Inflammation – Neuro and Otherwise
Inflammation has become an increasingly important topic in fibromyalgia. It’s clear that “central sensitization” – an increase in pain sensitivity engineered by the central nervous system – is present in fibromyalgia (and other chronic pain disorders). That central sensitization could be caused by an inflammatory process which produces pro-inflammatory nerve factors that send the pain-producing nerves into a tizzy.
Neuroinflammation could be responsible for many of the symptoms in fibromyalgia.
Neuroinflammation then is a major possibility in FM, but measuring it hasn’t been easy. Only recently have brain imaging techniques been developed that might be able to measure the neuroinflammation that’s present in FM. This study tried to get at the question of neuroinflammation in a different way.
Most studies restrict themselves to either the brain or the body, but this Swedish and Norwegian study did two things that were unusual. Instead of looking for a few cytokines or chemokines, it assessed the abundance of a very large (n=92) number of inflammation-related proteins, and it did so in both the spinal fluid and the blood.
Given how difficult it is to get spinal fluid, the study was a pretty large one involving 40 FM patients and 11 healthy controls.
Pain Res. 2017; 10: 515–525. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. Emmanuel Bäckryd,1,* Lars Tanum,2,* Anne-Li Lind,3 Anders Larsson,4 and Torsten Gordh3. Published online 2017 Mar 3. doi: 10.2147/JPR.S128508
Results
If FM is, at least in part, an inflammatory disorder, the FM patients should have more inflammatory proteins than the healthy controls. Given the evidence of central sensitization, one might have thought that inflammation would be more likely found in the cerebral spinal fluid, but in the end those signs showed up in the blood as well. This study suggested that both nervous system and systemic (body-wide) inflammation is present in FM – and interestingly enough – have some similarities.
The list of inflammatory proteins increased in FM was not a small one. Instead of cytokines, it was dominated by chemokines belonging to two groups: CC or CL chemokines. Produced by glial cells and neurons in response to injury, these types of cells trigger the release of cytokines. An important pro-inflammatory cytokine called IL-8 which has been found in FM spinal fluid studies was present as well.
One of the chemokines found elevated in fibromyalgia called fractalkine (CX3CL1) may, researchers believe, be the key player in the production of chronic pain. A recent review suggested it was the central nerve factor involved in turning on the microglia. In fact, one animal study was able to prevent the development of pain sensitivity and allodynia by eliminating a factor called cathepsin G which triggers the production of fractalkine. Inhibiting the production of cathepsin is a possible novel therapeutic approach to pain.
If fractalkine is as big as deal in FM as the authors of this article believe, FM patients might be in for some good news at some point. Several fractalkine inhibiting drugs are in clinical trials. According to one report, blocking fractalkine signaling significantly reduced the severity of Crohn’s disease and rheumatoid arthritis. Encouragingly, the drug worked in patients who hadn’t responded to autoimmune drugs in the past.
Again encouragingly, the authors noted that similar immune proteins were found in people with FM and those experiencing chronic back pain after disc herniation. Why one person recovers from a herniated disc while others remain in pain is unclear, but these two studies suggest that the ongoing presence of immune mediators may play a key role. They suggest that a core inflammatory process may be behind many chronic pain states.
This study’s conclusions were exciting because while neuroinflammation has long been suspected in fibromyalgia, finding evidence of it has been difficult. One problem has been that it’s simply not easy to detect the low levels of inflammation believed to be present.
That’s starting to change and we should be able to look forward over the next couple of years to more and more studies assessing this possibly vital component of FM. The presence of increased levels of inflammatory proteins in the cerebral spinal fluid bathing the brain in this study suggests that inflammation is indeed present in the brains of FM patients.
Why the inflammation is present is, of course, a whole other question. A breakdown in the blood-brain barrier, a pathogen in the brain, blood flow issues, or even an immune response in the body could cause an inflammatory response to occur in the brain. The increased levels of inflammation in the blood found in this study suggest that infection in the body could contribute as well. It would do this by sending messages zinging up to the vagus nerve to the brain which trigger microglial cells to produce fatigue and pain symptoms.
Treatment?
Linda Dobberstein, a chiropracter and clinical nutritionist, believes that a “sick brain” that’s pounding out stress signals to the body may be causing most of the problems in FM including gut issues, lactic acid production, sympathetic nervous system activation, hormones and lymphatic congestion. Dealing with these peripheral issues does help, but the brain is the real problem and until that is addressed she believes most of the symptoms associated with FM will remain.
If neuroinflammation is present in FM what might be able to put the fire out?
In a recent blog Dobberstein presented evidence suggesting that carb-lovers with FM might want to cut back. A 2016 study found a high fructose diet resulted in the production of high levels of fractalkine in mice and neuroinflammation in their hippocampus and hypothalamus. If that’s so it’s possible that high-carbohydrate diets could affect memory, learning and produce fatigue and many other symptoms. Given that most anti-inflammatory diets do restrict sugars and carbs, a high carb-neuroinflammation connection might not be surprising. (Adding curcumin, interestingly, reduced the inflammation in the mice.)
Dobberstein is not a fan of the FDA approved drugs in FM, and suggested a number of ways to fight the inflammation. (For those who can handle it, Savella does appear to reduce neuroinflammation). Taking magnesium can reduce IL-8. Chondroitin, glucosamine,hyaluronic acid and boswellia serrata may be able to quench several inflammatory chemokines such as IL-8. Omega-3 fish oil and DHA may be able to regulate glial cell activity, and antioxidants such as Grape seed extract, cordyceps, and curcumin (with bioperine) and CoQ10 can help calm the microgila as well.
- Check out some way to naturally reduce inflammation here
Dr. Ginerva Liptan suggests that low dose naltrexone, tumeric, green tea and cannabis may help. The antioxidant and anti-inflammatory properties of tumeric are being studied in Alzheimer’s. Dr. Younger is currently testing a wide range of herbal products to see if they reduce neuroinflamation in people with Gulf War Syndrome. Given Shungu’s recent finding (unpublished) that N-acetyl-cysteine (NAC) increased brain glutathione levels and reduced brain lactate levels in ME/CS patients, it may be another possibility.
Conclusion
It’s good to see objective evidence of inflammation show up in FM, both in the spinal fluid and the blood. It’s even better to see factors that are associated with chronic pain and even memory issues in other diseases such as fractalkine show up in fibromyalgia. If a factor such as fractalkine shows up in enough diseases (it’s been found in FM, Alzheimer’s, diabetes, Crohn’s disease, etc.) drugs will be developed for it. At least two fractalkine drugs are in the early stages of testing. Hooking onto other disease findings and their treatments may in the end be an important factor in finding relief from FM.
For more on neuroinflammation in fibromyalgia see:
- Genes May Be Causing Neuroinflammation and Pain in Fibromyalgia
- The Brain Game: The Search for Neuroinflammation in ME/CFS and Fibromyalgia
- Fibromyalgia – Neuroinflammatory Disease? Savella – Anti-inflammatory?
- The Neuroinflammation Man: Jarred Younger on Inflammation
- Low Dose Naltrexone, Inflammation and Pain: A Different Approach to Fibromyalgia
- Microglial Inhibiting Drugs and Botanicals to Combat Neuroinflammation
Spirulina might be an option for Fractalkine induced Neuroinflammation too…see this study
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0045256
Thanks David 🙂
Turmeric, ginger, cinnamon in coffee with lots of full fat coconut milk and stevia. Yummmmm! Seems to help me. Pain being my worst symptom.
Also thinking that thinning my blood with herbs and upping acetylcholine having a positive effect. On an upswing.
Issie
OMG! I have Fibro and Crohn’s Disease, this recent study is so exciting for me as I might get my life back. I have recently gone into remission of Crohn’s and my Fibro is manageable at the moment since I started taking caprylic acid, CQ10, Magnesium and strong probiotics over 8 months ago and now each day is slowly getting better. Compared to even just a year ago the difference I am feeling is amazing. I really hope they are able to continue the research and finally come up with something for us all but to be honest, I’m afraid to get my hopes up as each time I see new research that looks promising they’ve been dashed but I guess that’s how progress is made. This however looks very promising and I’m keeping my fingers crossed.
Congratulations Sharon. What kinds of probiotics are you taking?
I can’t speak for Sharon but, if she doesn’t get back, will tell you my son with Crohn’s was “prescribed” VSL3, “Probiotic Medical Food”, 112.5 billion bacteria per capsule. It is not prescription but is specialized and has to be special ordered by most pharmacies and needs to be refrigerated. Not cheap, fifty bucks for 60 caps, 2 per day.
This is very helpful evidence.
It took over 10 years for me to find out what was causing many of the issues I had been experiencing. I am someone who was diagnosed with fibromyalgia by 3 different specialist, but several years later discovered that the fibro symptoms were actually due to a chronic enterovirus.
I believe that many patients who are diagnosed with FM, actually have some type of chronic enterovirus. Unlike FM, you can actually test for these enteroviruses (blood and stomach biopsies).
I have to agree with this article though. I get severe swelling in my brain on occasion, and have had to go to the hospital on two different occasions to control the unimaginable pain that stemmed from the swelling.
On one occasion the hospital did a spinal tap and noted that my ICP (intracranial pressure) was 26. Which is well over the standard for “normal”. Since that experience, I am a firm believer that these enteroviruses cause many of the symptoms of Fibro. Because these virus travel through the Central Nervous System, it is very logical to believe that these virus move into the brain and cause swelling.
Thanks for mentioning intracranial pressure. My intracranial pressure is high as well. I believe a doctor in Canada is looking into this. Have you been able to do anything for your enteroviruses?
This is all helpful and not at all contradictory to my conclusions so far about what FM “is”. I would just caution against focusing on “central nervous system malfunctions” as “the cause of FM”, at the expense of the possibility that physiological damage is the initiator and everything from then on is a cascade of effects and causes.
Invasion of tissue by toxins, undiagnosed infections, trauma, and inappropriately tensed muscles 24/7 (as a stress response), are all likely initial causes, and probably often present in combination. All the CNS dysfunction perfectly logically could be consequential rather than the source of the problem.
I surmise that the mechanism for the advance of FM is toxins and dehydration causing the myofascial ground substance to become sticky and lose its lubricant properties, and muscle fibres becoming stuck and knotted and tight-banded, particularly as the muscles are in a state of contraction for extended periods, generally inappropriately. If this is the case, suppressing pain by means of interfering in the neuroinflammatory pathways, will be a useful addition to the multi-disciplinary toolkit for pushing back FM, but will not be a “cure”, any more than painkillers are a cure for a brain tumour.
The observations about the low carb diet are very confirming of my own experience. I also surmise that the low carb diet reduces the toxicity in the neuromuscular system because the waste products from burning sugar for energy are different to those from burning fat. FM is affecting each energy metabolic pathway and the muscle fibres involved (3 different types), in different ways.
It is my strong belief that this is where FM research should be focusing.
Thanks Phil. I think the evidence of inflammation in the body supports your idea. It was interesting to learn that inflammation in the body can produce or contribute to neuroinflamation in the brain.
Have you tried a low-carb diet yet? I’m in the midst of one – struggling towards ketosis 🙂
https://www.healthrising.org/forums/threads/struggling-toward-ketosis.5403/
I have always found the Zone diet to be best for keeping the body wide aches of fibro at bay. This diet is based on a balance of the macro nutrients. There is no need to go very low carbs if kept in balance with the protein and fat. The balance should be 30% protein, 30% fat and 40% carbs. The carbs should also be mostly favourable ones, ie. low glycemic index, and only a very small proportion of unfavourable, ie. high glycaemic index. If doing the Atkins, one should only completely avoid carbs for no more than 2 weeks before slowing introducing carbs.
Absolutely, low-carb is one of the elements in my successful self-experimental protocol, I have been on such a diet since late 2013.
I don’t think I would have made such an impressive improvement without it, but I also don’t think the low-carb diet on its own would achieve much. The other tactic of primary importance, is plenty of exercise at the right intensity (not too much, not too little). Then there are several other tactics that I believe to be helpful. It is quite likely that I could not do without mega-doses of magnesium, in fact I was repeatedly and severely attacked by calf muscle cramps soon after going on the low carb diet, and each time this was resolved by increasing my magnesium dosage. That is, I suffered repeats of these attacks a few weeks after increasing my magnesium intake, and increased it again. Once I reached around 2000 mg per day, and using several different forms of magnesium, the cramp attacks stopped altogether. When I have attempted to reduce the dosage, I have had another cramp attack.
Hair mineral analysis tests consistently showed low magnesium until I had been taking 2000 mg daily for several months. Then, it finally went “too high”. Along with this, calcium, which had been way too high for decades, finally dropped into the normal range.
I think calcium is one of the ingredients in the “gunk” that makes the myofascial ground substance “sticky”. Along with toxic elements, toxins from undiagnosed infections, and lingering by-products of anaerobic exercise (lactate?) which the FM-afflicted physiology has lost the ability to clear, for some reason. Hence the essentiality of moderate intensity of exercise, which helps gradual flushing of the muscles. Too-high intensity generates more toxins, but insufficient movement daily just leaves muscle tissue stuck and un-flushed.
As always – thanks Phil.
I agree with you
Phillip, regarding muscles:
I would love to see research focusing on the connective tissue within and around muscles. Aqua exercise is recommended for connective tissue disorders. Not sure about the science, but it seems that muscles can be strengthened while sparing connective tissue in water. If the muscle fibres (which are not connective tissue) were the problem,then it would be hard to strengthen muscles even in water. FM was at first thought to be connective tissue but that idea was abandoned – according to the preamble of this study, because it was found the connective tissue was not inflammed. But that’s not the only marker of a connective tissue problem. https://www.ncbi.nlm.nih.gov/books/NBK279092/
Therefore, is it the muscle fibres or the connective tissues:
“The endomysium is the connective tissue that surrounds each muscle fiber (cell). The perimysium encircles a group of muscle fibers, forming a fascicle. The epimysium encircles all the fascicles to form a complete muscle. A tendon is a cordlike extension of the preceding three linings.”
http://www.ivyroses.com/HumanBody/Muscles/Muscle_Structure.php
I don’t have fibro, but I have found that people with fibro will have pain set off by deep touch or injury. Would make sense that pain is bad if connective tissue is vulnerable and gut mucosal barrier, skin barriers, connective tissue in muscle being damaged through biochemical processes (diet, drugs, etc.) or touch.
Interesting! “Not sure about the science, but it seems that muscles can be strengthened while sparing connective tissue in water”
Appreciate your interest, Laura.
I am presuming that it is possible for the myofascia to be “stuck” as I hypothesize, without the myofascia itself being detectably “inflamed”. Dommerholt and Gerwin, Devin Starlanyl, Travell and Simons, and others, are constantly battling the mainstream medical “experts”, because any hand-on therapist can feel the deformities in the muscles, the lumps and tight bands, yet the mainstream medical “experts” want more proof than that, before they accept that this is playing any role in patients problems! Starlanyl does quote a study by J P Shah and co-authors, that finds elevated levels of “biochemicals associated with pain and inflammation”, that are potentially leaching from these muscle tissue deformations.
Far too much research is proceeding along the lines that CNS dysfunction is the beginning and end of FM, when there is obvious manifestations of physiological “deformities” in muscle tissue in literally dozens of locations around the body. Hands-on therapists of all kinds that I have gone to for more than 20 years, all regard this as self-evident. This lumpiness and corrugation of muscle tissue has been slowly diminishing as I have improved through multi-disciplinary self-help.
Starlanyl and the others call these spots “trigger points”, which I and others think is a most unhelpful label. They do act like the traditionally-defined trigger points, in that they refer pain all over the place when provoked, but tumours probably do that too, and it makes no more sense to use the label “trigger point” in that case. These nasty toxic clumps of stuck muscle tissue deserve a proper medical name of their own. “Fibrococele” or something like that.
It’s interesting they never consider environmental toxins that some people cannot detoxify or react to such as mold, pesticides, gluten or even consumer products like perfumes and cleaning products as a possible cause, or at least contributing factor, for the inflammation. Avoidance of these substances is not a cure but for some it can be safe and relatively easy treatment. It would be nice to see a similar study in ME/CFS patients, or has one been done?
Absolutely agree with that as part of the mechanisms I am suggesting. In my case, a toxic element, cadmium, was the “nasty”. But a large number of things that are simply all “toxins”, probably suffice as ingredients in contaminated myofascial ground substance, to produce the same stickiness as opposed to the lubricity that is supposed to be present.
Things are about to get even more complicated. A talk on the currently airing micrbiome summit has confirmed the existence of a separate brain microbiome..different in make up to the gut biome and skim biome. This will also produce interesting outcomes in the area of FM and ME/CFS. The talks are still on line today. Marco Ruggiero is the speaker. It’s 90 minutes or so but the best bit about the braim is towards the end.
Interesting! I thought his talk would be a highlight. Thanks for passing that on.
Please keep me informed!
If it is proven that there is neuroinflammation in fibromyalgia and ME, this backs up other research that has recently found it to be an autoimmune disease. Neuroinflammation is often caused by autoimmunity.
I have FM and have found that the only exercise I can tolerate focusses on connective tissue. In fact, it has been very helpful in reducing my pain. I do 30 minutes every other day.