The Subset Researcher

red ball in silver ones

Dr. Natelson believes its time to devote resources to busting up chronic fatigue syndrome into its constituent parts

Virtually everybody for decades has believed ME/CFS is larded with subsets and everyone agrees we must find them yet very few researchers, through lack of money or initiative, have actually looked for them in an organized fashion. Dr. Natelson has  and in this review article, published in a journal with the catchy name “The Frontiers of Physiology”, he’s imploring others to do the same.

He’s also telling research community that this ‘wastebasket’ disorder you’ve turned your noses up for so long can and is being tamed.  Dr. Natelson, an ‘old-school’ researcher who parses his words carefully, doesn’t move until he’s got his ducks in a row and the publication of this review article suggests he’s pretty confident.  With a new  NIH grant coming through, it’s also possible Natelson is sitting on some nice strong data. (Or that he just wants help 🙂 or both.). Whatever the reason,  in this article Natelson wraps his research findings over the past five or ten years with the proposal that this disorder is ripe for splitting.

Front Physiol. 2013; 4: 109. Brain dysfunction as one cause of CFS symptoms including difficulty with attention and concentration. Benjamin H. Natelson1,2,*

The New ‘Dropsy’

Because CFS is defined using a clinical case definition, patients with this diagnosis must constitute a heterogeneous group, probably with multiple causative agents

Natelson starts by asserting that the nature of the ME/CFS definition means ME/CFS MUST have subsets and will likely have several causes, and he compared the current state of affairs to the  18th century when the term ‘dropsy’ term applied to people with swelling in their limbs probably due to congestive heart as well as other organ failures.

Chronic fatigue syndrome’s tendency to co-appear with fibromyalgia and other disorders has lead some researchers to suggest it’s nothing more than a somatization disorder.  Early on, however, Natelson determined that a diagnosis of somatization disorder simply depended on whether their symptoms were coded as psychiatric or physical. Nearly every ME/CFS patient met the classification of somatic disorder if their symptoms were classified as psychiatric, but if those same symptoms were classified as physical, the somatization label disappeared, so with Natelson’s research consistently turning up physiological abnormalities, he dropped  the somatization idea and moved on.

The Mood Disorder Conundrum

“..Our working hypothesis (is) that the group of CFS patients with no co-existing psychiatric problems has an underlying brain disease “

Early on Natelson took an interesting cut at this disorder, stratifying his patients into groups depending whether they’d been diagnosed with an mood disorder and the results were startling;  he found alot more neurological problems in the  ME/CFS patients without mood disorders than in those with them.  He found that ME/CFS patients without mood disorders  had….

  • Significantly worse neurological test results
  • Significantly higher number of MRI  abnormalities  (usually in the frontal lobe)
  • Significantly worse physical functioning
  • More spinal fluid abnormalities (white blood counts/protein concentrations)
  • More areas of reduced cerebral blood flow (than patients with current depression)
  • Higher ventricular lactate levels in the brain (p<.07)

Than the patients with mood disorders.  It was remarkable to see ME/CFS patients without mood disorders racking up more severe results on brain dysfunction that patients with ME/CFS but there we were.  Not only did they have more central nervous system abnomalities but they were worse functionally,  as well, which should have lead to, …a great incidence of mood disorders…but the evidence suggested not. In fact,  one wonders if the suggests this was a mood disorder resistant group.

The Fibromyalgia Connection

Comparing neuropsychological (cognitive) test results between ME/CFS patients with and without fibromyalgia, Natelson didn’t just find more neuropsychological test results in the ‘pure’ ME/CFS patients; they were the only ones to have neuropsychiatric (cognitive) issues and Natelson which suggested people with FM do not have significant cognitive issues.

The fact that people with fibromyalgia appear to have double the number of psychiatric issues as people with chronic fatigue syndrome, provided a bit more foundation for Natelson’s theory that ME/CFS patients without co-existing psychiatric diagnoses have an underlying ‘brain disease’ that’s causing their fatigue and cognitive issues.

Put everything together and you may have a group of ME/CFS patients with a brain disorder that’s showing up in the form of high rates of lactate in the brain and small nonspecific MRI white matter abnormalities, occurring mostly in the frontal lobes of the brain.’

Dr. Natelson has two theories about what’s going on in this group.

Dr. Pall in the Limelight: Theory #1

” Our current working hypothesis—that a subgroup of patients with CFS has an underlying neurological disease which leads to the symptoms of fatigue and cognitive dysfunction.”

Two theories might explain what’s causing this ‘neurological disorder’. The first suggests  a depleted antioxidant system (aka Pall), in the form of reduced glutathione (aka Konynenburg), is resulting in the formation of more free radicals  (isoprostanes – aka the MERUK studies) which slam the membranes of brain cells in the frontal lobe causing them to function poorly.

Are free radicals pounding some ME/CFS patients brain cells hard enough to cause small lesions?

Are free radicals pounding some ME/CFS patients brain cells hard enough to cause small lesions?

Natelson’s work with Dr. Shungu suggests glutathione levels (the main antioxidant) in the brain have  taken a huge hit. Finding glutathione reductions elsewhere has proven difficult but Shungu’s finding of a 36% reductions of glutathione  in the most energy intensive organ in the body – the brain – may be highly significant. The increased brain lactate levels (a byproduct of anerobic respiration) found by no less than three studies, fit right into Natelson’s scenario of impaired cellular metabolism.

( When Natelson re-evaluated the data from a 2009 study finding higher lactate in ME/CFS patients than people with anxiet  he found that ME/CFS patients without mood disorders tended to have higher lactate readings. Shungu, however, did found similar brain lactate levels  in people with ME/CFS and major depression in two studies. Those studies bring up the question why patients with major depression might have reduced brain GSH/increased lactate levels but not ME/CFS patients with depression.)

Not the Mitochondria

What doesn’t appear to be  fitting, Dr. Natelson believes, are theories suggesting that busted up mitochondria are the problem. (Some studies do suggest that but, in general, the research appears to be leaning the idea that blood flow problems are whacking the mitochondria’s ability to produce energy  instead the mitochondria themselves being messed up. ) Dr. Natelson noted  his research suggests the mitochondria themselves are in pretty good shape in ME/CFS.

That the free radicals found in ME/CFS (the isoprostanes) are also potent vasoconstrictors, ie they like to  tighten up blood vessels, is like icing on the cake in a population that betrays many signs (cognitive problems, orthostatic intolerance)  that suggest that not a whole heck of a lot of blood is getting to the old brainpan and several studies have showed reduced blood flows to the brain.  (Given Natelson’s focus on brain blood flows it’s interesting that Baraniuk’s brain proteome study also implicated the blood vessel problems.) Throw in Baraniuks findings of increased rates of migraine in this disorder and you’ve got a pretty darn good basis for the idea that brain blood flows play a important role for some patients.

Orthostatic Train Wreck:  Theory #2

The second theory suggests orthostatic intolerance problems are causing reduced blood flows to the brain, hypoxia induced brain lesions and cognitive problems.

A Look Back

Researchers thought delayed hypotension (sudden drops in blood pressure after standing) might just be it when it was found in ME/CFS almost twenty years. The nearly identical symptoms and a promising first study (that first study effect….) primed the field for a good deal of investigation into OI.

Delayed hypotension didn’t pan out in ME/CFS but it pointed in the direction of postural or orthostatic tachycardia, a condition in which the heart rates races upon standing. POTS  is a big deal in ME/CFS but in an interesting way. It appears to be rampant in ME/CFS adolescents but is much less prevalent (10-25%) in adults. When you’re talking about 10-15% levels you’re at about the norm for the population at large.

Something New

Or is an unusual form of orthostatic intolerance causing hypoxic conditions that cause small lesions in some people with ME/CFS?

Or is an unusual form of orthostatic intolerance causing hypoxic conditions that cause small lesions in some people with ME/CFS?

POTS may be punking out as an explanation for many ME/CFS adults problems with standing but then something called ‘orthostatic hyperventilation’ showed up. This problem, which is characterized by low end-tidal CO2 values,  appears to show up in about 20-30% of  adult ME/CFS patients; about double the incidence of POTS, and it’s hardly ever found in healthy population (3%).  Just looking at females, you find the girls, out in front again (:)) with 35% testing positive for OH (probably lowering the male percentage to a dismal 15% or so.).

If you believe, as I do, that the more they find wrong the quicker they’re going to be able to fix what’s broken – that’s good news for them. Orthostatic hyperventilation, then, provides a cleaner differentiating factor in ME/CFS than the better-known POTS; it’s more common in ME/CFS and it’s less common in the population at large.

When you think ‘hyperventilation’, anxiety and images of bag-breathing come to mind but the anxiety angle did not pan out and that lead to the last theory; the very elegant idea  that the hyperventilation in ME/CFS  – in a manner very similar to POTS, which remember has mostly not present in adults – is a physiological response to the lack of blood available.  Natelson believes the low blood flow to the brain probably is most evident in the  orthostatic intolerant group.

Dr. Natelson does not address why the switch from heart racing to ‘breath-racing’  is occurring. It’s not clear if  adolescents tend to outgrow POTS or if it and orthostatic hyperventilation are simply consequences of getting this disorder at different times of ones life.  It might not be that surprising that ME/CFS might show up differently depending on when you get it. The consequences of being exposed to a pathogen or toxin, after all, can vary dramatically depending on what stage of life you’re in.

Getting exposed to Epstein-Barr Virus, for instance, as a child usually results in a mild cold but being exposed to that same virus as an adolescent often results in infectious mononucleosis. In her NSU talk Dr. Hornig referred to the increased risk of schizophrenia that  adolescents but not adults face when exposed to marijuana.

Natelson suspects this group has high rates of cognitive problems, low rates of mood disorder, low blood flows to the brain and ‘lesions’ in their frontal lobes.


Natelson’s thrown orthostatic intolerance into research mix and his next round of studies will be able to tell what roles oxidative stress and orthostatic intolerance play in this group of cognitively challenged, functionally inhibited, lactate rich, frontal lobe wounded patients without mood disorders.  Natelson appears to be on the track to defining and even explaining what’s going with a significant subset of patients.

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