Dr. Ronald W. Davis Answers Patient Questions: Q and A follow-up to 2/21/17 Research Update

[Sushi]

However, I would not be at all surprised to learn that pushing through the initial illness caused us not to recover and for ME to then develop.

I think that was true for me. Also, as a very long term patient, I didn't know the damaging effects of getting into PEM and regularly did so--there was no information, I didn't even have a name for my illness.

Then 11 years ago (also before I knew anything) I did some intense aerobic exercise for a week (I had a house-guest who was pushing me to accompany her) and I took a huge nose dive that I have never recovered from. Then there is the daily "pushing" of feeding and caring for oneself that is heightened if you live alone. If you don't find a way to feed yourself, no one else will.

 

[Alvin2]

Then there is the daily "pushing" of feeding and caring for oneself that is heightened if you live alone. If you don't find a way to feed yourself, no one else will.

I can personally relate to this

 

[nandixon]

If the Citric Acid Cycle is impaired or glycolysis is shut down, how does this explain PEM? There may be a ready explanation and I would be interested in hearing it. As PEM is unique to this disease any hypothesis of course must account for it so I am sure Ron Davis has an explanation as he has said this may well be the heart of the disease.

The Citric Acid Cycle (Krebs Cycle)/glycolysis impairment is presumably a downstream effect of whatever the problem is that's causing ME/CFS. An impaired Krebs Cycle would cause both the energy impairment seen in this disease pre-PEM and also the further exacerbation of energy impairment during PEM. But I don't think an impaired Krebs Cycle would cause the PEM as a phenomenon in and of itself.

So I think the question to ask instead is, what would cause both the impairment of the Krebs Cycle and also the PEM?

An impairment of mTOR (mTORC1) could do this. (Note that the pyruvate dehydrogenase (PDH) complex - which provides acetyl-CoA for the Krebs Cycle - is downstream of mTORC1.)

I basically answered why for a related question previously here, but to paraphrase:

Exercise, specifically resistance training/anaerobic exercise, has been found to activate Akt/mTORC1 in healthy people.

Endurance training/aerobic exercise does not activate Akt/mTORC1, healthy or not.

But over-training (e.g., marathon running) in healthy people actually de-activates the Akt/mTORC1 pathway.(!) You see this manifested, for example, in marathon runners being found to be immunosuppressed (e.g., having increased Treg activity) after a race. (Under-activation of Akt/mTORC1 leads to immune suppression by increasing Treg activity.)

So maybe in ME/CFS, doing what in healthy people is a normal level of exertion, for us is the equivalent of over-training, and that's why Akt/mTORC1 may be under-activated or inhibited.

As far as what (autoantibody, blocking protein, etc) might be causing the mTOR/mTORC1 pathway(s) to be impaired in that way, well, that's what we're hoping Dr Davis and others can figure out. But a problem with mTOR can in fact explain both the Krebs Cycle problem and the PEM.

 

[Nickster]

He's hoping for months.

Oh Janet, thank you for bringing hope! I just had a horrible night with my CFS/ME 25 year old son. I keep telling him that we have some things in the "works" and I think it really is going to WORK!

 

[kikala]

I've been following this thread with great interest, and am so, so appreciative of Ron's passion and brilliance.

A bunch of people brought up fears that their illness happened or became worse because of their Type A personality or because they pushed too much. I know pushing can make things worse, but also want to let folks know that there are plenty of people (or, at least, me ;-)) who didn't push but have still stayed sick or progressed downward.

I first got sick in 1990, with an acute onset after a debilitating GI bug. Before that, I was active physically, but not particularly into pushing-- a friend and I called what we did "free running" -- we'd start out, then just see how we felt and stop whenever we felt like it ;-). No plans for building up or training.

I recovered from the acute GI symptoms, but about 10 days later I woke up with a debilitating, crushing fatigue. I was immediately worried because I had never felt anything like it -- it was unrelenting and creepily unresponsive to rest, and worsened with any activity. About 10 days into it I got really scared -- I had a former room mate who had been sick for years, and the previous year (1989) I had read the article in Rolling Stone about the CDC and CFS and became convinced that this was what she had. So I knew early on that it could be bad.

For a bunch of reasons, I was able to not push. For one thing, I felt so horrific when I did. I was very in touch with my body and had a healthy self-esteem, and didn't doubt my experience or that I was sick. And I was lucky enough to have parents who supported me emotionally and financially.

So I rested and got body work and had lots of folks helping me out. And still, l was slammed. Had 2 years of severe, and then I did have some episodic improvement. I was still often crashed, but I also had periods where I felt OK (not well, just not so completely sick) as long as I slept 10 hours a day, rested twice a day for a half hour each, and curtailed any physical activity.

Unfortunately this didn't last, and despite all my self-care and aggressive resting, the last 2-3 years I've been crashed far more often than I've been in an OK period. Very much struggling with it.

So those of you who have pushed -- don't beat yourself up. Maybe you would have been just as sick if you hadn't. This illness has no mercy.

 

[Alvin2]

So those of you who have pushed -- don't beat yourself up. Maybe you would have been just as sick if you hadn't. This illness has no mercy.

The idea is that you will likely go downhill either way but overdoing it will make it happen faster and worse.

 

[perrier]

Oh Janet, thank you for bringing hope! I just had a horrible night with my CFS/ME 25 year old son. I keep telling him that we have some things in the "works" and I think it really is going to WORK!

I'm in the same boat. Months is about all we can manage

 

[Marky90]

Yeah I have to agree Kikaka. Actually what has struck me is that there seems to be no obvious pattern at all when it comes to who gets better and who gets worse.Except: Quite a few patients gets worse from overexertion. I know almost zero patients who have rested their way out of this, resting is more a forced consequence of the disease, and sometimes a precautionary measure. The disease mechanism seems almost completely independent of our actions and thoughts, which often is the case in serious chronic conditions!

 

[Louie]

I've been following this thread with great interest, and am so, so appreciative of Ron's passion and brilliance.

A bunch of people brought up fears that their illness happened or became worse because of their Type A personality or because they pushed too much. I know pushing can make things worse, but also want to let folks know that there are plenty of people (or, at least, me ;-)) who didn't push but have still stayed sick or progressed downward.

I first got sick in 1990, with an acute onset after a debilitating GI bug. Before that, I was active physically, but not particularly into pushing-- a friend and I called what we did "free running" -- we'd start out, then just see how we felt and stop whenever we felt like it ;-). No plans for building up or training.

I recovered from the acute GI symptoms, but about 10 days later I woke up with a debilitating, crushing fatigue. I was immediately worried because I had never felt anything like it -- it was unrelenting and creepily unresponsive to rest, and worsened with any activity. About 10 days into it I got really scared -- I had a former room mate who had been sick for years, and the previous year (1989) I had read the article in Rolling Stone about the CDC and CFS and became convinced that this was what she had. So I knew early on that it could be bad.

For a bunch of reasons, I was able to not push. For one thing, I felt so horrific when I did. I was very in touch with my body and had a healthy self-esteem, and didn't doubt my experience or that I was sick. And I was lucky enough to have parents who supported me emotionally and financially.

So I rested and got body work and had lots of folks helping me out. And still, l was slammed. Had 2 years of severe, and then I did have some episodic improvement. I was still often crashed, but I also had periods where I felt OK (not well, just not so completely sick) as long as I slept 10 hours a day, rested twice a day for a half hour each, and curtailed any physical activity.

Unfortunately this didn't last, and despite all my self-care and aggressive resting, the last 2-3 years I've been crashed far more often than I've been in an OK period. Very much struggling with it.

So those of you who have pushed -- don't beat yourself up. Maybe you would have been just as sick if you hadn't. This illness has no mercy.

I agree. There is an unfortunate underlying current of blaming oneself for being so sick because of trying to live life. There are many people who continue to get worse despite never overdoing it. I have been exceedingly careful the last 15 months with energy expenditure and yet I continue to get worse.

 

[Janet Dafoe]

Oh Janet, thank you for bringing hope! I just had a horrible night with my CFS/ME 25 year old son. I keep telling him that we have some things in the "works" and I think it really is going to WORK!

Oh isn't it just SO AWFUL?! We try to pantomime to Whitney that his father is making progress and something will happen soon. And he just looks at us with tears in his eyes desperately pleading for it to be soon. It breaks my heart every time. We're all hanging in there hoping we can last until it's figured out. ❤️

 

[Janet Dafoe]

Ben, is this different to the impedance test and also to the 'iPhone' test?

Yes it is.

 

[Laelia]

I'm wondering if the mTOR mutations found in the two ME/CFS patients being studied were hereditary or acquired mutations (if known)?

 

[Simon]

What about Orexin?

Robert Danzer talked about this at the CMRC conference a couple of years ago, and I blogged about it on Health Rising (nb long intro by Cort)
Dantzer on "The Neuroimmune Basis of Fatigue" - and Chronic Fatigue Syndrome - Health Rising

From the blog (my bold in first para):
Orexin – The key to Inflammation-related Fatigue
Professor Dantzer finished his presentation by describing a recently-discovered system in the hypothalamus of the brain that plays a key role in regulating energy levels – and could be a target for drugs to treat fatigue. The orexin system senses metabolic status and the balance between feeding and energy expenditure. It responds to glucose as well as leptin, a key molecule signalling energy levels that has been implicated in CFS/ME).

Is orexin the link between the metabolic and immune (leptin) problems in ME/CFS?

[Younger’s research suggests leptin, a substance tied to both metabolism and microglial activation, could be a key driver of the immune activation found in ME/CFS. Younger, who is now director of the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama, recently scored a major NIH grant to extend his research into leptin and immune activation in ME/CFS.

• See Tweeting the Stanford Symposium for more on leptin and ME/CFS ]

The orexin system also plays a role in sleep versus wakefulness. Unlike healthy rats, those given LPS fail to become more active at night. What’s really interesting is that the reduction in activity correlates with reduced levels of orexin. However, rats given orexin as well as LPS don’t show any reduction in activity, suggesting that orexin plays a key role in activity levels.

Orexin as a Treatment for Fatigue?
Researchers suspected that orexin may play a similar role in the cancer-related fatigue resulting from chemotherapy. They found that giving mice chemotherapy did indeed lead to lower levels of activity, indicating fatigue and a reduction in their orexin levels.

Crucially, giving mice orexin alongside the chemo restored their activity levels, again suggesting reduced orexin played a central role in fatigue. He said that there are now drugs for narcolepsy targeting the orexin system, and perhaps they could one day be used for fatigue too.

Professor Dantzer said his group are working on a test of orexin as a treatment for cancer-related fatigue.

 

[duncan]

Crucially, giving mice orexin alongside the chemo restored their activity levels, again suggesting reduced orexin played a central role in fatigue.

In some channelopathies, treatments target specific symptoms, since that often is all clinicians can offer - they can't undo the actual channelopathy itself. This is true for many diseases.

ME/CFS poses a different and even unique dilemma. It also can be characterized by a cluster of symptoms -- many symptoms that present differently in patients, almost like a Chinese menu. A major, arguably unique, problem it imposes on proposed therapies, however, is PEM. Whatever treatments are thrown at ME/CFS, PEM has to be factored in. NOT anticipating the impact of a therapy on PEM could prove disastrous.

So, when someone equates ME/CFS with fatigue, and tries to introduce an intervention that mitigates that solitary symptom and in fact observes (without feedback) greater activity, there may be ramifications to that activity that actually worsen the condition of a given patient. Adderall, anyone? Amphetamines?

These are all downstream effects, and singling out a solitary aspect to try to fix may cause more harm than good.

 

[slysaint]

Whatever treatments are thrown at ME/CFS, PEM has to be factored in

I was just reading the QandA section on the MEGA website and having said they will include PEM as a prerequisite symptom for participants, they have yet to decide how to define it.
Hopefully Ron Davis and his team will be able to come up with something that identifies exactly what 'it' is, and show those less enlightened 'researchers' which treatments/therapies may be beneficial and those that are/could be harmful.

 

[Alvin2]

Orexin – The key to Inflammation-related Fatigue
Professor Dantzer finished his presentation by describing a recently-discovered system in the hypothalamus of the brain that plays a key role in regulating energy levels – and could be a target for drugs to treat fatigue

I don't think Orexin has much to do with ME/CFS, or is barely peripherally involved as best, when you first wake up and feel groggy, thats because Orexin is not yet activated. Once its activated it coordinates wakefulness, without it you would have sleep attacks, cataplexy and massively abnormal amounts of REM sleep (Orexin is part of a REM on/off switch).
Modafinfil and Armodafinil are the common stimulants for narcolepsy and have little effect on CFS/ME.
Dexedrine is sometimes used and will work for some CFS/ME symptoms becasue its a dopamine pumper, it was used by fighter pilots in wars to function for long periods without sleep. Its no cure for anything.

 

[Nickster]

Oh isn't it just SO AWFUL?! We try to pantomime to Whitney that his father is making progress and something will happen soon. And he just looks at us with tears in his eyes desperately pleading for it to be soon. It breaks my heart every time. We're all hanging in there hoping we can last until it's figured out. ❤️

Yes it's heartbreaking to see my son this way and he has that same desperate look in his eyes and I truly empathize with everything you are going thru. It feels like we are all so much stronger than we think (some days I feel like concrete and some days I fell like quicksand). Stay strong and hang in there!!!

 

[maybe some day]

So those of you who have pushed -- don't beat yourself up. Maybe you would have been just as sick if you hadn't. This illness has no mercy.

Words to live by. I was active also but never pushed myself. When I got tired I stopped. Took care of myself..and now I have this illness to thank for. I wonder if I ate like crap..smoked, couch potato, etc, if I would got cfs. You are so right..its a barbaric illness that leaves no mercy. It leaves absolutely nothing unturned in its wake. Tsunami comes to mind

 

[lintonthepenguin]

When I listen to Dr Davis's current understanding of how ME/CFS works, while I certainly don't doubt his hypothesis/understanding of the disease (he's a remarkable scientist and has access to a lot of data and knowledge that I certainly don't), one question does come to mind.

If the fundamental issue with ME/CFS is essentially an issue with something in the serum preventing cells from being able to produce energy normally, how does that fit in with all the various immune system-esque symptoms that ME/CFS patients experience (sore throats, lymph node stuff, etc)? Is it possible that there are two different mechanisms causing both the metabolic and immune-esque symptoms, or is it possible that issues with the metabolism are somehow indirectly causing immune-style symptoms to manifest?

Anyone have any insight?

 

[shannah]

Yes it's heartbreaking to see my son this way and he has that same desperate look in his eyes and I truly empathize with everything you are going thru. It feels like we are all so much stronger than we think (some days I feel like concrete and some days I fell like quicksand). Stay strong and hang in there!!!

Yes, we could start a mother's club couldn't we. Such tragic stories...