Despite the current lack of consensus as to the underlying biological basis of CFS, there is considerable evidence … to highlight an abnormality of the autonomic nervous system as a unifying pathological factor. Newton et. al. 2013

A fascinating case of research confluence took place a couple of years ago which suggested that hyperadrenergic POTS and chronic fatigue syndrome (ME/CFS) patients may not be as far apart as they seem.

The two diseases share similar symptoms and some findings.  Problems with blood pooling and/or the brain have sent norepinephrine levels soaring in hyperadrenergic POTS patients. Norepinephrine levels have not been well studied in ME/CFS but one larger study found increased levels.

POTS chronic fatigue syndrome similariteis

POTS and ME/CFS are similar and different. Are different processes causing similar problems in both diseases?

POTS, however, is not present in all or probably most ME/CFS patients.  Grubb warned about placing too much importance on POTS criteria, but a large Australian study (n=306) nevertheless found POTS present in just 11% of ME/CFS patients.  Those POTS-positive ME/CFS patients, interestingly, tended to be younger than the non-POTS patients.  Newton’s large (n=179) U.K. study produced similar findings. POTS was present in about the same percentage of patients (13%), who tended to be younger than non-POTS patients.

The overlap between POTS and ME/CFS appears to be much greater than the overlap between ME/CFS and POTS; that is, far more people with POTS appear to meet the criteria for ME/CFS than vice versa. (Compare the 64% of POTS patients which met the criteria for ME/CFS with the 10-15% of ME/CFS patients who met the criteria for POTS in Biaggioni’s 2012 study.)

That discrepancy makes sense given the more rigorous biological criteria for POTS and less rigorous, symptom-based criteria for chronic fatigue syndrome. POTS may be a syndrome – a biological state which can be caused in a variety of ways –  but ME/CFS is still something of a waste-basket disease. God knows how many subsets are present in it.

Stagnant Hypoxia

Upon being tilted up, the POTS patients had an immediate thirty percent reduction in cerebral blood flow.  Struggling to make up the deficiency, their hearts exploded into action – almost doubling from a normal 78 bpm to 130 bpm. That compensation appeared to have at least partially worked as their cardiac output (pumped blood volume) remained stable.

Yet thirty percent less blood was reaching their brains.  As noted above, at the same time their hearts were pounding away, chemoreceptors – picking up signs of reduced blood pressure – triggered their breathing pattern to change resulting in hyperventilation.  (Some studies suggest the chemoreceptors in POTS may not be operating properly). The hyperventilation sent their CO2 levels lower, which in turn caused the blood vessels in their brains to constrict, possibly reducing blood flows – and oxygen delivery (whoops!) – to the brain.

stagnant hypoxia chronic fatigue

Stagnant hypoxia occurs when oxygen-rich blood flows too slowly to deliver adequate amounts of oxygen.

A condition called ischemic or “stagnant” hypoxia resulted. Stagnant hypoxia occurs when the blood oxygen content is normal but the blood is flowing too slowly to deliver normal amounts of oxygen.  (That condition sounds tailor made for ME/CFS patients, who typically have normal blood oxygen levels but appear to utilize that oxygen properly).

Remarkably, the researchers were able to resolve these hyperadrenergic POTS patients’ mounting problems in the simplest way possible – by giving them CO2. CO2 normalized the blood flow to their brain and stopped their tachycardia (rapid heart beats).

One group of POTS patients called “cerebral blood flow driven POTS” takes a slightly different pathway, but ends up in the same place. This group, which experiences shortness of breath when they stand, is characterized by large initial drops in cerebral blood flows when they stand up.  The immediate large drop in blood flows to the brain causes stagnant hypoxia to occur, which activates the chemoreflex, which produces hyperventilation, which results in reduced CO2 levels, sympathetic nervous system activation and rapid heart beats (tachycardia).

A Chronic Fatigue Syndrome (ME/CFS) Connection?

Although conventionally CFS has been considered to be a disease with primary CNS pathologies and secondary peripheral consequences, our results point to possible alternative disease mechanisms. It is possible that CFS is driven by a primary peripheral abnormality … where a compromised skeletal muscle cellular membrane function underpins the observed abnormalities. “ He et al. 2013

Those results were eerily similar to Dr. Newton’s 2013 findings in a small group of ME/CFS patients.  Newton used the Valsalva maneuver instead of the tilt table test to stress her patients, but also found reduced cerebral blood flows she believed were likely associated with hyperventilation and reduced CO2 levels.  To make matters worse, dropping blood pH levels triggered the “Bohr effect”, which reduced CO2 levels further.

The kicker was that Newton was able to link the constricted brain blood flows – not to a primary brain problem or blood pooling – but to increased acidity in the blood (decreased blood pH) caused by energy production problems in the muscles.

Vermeulen also concluded that the reduced aerobic metabolism he found was probably caused by problems with oxygen delivery and its result – stagnant hypoxia.  Natelson similarly concluded that low blood flows were responsible for the twenty percent drop in aerobic capacity he found in people with ME/CFS.

Both suggest that energy production problems in ME/CFS are more likely caused by delivery issues; e.g. blood vessel problems, than due to problems with producing energy at the cellular level.

The same may be true in fibromyalgia, where studies suggest that hypoxia – produced by low blood flows – is causing pain and fatigue and even allodynia.

Are Oxygen Starved Tissues Causing Pain and Fatigue in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)?

When Touch Hurts and Blood Matters: Getting at the Pain in Fibromyalgia and Chronic Fatigue Sydnrome (ME/CFS)

Different Paths – Similar Results?

Newton’s study suggested that ME/CFS and hyperadrenergic POTS patients may take different paths which end up in the same end result – constricted blood vessels which reduce blood flows to the brain.  In hyperadrenergic POTS, blood pooling problems in the lower body are a main cause, while in ME/CFS, problems with energy production and reduced blood flows to the muscles may be. Both result in hyperventilation, reduced CO2 levels and reduced blood delivery to the brain. (Reduced blood flows to the brain have been documented in both conditions.)

Damage to the nerves lining the blood vessels in the lower body plays a major role in POTS. Newton’s study and others suggest problems with the small blood vessels may be impeding oxygen delivery to the muscles in ME/CFS.

The Blood (Volume) Will Out: Is Ischemia A Key in Both POTS and Chronic Fatigue Syndrome?

Unfortunately, we don’t know much about energy production in POTS. It’s possible similar energy production problems exist in POTS – just not to the same extent.

It’s tempting to think of POTS as ‘ME/CFS-plus-orthostatic intolerance’ except for the more severe exercise issues in ME/CFS. Moderate exercise, in general, appears to be much better tolerated in POTS and fibromyalgia. Given what we know about the history of these diseases, that makes sense.

It was ME/CFS experts, after all, not POTS or fibromyalgia specialists, who coined the term post-exertional malaise (PEM) decades ago. PEM is considered to be the core symptom in ME/CFS, while dizziness/fainting and widespread pain are core symptoms for POTS and fibromyalgia. Very carefully fine-tuned, heart rate-based “exercise” programs have been produced for ME/CFS but not, to my knowledge, for POTS or FM.  Energy production has become a major research topic in ME/CFS, but not yet in these other diseases.

Exercise appears to be a more dicey proposition in ME/CFS, possibly because energy production problems in the periphery (the muscles) are a more fundamental issue. Severe fatigue, however, is very common in POTS and FM as well; post-exertional malaise is present in all three diseases, and few, if any, patients are running marathons. Energy production problems may be more severe in ME/CFS while problems with cardiovascular control (racing heart upon standing) play a more significant role in POTS.

All these diseases, though, probably share autonomic nervous system problems, issues with orthostatic intolerance, reduced blood volume, autoimmunity issues, and probably problems with energy production.  Large studies which probe these diseases in tandem in an attempt to find core abnormalities and differentiating factors would be fascinating, and might end up creating a new set of disease entities.

Boston pulmonologist David Systrom and neurologist Anne Oaklander may be able to provide some answers to these complex questions. Systrom has invasive exercise data on a large set of ME/CFS, POTS and FM patients. Anne Oaklander uncovered the small nerve fiber problems in FM. Both believe autoimmune processes which affect the autonomic nerves across the body probably play a large role in these diseases. I don’t know if Systrom and Oaklander are working with dysautonomia specialists, but combining Systrom’s CPET data with Oaklander’s small fiber data and tilt table data could begin teasing out who has what.

This kind of analysis is underway, on a smaller scale, in ME/CFS in the NIH’s intramural study which is combining exercise, tilt table tests, energy production testing, small nerve fiber testing and much more.  A blog on that study is coming up.

Articles From the 2018 Dysautonomia Conference

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