Founder of Health Rising and Phoenix Rising
Julia Newton has produced quite a track record on ME/CFS - in particular on autonomic nervous system dysfunction. She's rather quickly become a real leader - a seminal figure in ME/CFS research. Dr. Newton with a not very big budget may have found:
The Basis of Fatigue for ME/CFS and Other Disorders ?
- 90% of ME/CFS patients have some form of orthostatic intolerance. That finding immediately puts the focus on blood flows and the autonomic nervous system.
- The fact that other fatiguing disorders have similar scores suggests that problems with blood flows and autonomic nervous system functioning may inherently cause fatigue. It also suggests that some of the answers for ME/CFS may come from research into other disorders. That's good news given the poor funding for ME/CFS.
- Those blood flow problems could be augmented by findings of reduced blood pressure in ME/CFS patients. While low blood pressure don't cause ME/CFS they're another sign that ANS is having trouble moving the blood where it should go.
- Upstream - New studies underway suggest stressing the autonomic nervous system causing blood flows to the brain to diminish - causing cognitive problems. In an amazing coincidence Dr. Newton found a similar mechanism occurring in ME/CFS patients that is occurring in POTS patients. Dr. Shungu has found high amounts of lactate in the brains of ME/CFS patients - precisely what Dr. Newton's study suggest are happening in the muscles. (See below).
- Downstream - Studies suggest the muscles of ME/CFS patients are producing HUGE amounts of acid when they exercise. These are not just incrementally increased amounts of acid - the muscles in ME/CFS may be producing 20x's the amount of acid as the muscles healthy people. A recent modeling study for ME/CFS suggested that this acidification may be the key factor in the mitochondrial breakdown that may be appearing in ME/CFS. High acid levels appear to cause the mitochondria to deplete their reserves leading to a prolonged recovery period; i.e. post-exertional malaise. See Mitochondrial Depletion Could Underlie the Energy Production Problems in ME/CFS
- Both - In a remarkable study Newton found that poor pH handling by the muscles appeared to be triggering reduced brain blood flows and cognitive breakdowns in ME/CFS. About the same time the same finding was produced by another group in POTS patients.
- Dr. Newton has been able to isolate muscle cells in the lab. Her muscle studies suggest the muscle acid problems may be reversible
- New research suggests that about a third of ME/CFS patients hearts are producing so little energy that they fulfill the criteria for subclinical cardiomyopathy. You have to go back to Peckerman's findings over ten years ago to find similar findings. Unfortunately when Natelson's research unit was closed Peckerman's work stopped.
For more on Dr. Newton's work
- Newton Study Suggests Muscle Problems Whack the Brain in Chronic Fatigue Syndrome
- Dr. Newton Talks! On Reversing Acidification in the Muscles, Blood Vessels, Abnormal Stress Responses and Aging in Chronic Fatigue Syndrome
- Newton’s Apples: Exploring the Ellis Interview with Dr. Julia Newton on Chronic Fatigue Syndrome
We can measure dysautonomia using very simple clinic based tools. The orthostatic grading scale is one example of this and if we measure this in a range of fatigue-associated chronic diseases, such as CFS, patients with fatty liver disease, vasovagal syncope or Sjogrens syndrome, then what we see is a wide spread of scores. We also see that all the control participants have values of four or below, which does not suggest orthostatic intolerance or autonomic dysfunction. A significant proportion of the fatigue-associated diseases do have high scores on the orthostatic grading scale.
When we summarise those, what we find is that in CFS patients, almost 90% of them will have scores of four or above, scores consistent with orthostatic intolerance, and that other fatigue-associated diseases also have higher than expected scores.
In all of the conditions that we have studied so far, higher scores on the orthostatic grading scale are associated with increased fatigue severity, suggesting that the two may be related. This led us to speculate a number of years ago that dysautonomia-associated fatigue is a common underpinning finding in patients with fatigue and that in CFS/ME a large proportion of patients will have dysautonomia associated fatigue compared to much a smaller proportion in other chronic diseases.
If we think that symptoms of autonomic dysfunction are common in patients with fatigue, what about objective abnormalities of the autonomic nervous system? The most simple measure would be to measure that head of steam, the blood pressure. If we do that using 24-hour blood pressure recordings we can see that in patients with CFS, compared to matched controls (we’ve done this assessment in more 100 patients with CFS/ME and their matched controls), patients with CFS have significantly lower blood pressure over 24 hours compared to controls, suggesting that the head of steam is lower.
If we use a range of other autonomic measurements we have consistently shown that abnormalities of autonomic dysfunction are more prevalent in those with fatigue compared to non-fatigued individuals and in CFS/ME patients compared to controls.
But what might that mean for patients? If we think about the consequences of autonomic dysfunction and the extreme end of things, where blood might not get to the brain, individuals may ultimately blackout. We can test for this using standardised clinical tools such as the head-up tilt test.
We have performed this test in patients with fatigue-associated diseases such as fatty liver disease and found that this is significantly more common in patients with fatigue-associated diseases. We have also performed a head-up tilt test in 64 patients with CFS/ME and matched controls, and been able to show that:
· patients with CFS/ME have a higher than expected history of loss of consciousness
· their tilt test is more likely to be positive consistent with neurally mediated hypotension
· and an unexpected finding (which we have now replicated in three series of patients with CFS/ME) is the finding of an increased prevalence of a condition called position or postural tachycardia syndrome, which is a recognised form of dysautonomia which may be amenable to pharmacological therapy.
So, why might these abnormalities be arising in patients with CFS/ME? They may be upstream – so brain abnormalities of autonomic centres – or downstream in terms of problems of the vascular system. Our research at the minute is focusing on trying to elucidate which of these is the most likely to be the underpinning problem with a view to developing therapies that will address these primary abnormalities.
In terms of upstream, at the moment we are just finishing off a series of studies where we have been performing brain MRI, we have been looking at blood flow to the brain in response to stressing the autonomic nervous system and looking at how that relates to performance on cognitive tests.
We have been able to show that objective cognitive abnormalities are present in patients with CFS compared to controls and that how blood flows to the brain during stresses of the autonomic nervous system appears to associate with how CFS patients perform on cognitive tests.
Downstream, we have been looking at muscle MRI and asking patients with CFS/ME to exercise in the MRI scanner and we have been observing how acid accumulates in the muscle as patients exercise. We have been able to show that patients with CFS/ME accumulate huge amounts of acid in their muscles when they exercise, so their pH is very low, generating something like 20 times more acid exposure for their muscles compared to matched controls. They also have difficulty getting rid of excess acid between bouts of exercise.
We have been taking muscle biopsies from those patients who have had MRI scans and growing these in the laboratory, and have developed a system whereby we can exercise those muscle cells in the laboratory to known amounts of exercise.
We have now developed a protocol that allows us to visualise the muscle cells as they exercise. That has huge advantages for us in that we can now, outside the human body, begin to explore the affects that drugs or molecules will have upon exercising muscle and by introducing nanosensors into the system we can detect acid accumulation and oxidative stress so that we can begin to look at how we can best modify that.
To give you one example, we have been looking at cells and the effect of a molecule called dichloroacetate which we know blocks acid and when we apply this into our exercising system we are able to see that the abnormalities of acid handling that seems to occur in CFS muscle cells is reversible, which is very exciting because it means that we can now begin to tease out where those abnormalities may lie.
Finally the other area that we are interested in is in cardiac MRI and we have been developing techniques whereby we can visualise the hearts of patients with CFS/ME. We have been able to explore how hearts use energy and a way of measuring that is with something called the PCR ATP ratio. I am reliably informed that a value of less than 1.6 is consistent with a subclinical cardiomyopathy and a third of the patients that we have seen are showing values consistent with this level of dysfunction.
In terms of the support that we receive, what is really important to us is that we have very strong support from the patient community. Some of our work going forward is supported by the Medical Research Council, but Action for M.E., ME Research UK, and the ME Association have very kindly been supporting the projects that we have been doing in Newcastle.
Just to summarise, I believe that our studies from Newcastle are beginning to confirm that there are autonomic abnormalities in patients with CFS/ME and fatigue associated disease which may ultimately provide a therapeutic target in this patient group. We have consistently been able to show brain, cardiac and muscle abnormalities using state of the art MR technologies and the important thing is that we are finding that are similar findings in fatigue associated chronic diseases. So lessons that we can learn from some fatigue associated diseases may be transferable to CFS/ME.
In conclusion I hope you agree that CFS/ME is a chronic disabling disease with genetic backgrounds triggered by infection with a link to psychosocial stressors. Fatigue is a common problem that affects patients with a range of chronic diseases and there are increasing amounts of evidence to support very specific physiological abnormalities which might ultimately inform treatments.
Symptoms are very common of autonomic dysfunction and there are objective abnormalities the degree of which are associated with fatigue severity. At the moment there are still no curative treatments, so there is still considerable work to be done and it is really important that we harness national and international expertise to ensure that this work ultimately leads to benefits for patients.
Finally I would like to thank the organisations that support our work: the MRC, Action for M.E., the Irish ME Trust, ME Research UK and the ME Association. Thank you.