How an opioid drug called tapentadol (Nucynta) told us something about the small fiber neuropathy in fibromyalgia
Given the concerns about the use of opioid prescription drugs, the fact that one not called Tramadol worked in fibromyalgia may not elicit much interest. One the other hand, it may have told us something about a subject of great interest in FM – small fiber neuropathy (SFN).
Nucynta and tramadol attach to the μ-opioid receptors in the brain.
Tapentadol (Nucynta) is an opioid drug with some similarities to tramadol – the most widely used opioid drug in FM. Both attach to the μ-opioid receptor and increase norepinephrine levels. Unlike tramadol, though, Nucynta does not affect serotonin levels, and with its potency lying somewhere between tramadol and morphine, it’s a much stronger drug, and can produce more side effects.
I don’t believe tapentadol (Nucynta) is widely used in FM, but a fascinating FM tapentadol study has cropped up which sheds light on a seemingly entirely unrelated issue – small nerve fiber neuropathy (or polyneuropathy) – which is also found in chronic fatigue syndrome (ME/CFS) as well.
Earlier, the Dutch researchers had shown that tapentadol relieved pain in diabetes patients by enhancing the inhibitory pain pathways that run down from the brain and essentially turns off or reduces pain levels. Those same pathways – which are referred to as “conditioned pain modulation (CPM)” – have been shown many times to be impaired in FM.
In general, “pain should inhibit pain”; i.e. the same amount of heat applied twice in a row should result in a reduced sensation of pain the second time.
The Gist
- Nucynta is an opioid painkiller similar to Tramadol in some ways, but stronger (and with more side effects).
- The controlled pain modulation system is a descending pain inhibition process which reduces pain levels. It has repeatedly been shown in fibromyalgia to be balky.
- After a study showed that Nucynta was able to reduce pain levels in diabetes by enhancing the controlled pain modulation system, the drug was tried in fibromyalgia.
- The researchers found that Nucynta worked very consistently (85%!) in FM patients who did not have small fiber neuropathy (SFN) – a condition in which the small nerves in the skin or the eyes are damaged or lost. Nucynta both improved their controlled pain modulation process and reduced their pain levels.
- While Nucynta did improve the pain inhibition process in FM patients with SFN, it did not, however, improve their pain levels.
- It was not clear what was happening, but the authors posed two reasons: the FM patients with SFN were simply too sick to benefit or they had a different kind of FM entirely.
- There’s evidence for both answers: studies indicate that FM patients with SFN have more severe symptoms than those without it. Plus, the study suggested that the neuropathic pain the patients with both FM and SFN experience is not due to problems with pain inhibition. Dr. Oaklander believes that FM patients with SFN don’t have FM – they have small fiber neuropathy.
- The cause of the SFN in FM is still unclear, and basic processes that govern the small nerves may need to be elucidated before that becomes clear. Some believe that central sensitization causes SFN while others believe SFN may cause central sensitization.
- A recent study that found reduced small nerve fibers near the blood vessels suggested nerve damage could be impairing the microcirculation.
- On the bright side, more study into the SFN problems in FM is occurring than ever before, and SFN is being found in more diseases than before including post-COVID-19, post-treatment Lyme disease, ME/CFS and diseases like Parkinson’s Disease, ALS and Ehlers Danlos Syndrome.
- The treatment picture of SFN is complicated with a variety of drugs used which are helpful for some, but not in others. IVIG is an emerging possibility for FM, with one recent but small study finding it effective.
Diabetic patients, for instance, with more impaired CPM or pain inhibition pathways, benefitted more from Cymbalta (duloxetine) than those with intact pain inhibition pathways.
Since Nucynta is able to perk up the pain inhibition response, it made some sense to try it in FM.
The twist was small fiber neuropathy (SFN). SFN refers to the damage or destruction of small nerve fibers in the skin or eyes that carry sensory and/or autonomic nerve signals to the brain. No one knows why this is happening in FM, but it appears to show up in from 40-50% of FM patients, and about the same number of ME/CFS patients.
For some reason, these researchers took it upon themselves to also assess whether or not the 34 FM patients in this placebo-controlled trial had reduced numbers of small nerve fibers in the corneas of their eyes. It was a good thing they did.
The Study
The 34 patients in the randomized, double-blinded trial were started off on 50 mg of tapentadol twice daily. Each week, the dose was increased by 50–100 mg per day, to a maximum of 250 mg, two times a day.
During each of the five visits they made to the clinic during the 4 month trial, their pain inhibition pathways were assessed using heat and cold tests.
Results
Tapentadol did improve the pain inhibition response and significantly improved pain levels, but only in one group – the fibromyalgia patients without small nerve fiber damage. In fact, a remarkable 85% of the FM patients without SFN reported a significant improvement in pain. (While the authors reported that Nucynta or tapentadol is safer than drugs like oxycodone, they recommended that it be used for 3 months or less.)
Nucynta strengthened their pain inhibition pathways, but the FM patients with SFN didn’t experience any pain relief.
While Nucynta was able to improve the pain inhibition response in the FM patients with small nerve fiber damage, they did not experience any pain relief.
A recent study that found high levels of impaired pain inhibition in FM patients with SFN gave no reason to expect anything other than a positive result from a drug like Nucynta. It just didn’t happen – leaving us with a new medical mystery.
The authors suggested that FM patients with SFN may simply be sicker and less responsive to treatment. A large SFN study coming out of the Uceyler group in Germany suggests that FM patients with SFN do tend to be quite a bit sicker. They had more severe symptoms (higher pain intensity, were more impaired by pain, had higher disease, experienced more stabbing pain sensations and numbness and, not surprisingly, more anxiety) than FM patients without SFN.
If that’s true, then Nucynta just didn’t impact enough of whatever is causing their pain to make a difference. A drug like Nucynta could be helpful, but only in conjunction with other approaches.
The authors of the study also suggested that two distinct types of FM may exist – one type with SFN – and one without. The fact that the neuropathic pain scores in the SFN group were not correlated with pain inhibition scores suggested that a different component (like SFN) was causing their neuropathic pain.
The study was small and needs to be replicated before we can have confidence in its results – but it suggests, like the studies noted above, that SFN is not, as some researchers have believed, an add-on issue of little consequence. It’s either indicative of a more severe pain inducing process overall or of a different pain inducing process.
Causes of SFN
Unfortunately we don’t know what’s causing SFN. We do know that the SFN in FM appears to be different from the small fiber problems in diabetes, but tracking down the cause has not been easy. In a recent video presentation, Dr. Uceyler, a prominent SFN and FM researcher, asserted that we need to learn a lot more about small nerve fibers in general to understand what’s happening in FM.
Daniel Clauw has suggested a kind of brain-body merger. He believes the central sensitization in the brain may actually be causing the small nerve fiber problems in the body. The tapentadol study suggested we have a chicken and egg problem: they proposed that the opposite could be happening as well – that the small nerve problems in the body could be causing central sensitization.
All this goes to show is that while SFN is found in FM (and allied diseases like ME/CFS, interstitial cystitis, irritable bowel syndrome, and Ehlers Danlos Syndrome), the bad news is that we still don’t know why it (or central sensitization) is occurring.
The good news is that interest in SFN in FM is at an all-time high with studies emerging regularly. Recently, for instance, the Uceyler group dug a little deeper into the skin to find a reduction of small nerve fibers near the blood vessels. Cautiously interpreting the finding, Ucelyer noted that the finding fit with past FM findings suggesting that the microcirculation may be affected in FM.
That’s a very intriguing possibility given Systrom’s findings suggesting that impaired microcirculation may be contributing to the energy production problems in chronic fatigue syndrome (ME/CFS). (We clearly need more SFN research in ME/CFS).
Plus, SFN is popping up in more and more diseases. It turns out that the more you look for it, the more it’s there. It’s not so surprising SFN might pop up in diseases which share similarities with FM and ME/CFS such as irritable bowel syndrome and interstitial cystitis, or that it’s also shown up in post-COVID syndrome and post-treatment Lyme syndrome. It’s also showing up in diseases like Parkinson’s, amyotrophic lateral sclerosis (ALS) and inflammatory neuropathies.
Treatment
Effective treatment is, of course, the ultimate goal. The most common treatments (antidepressants, antiseizure and/or opioid drugs, lidocaine creams) may be helpful for some but clearly aren’t getting at the heart of the problem. Some drugs that are not commonly used (flupirtine, Infliximab, adalimumab, lacosamide) may be helpful in some cases. Of the fibromyalgia drugs duloxetine (Cymbalta) and pregabalin (Lyrica) can sometimes be helpful. (If you respond to Cymbalta, it may be because you have a problem with your pain inhibition pathways.)
IVIG is an intriguing possibility, but is expensive and hard to get. It is, however, commonly used to treat SFN in immune diseases like sarcoidosis. Fibromyalgia is not usually considered an immune disease, but Oaklander believes FM is misdiagnosed in patients with SFN: she believes that FM is SFN – and has some proof that it is immune mediated.
Oaklander has reported on IVIG’s success in children with SFN. Plus, a recent small case-report series found that IVIG improved both symptoms and small nerve fiber density in people with fibromyalgia. It will take more studies, but if they are done and that trend continues, at some point insurance companies will be more likely to pay for IVIG.
While we don’t know what’s causing the SFN in FM, ME/CFS, post-treatment Lyme disease and post-COVID 19 syndrome and the treatment options aren’t exactly exciting, it’s good to interest in SFN catch on. It’s also good to know that given the right opportunity those small nerve fibers can grow back. Hopefully we’ll get more answers in the not too distant future.
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Interesting blog, Cort, although taking about SFN is a lot like talking about fatigue–it can be present in so many conditions. In Ehlers-Danlos, some have estimated that about 40% have SFN and theorize it is related to POTS and other dysautonomias so common with EDS.
For myself, I cannot tolerate tramadol for pain. It doesn’t work and indeed causes migraines. I suspect I don’t have much SFN either. I passed my QSART too. But then again, I don’t think I have any fibromyalgic symptoms.
So many conditions have SFN associated with them including endocrine and autoimmune disorders (among other things). Almost all those diseases also have fatigue as a major component. It is also associated with genetic variants on SCN9A and SCN10A.
If you want to contemplate too much information about SFN, here is a good link; https://www.kumc.edu/Documents/neurology/small%20fiber%20grand%20rounds.pdf
Personally, like fatigue, I think there are probably too many sub-types of SFN to lump together and that pain theory is not completely understood. That being said, if a drug works (or doesn’t) even if it isn’t known why, that’s a useful piece of information to know.
Tramadol the same for me and I have EDS. Unfortunately I was tapered to it after the CDC guidelines. I did however feel like I had a type of serotonin sickness with it so interesting about that.
Yes, I think the very, very wide variety of treatment approaches demonstrates how variable SFN is. I was surprised listening to Dr. Ucelyer’s presentation how little we actually know about the small nerve fibers. We don’t even know all the different types of fibers. This is a field that seems primed for better understanding; it affects a lot of people yet not that much is known about it.
The SFN in FM, for instance, appears to be different from that found in some other diseases. It appears to affect both nerve density and nerve diameter as I remember.
I have tried Nucynta for SFN in my feet – peripheral neuropathy. Unfortunately, no help from Nucynta.
This condition has been around for me almost as long as CFSME. It went through phases over the years, from icy cold feet to numb and burning, then tingling and burning, and finally to life changing stabbing and burning pain.
I had to go to a pain clinic, MDs, right away. It has taken opioids to manage the pain to tolerable levels. I tried other similar-to-Nucynta rxs but only opioids have worked. Along the way I came upon research that concluded that drugs other than opioids only had a placebo effect level of controlling the SNF kind of pain. It’s regrettable due to the side effects and the difficulty getting doctors to prescribe opioids (due to abuse levels).
FWIW, I believe the SNF is related to the ME, both being of neurological origin, whether
onset after a virus or an immune dysfunction.
Cool to see all the research happening! I only wish I was younger so that I might benefit from it more by the time they figure something out. lol.
I was DX’d with both FMS and CFS more than 2 and a half decades ago and SFN has been my worst pain symptom since day 1. I always said I could tolerate all the other pain if I just could get control over the pain in my calves and feet. (I can’t wear shoes, or socks).
I never tried Nucynta but I tried just about every other drug for pain including those for seizures like Topomax without success or the side effects were intolerable. I was finally given a low dose opioid and have been taking that ever since along with a low dose of gabapentin, plus Ketamine nasal spray and Dextromorphane.
I also have a medical marijuana card but all MMJ does for me is to distract me from the pain. (I did talk to one patient who said MMJ made her nerve pain disappear!) That plus a move to the Deep South where I don’t have to deal with the damp cold weather anymore (I’m originally from the midwest) has helped me the most.
Now if I could just do something about the bone crushing fatigue (and brain fog!)
Cort, what do you think about covid vaccine for people with CFS?
I just got info today from EDS Society and there being issues with a couple people with MCAS. Here is the info they sent.
https://www.ehlers-danlos.com/eds-hsd-and-covid-19/
Also FDA is listing some side effects that they have found. And are monitoring for more.
https://www.fda.gov/media/143557/download
@Issie,
Thank you for the links. Yes, MCAS might be an issue.
Here is Pfizer’s document listing all the adverse reactions in their trials. Scroll down through the document to see the actual symptoms; https://www.fda.gov/media/144246/download
Almost the same e-mail address as yours!
I got some other info from a friend in Insurance, but didn’t list because I can’t verify the source completely. But the companies of the vaccine are not held liable for any adverse affects. It being so fast created and not long term testing and unknown long term results, and they are paying close attention to possible complications.
That paper said that UK doctors have been given a list of people who should not receive a vaccine. Mostly because it has not been tested out so well. But like I said, I can’t verify the sources from that paper. So pays to be cautious.
Too bad the paper you listed @Nancy B. had everything so mixed into the research data. The lay person would have a hard time seeing those potential consequences.
I know with my autoimmune issues, my doctor recently, told me to stay away from vaccines. My sisters docs said the same thing. My dads response with severe neurological issues to a flu shot is one genetic factor for our family. I’m glad my decision is sort of made for me. But, it pays to do your research.
For my family, we have to be super careful and hope for the best. There actually may be some genetic polymorphisms, I have, that may protect me against having it so bad, if I get it. Selfdecode genetics has COVID research out and you can check your genetics and get idea of how you might fare. Mine has mixed results.
Dr. Christiane Northrup – she of Oprah, PBS, ‘Women’s Bodies Women’s Wisdom’ fame (https://www.drnorthrup.com/) – has a video where she *strongly* advises against taking the vaccine. She details at length (approx. 30 min if memory serves) the medical and scientific reasons for her advice. I’d strongly suggest anyone considering taking the vaccine watch Dr. Northrup’s video and decide for yourself before deciding.
Since so many of us came down with ME/CFS after taking vaccines (I know, not everyone, but enough of us that it merits caution), and this is an entirely new type of treatment*, combined with the fact ME/CFS patients so often respond strangely to medication/treatment (either too strongly or not strong enough) I’d suggest caution is warranted.
As someone on this week’s Bateman call said: “This is a new type of vaccine that introduces a small piece of genetic material into the body to generate an immune response rather than using a whole inactivated virus.”
If anyone is interested (and I can find her video again) I’ll post a link. I haven’t watched the whole video, but the first 5 -10 minutes was enough to get the gist. It was certainly an eye-opener for me, and I’m glad I watched it.
Hmmm. I just found and watched the full-length video with Dr. Northrup. It’s much more new age-y and ‘peace, love, and meditate’ ‘get in touch with your higher power’ -ish than I’d expected. Very disappointing. She does no credit to herself with some of her out-there positions.
However, some of the things she’s asserting (like the complete failure rates and dangerousness of RNA vaccines to date, and the test subjects getting much worse illnesses after vaccination) are things I’d already known about prior to watching her video, so some of the things she’s talking about have merit. Also, her mention of the Tuskegee study is apt.
I know there are better warning videos out there by very credible physicians and researchers – whose voices are being heavily censored – so I hope people will research this for themselves before committing either way. Just be aware that there is heavy censorship atm, so finding critical information isn’t easy.
Could there be side effects of vacination? I bet there can, especially for the immuno compromised.
Having a flue shot was not a problem for me pre-ME. Since having ME, it’s quite a bit more difficult to digest.
That said, could an active infection with Covid19 have side effects? You bet it does! Among the worst side effects is death, like in permanent death. So far, over a million people in the world and about 300’000 in the US have experienced this rather damaging side effect.
There are a slew of other still severe side effects, like up to 50% fibriosis in the lungs, prolonged severe fertility problems in men, ME-like post infectious disease…
The choice of having or not having this vaccination isn’t as simple as chosing to not have the measles vaccine. If you don’t take the measles vaccine, chances are pretty good you’ll never get it anyway since enough other people have had the vaccine. As long as X% of the population is immune to the disease, there is herd immunity.
With Covid19, things are different. Covid19 is about the most contageous viral disease the world has ever seen. Even with partial lockdowns and a very restricted social lifestyle in much of society this virus barely can be tamed from spreading. Even in a full lockdown the virus achieves an R or reproduction value of close to 1. Once it gets above 1, the epidemic starts to grow again.
The challenge with Covid19 will likely be that the “usual” 65+% of people being resistant to the disease won’t be enough to create herd immunity. Why? Herd immunity is the thing that brings the R or reproduction value below 1 making new local eruptions self-extinct after a while. That is easier to do if the virus isn’t so incredible good at spreading itself.
Therefore it makes sense for Covid19 needing quite a bit more then 65% of people being resistant against it, at least if combined with a normal non restrictive social lifestyle.
=> The big difference with not having common vaccinations here IMO is that it will require VERY strict self isolation for over more then a year in order to avoid having actual Covid19 when not vaccinating.
Reported “side effects” of Covid19 and side effect occurance rates are far higher then reported side effects of the Covid19 vaccine. So for those not having vaccination: take utmost care to avoid near any physical social contact till the pandemic is gone AND know you still will have to be lucky. If your healthy beloveds had the vaccine, you’ll depend a bit less on luck but still will and will need rigorous self isolation for at least another year.
Even with a vaccine know this COVID virus is mutating and there are already other strains out there.
I have a friend who was in the study group and took the vaccine. Both she and her son got COVID. They told her it was another strain of the one she was vaccinated against. They hoped the vaccine would make the other strain less problematic. But it is still an unknown with unanswered questions. She has, however recovered.
This virus can also be gotten more than once. Workmate friends, have documented that he and his wife have had it twice. Proven with positive testing, both times.
This thing just keeps giving.
To vaccinate or not to vaccinate?
Just read that there were at least 4 cases of Bell’s Palsy in the first group of Pfizer vaccinations… Fortunately Bells usually isn’t permanent.
As I continue to ponder the question of vaccinating, I realize that there are at least 20 major companies developing vaccines. Some are working on the older methodology of weakened or non-viable virus while Moderna and Pfizer are using the newer mRNA technology.
I wonder if people might, if they wait a bit longer, have a choice as to which vaccine they might take? Even if a vaccine has a lower protective effect, if it has a better safety profile wouldn’t that be better than a less well researched mRNA type for people in the ‘questionable category’? Currently it feels like we are being ram rodded into a choice of one.
Another issue is how long will any vaccine protection last? So far, it has only been about 4 months because the vaccine deployment has come only recently. Corona viruses, think the common cold, seem to be very resistant to prevention and reappear year after year. And there are, as mentioned, mutations to the viral strain.
One good result in the Pfizer trial is that older people, in general, seem to have less serious side effects, although many others have worse side effects after the second shot.
My worry is that messing, in an unnatural way, with the body might cause some unexpected result in another body system–and maybe it might even be so delayed as to remain unsuspected. On the other hand, Djurgen makes a good point that the Covid infection and the (hopeful survival) aftereffects could be worse.
@Nancy B:
I had the same thought. As far as I know, the Johnson and Johnson and Astra Zenica vaccine candidates are two vaccines based on older technology that are in fairly advanced stages of develoment but lagging the mRNA vaccine candidates a bit in time. One of them has lower protection rates then the exceptional high 90+% the mRNA vaccines have. I think it’s around 65%. Numbers on the other are in the works I think. I think the one with 65% protection only requires a single shot too.
So it might be good to keep an eye out for them if you are not priority enough to have access to vaccination in the comming months anyhow. It would require better social distancing because it protects less (and that is even in the general population) untill this pandemic largely has been eradicated.
I’m going to try to get doctors on the record about this. For me, I think I’m going to cross my fingers and take it. I don’t have a record of bad responses to vaccinations. The problem is that except for some I took for college decades ago I haven’t had any. The fact that the Pfizer vaccine appears to help prevent severe illness is a big plus for me, though.
Mrna has never been used, so that equals a big unknown for short or long term side effects.
The speed to market obviously means less safety data.
Astra Zeneca uses older technology. They made a mistake in clinical trial dosing. This resulted in realizing that 1 dose had 90+ immunity, and 2 doses was much less successful.
In other words, a screw up showed that double dosing was less effective.
Who knows if the Pfizer dose is correct?
Rushing any product to market is difficult and risky….
https://www.euronews.com/2020/11/26/astrazeneca-reveals-dosing-mistake-in-coronavirus-vaccine-trials
https://www.theguardian.com/science/2020/dec/13/autoantibodies-may-be-driving-severe-covid-cases-study-shows
This made wonder if those prone to autoimmune diseases should take the vaccine. It has already triggered extreme reactions in those needing epi pens….
I didn’t want to agree to cookies on the link Jessica posted from the euro paper. Found it elsewhere.
https://www.nytimes.com/2020/11/25/business/coronavirus-vaccine-astrazeneca-oxford.html
Hey Javen, If you don’t mind anecdotal evidence, me (!) I have both CFS and FM and I didn’t have any problem with the vaccine that I received in late April. I did have the typical 2-3 days of feeling poorly after the second shot but after everything I’ve dealt with having CFS/FMS it was no big deal at all.
Also, I don’t know about you but ever since I contracted CFS/FMS I never come down with colds or the flu anymore but the vaccine side effects felt a lot like a mild flu to me but it didn’t last as long as that typically would.
Just had another thought about Nucynta; it is metabolized outside the usual CYP450s of other opioids. Usually the other opioids use the 3A4 and 2D6 enzymatic pathways where as Nucynta does not inhibit or induce any P450s. That could be another reason (genetics) why it might work for some and not for others just as genetics could affect who gets SFN.
@JAVEN,
I have the same question and even though you are asking Cort, for myself, and for most of us, it will be long enough to wait until we have an opportunity to get a vaccine. The longer the wait, the more information will come out. Currently it is not advised for people with significant allergic reactions and today I read that people with solid cancer tumors should probably wait too. Something about the lipid envelope surrounding the vaccine molecule being ‘sucked’ up by cancer cells so the potency might be reduced–but more research is needed.
I’m most worried about it triggering a worse fatigue reaction than I already have. I also read the Pfizer report and unfortunately it doesn’t mention anything like ME/CFS in the side effect list. I can post the entire report if anybody is interested.
Patience…
I do have SFN and FMS, POTS and EDS and ME. A combination of a very small amount of Tramadol and Bentyl and rotating on and off had been my best thing for all of them. I’m no longer on them regularly. Just when having a very bad flare.
Other things I’m doing seem to be almost as affective with less side effects and better long term results, I think. Getting MCAS better (and not taking antihistamines to do this) has been a big help.
I have EDS and when we aggressively treated my MCAS that flu like feeling better and pain better and after one of the other studies sorry I cannot remember ive gone back to a daily sudafed.
@kathy, Sudafed is more decongestant and not antihistamine. Some people feel it helps POTS symptoms for when we need to be sharp and on. Have you looked into POTS with your EDS, because if you feel you have MCAS, it is what we call the trilogy. All 3 go together.
I wonder with those who tried Tramadol, how low a dose did you try?
I take between 1/4 to a 1/2 pill and at very most 1 pill of the lowest dose there is. I also rotate on and off it. It stops working. Most people up their dose and people start making it higher and higher with rebound possible complications. Not to mention addiction issues. The idea is to “tweak” channels to get them to work in the desired response. Not to directly supply what is missing and stop the body from producing or modulating what it needs to do. (I don’t take enough to get me all the way out of pain, just to take the edge off.)
Tramadol works on ALLLLLL the neurotransmitters. It used to be used off label for those who were “resistant” to SSRI or SNRI or that didn’t work. But Tramadol also works on NMDA or glutamate channels. It also has very mild calcium channel blocking properties.
For those of us with MCAS and need of pain medicines, Tramadol is one of the least offensive for potential mast cell over response. Possibly because of its mild calcium channel blocking abilities. GastroCrom does this too. (GastroCrom is a mast cell stabilizer and given to those of us with severe MCAS. It is the one thing I keep handy. Almost more so than my epipen. But I’m no longer on antihistamines. There is a thread on Healthrising explaining that one and why I no longer take them. Also what I do instead to reset my receptors.)
Dejurgen is wanting me to talk about calcium channels as it ties closely into our hypothesis and realization of the connection with glutamate. I’ll try to come back and add that later. Or I’ll see if he will be my voice. As he is mostly “our” voice. We research together, but he is our spokesman. He tells things more technical and I’m more of the Summary type.
Issie has some succes with minute quantities of Tramadol and Gastorcom when she feels certain specific things happen in her body. That makes sense in the light of the lengthy “spinal cord escalator” theory below.
Calcium channels are part of the “signal transferring pathway” along the spine. Influence those and you influence the whole glutamate signaling mechanism including how easily (nerve and other) neurons fire. That can help “calm and tame” the system.
It’s just not that easy as taking them and taking plenty of them. Those drugs do not only affect the calcium channels of nerve neurons. They also affect blood flow throughout the body and opiod receptors and… many more things.
So while taking some of those drugs could improve calcium channel behavior (that has a clear inlfuence in the whole process of glutamate excitotoxicity), it also will for example influence blood flow to these very same neurons. If that messes up the production of optimal quantities of ATP it could partly ruin the defensive mechanisms to clean up excess intercelluar glutamate for example. This is but one of many many things that the drug could make worse.
So, it’s about a difficult balance and trying to find the optimum “setting” for each and every individual and as good as possible adapted to the needs at any moments of patients. One moment we will need tweaking in this direction, another moment in the opposite direction.
As Issie and I learned, even tiny amounts of drugs or even considered mild and safe supplements can provoke surprisingly big reactions with us. That seems to point that the body does already a fairly good job at optimising our body workings *within the limited wiggling room our health provides*.
So for such strategies to have success it needs to be tailored to individual (epi-)genetic weaknesses our bodies have to work around. And it will require good protocols once developped by science or very keen senses for now. When it comes to keen *and* precise senses, those of Issie are hard to match. I can’t tune things so finely as she does even if I consider my senses reasonably keen and I have some help of fairly elaborate insights. So your mileage may vary from Issies.
For now: consider starting many drugs and supplements on quite lower then typical doses. Where appropriate: alsways consult your doctor first.
Vert interesting read Cort. Thank you! I have severe FM and after a lot of trial and error, we finally found that nucynta with butrans helps relieve some pain to a more tolerable level. The pain just keeps getting worse over time. Hopefully they find a cure or better treatment for this most awful disease. Thank you again for your excellent work and keeping us apprised of all the up and coming news.
Cort,
I trust it’s brain fog on my part, but could you explain the relevance of this statement?
“For some reason, these researchers took it upon themselves to also assess whether or not the 34 FM patients in this placebo-controlled trial had reduced numbers of small nerve fibers in the corneas of their eyes. It was a good thing they did.”
Also, are there any indicators as to whether someone is, or is not, dealing with SFN? Years ago I developed painful peeling (and bleeding) skin on the soles of my feet, which the pharmacist said was peripheral neuropathy, but my doctor never seems to acknowledge (it got buried amongst several other new symptoms which cropped up at the same time). Could this be related, or something else entirely?
Also, pretty much any new med has a good likelihood of sending my pain through the roof. Trying to find a new BP med has been sending me crashing. Have any of these researchers looked into how well other medications impact (or don’t) pain in patients with SFN?
I am having trouble getting sfn diagnosis also—-
You can add a few more conditions with damaged nerves.
I’ve been tracking B6 status for about a year now in different communities.
It was prompted by discovering that even though I have findings pointing to B6 deficiency, in blood tests it is high.
The B6 vitaminer measured in blood tests in pyridoxal 5’ phosphate (PLP or P5P for short)
In the hEDS, ME/CFS and fibromyalgia communities, and in forums where there are individuals ill of health and not able to get the attention/care of doctors and the medical establishment – many fit the symptoms of the above clinical diagnoses – one can observe the following trends:
In the absence of supplementation:
* high PLP
* high PLP / low ALP
* unknown PLP level / low ALP
We don’t know how often this happens since B6 is not regularly tested for.
With supplementation:
* A marked sensitivity usually resulting in disturbed sleep and neurological symptoms.
* B6 ‘toxicity’ from sustained supplementation at small/normal/large doses of either Pyridoxine Hcl or P5P, resulting in small fiber neuropathy.
– – – – – – – – – – – – – – – – –
Tissue non-specific alkaline phosphatase (a form of ALP) is an enzyme with a number of functions – one among them is to convert pyrodoxal 5’-phosphate and pyridoxamine 5’phosphate to B6 forms that are able to cross the cell membrane and the blood brain barrier. Inside the cell/brain, they are again changed back to PLP by different enzyme and steps. There it can go about carrying its function as a co-factor in over 200 enzymatic reactions.
Hypophosphatasia is a genetic condition affecting tnsALP. The biomarkers for diagnosis are consistently low ALP, high PLP, and high phosphoethanolamine when testing is available for it. Some have normal PLP. An ‘ultra-rare form’ affecting a different gene, PHOSPHO1, presents with high B6 and normal ALP. Levels can fluctuate. There are childhood and adult onset forms and vary in severity and presentation. In the medical literature it is mostly known as affecting bones and teeth, sometimes kidneys, lungs and the brain. Spend some time with individuals affected by it, and you will learn they also experience osteoarthropathy, chronic pain, fatigue, muscle pain and digestive distress. Neuropathy/small fiber neuropathy/Reynaud’s usually correlate to episodes of high PLP.
There is only one metabolic study from the cerebrospinal fluid of a mouse model of the disease. It would be interesting to see if there are overlapping findings with the metabolic studies in ME/CFS. ALP also participates in B1 metabolism (I haven’t studied this yet), which potentially could be affecting the PDH complex and the citric acid cycle (and nerves!)
Some with hEDS/ME/CFS/FMS are at a later point correctly diagnosed with HPP. It gets a bit confusing because there are overlapping symptoms.
“Nineteen patients met our inclusion criteria (n = 2 infantile, n = 6 childhood, n = 10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n = 7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia.”
https://pubmed.ncbi.nlm.nih.gov/30655187/
“Up to 19% of FM patients in our population were found to have consistently low levels of ALP and high suspicion for undiagnosed underlying HPP. None of the patients had Vitamin B6 level checked or genetic testing done which suggests the diagnosis was not suspected despite the similarity of clinical symptoms and low ALP levels. It is increasingly important to diagnose these patients with HPP given treatment availability and to avoid bisphosphonate use to prevent worsening bone fragility. Furthermore, our data supports screening for this condition as a part of the initial workup of FM.”
https://acrabstracts.org/abstract/hypophosphatasia-may-be-misdiagnosed-as-fibromyalgia-a-single-center-experience/
– – – – – – – – – – – – – – – –
I do know of a few with low ALP/high B6 combo that have ruled HPP out with genetic testing.
What could be causing it then?
* There are common variants in the ALPL gene affecting PLP that are being studied:
“The Alkaline Phosphatase (ALPL) Locus Is Associated with B6 Vitaminer Levels in CSF and Plasma”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357176/#B19-genes-10-00008
and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478949/
* ALP may be low for other reasons – zinc/magnesium deficiencies for example. I’m not sure that there are studies that show what is happening to B6 in those cases.
* Something in the dysfunction of ME/CFS is causing disruptions in B6 metabolism; it may or may not involve ALP.
– – – – – – – – – – – – –
There are two things happening: there is the high levels of free PLP circulating in the blood stream, and then there is the low availability of PLP intracellularly. Either one or both of them are contributing to the sensory neuropathy phenomena. The mechanisms involved, wether direct or indirect – we would need research to answer this.
– – – – – – – – – – – – –
What it means for now for those with ME/CFS FMS hEDS:
* You can ask your doctor for B6/PLP blood test. (urine B6 tests a different B6 vitaminer).
* Test ALP at the same time.
* Take a look at your ALP history – it’s a routine test included in the basic liver panel so you probably have had it checked numerous times. What is considered low for HPP is different from the lab ranges – it is age and sex dependent. You can check towards the bottom of the page here https://hypophosphatasia.com/hcp/accurately-diagnose/low-alp-can-differentiate-hpp
* Exercise caution around supplementation. Check all your supplements, sometimes its included with other nutrients and definitely in B-complexes and multivitamin formulas.
* You can read up on the symptoms of HPP at hypophosphatasia.com or softbones.org There’s a post on the forums about it with links.
The kicker is that some do have B6 deficiencies and no funny business in their B6 metabolism ! Testing could let you know too.
– – – – – – – – – – – – – – –
I know of another disorder where B6 is sometimes affected. I have an idea that links it to ALP via a different mechanism, and it may relate to those that don’t have HPP. I would need to collect data from individuals with that disorder and see if there is a correlation that could corroborate this idea.
P.S> The 19% of patients with low ALP is out of a study of 305 patients… that’s no small peanuts. I am a strong proponent of this being in the panel of diseases and conditions investigated before someone gets slapped with a clinical diagnosis of FMS… We need another study further looking into how many of those do go on to confirm an HPP diagnosis.
I heard of someone in England, at the ME/CFS clinic her doctor noticed the low ALP and sent her off to the HPP specialist, where she was diagnosed. He commented she was the fifth patient he had referred.
There is a similar account of a genetics clinic in the States that checks their hEDS patients for ALP routinely.
This is anecdotal. We take note.
@Meirav, we have talked at length about B6 and possible connections. I have since learned I have neither low ALP, but high and my B6 is in mid normal range. So this may apply to some, but not all of us with EDS and ME or FMS.
I do feel there is a connection possibly with B6, but don’t feel that Hypophosphatasia is “my” connection. Quite the opposite for me. Not to say that it isn’t for all, as it could play a part in some subset types.
Maybe your ideas can detect new subgroups in this disease and better ways to detect and treat them. As with all of our hypothesis, further research is needed to confirm or deny them.
Issie, that’s crummy about your high ALP. There is a test that measures the activity of each ALP isoenzyme – it could perhaps give you better insight as to which organ is involved. Perhaps you and your doctor are already looking into it.
As one can see in your case, your plasma B6 levels are normal (I’m assuming the vitamin that was tested was PLP), your ALP is high, you do not have Hypophosphatasia – yet as you had shared, you have unfavorable symptoms with B6 supplementation. Whether it is due to its direct or indirect action – that is as of yet unknown.
A couple of things to clarify:
The issues with B6 metabolism are findings – real data from individuals
Across different communities – hEDS, ME/CFS, FMS and in unidentified illnesses neglected by the medical community. It’s been observed in the lowering oxalates group for a few years already.
For a few, it will be connected to Hypophosphatasia (HPP) and it will turn out that they had been misdiagnosed all along. Interestingly, a significant number of individuals within the low oxalates group has polymorphisms in the ALP gene, and some discovered they have HPP. The thing is this is so easy to check too: people most likely have test results sitting in their medical files as it is part of the standard liver panel. Doctors usually disregard low levels and labs set their ranges differently as well, so it may have been missed.
Low ALP levels can be due to other reasons – properly investigated, one can arrive at its cause.
There may be different etiologies to what is making B6 go wonk. It may be that these conditions may share mitochondria dysfunction at their core. That – is for the researchers to figure out and shine light into our world.
What can one do in the meantime?
* Check B6 (PLP) and ALP levels with a blood test
* Go over ALP history from past blood tests.
* If B6 and ALP are normal, keep a keen eye when supplementing B6 (either Pyrodoxine or P5P). Some do need and do benefit from supplementing.
* Raise awareness
I hope the research can also discover better biomarkers for identifying who has issues with B6 metabolism.
The heartache that I feel with each new week as I learn of
yet another
individual that supplemented B6 and ended up with small fiber neuropathy.
‘B6 Toxicity’ they call it,
there are support groups for this phenomena
In good health –
“While we don’t know what’s causing the SFN in FM, ME/CFS, post-treatment Lyme disease and post-COVID 19 syndrome”
Issie and I may have made headway recently. Key to that are Issie’s long running keen experiences and observations with and developped ideas about excess glutamate trouble, Cort’s 2019 blog https://www.healthrising.org/blog/2019/08/12/brain-small-fiber-neuropathy-fibromyalgia-chronic-fatigue/ and my ability to link things in surprising ways.
Key in the research paper is:
“Harte and Watson’s novel idea proposed a very strong brain/body connection existed indeed. They proposed that hyperactivity in the insula is producing such strong pain sensations that the body was effectively burning out the nerves in the periphery in an attempt to stop them.
Increasing the glutamate levels in the insulas of rats resulted in increased sensitivity to heat and pressure and – a reduction in the nerve fiber density in the rodents’ hind paws.”
The hypothesis they started with sounded near insane the first time I heard it. Even worse to me, injecting glutamate excess in the brain resulted in small fiber nerves in the pawns to be burned out? It almost sounded like blasphemy to me. It couldn’t be right yet the research they did sounded well done. This couldn’t be possible could it???
Then it recently came in a moment of inspiration: the combo poor ATP production, extracellular glutamate excess, oxygen supply problems and ROS problems had to travel up and down the spinal cord!!!
It was a moment of baffling weirdness. The spinal cord might have been hidding for all that time in plain sight! And it would connect so many weird things related to ME like how EDS, IBS, spinal instability or brain stem compression were involved in this!
So below a small summary of those ideas. Warning: they WILL be VERY TECHNICAL!
Let’s talk about the concept of “glutamate excitotoxicity” first. It is key and central in this hypothesis.
When neurons, that is brain and nerve cells, communicate with each other they don’t use actual electircal currents on copper wires like computer chips do.
Neurons expell chemical messengers outside their cells nearby the neuron they want “to pass a message too”. When that messenger molecule builds up enough in numbers, some of it attaches to a receptor and that receptor is like a big red button being pushed for the neuron receiving the message to do some action.
That action consumes quite a bit of energy and oxygen. If that action is “message the next neuron in line” then the currently working neuron will expell on its turn the same type of messenger molecule nearby the next neuron to be contacted.
It would be easier to explain with plenty of pictures, but let me try in words. Transporting a signal allong a long nerve is a bit simmilar to transporting a single bucket of water along a line of rudimentair human fire fighters. It’s a bit an overly big simplification, but it gives the idea.
The humans stand in fixed positions, just like the neurons do along a nerve. The bucket of water is replaced by a chemical messenger molecule, glutamate in this case.
The oversimplification is this: in the human fire fighter chain the same bucket is passed from the start till the end of the chain. In human nerves each chemical messenger molecule makes only a trip from one neuron to the next neuron and is then taken up by the neuron. When the last activated neuron passes the message itself it releases new messenger molecules from it’s own storage. So the same messenger molecules doesn’t travel from start till end of the chain.
So let me refine this “human message chain” in a somewhat gross way:
A group of kids developped a game. A few dozen of kids stand blindfolded in a line. They’ll try and communicate along the line without speaking. When the kid at the starting point of the line wants the kid at the end point of the line to shout, he’ll spit on the face of the kid next to him. That kid then will turn his face to the kid next to him and produce and use his own spit to spit in the face of that kid. Then that kid will turn his head towards the next kid… till the last kid is spit in the face and knows that as the agreed upon signal to shout.
Now both in the brain and the spine much of the “kids example” is done by neurons receiving a load of signaling molecules, see the reception of these signal molecules as a sign to take action and then produce their own signal molecules “to dump in the face of the next neuron”.
In many cases, the used signal molecule is glutamate.
Now let us refine the problem of “glutamate excitotoxicity”.
When neurons fire, they release glutamate from their own storage *in between* themselves and the next neuron. That glutamte thus comes from the internal storage inside the first neuron and is dumped *in between* the two adjacent neurons. The first neuron dumps it near the place where plenty of glutamate receptors of the next neuron are located.
The first neuron dumps the released glutamate in a broad but narrow gap in order to have most of the dumped glutamate being very near to the receptors of the neuron and in order for the next neuron to be able to clean up the glutamate that is dumped in that place. See https://en.wikipedia.org/wiki/File:SynapseSchematic_en.svg
The shape is broad yet narrow so that most glutamate will remain in that narrow gap. That makes it easier to get signals well transmitted to the next neuron and to clean the glutamate in that space up each time after a signal has been transmitted.
That last action is important as, after the initial activation of the next neuron by glutamate binding to one of its receptors, only that glutamate is removed from that void in between the two neurons. There is enough glutamate in that void left to trigger another (or the same) receptor later and hence duplicate or triplicate the message. That is undesired as it’s like speaking with echos in your voice. That is also undesired as it would cost double or tripple the amount of energy to get things done? Why? Each activation of a neuron receptor by glutamate sets a chain of events in action that cost quite a bit of energy (ATP).
Despite the shape to the gap between two neurons being made specifically to be able to use less glutamate for the signalling and having less glutamate leak out of that narrow gap, there always will be some of it leaking out of it (all around the open space between individual neurons).
The neurons will have to work (use ATP) in order to clean up that excess “intercellular glutamate”.
Why? If it would pile up then glutamate concentrations everywhere in the space between neurons would increase. Thus glutamate concentration in that narrow gap (and thus close to glutamate receptors!) would start to increase. Chances that some of that undesired “leaked” glutamate would reach and bind to the glutamate receptor of the next neuron increase. That next neuron then would see no difference from a “real” glutamate signaling from the previous neuron and start to work and use ATP to pass the faulty “message” to the next neuron.
In this way faulty “extra” signals arise in the nerves, possibly creating faulty pain signals or jerky movements in the limbs (depending on the type of nerve activated). Such increased “average, background” signaling form brain to muscles for example also could signal enough parts of the muscle to create an “increased chronic contraction of the muscles”. That is very common in ME and FM. We “can’t relax” (our muscles) as psychologists and physical therapist say.
In the brain, this could easily produce extra neuronal activity with less precision (as information is “poluted” by wrong extra signals and impulses. That aligns closely with both our brains “lighting up like a Christmass three” and all over the place with every sensory stimulation, sensory overload and brain fog (as information processing is rather imprecise).
Unfortunately, it gets worse, a lot worse. We haven’t reached the part of true glutamate excitotoxicity yet.
Each activation of neurons by glutamate does cost energy or ATP. It also decreases the “voltage potential of neurons” as the whole chain of events does us electrical charged ions (like calcium and potassium ions) somewhere inside the cell.
From https://en.wikipedia.org/wiki/Excitotoxicity
“it has been noted that extrasynaptic NMDA receptor activation, triggered by both glutamate exposure or hypoxic/ischemic conditions, activate a CREB (cAMP response element binding) protein shut-off, which in turn caused loss of mitochondrial membrane potential and apoptosis.”
Apoptosis is “the ulitmate in inflammation”: self destruction of the entire cell. So if it is self destruction of very hard to replace neurons that is a very bad thing.
When the problem gets bad, it easily becomes a runaway problem: a few too many “excessive or faulty” neuronal activations by too much glutamate does consume quite a bit of energy and with it ATP and oxygen.
Cleaning up some of that bad excess intercellular glutamate is done by active glutamate transporters. Those “pump” excess glutamate away form the space in between neurons into the neuronal cells storage for later use. That active pumping however does cost ATP. If oxygen or blood or glucose supply is low AND the neurons are already consuming excessive amounts of ATP due to too much faulty neuronal triggering, then there is a risk that the neuron’s glutamate transporters will no longer have enough energy (ATP) to clean up all that excess intercellular glutamate.
That would further increase the problem as less “cleaning up” of intercellular glutamate means even more glutamate piling up everywhere in between the cells, increasing chances for even more “false neuron activation” and that costing even more energy and leaving even less energy to clean up the excess intercellular glutamate.
Unfortunately it gets even worse. When neuronal ATP (production versus consumption) is *really* short, those glutamate transporters start to *reverse* meaning that they now actively start transporting glutamate from inside the cells and dump it everywhere in between the cells, leading to so much neuronal glutamate receptor activation that the neurons literally work themselves to death and self destruct. That is “neuronal excitotoxicity”. That mess then needs to be cleaned up by the immune system, removing the now death neuronal cell..
With that mess, a very strong burst in oxidative stress happens. That oxidative stress also can impair ATP production long before the neurons go into selve destructive mode.
In short: When enough neurons in the brain or along a nerve are somehow “overactivated”, they can become more and more “surrounded” by a pool of glutamate and oxidative stress that will increase the need for good blood flow in two ways: cleaning it up will cost plenty of energy/ATP/oxygen and a good blood flow can help remove (spread towards less affected parts of the body) some of the dangerous waste like excess intercellular glutamate, oxidative stress and lactate (as when energy needs to clean the mess up grow rapidely, the neurons *WILL* need (a lot of) anaerobic energy production in order to survive. As excessive ROS is one thing that can cripple mitochondrial ATP production, (massive) anaerobic energy production
will become even more important for neuronal survival.
So, for the brain when exerting too long, parts of the brain can see an increase of that vastly toxic mess surrounding them. Those chemicals will spread and difuse to the surrounding parts of the affected brain areas when not pacing drastic enough for long enough time.
For the nerves, they sort of are located in a tube. That sort of *might* help reduce the leak of this toxic mess a bit. But when one neuron is “overactivated”, it will release plenty of extra glutamate siignaling and nearby ROS with a big chance of “overactivating” the next nerve neuron, that in turn will be “overexcited” and have a big chance overactivating the next neuron…
=> That basicaly is the concept of “the combo of intercelluar glutamate and high ROS” traveling up and down the spinal cord.
=> This concept of “the combo of intercelluar glutamate and high ROS” traveling up and down the spinal cord comes with a few needed additional components to IMO help understand the role of it in ME/FM/IBS/POTS/…
A) Increased inflammation of the brain somehow needs to be able to trigger that to “entice” the first neurons of the nerve to become overloaded with this toxic “excess glutamate and ROS” combo so that this combo then can travel downwards along the spine towards the “limb and organ end points”.
As both the brain consists largely of neurons and so do the nerves, well this connection seems quite likely to be there if inflammation in the brain is too high. There will be extra / excess inflammation / intercellular glutamate / ROS in the brain including near the starting point of the nerves.
Note: this (departure and arival of large nerve bundles ) will be in the brain stem, so an inflamed brain stem will be a “good” trigger of this hypothetical “inflammatory glutamate / ROS signaling” traveling along the spine.
B) At the end point, an inflamed / overstimulated nerve as in this hypothesis needs to be able “to do bad things”.
With us explaining how it could cause chronic muscle contraction, that will have some cost and damage to the body. Now think about blood flow too. Blood vessels contract and dilate by nerve signals comming from the brain giving them orders. Orders to contract. If those nerves get overactivated: chronic too strong contraction of the blood vessels and chronically impaired (reduced) blood flow creating poor blood flow, poor toxic waste removal, extra oxidative stress…
When I presented Issie with this hypothesis, she did found and understood the importance of this key paper to further explain the true potential of this hypothesis: https://journals.sagepub.com/doi/full/10.1177/1744806920914204 with title ”
Peripheral glutamate receptor and transient receptor potential channel mechanisms of craniofacial muscle pain” from Man-Kyo Chung and Jin Y Ro.
Figure 1 of that paper is rather interesting: nerve ends can be triggered to release glutamate from themselves and dump it into the surrounding tissue. (organs on one end, brain on the other).
“Figure 1. Model of glutamate receptor-TRP channel mechanisms in craniofacial muscle hyperalgesia.
Two TRPV1-expressing afferent terminals within masseter muscle are diagrammed. TRP channels contribute to both glutamate release from masseter afferents and their sensitization.”
=> Pain sensing nerves in the limbs could hence be affected by brain inflammation “travelling” down the nerve “by riding a combined glutamate / ROS” toxicity wave. That could trigger the nerve end points in the limbs to release massive amounts of glutamate. That in turn would trigger the local pain sensing nerves to fire plenty and plenty of (pain) signals towards the brain. That sounds afwully close to neuropathic pain and FM pain.
=> That massive firing of the local pain sensing nerves could do just the same as what glutamate excitotoxicity does in the brain: kill neurons. Worse, in the periphery (like the skin) blood flow is quite a bit reduced in ME/FM/… patients as blood volumes are reduced, heart pumping volumes are recuded and increased nor-adrenaline levels redirect blood away from the “less urgent tissues” like the skin to the “more urgent tissues” like the brain and liver.
Well, that would reduce the supply of enough blood, glucose, oxygen… from the skin including the nerves in the skin. So hence the skin nerves would not only be overstimulated, but they would have poorer access to the vast resources needed to build plenty and plenty of ATP quickly in order to stave of the deadly (to the nerve endings) effects of the glutamate excitotoxicity.
=> Result: (vast) neuronal overactivating at the limbs nerve ends and too few ability to produce copious amounts of ATP to protect these neurons from it = almost inavoidable neuronal death of those nerve endings? So glutamate injected in the brain could *indeed* burn away periphal nerves?
On top of that, this hypothesis involves an “excessive glutamate AND ROS combo”. ROS (and the hydrogen peroxide component of it in particular) atracts and activates immune cells. In this hypothesis that would be near the nerve endings, further increasing the pressure on them.
=> Did we found a key component of how “inflammation can travel up and down the “spinal cord escalator””?????????? I think we might actualy!!!
For the upgoing part, we need C.
C) Inflammation caused by either overexerted “periphal cells” like overused muscle cells or an active infection or an (over)active immune system will create plenty of ROS and inhibit (the energy production of) the local mithochondria of the nerve endings (at the end point / limbs and organs side).
That extra ROS is one part of the “glutamate ROS” combo supposedly traveling up and down the “spinal escalator”.
The inhibition of mitochondria due to the extra ROS (and things like highly toxic HOCl produced by the immune system) cripples the nerves ATP production, making it harder to defend against possible intercellular glutamate leak. So even without extra pain nerve triggering by swollen tissue, glutamate signalling may go up as the nerves have less energy to recycle and clean up glutamate surrounding them. That, with a bit of bad luck, can be enough to complete the “glutamate / ROS” combo travelling up the spinal cord. When blood flow was already poor, things get even a lot harder to stave off.
=> We also have a clear path to the combo “glutamate / ROS” to signal a wave of inflammation from the limbs and organs along the spinal cord towards the brain.
In this hypothesis, an inflamed brain and more so brain stem could travel down the spinal cord and provoke both nerve activation, inflammation near this nerve ending AND increased immune activation near those nerve end points.
Revered, both chronic inflamation near the organs or limbs and strong or chronic infection near the organs or limbs could send up an inflammatory wave towards the brain(stem).
=> So inflamation and imune activation of the body could increase brain inflamation by this mechanism AND brain inflamation could increase body inflamation and imune activation.
=> On top of that, this mechanism would disturb near all signalling between brain and organs disrupting homeostasis and creating poor stearing of the heart, liver, lungs, adrenals, kidneys, muscle… basically EVERYTHING. For starters it would have a high chance to put chronic strain on skeletal muscles and chronically overcontract near all blood vessels vastly disrupting blood flow.
=> All of that is IMO more then enough to leave a “prone” person crippled for life.
With “prone” I mean that people with certain hidden genetic weaknesses have less chance to recover then those who haven’t such.
That could be people with crippled glutamate transporters, crippled amino acid regulation (for example a crippled CBS gene or urea cycle problems), people with mitochondria problems, prople with glycogen sotrage diseases, people with mucus genetic defects…
This hypothesis would help explain plenty of new observations, like:
* Increased brain stem compression possibly triggering this array of linked diseases.
* Neck problems, due to things like whiplash, EDS, infection or immune system damaging shackles… increasing risks of triggering this array of linked diseases. Both compression and nearby inflammation / infection / imune activation near the spinal cord increases chances for this system to be caught of balance.
* Nerves being burned out by the brain or injecting glutamate into the brain.
* Signalling between the gut and the brain. Remember that decreased blood volumes and blood flow seen with us plus increased “fight or flight” hormone noadrenaline redirecting blood away from the “less urgent” digestive tract” towards brain and liver would leave the *very high number* of gut nerves very prone to this “inflamatory glutamate / ROS spinal escalator”. Brain inflammation would upset the gut nerves AND imube system and upsetting the weakened gut nerves the least would trigger a lot of brain inflamation and upset.
* Chronic contraction of muscle and blood vessel muscles.
* The very strong inhibition of all parts of our bodies when we exert a bit too much, have some sensory overload, a small infection…
Forgot:
This idea may also help explain why SO many pain drugs also exhibit anti-inflamatory properties and vice versa.
Now I’ll really try and get some much needed rest ;-).
This hypothesis also potentially cross links with several auto imune disease. Increase chanches for auto imune diseases are common with us.
In hte “inflamatroy spinal cord escalator” idea, those would correspond with “additional epi-genetic weaknesses” along this entire line.
* Weak myelin protecting the spinal cord tubes? Chances of trouble to leak outside the enclosed channel and the immune system “joining the party” further breaking down the protective myelin “insulation” of the nerves.
=> nerve (insulation) itself weak point
* Weak motor neurons? Motor neuron degradation like in Parkinson Disease. It’s IMO more difficult to route around damaged motor neurons (that are at the brain end of nerves controling the muscles) then to route around “general neurons somewhere mid brain”.
=> starting point of nerves in the brain weak point
* Weak thymus? Myestina Gravis
* Weak blood vessles? Blood vessel auto immunity
* Weak pancreas? Diabetis
* Weak gut? Crohn’s Disease
*…
=> weaknesses in individual organs or parts of it / at the organ endpoint due to increased inflammation and imune activation at those points.
=> I wouldn’t be surprised if many auto immunity disease show significant small nerve fibre damage in a high subgroup of cases. Maybe there is already some data on that?
Now trying to rest again. My brain is struck by glutamate over excitation ;-). Hard to calm down now.
It would also help to explain why, during too intense social interaction, one of the first warning signals of me way overdoing it is pain flaring up massively and so quickly all over my body. That is, if slurred speach or confusion isn’t the first warning signal; those often come however only later.
Too intense brain usage cause increased brain inflamation. When that builds up and reaches the brain nerve starting points, chances increase that it will travel down rapidly increasing numbers of nerves. When inflammation travels down pain sensing nerves, the organ end points get agitated and inflamed. That releases plenty of pain and invites the imune system “to join the party”. The excess glutamate alone should create massive pain flaring up all around these nerves.
The next big event when that is happening is me being near unable to move my legs. I improved walking capacity a lot since being at worst, up to being able to walk near a kilometer on a good day. But when that thing happens at social gatherings I very rapidely start to have to crawl over the floor, losing strength to walk straight or at all. It also happens when I do other “to intense mental activity”. Like once when I tried to peel three apples trying to help my mom preparing a dish. The combo muscle work and eye hand coordination “killed me” before finishing apple three. I literally had to crawl on the ground and find support by the walls to get slowly to the nearest bed.
That would be an example oif the brain shutting down as much activity as possible in order to try and protect the spinal cord and motor neurons attachted to it.
The idea would also help to explain why we are often able to “push through” a lot when we need to or when we are in different circumstances increasing our energy production (like a very uplifting emotional setting):
Our brain cells and other body cells IMO still have plenty of capacity to do work left. It is our brains and chemistry inhibiting our energy production and use so much in order to protect key vulnerable parts of our body: the spinal cord and nervous system.
A temporary change in chemical balance could override part of that safety system, at the increased risk to burn an additional nerve or two or more. That could be a dopamine or oxytocin or nor-adrenaline or even alcohol induced change in balance. Or it could be some (by the body) unexpected helpfull supplement or drug. Helpful to increase energy production, till our brains realise that that will put our spinal cord and nerves even in more danger.
That temporarily could increase energy production a lot, at the risk of further agitating and puting pressure on the key nerve system.
That said, some hormones do help in fighting part of the underlying troubles too like helping in fighting oxidative stress or modifying the NMDA receptors. Creating a *long term* beneficial shift into that homeostasis ourselves isn’t easy at all. It’s FAAAAAAAR more difficult then the “just be happy”, “just worry less”, “see you can do more, just push yourself a bit more” nonsense they tell us.
When Issie read this comment she was concerned that people may read it as me having an alcohol problem or so. That is not the case. What I meant is the folowing:
“Yes, drinking a few ocasional glasses of alcoholic drinks like wine at new years eve gives me a temporary boost in energy. It produces plenty of NADH (a high energy molecule) quickly and likely overrides some “brain safety protocols” trying to protect our body from permanent damage.
Drinking alcohol protected very few people from permanent damage be it brain damage or crashing drunk so why would it be good at inhibiting ourselves in order to protect our spinal nerves?
So while many ME/… patients get MCAS straight after drinking a glass of wine, I more then once got a noticable boost in energy first and payed for it later.
This one needs more explanation:
“The very strong inhibition of all parts of our bodies when we exert a bit too much, have some sensory overload, a small infection…”
For years it has intrigued me that we need very sensitive measurments to see a low grade chronic inflammation in ME/… patients brains as seen by this Japanese research and others later. Yet, even such low amounts of chronic inflamation hit us very hard.
Bit by bit, it became clear that the brain needs to protect itself quite a bit better against too strong inflammation because:
* the brain is far more prone to this runaway glutamate / ROS excitotoxic combo then many other parts of the brain.
* brain cells are much much harder to repaire then most other cells. So each individual loss of cells is much more dramatic with brain cells then for example skin cells as those later can repair fairly well.
That may be the key to where the actual inhibition of our body / energy / abilities resides:
=> The spinal cord!!!! The one “hiding in plain sight”.
Why? The brain seems to work a lot harder in order to try and keep inflamation in the brain in check then it seems to work to try and keep inflamation in check in the skin or leg muscles. Why? Ability to repair and fix the death or broken cells.
Why does this point to the spinal cord as possible key in our disease? Well, the brain at least has some “fair” repair capacity. Every time we enjoy too much alcohol, millions of our brain cells die. Like in being permanently death afterwards. That is bad when doing that for years and even once in a while. But as long as it is only once in a while other parts of the brain can take over and learn the skills that are broken by these death brain neurons.
Brains have some limited capacity to regrow death neurons, opposed from what was believed earlier. But the true strength of the brain is its ability to shift tasks to other healthy neurons if some die. Each neuron has plenty of connections to other neurons and it can grow new connections to other neurons as needed.
So, when a minor hit strikes the brain other cells can take over without us even noticing it. When a strong hit like a minutes lasting block of blood vessels to a particular part of the brain hits us, we lose abilities and in some cases can relearn them by hard revalidation training shifting the needed function to an entirely new area of the brain.
Now think about nerves, think about the human fire fighting squad. If people are unable to move from their current position and one or two people in that row are missing, the entire fire fighting line is utterly broken. EVERY single element of that line has to be functional and up and running. Miss one and havoc appears!
So where the brain can “tollerate” some low loss of neurons, a similar percentage of loss in spinal nerve neurons is catastrophical. The nerves need every element in the line to be working and have no option to sent the signal along a neighboring lines (as the brain does have). The nerve’s neurons can’t shift work to other nerve neurons. There is some very limited repair capacity but that mechanism is way less powerfull compared to what the brain can do with being able to do some limited repair PLUS shifting the workload to nearby cells.
=> The brain IMO must be VERY VERY strict on controling loss of (key) spinal cord nerves. Far smaller percentages of losses of neuronal cells create havoc in the spinal cord compared to the brain.
=> The brain IMO needs to be much more strict in controling neuronal inflamation in the spinal cord then in the brain. Even in the brain there must exist sime hierarchy like protecting the brain stem more.
=> (One of ) The best way to protect spinal cord neuronal cells against excessive neurotoxicity is to inhibit their speed of glutamate signalling. That is bassically done by trying to shut down activity that needs to use the spinal cord as much as possible, both directions.
=> IMO with any (or most) human activity the spinal cord is the first to suffer devastating blows if activity is too high. Hence inhibiting activity primairly to try and protect the spinal cord long before the brain or muscles are in true danger is a or the key driver for the brain to inhibit our energy consumption and activities soooo much.
=> This may explain why so many of us and so many doctors think our bodies overreact when inhibiting us. It seems like our muscles and our brains could do more without getting that bad into trouble. But looking at individual brain cells or imune cells or muscle cells and see how much “abuse” they can withstand may be not a good measure for how much our brains HAVE to inhibit our activities. Long before entire organs like muscles or the brain are at bad risk, the spinal cord likely WILL be burned out like a copper wire conducting too much current. Not the entire wire will be gone, but even a single opening disrupts the signal flow.
=> Inibition IMO is NOT exagerated in most or near all of the ME/… cases. We may be able to do more with stimulating drugs, but at the risk of not only burning the periphal pain sensing nerves as seen in multiple recent researches, but *?*!*?*at the risk of burning too many strings of our spinal cord itself*?*!*?*.
That may also explain the comon “I took this drug that should increase mitochondrial energy production and it worked great for one or two days and I got worse again after it” observation. FIRST we may need to control spinal cord inflamation before trying to increase energy production and consumption. I know, better energy production might help better protect the spinal cord and nerves too IF nothing else like crippled (spinal) blood flow impairs that option.
See also the first 40 seconds of the video included in https://en.wikipedia.org/wiki/Neuron
A few quick additions after this “wall of text”:
* Estrogen affects the glutamate system. This may help explain why women are extra prone to this set of diseases. From a paper I am too tired now to get a proper referrence:
“”Masseteric injection of ketamine attenuates pain and mechanical hyperalgesia evoked by masseter injection of glutamate in men, but this effect was not observed in women.51,92 Estrogen upregulates NMDA receptor subunits, which may lead to sex differences in NMDA-evoked masseter afferent discharge.””
Note: the NMDA receptor is a main glutamate receptor.
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Thanks a lot to you Issie; withou you as my research partner I likely never would have come this far in my entire lifetime!!!
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Thank you deJurgen and issie for your hard work. Did you come up with ideas how to protect brain and spinal cord from too much glutamate?
Hi Dovile,
Thanks for reading and commenting. That way we’ll know that at least one person read it ;-).
We are working on that one and slowly moving forward to sort of test this hypothesis and ways to try and work around it.
“Just” “simply” calming this one down wont be enough IMO, but we have some ideas lined up. So far, we feel it will only be a partial help and will require tayloring to underlying individual weaknesses. But the combined amount of health improvement that many small changes gave me so far massively changed my quality of life so far yet.
To give away a useful thing now: for those feeling inflamed and with weak legs after an overly (well, just body temperature is already too hot for me) hot bath: better don’t do that. That is not saying however that cold baths and showers are a real solution. But knowing that a bad thing (for those patients experiencing this) might be worse then they thought is a starter.
By using less pleasant tepid bath water (as a result of this idea) rather then hot bath water I can prevent much of the inflamatory feeling bathing or showering gave me before. Issie has less good experiences with it however, so as said individual tayloring is needed. And no, adjusting bath and shower temperature alone no where near close will heal me! But even small improvements in health can make real improvements in quality of life!
For me, cold makes me hurt worse. I have to have more warm water. But too hot will cause mast cell issues and more POTS. But cold makes me hurt more. A heating pad is my friend. Here is some information on ideas of heat for those with lower body temperatures, which mine is. And Dejurgen body temperature is warmer.
https://www.marioninstitute.org/low-body-temperature-and-illness-living-with-rigor-mortis/
And
http://drsusanmarra.com/low-core-body-temperature/
I also had found a study on some genetic polymorphisms and a need for either heat or cold for pain and inflammation. And from a small survey I did. More males like it cooler water for pain and more females like it warmer. (I’ll try to locate that study on genetics and gender.)
I had said I would come back and put more about calcium channels, as this ties in with glutamate and pain. I’m putting it here so it doesn’t get lost.
Calcium channels have been noted in several studies with causing issues in ME/CFS. One very important study is known as the Griffith study out of Australia. These show issues with TRMP3 genes and snps associated with them.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217865/
AND:
https://journals.sagepub.com/doi/full/10.1177/0300060516671622
This article has several linked articles in regards to these calcium channel disruptions listed in the text.
https://www.sciencealert.com/one-of-the-biggest-myths-about-chronic-fatigue-syndrome-just-got-destroyed
There was a blog by Remy on Health rising forum listing the TRMP genetic markers to look at in regard to this study. Of which ME/CFS people have polymorphisms on. (Remy and I both had polymorphisms on all 5 out of 5.)
https://www.healthrising.org/forums/threads/23andme-trpm3-snps-for-cfs-griffiths-research.5396/
She also wrote a series of blogs on calcium channel blockers and her experience with those. Dejurgen and I have comments on those blogs/threads that may add to the information and why they work, and the connections we find with this.
First blog of Remy
https://www.healthrising.org/blog/2019/06/10/nimodipine-beating-chronic-fatigue-guide-downing-orr/
Second blog of Remy
https://www.healthrising.org/blog/2019/06/12/nimodipine-calcium-channel-blocker-fibromyalgia-chronic-fatigue-pt-ii/
Instead of me rewriting what is there, these articles will give you more of an overview and how it all ties in. Remy did a really good job on these.
Calcium channel issues have been part of my hypothesis along with glutamate issues for a decade now. Nice when science and hypothesis start proving themselves out!
Thanks to Dejurgen, much of the puzzle on this is coming clearer. Love it when the picture starts coming more into view.
Hi Issie and Dejurgen,
Do you think that having cold or hot bath somehow impact glutamate behaviour?
I am a fan of glutamate theory after reading Dr Goldstein’s books and experiencing viral meningitis a year ago. I literally got peripheral neuropathy as a symptom (feet and palms super itchy and painful) straight at the onset of the illness with other neurological symptoms a week into illness (ataxia). My theory is that my autoimune system started atacking certain neuro proteins, maybe producing anti-GAD antibodies which would have stopped production of GABA and make glutamate go out of control. Maybe even some other antibodies against neurons and nerves (note: I was not tested for those antibodies so it is only my own theory).
Interestingly an infectologist gave me a course of calcium channel blocker saying it will bring more oxygen to the brain. It helped me to get better to be able to return back to work after 3 months. However nerve pain in my feet, palms and chest stayed as an ongoing symptom together with fatigue. I have to say that during the year I had periods where I felt like having mini meningitis for few weeks (headaches, extreme cognitive impairment, memory loss, extreme brain fog, muscle stiffness and ataxia like gait). I started taking low dose of Clonezapam and it helps me avoid those periods of mini meningitis coming again and again.
Just wanted to explain my interest in your theory and give some perspective from someone who is going through (I believe) glutamate/gaba imbalance issues.
Thanks for the question Dovile.
The water baths don’t necessarily affect levels of glutamate. Though if it is enjoyable to you, could up your dopamine and possibly then oxytocin a bit. But it could help inflammation in the spinal cord and surrounding areas. Think of when straining an ankle, the first thing to take down swelling is cold packs. But for muscles hurting its warmth. It depends on what is going on in the spine and apparently our own individual genetics and gender.
(GAD) antibodies can be a possibility of a “cause” for issues with it being too high.
https://en.wikipedia.org/wiki/Glutamate_decarboxylase
Glutamate decarboxylase is the enzyme that converts glutamate to GABA and helps keep a good balance between them. Antibodies against that enzyme can interfere and cause issues with that balance. They can check for those antibodies. There has been a lot written by others on what that can cause. There is both a book and movie of a girl DX with this and her doctor in Tucson figured out what was going on with her. Its called “Brain on Fire”.
But even if there are not antibodies to GAD (and there aren’t with me) there can be wonkiness in how it works and the pathways things take. Since glutamate is a necessary thing for helping with our brain function, forming memories and other things…..we don’t want to take it down too far. But what appears to be a problem is the close connection of glutamate which is excitatory and GABA which is calming. The pathways are the same. And if I take something that is GABA or should turn into GABA, and be calming, instead it paradox with me and turns into glutamate and excitatory. (Think of GABA supplements or GABApentin – used for neuropathy. When GABA should help those things and help pain, it does me the opposite and turns into glutamate.) So this one is very tricky. It is very hard to find the right combinations and to know where along the pathway to tweak its function as to whether you are successful in accomplishing desired results.
They are now testing POTS people for these antibodies. But in my case, that was where the testing on that ended. Thankfully more is being done and it is being researched more and talked about as a “cause” of issues with sympathetic nervous system issues and inflammation.
I have found several things to help me. The medicines I listed above. And there are some herbals. We are still “tweaking” this and doing self experiments. We do intend to write about them when we have it more firm and less of an experiment. But so far, we are making some good progress. I seldom have to take the medication. With me there was some environmental triggers but also some bad wonky genetics.
It does appear that things that address opiate receptors and calcium channel receptors to be the best benefit. I have recently been playing around with cannibidiol receptors (but not CBD OIL, break down components of it) and that seems helpful too. With these they require some really keen observations and knowing which one to use and when. A lot is related to timing. I know this makes it sound complex and hard to do, and it is. That’s why we don’t just throw names of things out there without good testing and knowing what it will do and possibly side effects. AND…..this is the Big AND…..we have found we need tiny, tiny amounts to get the body to turn on or off its own receptors and work on its own. This is not only medicines, but herbals and other supplements. We are trying to support the body own process to do as it should, not take over and force it when its either too weak or wonky to go the right direction. Its a gentle thing not a forced thing. That way, it will be more long lasting and hope to bring the body back to homeostasis.
Thank you Issie for your comment.
Gaba indeed can be turned into Glutatame. And GABA itself is made of Glutamate using GAD as you mentioned. Gabapentin just happened to have ‘GABA’ in its name, but the mechanism of it actually is nothing to do with GABA. Its mechanism of action is very well explained in YouTube video called “Pharmacology – Antiepileptic Drugs (Made Easy)”. Highly recommended video to understand how Ca, Na, Cl channels work as well as various types of Glutamate and Gaba receptors and different drugs affecting all those components, they mode of action and side affects.
If you have not read I highly recommend Goldstein’s book Tuning The Brain. It is extremely scientific stuff, but I think you would be very fascinated, especially that you have such great understanding on how brain and neuro networks work.
@Dovile,
I watched the video you suggested and did a bit more research as I know my response to GABApentin was a paradox response (did the opposite of what was expected) and not a desired calming affect. This video suggest it works on calcium channels and according to the paper I will list that is partially correct. But it is supposed to up GABA and has been proven to.
GABApentin does change enzymes controling GABA production and deconstruction / conversion away from it.
The increase of GABA however does seem to work through increasing GAD activity (converting glutamate to GABA) and *in addition* GABApentin works on calcium channels (blocker) too. GABApentin seems to modify activity of two enzymes: one that creates more GABA and one that slows removal of GABA.
I did find the video interesting but it didn’t really get to the complete breakdowns of the functions of each medicine. I did also watch some surrounding videos that I found interesting there too. It would still be over the heads of many. But I like the science and the technical. And what I don’t yet know, gives me something new to learn.
With my attempting to up GABA, things (including this drug) has a paradox affect on me and it doesn’t have the desired response.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499716/#:~:text=Gabapentin%2C%20marketed%20for%20the%20treatment,on%20glutamate%20are%20not%20known.
Gabapentin, marketed for the treatment of seizures and neuropathic pain, has been shown to increase in vivo GABA concentration in the brain of both rodents and humans. Gabapentin effects on glutamate are not known.
Gabapentin is a lipophilic compound that was initially synthesized to mimic the chemical structure of GABA by addition of a cyclohexyl to its backbone (Honarmand et al, 2011). Although it is rapidly absorbed, readily crosses the blood–brain barrier and is orally active in several animal models of epilepsy, gabapentin neither binds to GABAA or GABAB receptors nor is it metabolized to GABA (Goa and Sorkin, 1993; Kammerer et al, 2011; Taylor et al, 1992). Research regarding gabapentin’s effects on GABA and glutamate synthetic and metabolizing enzymes reveals a complex pattern of activity and provides an incomplete explanation for its anticonvulsant effects. Gabapentin stimulates GAD at drug concentrations of 1.0 to 2.5 mM (Silverman et al, 1991; Taylor et al, 1992) and inhibits the GABA-catabolizing enzyme, GABA-transaminase (GABA-T) at high concentrations (23-25 mM; Taylor et al, 1992) with relatively weak effects on GABA-T at lower concentrations of 10 mM (Goldlust et al, 1995). Gabapentin increased GABA turnover in 11 out of 12 brain regions tested, but the temporal effect of the drug varied from region to region (Loscher et al, 1991). Other possible mechanisms of action include inhibition of neuronal calcium influx (Fink et al, 2000), binding to α2δ calcium channel subunits (Gee et al, 1996) and activation of glutamate dehydrogenase (Cho et al, 1998).
Although the mechanism of gabapentin therapeutic action is unclear, human subjects studies suggest that its administration leads to an overall increase in central GABA levels.
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I will look into the book. Thank you for your suggestions. The more I learn the more I realize how little I know and that there is so much more yet to explore.
dejurgen, you said:
………..That way we’ll know that at least one person read it ;-).
and you said:
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Thanks a lot to you Issie; withou you as my research partner I likely never would have come this far in my entire lifetime!!!
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dejurgin, both your and Issie’s joint team efforts and insights are so welcome and gratefully acknowledged.
Were i to write ‘thank you’ to you both as often as i feel, the pages of Healthrising would be hard to read for space being filled with my ‘thank you’s’ to you both especially. (and from other silent readers also to you both.)
Tho it seems that you are writing into an empty auditorium, it is filled with friends who are glad you are willing to share your thoughts, ideas, and supporting resources.
The puzzle is multi-dimensional, and you both help to fill it out.
I am glad that you are wise and take needed breaks, and i realize that you both give of yourselves more than you might if you both were using your energies for yourselves.
Thank you both for your vision that includes sharing your personal realizations and hard won efforts to further knowledge, understanding, and health.
Thanks so much for the heartfelt words of appreciation sunie. Both Issie and I deeply appreciate them!
Trying to keep up puting up a fight against this impossible disease as a healthy researcher must be hard.
Trying to do so as a weakened patient without formal medical schooling is very challenging.
Trying to do so and decide to use our keen sense while a crash is happening, as that is when we learn the most, well… more then a bit insane.
Keeping up such insanity isn’t easy ;-). And your warm words help us going another round. Thanks!
dejurgen and Issie.
Dejurgen and Issue – thank you so very much for your thoughts and comments on this issue. I just finished reading it, and I’m so impressed. (By the way, I worked at Stanford University School of Medicine writing about medical research for the lay public, so I know how very difficult it is to translate technical material into lay language. Dejurgen, you have done it superlatively. I’m soooooo grateful!
We’re glad to hear our attempts to try and explain things more clear are starting to work out. Getting things out clear is/was another obstacle to going to publication of more of our ideas.
And thanks for the kind words, they are felt and appreciated.
Thank you sunie and Susan S. , we sure are appreciative of your commendations.
We know what we talk about is not along a “light reading” subject line. We try to go deep into the science and make things make sense. Tie together what seems to form a more complete picture and present it with both technical and summary in hope that those researchers and doctors who see it, can see the science. But the patient can see the hope in what we present. If we can get our WHYS, then we maybe can make a difference in our quality of life. Dejurgen and I try to look at the lflip side of the coin and try to see other possibilities in what we experience and then try to tie science to what we observe. We are of the opinion that a lot of our “symptoms” are compensations. And we need to get to the core before we start tweaking what might be a very necessary compensation and the lessor of two evils. As Dejurgen mentioned, we plan soon to start sharing more of our hypothesis and ideas. Its in the works. We both feel encouraged and we both have improved our quality of life. We have found some nice ? bandaids. We plan to share that with others. There is HOPE!