Autonomic Dysfunction as a Result of LOW SNS/NE.

[Remy]

I've been laboring under the assumption for the past few years that many of my symptoms (fatigue, migraine, orthostatic intolerance) were caused by a overactive SNS. I've just read an article that has turned my worldview on its ear...

Basically, the article is saying that migraine and autonomic dysfunction is caused by low SNS activity...stress causes excessive SNS activity and when that is no longer sustainable, the SNS function is reduced significantly and NE levels drop.

Autonomic dysfunction symptoms like dizziness, neck pain, syncope and temperature regulation problems occur as a result of hypoperfusion to the relevant areas of the body. Dilation occurs because NE is too low to balance out the neurotransmitters like dopamine, prostaglandins and adenosine.

This may also be where the increased adenosine levels are coming from in MECFS that some of us have seen on our methylation panels...as a result of autonomic dysfunction as a result of low SNS and low NE.

Headache. 2004 Jan;44(1):53-64.

Migraine: a chronic sympathetic nervous system disorder.

Peroutka SJ.
Abstract

OBJECTIVES:

To determine the degree of diagnostic and clinical similarity between chronic sympathetic nervous system disorders and migraine.
BACKGROUND:

Migraine is an episodic syndrome consisting of a variety of clinical features that result from dysfunction of the sympathetic nervous system. During headache-free periods, migraineurs have a reduction in sympathetic function compared to nonmigraineurs. Sympathetic nervous system dysfunction is also the major feature of rare neurological disorders such as pure autonomic failure and multiple system atrophy. There are no known reports in the medical literature, however, comparing sympathetic nervous system function in individuals with migraine, pure autonomic failure, and multiple system atrophy.
METHODS:

A detailed review of the literature was performed to compare the results of a wide variety of diagnostic tests and clinical signs that have been described in these 3 heretofore unrelated disorders.
RESULTS:

The data indicate that migraine shares significant diagnostic and clinical features with both pure autonomic failure and multiple system atrophy, yet represents a distinct subtype of chronic sympathetic dysfunction. Migraine is most similar to pure autonomic failure in terms of reduced supine plasma norepinephrine levels, peripheral adrenergic receptor supersensitivity, and clinical symptomatology directly related to sympathetic nervous system dysfunction. The peripheral sympathetic nervous system dysfunction is much more severe in pure autonomic failure than in migraine. Migraine differs from both pure autonomic failure and multiple system atrophy in that migraineurs retain the ability, although suboptimal, to increase plasma norepinephrine levels following physiological stressors.
CONCLUSIONS:

The major finding of the present study is that migraine is a disorder of chronic sympathetic dysfunction, sharing many diagnostic and clinical characteristics with pure autonomic failure and multiple system atrophy. However, the sympathetic nervous system dysfunction in migraine differs from pure autonomic failure and multiple system atrophy in that occurs in an anatomically intact system. It is proposed that the sympathetic dysfunction in migraine relates to an imbalance of sympathetic co-transmitters. Specifically, it is suggested that a migraine attack is characterized by a relative depletion of sympathetic norepinephrine stores in conjunction with an increase in the release of other sympathetic cotransmitters such as dopamine, prostaglandins, adenosine triphosphate, and adenosine. An enhanced understanding of the sympathetic dysfunction in migraine may help to more effectively diagnose, prevent, and/or treat migraine and other types of headache.

 

[Who Me?]

So this coild explain why I don't sweat and can't tolerate heat?

What's NE? Norepinephrine?

 

[Remy]

What's NE? Norepinephrine?

Yes.

 

[Snow Leopard]

Migrane is quite different to our illness and so I'm not sure what we can learn from that.

But both high and low levels can of course cause serious problems.

I'm not seeing evidence for diminished NE in POTS or CFS patients.

http://www.sciencedirect.com/science/article/pii/S0002962915407906
http://www.nature.com/pr/journal/v48/n2/full/pr2000180a.html
http://pediatrics.aappublications.org/content/120/1/e129.short
http://www.sciencedirect.com/science/article/pii/S0002934305004468 (no difference found... Note, this is not a Georgia CDC study, its from the less controversial Wichita cohort)
etc. (There might be more).

But, but, but...
The results of the Light et al. post-exercise studies are intriguing, with the increase of beta-adrenergic receptor expression - which suggests, that either the cell thinks it needs more beta-adrenergic receptor activity (lack of NE or E post exercise? lack of Cyclic adenosine monophosphate activity in the cell?) or that these pathways are being switched on in the cell when they shouldn't be.

 

[Remy]

Migrane is quite different to our illness and so I'm not sure what we can learn from that.

It's not quite different to *my* illness. In fact, migraine and autonomic dysfunction basically are my illness. Along with the hormone and immune dysfunctions, of course.

If more than 75% of MECFS patients experience migraine, it's hard to believe it's not relevant to our illness, even if it's not exactly the same for everyone.

Dysautonomia isn't just POTS.

http://www.cortjohnson.org/treating...nd-chronic-fatigue-syndrome-and-fibromyalgia/

 

[Snow Leopard]

If more than 75% of MECFS patients experience migraine, it's hard to believe it's not relevant to our illness, even if it's not exactly the same for everyone.

I've never heard of rates that high! I was under the impression that most ME CFS patients experience headaches (sometimes severe ones!), but not migranes.

 

[Remy]

I'm seeing quite a few things that suggest low NE in MECFS. Of course, there could always be subgroups though.

Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome.
Strahler J, et al. Biol Psychol. 2013.
Show full citation
Abstract
Chronic fatigue syndrome (CFS) is characterized by fatigue lasting 6 months or longer. CFS has been associated with a disturbed (re-)activity of the autonomic nervous system. However, the sympathetic adrenomedulla (SAM) remains under-examined in CFS. To investigate SAM reactivity, we implemented a submaximal cycle ergometry (ERGO) and a pharmacological test (Insulin Tolerance Test, ITT) in 21 CFS patients and 20 age-, sex-, and BMI-matched controls. Plasma norepinephrine and epinephrine were collected once before and twice after the tests (+10/+20, and +30 min). Lower baseline levels and attenuated responses of epinephrine to the ERGO were found in CFS patients compared to controls, while the groups did not differ in their responses to the ITT. To conclude, we found evidence of altered sympathetic-neural and SAM reactivity in CFS. Exercise stress revealed a subtle catecholaminergic hyporeactivity in CFS patients. It is conceivable that inadequate catecholaminergic responses to physical exertion might contribute to CFS symptoms.

 

[Snow Leopard]

I'm seeing quite a few things that suggest low NE in MECFS. Of course, there could always be subgroups though.

That study is interesting - note that it suggested hyporeactivity to exercise - so it might not be the baseline levels that are important, but rather the response to activity.

 

[Remy]

That study is interesting - note that it suggested hyporeactivity to exercise - so it might not be the baseline levels that are important, but rather the response to activity.

It says lower baseline too, though.

Mostly I was just floored to think that low NE might in any way, shape or form be responsible for my symptoms. I plan to do lots more reading.

 

[weyland]

Migrane is quite different to our illness and so I'm not sure what we can learn from that.

Both have been related possibly to low serotonin levels.

I've never heard of rates that high! I was under the impression that most ME CFS patients experience headaches (sometimes severe ones!), but not migranes.

I would call the headaches that I get with ME migraines. I've suffered from migraines since I was a teen and the migraines I get now with ME are more severe and more frequent.

 

[weyland]

I've been laboring under the assumption for the past few years that many of my symptoms (fatigue, migraine, orthostatic intolerance) were caused by a overactive SNS.

Should be pretty easy to test. Standing test or tilt table with plasma NE determination. Obviously those with hyperadrenergic POTS don't seem to be suffering from low NE.

 

[weyland]

The results of the Light et al. post-exercise studies are intriguing, with the increase of beta-adrenergic receptor expression - which suggests, that either the cell thinks it needs more beta-adrenergic receptor activity (lack of NE or E post exercise? lack of Cyclic adenosine monophosphate activity in the cell?) or that these pathways are being switched on in the cell when they shouldn't be.

Perhaps it depends on what cell type you're looking at. Lights were looking at white blood cells. Receptor expression on SNS cells could change in a totally different way after exertion. Little bit harder to test that in the same way.

And then there's the beta2 adrenergic receptor autoantibodies the Germans found...

 

[Remy]

Should be pretty easy to test. Standing test or tilt table with plasma NE determination. Obviously those with hyperadrenergic POTS don't seem to be suffering from low NE.

Maybe they are suffering from the receptor hypersensitivity caused by low NE rather than high NE? I'm not sure though...

Sorry you have suffered with the migraines too, @weyland. They do suck.

 

[Veet]

It says lower baseline too, though.

Mostly I was just floored to think that low NE might in any way, shape or form be responsible for my symptoms. I plan to do lots more reading.

Please keep sharing your reading. I had no idea so many people are also suffering w/ migraines along w/ everything else.

 

[weyland]

Maybe they are suffering from the receptor hypersensitivity caused by low NE rather than high NE? I'm not sure though...

But their plasma NE (and E) is always high when upright, so you'd think their receptors would be normal or even downregulated.

How do your OI symptoms manifest?

Sorry you have suffered with the migraines too, @weyland. They do suck.

Thanks, they are bad. Luckily I'm down to only about 1 per week these days. I can easily see how frequent migraines can be totally debilitating, especially when you factor in the pre and postdrome symptoms. You can easily lose 2-3 days of a working brain on one migraine.

 

[Remy]

How do your OI symptoms manifest?

Mostly as dizziness. I get lightheaded when I stand up too fast. And avoid hanging my head over for too long to tie shoes etc. I'll get the sweating, anxiety and blurred vision under exertion at times too.

I can easily see how frequent migraines can be totally debilitating, especially when you factor in the pre and postdrome symptoms. You can easily lose 2-3 days of a working brain on one migraine.

The last 18 months I was working, I had a migraine every day. I didn't have a lot of pain with my migraines, but all the other symptoms. It was truly awful. Now I'm down to just a couple a month but it fluctuates like everything else.

I never in a million years put it together with the autonomic dysfunction. I mean, I knew they happened together, but did not realize they shared a common cause.

But their plasma NE (and E) is always high when upright, so you'd think their receptors would be normal or even downregulated.

Good point.

I have zero interest in having a tilt table test done right now but I'm thinking about adding some tyrosine to my life. It should be easy enough to tell if it makes things any better (or hopefully not) any worse.

 

[Cort]

Please keep sharing your reading. I had no idea so many people are also suffering w/ migraines along w/ everything else.

Check out this poll! (and please take it if you haven't)

http://www.cortjohnson.org/forums/t...raine-test-do-you-suffer-from-migraines.2550/

Baraniuk found very high rates of migraine in ME/CFS and rates may be even higher in Fibromyaligia. I'm beginning to wonder if migraine might be the most or one of the most common comorbid disorders in both diseases. That's pretty wild considering I don't think it was even mentioned four or five years ago.

 

[Paw]

I would characterize my chronic headaches as migraines, but I get them far less frequently now that I've been taking duloxetine (serotonin) for the past few years. (Hard to tell for sure, though, since I've simultaneously been working on lowering my BP.)

As for norepinephrine... strangely, bupropion was the only thing that consistently helped my energy (I could not tolerate anything else in the dopamine chain). Then, after about six successful months on the bupropion it very suddenly stopped working, and started making me just as sick as more conventional stims.

Interesting to hear more evidence of autonomic nervous system involvement, as I have documented autonomic neuropathy, and have long suspected the central key to my illness may lie in the dopamine chain. Another example of how there may be many different routes to similar debilitations.

 

[Remy]

@Strike me lucky, Probenecid increases NE in the brain...hmmm. Maybe it was not the cidofovir that was helping...

Arch Gen Psychiatry. 1978 Feb;35(2):237-40.
Probenecid-induced norepinephrine elevations in plasma and CSF.

Lake CR, Wood JH, Ziegler MG, Ebert MH, Kopin IJ.
Abstract

Probenecid administered in divided oral doses totaling 100 mg/kg increased levels of norepinephrine (NE) in plasma and cerebrospinal fluid (CSF). This technique is commonly used to measure the rate of accumulation of acidic metabolites of certain brain neurotransmitter biogenic amines in CSF after blockade of their transport into blood. Since levels of 3-methoxy-4-hydroxy-phenylethyleneglycol, a neutral metabolite of NE, are also elevated after high oral doses of probenecid, the increases of CSF and plasma NE levels may be directly related to probenecid-induced release of this amine from noradrenergic neurons. In patients who experienced nausea or vomiting there were lower levels of probenecid in CSF, probably secondary to diminished absorption of the medication. These patients also had lower levels of NE in plasma than did patients who remained asymptomatic.

 

[Strike me lucky]

@Strike me lucky, Probenecid increases NE in the brain...hmmm. Maybe it was not the cidofovir that was helping...

My first thoughts are that i wonder if probenecid increases blood levels of NE like it does with some drugs? I will have a read into though. Its amazing the other effects of drugs that arent commonly known about.