascia in patients. I don’t understand why this isn’t the main focus of researchers. It is much more plausible that high levels of toxins lead to adhesions, which lead to pain, which then causes the nervous-system issues. But I would accept the possibility that nervous system dysfunction leads to tightened fascia, leading to reduced hydration and reduced flows of interstitial fluids.
It would be interesting to see if the FM patients currently not showing small fibre nerve loss, do show it in a few years. Was duration of FM in each patient one of the variables studied? I know I spent years getting worse. The studies we need, should also be “time series” based, not just “cross sectional”. The best studies would be collecting data on healthy people, that would eventually show which indicators started to decline first in those who ultimately get diagnosed with FM.
There could be a third option like:
Something causes local damage to tissue including blood vessels and nerves and that by itself causes pain.
Such thing could be oxidative stress or mast cell triggering for example.
I do find “SFN was not associated with glucose problems in FM” interesting.
In diabetes, there are obvious glucose problems and it goes hand in hand with loss (death) of nerves due to starvation.
But a significant subgroup of FM patients has, just like (probably even a larger percentage of) ME patients, reduced blood volume and blood flow. Due to blood consisting over 40% of relatively large RBC, blood has special blood flow characteristics. One of them is that when the speed of blood flow decreases, blood becomes more sticky. When it becomes more sticky, speed of blood flow decreases even further.
I also argued that, when blood volume and blood flow decreases considerably, that the smallest capillaries are hit far more then the larger blood vessels. That is: the smallest capillaries see a far greater percentage reduction in blood flow then the larger blood vessels when a patient has reduced blood volumes.
That makes blood flow in the large veins and arteries relatively normal, but blood flow in the small capillaries very limited. Blood flow there becomes slow and blood sticky. Just like in patients with diabetes. Where too much glucose makes blood sticky in all vessels in diabetes, too few flow makes blood only sticky in the smallest capillaries in many ME/FM patients.
If slow sticky blood causes nerves to die first in the periphery in diabetes patients, is that any different from slow sticky blood causing nerves to die in the periphery in ME/FM patients with reduced blood volumes?
On top of that patients with FM/ME have problems with hypoxia, ROS, fibrin in their blood, lack of dilating NO… making blood flow in the tinniest of vessels even more difficult.
It seems to me that whatever causes these blood flow problems in mainly the smallest capillaries in ME/FM is more then enough to cause the nerves suffering and dying. All neuron related tissue is prone to lack of oxygen and plenty of metabolic waste is toxic to them. When at the verge of dying, sending out an SOS in the form of pain is more then reasonable.
Another thing in play can be the study Issie pointed too in previous blog, that IgG from FM patients causes FM symptoms in rats while IgG from healthy persons doesn’t. It may point to antibodies to either nerves, blood vessels or other tissue. As several previous studies showed increased amounts of antibodies to blood vessels (and it fits with previous paragraph) that could be a good candidate to further derail blood flow in the smallest capillaries with all problems that causes.
As larger scale blood flow problems can cause entire limbs (like toes to legs needing to be amputated) to go necrotic in diabetes due to poor blood flow, it would not be unreasonable to expect the bodies of ME/FM patients to be littered with tissue in very poor condition, producing plenty of waste, dysfunction and pain. That could indirectly affect fascia too, and potentially decrease the desired fluid flow in fascia. As fascia fluid can transport lactate and all water-like liquids can transport (a quite small amount of) oxygen and fair amounts of CO2 fascia problems may compound to poor distribution of things these cells at the smallest capillaries need and removal of their metabolic waste.
The skin is an obvious place to be fed by a large percentage of the finest of capillaries. But in all tissue the blood vessels have a branched structure like the twigs of a tree or its roots. That means that all tissue has plenty of “dots” being dependent upon the smallest of capillaries for being provided with energy, oxygen, anti-oxidants, minerals and released from their waste products.
As the skin is an entire surface with a very high percentage of small capillaries, it is likely the easiest place to find these dysfunctions. But all tissue is prone to having such “dysfunctional dots” littered all over them. Organs more prone to poor blood flow are more prone to it. Think about limbs and the head with its brain and eyes. As eyes are full of nerves and IIRC are already dependent on oxygen from the air to meet their minimal oxygen requirements, even a small reduction in blood flow may show strong symptoms.
Note: when I (ME/FM patient) am at worst, my tears feel like burning chemicals. If they accumulate near the edge of the eyes pointing to the nose, they feel almost as burning and irritating as the partly diluted 3% hydrogen peroxide solution I use for cleaning my contact lenses. That solution is not supposed to end up in my eyes but with brain fog I sometimes put my lenses back in before sleeping after they have been in the liquid for only 1 to 2 hours and the platinum catalyst disk hasn’t neutralized the liquid yet. If tears flow down my skin my skin burns too.
When very tired I often have tears out of pure fatigue too. People say tears remove toxins, but science hasn’t been able to prove that yet.
Having looked a bit further in what Lilpink/Cort/Gemini/Issie wrote in the previous blog it seems that the antibodies in the study mainly target the nerves themselves biorxiv.org/content/10.1101/713495v1, download PDF:
“Sensory nerve fibres in ex vivo skin-nerve preparations from mice treated with FMS IgG were hypersensitive to mechanical stimulation. Immunohistochemical analysis revealed that IgG from FMS patients specifically labeled satellite glial cells and myelinated fibre tracts, as well as a small number of macrophages and endothelial cells in mouse dorsal root ganglia but not skin, muscle, spinal cord and brain.”
Also: “Administration of IgG from FMSpatients increased mouse pain sensitivitiesto stimulation with mechanical pressure and cold.” could point to why FM patients have increased sensitivity to some things and reduced to others.
These IgG seem to affect (increase) cold sensation of the nerves themselves directly hence increased sensitivity. Heat IIRC is sensed through the production of Heat Shock Protein (HSP). If these IgG antibodies did not increase the nerves sensitivity for these HSP then the smaller number of fibers would reduce heat sensitivity in FM patients.
There still seems to be a link to blood flow too in sciencedirect.com/science/article/pii/S0304395913005551 (where they combined giving mice IgG from FM patients with creating a small wound by creating a small incision) :
“CRPS patient IgG treatment significantly increased hind limb mechanical hyperalgesia and oedema in the incised paw compared with IgG from healthy subjects or saline.”
When creating oedema, either inflammation, reduced blood drainage and or reduced lymph drainage may be at play. Maybe proper signalling of the nerves is important to create an appropriate healing/inflammatory reaction, with appropriate meaning not too few nor too much and ending when it’s no longer needed?
Poor signalling may lead to poor healing of damage and or too much inflammation. That over time may lead to accumulating damage and hence more (but still not appropriate) inflammation. That may impact local blood flow and nerves. That may create tissue and nerve damage with cell death. Cell death creates the need to clean death cells up. That involves the immune system and antibodies. Too much to clean up may create auto antibodies to nerves, tissue, blood vessels around the problematic spot. All of that may create poor signalling leading to poor healing of damage, closing the vicious circle.
Just an elaborate attempt to keep the blood flow problems still in the running and to allow for different “entry points” to FM as I highly valuate Philip’s observations and they don’t fit the IgG research as it is IMO.
If the body would have too much of these problematic spots, then it would both have accumulating damage and widespread inflammation and edema.
As body wide inflammation and edema would result in people looking like a hot swollen purple balloon (and that looks *very* unhealthy even in the short run IMO) the body may try and temper both inflammation and edema by removing water from the body. It’s hard to both have massive purple and swollen tissue when having too few blood.
I think the main point of the study is that FMS may be an autoimmune problem where body attacks self. In this case it’s the nerves. If rats reacted to IGG from injection of those with neuropathy, but not those without— appears to be a strong connection with the function of IGG (or basically the immune system and antibody function). This causing nerve damage and pain and possibly body wide inflammation.
Once again back to my conclusion of the core issues—- Autoimmune and inflammation.
THIS is going to be an exciting paper. 🙂
@Cort. Check your email. I sent you a transcript of it.
Certainly possible that something else that is causing the pain is causing the small nerve fiber loss. It’s a mystery to me too why those adhesions are not being looked at more.
If the small nerve fibers -which may include autonomic fibers – are interrupting blood flows to the muscles, and proper muscle functioning – then you have a nice potential cause of the whole shebang I would think. (Why are there more toxins in the fascia? Reduced blood flows seem like a great possibility.)
Unfortunately the duration of FM was not, to my knowledge assessed. Since aging naturally leads to reduced small nerve fibers that was assessed and the older the healthy controls were the fewer fibers they had. That was not true in FM patients.
Uceleyer now has a nice set of FM patients without evidence of SFN or SFP rather. Hopefully she will be able to follow them over time.
Agreeing – makes more sense pain is damaging nerve fibres… but I am only a patient not a MD…
However, as Cort noted, they are using IVIG in some cases. This is taking antibodies from hundreds of other people and infusing that. Basically giving you other people’s IGG. It carries with it a warning the same as a blood transfusion. I qualify for this as I have near no IGG resistance for any of the 26 types pneumonia I was checked for and have Hypogammaglobulinemia. I decided not not go this route. With my low immunity I didnt want to expose myself to getting something else in my body that I couldn’t fight off. No guarantee that this wouldn’t happen. It is thought that you’d have more resistance because you have other people’s antibodies fighting for you. But if injecting a mouse with IGG from a person with neuropathy gives it to them…..what else could IGG from a person with other autoimmune connected things could it give to me. Mayo wasn’t happy with me for refusing their “advice”. But my reasoning made more sense to me than what was proposed. They had me sign a paper in presence of two doctors saying I had been warned that my refusal would possibly cause me death if I got pneumonia and that I had been warned.
I’m certain I’ve had low IGG my entire life and I did have pneumonia in my 20s, before being DX, and though I nearly did die —- I survived.
Don’t these foreign IgG things disappear out of the body over time? Would have been interesting to follow up on the mice long after they were administered them to see if the symptoms vanished again…
Yes and it requires monthly infusions that are very costly. With exposure to hundreds more people’s antibodies. My POTS friends that have done this, only one has stuck with this. She seems to find benefit from it. There have been others with other autoimmune issues who find benefit too. I have not asked either of the two I know if their IGG was found low. As IVIG is being used off label for some conditions. But neither of them are well and it has not “cured” them.
Many thanks ?? for sharing this
MRIdye.com
Gadolinum gave me fibromyalgia and Mast Cell Activation Syndrome.
https://www.sciencedirect.com/user/identity/landing?code=I7fezt6b8OvA08hlEUIDFb2y11rvohniVhSIg6KZ&state=retryCounter%3D0%26csrfToken%3Dff1a7574-5971-40f2-b4bf-1ebae30abb56%26idpPolicy%3Durn%253Acom%253Aelsevier%253Aidp%253Apolicy%253Aproduct%253Ainst_assoc%26returnUrl%3D%252Fscience%252Farticle%252Fabs%252Fpii%252FS0306987719303263%26prompt%3Dnone%26cid%3Darp-78e42c64-f7bb-444f-8e90-e71c3ce8aedd
How did you get this sorted? How did you detox? I’ve had so much of this as I have to have yearly MRI for brain tumor and other issues they watch.
Been trying for IVIG for 11 months and insurance is still denying.
I pay $1k/month for a high level PPO but they say IVIG is not approved for small fiber neuropathy.
I have a progressive form of dysautonomia that started when I was 12 (I’m 29 now and mostly bed or house bound).
It looks like I may never get to try IVIG (or Hizentra IgG subQ)
I go to my Rheumy today for small nerve fiber neuropathy test. He has new test equipment. I’ll write after diagnosis.
Good luck. Please let us know how it goes.
Usually Small Nerve Fiber Neuropathy isnt validated from a test? Even if it did, its merely a confirmation of what you already know…
Whats the update?
Best,
Dan