Phoenix Rising- A Chronic Fatigue Syndrome (ME/CFS/FM) Newsletter (Feb 2008)

Dr. Holtorf on WebMD – WebMD – one of the largest medical information sources on the web – featured a story on low dose hormone (cortisol) supplementation by Dr. Holtorf, the founder of the Holtorf Medical Center. Dr. Holtorf developed the protocol the Fibro-Fatigue Centers use.

E-medicine ME/CFS section largely characterizes ME/CFS as an immune disease.

Jury Slams Insurance Company in CFS Lawsuit! – a San Diego jury slammed Prudential Insurance company for terminating a CFS/FM/Lupus patient’s disability payments. They found them liable for $14 million dollars in punitive damages – said to be an unusually high amount.

ProHealth Q&A Session (held Feb. 1) with Dr. Charles W. Lapp, MD. – a World Authority on ME/CFS/FM Evaluation and Management ImmuneSupport.com

ProHealth Chat Session with Cort Johnson (the publisher of this newsletter) – a much lesser authority. Still this very long chat session covered a multitude of topics including potential research breakthroughs, where the fatigue in ME/CFS may come from, the Ashok Gupta Amygdala program, the stress response, infection in ME/CFS, the CDC, the CAA and more.

Dr. Paul Cheney will be the opening speaker at the 15th International Symposium of Functional Medicine in Carlsbad, CA on Thursday May, 22. This is a high profile meeting with 800 to 1,000 attendees gathering from around the world for the four-day conference. In his talk “Chronic Fatigue Syndrome, Oxidative Stress, and Pain: A Physician’s Personal and Professional Journey Through the Functional Medicine Model” he will be presenting his current diagnostic and therapeutic model for CFS.

Chronic Fatigue Syndrome (ME/CFS) Treatment Trial. The University of Medicine and Dentistry of New Jersey, in cooperation with Jazz Pharmaceuticals, is recruiting people with CFS for a study of the effects of the sleep medication Xyrem. Details about the study appear on ClinicalTrials.gov.

The CFIDS Association of America (CAA) will have only the second Congressional briefing on ME/CFS in twelve years in 2008. They will invite a panel of CFS experts to discuss current research highlights and opportunities to shape funding requests and agency directives. There will be no Washington, D.C., Lobby Day but a Virtual (online) Lobby Day will take place. Stay in touch with them through the Grassroots Action Center listerv. Enroll today at https://capwiz.com/cfids/mlm/signup/ so you receive advance notice of events and regular updates on issues of interest.

Recognition for Chronic Fatigue Researcher Dr Rosamund Vallings, a longtime chronic fatigue syndrome researcher/physician (30 years!) was made a Member of the New Zealand Order of Merit in the New Year honours list. She is thought to be the only practitioner in New Zealand who specializes in ME/CFS.

The Whittemore-Peterson Neuro-immune Institute Website is up on line.

The CDC and Chronic Fatigue Syndrome: Altered Selves?

A Big Fish In A Small Pond: The Centers for Disease Control’s (CDC) chronic fatigue syndrome (ME/CFS) research program is not a large one by medical standards; it’s funding peaked at about 8 million dollars a year a couple of years ago and is now down to about $4,000,000 a year. But since the disbanding of the CFS Cooperative Research Centers in 2002 by the NIH it’s the only ‘large’ chronic fatigue syndrome (ME/CFS) research program in the United States. Indeed it and the Japanese program are the only ‘large’ ME/CFS research programs in the world.

Beside research the CDC has played the dominant role in defining chronic fatigue syndrome (ME/CFS) and an important role in elucidating the prevalence, economic costs and disability associated with the disease. It is the only federal institution that has a training program for physicians, it has the largest federal website on ME/CFS and it recently used ME/CFS to kick off it’s first ever media campaign on a disease.

All this activity means the CDC’s chronic fatigue syndrome (ME/CFS) team, lead by a Dr. Reeves, a vigorous if controversial figure, is a big fish in the small pond that is ME/CFS. What the CDC says has the potential, at least, to make a large difference in how ME/CFS is viewed. While the CDC has obviously never been in lock step with the ME/CFS research community some recent evidence suggests they are moving a new direction.

History: 2000-2007 – Since 2000 the CDC research team has been a pioneer in gene expression research and in using innovative, multi-disciplinary means to study ME/CFS. The Pharmacogenomic’s papers which combined data mining and information systems experts, geneticists and biologists set a benchmark for innovation. For the last five or six years the CDC CFS research team, originally composed mostly of virologists, has eschewed its immunological base to take a primarily neuroendocrine approach to the disease. As the CDC drifted away from immune research, however, the creation of the Peterson-Whittemore Neuro-immune Institute and Dr. Chia’s and Dr. Montoya’s findings suggest a new front on immune issues has opened.

The advent of a controversial new definition for ME/CFS (Empirical Definition) in 2005 indicated a substantial split between the With the advent of this theory paper the CDC’s research team appears ready to take its first more or less complete stab at explaining ME/CFS. CDC’s view of CFS and a significant group of other researchers has occurred. In an attempt to move from a fatigue to an ‘unwellness’ based definition the CDC discounted fatigue and added an emotional aspect to the definition for the first time. At the same time a coterie of other researchers mostly associated with International Association of Chronic Fatigue Syndrome/ME (IACFS/ME) were focusing more closely than ever on a special kind of fatigue called ‘post-exertional malaise’. As post-exertional malaise essentially disappeared from the CDC’s Empirical Definition of ME/CFS this group created pediatric and adult definitions which placed it front and center.

With the advent of Dr. Jones theory paper – the first by a CDC CFS researcher that I know of – the CDC’s research team appears ready to take its first more or less complete stab at explaining ME/CFS. This paper suggests that Dr. Jones, if not the CDC team itself, feels the pieces are beginning to come together. Dr. Reeves recent talk at the Nov. 07 CFSAC meeting suggests he is in agreement with at least the broad outlines of the paper. Given the CDC’s clout this paper is an important event in the field of ME/CFS research.

In this issue of Phoenix Rising we’ll first take a look at the theory paper and then provide Dr. Reeve’s overview of the CDC’s research program at the Nov CFSAC to get an overall direction of where this program is headed.

An Altered Self in CFS?

Jones, J. 2007. An extended concept of altered self: chronic fatigue and post-infection syndromes. Psychoneuroendocrinology. Feb;33(2):119-29.

This is the first CDC ‘theory’ paper I can remember reading. More designed to provoke discussion and thought than to explain CFS it focuses on a new interpretation of chronic fatigue syndrome (ME/CFS).

Dr. Jones first identifies what he believes chronic fatigue syndrome (ME/CFS) is and is not: is it a disease or an illness? A ‘disease’ (e.g. infectious mononucleosis) is a state of ill health characterized by ‘overtly abnormal findings’. An ‘illness’ is a state of poor health in which ‘overtly abnormal findings’ are not found; chronic fatigue syndrome, he believes, is an ‘illness’.

An ‘illness’ is a state of poor health in which ‘overtly abnormal findings’ are not found; chronic fatigue syndrome, he believes, is an ‘illness’.

To back up this characterization he notes the many ‘inconclusive’ attempts to tie CFS to a specific pathogen and the over 100 immune studies that, despite the immune alterations found, have often had inconsistent results. He also notes the HPA axis abnormalities and increasing evidence of sympathetic nervous system problems and the potential for these problems to cause immune disruption and autonomic and behavioral problems. Despite these abnormalities he believes chronic fatigue syndrome (ME/CFS) is an illness.

Dr. Jones doesn’t suggest that there are no abnormal findings in chronic fatigue syndrome (ME/CFS); he simply appears to believe they not ‘overtly abnormal’ enough or significant enough to cause an ‘illness’ of this severity.

Laymen’s Speculation – We can now point to many abnormalities in ME/CFS; NK cell dysfunction, low blood volume, low HPA axis dysfunction, brain atrophy, etc., very few of which appeared to have really ‘wowed’ the medical research community. Some appear to be only mildly abnormal (HPA axis functioning) while others may be too new (RNase L fragmentation, pathogen studies) for the research community to know what to do with. Some are just plain inconsistent (cytokine studies, etc.).

When taken in total he believes these abnormalities are important but they’re not so much important in and of themselves as what they signify. They indicate to him a failure of the brain to adapt that’s probably centered in the stress response system. This is where the HPA axis and autonomic nervous system and immune abnormalities come from; ME/CFS patient’s brains are not responding well to the everyday demands put on them – they’re basically stuck in a kind of maladaptive state.

An Altered ‘Immune Self’. In order to frame his ‘altered self’ theory Dr Jones introduces examples of the type of ‘self’ he is referring to. Several types of altered immune ‘selves’ have been found. One occurs in autoimmune disease in which the body mistakes itself for a pathogen and attacks itself. During an infection the immune system in conjunction with the brain produces a different kind altered ‘personal’ self which shows up in what researchers call ‘sickness behavior’.

The infectious illness process affects our physiology (fever, swollen glands), mental processes (slowed thinking), sensory system (fatigue) and emotions (irritability, a desire to be alone). Researchers speculate that these changes are the brains way of getting us to devote energy to getting well and isolate us in order to thwart the spread of infectious diseases. They have documented changes in the central nervous system (prefrontal cortex and anterior cingulate) that occur during ‘sickness behavior’. This is powerful evidence that far below our level of consciousness the brain can instill physical, mental and emotional states that it has decided will help us survive. Intriguingly brain imaging studies have documented abnormalities in these same regions in chronic fatigue syndrome (ME/CFS).

An Altered Central Nervous System Self – Given the similarity between ‘sickness behavior’ and ME/CFS its not surprising that the altered self that occurs during infection plays a key role in Dr. Jones theory. Symptomatically ME/CFS patients do look a lot like people with a chronic infection; they’re very fatigued, they’re sleepy, their muscles hurt, they’re a bit irritable, they have trouble thinking, and they often become quite isolated.

But while many cases of chronic fatigue syndrome (ME/CFS) start with an infection Dr. Jones believes a different kind of ‘altered self’ – an ‘extended altered self’ – is present. Why? Because studies have not consistently found the kinds of wildly altered immune processes known to create sickness behavior in infection. ME/CFS studies, for instance, that measure cytokines which are believed to be the chief agents of sickness behavior, have had inconsistent results. Dr. Jones believes something else is at play. That something else relies heavily on a relatively new theory about how the brain works called ‘interoception’

Focus On Interoception

Recent theories posit that a portion of the brain unique to humans (called the anterior insula) builds representations or pictures of the body. These ideas appear to have been prompted by the discovery of a set of very small nerves paralleling the sympathetic nervous system which deliver enormous amounts of information on the temperature, blood pressure, pH, lactic acid, histamine, serotonin, etc. levels in the body to the lower part of the brain. In humans the information appears to be sent to areas on both sides of the brain where researchers believe a picture is formed of the body’s functioning. They believe the brain uses this ‘picture’ to generate both conscious (emotional/cognitive) and unconscious responses (blood pressure, heart rate, etc.) to maintain the body’s well-being or homeostasis.

Researchers have just begun teasing out which parts of the brain are responsible for maintaining the different kinds of homeostasis found in the body. They are mostly found in the prefrontal cortex and anterior cingulate regions mentioned above and connect with areas in the midbrain and brainstem.

The Altered Self in Chronic Fatigue Syndrome. This interoceptive self is a third kind of self; one built by the brain to monitor and respond to the signals of the body. This is the ‘self’ that Dr. Jones believes is dysfunctional in chronic fatigue syndrome (ME/CFS). Dr. Jones theory suggests that at very deep level the brain has become confused or stuck in a maladaptive state. If I’m reading this right Dr Jones believes the brain

“this essay (is)…based on the premise that the illnesses in question stem from responses to previous infections and not to ongoing viral or immunologic factors”

still thinks the body has an infection and its sending out message consonant with this idea; it’s telling the body it’s fatigued, that it should slow down, that’s it dangerous to move, etc. It does this by prompting certain thoughts and by altering the physiology of the body. Dr. Jones believes the ‘sickness behavior’ found in chronic fatigue syndrome (ME/CFS) was once driven by an infection but is now being driven by the brain; it has become stuck in sickness mode. This brain driven process is causing many of the endocrine and immune abnormalities seen in ME/CFS.

Something must be causing this aberrant brain behavior and high up on the list of Dr. Jones suspects are immune processes in the brain. He proposes that future research projects examine ‘immune/inflammatory system products’, and both brain (and body) microglial cells and astrocytes as well as indications that the autonomic nervous system is altered. Microglial cells man the first line of immune defense in the central nervous system. Astrocytes are nerve cells.

Researchers are beginning to figure out why some individuals may be more disposed to enter in ‘sickness behavior’ mode than others. They’ve found, for instance, that a hyperactive stress response and increased levels of several cytokines (IL-6, TNF) appear to predispose cancer patients given the immune factor, Interferon alpha (IFN-a).

Since ‘sickness behavior’ is a ‘danger-driven’ process that activates the stress response many of the problems in ME/CFS could be due to a chronically activated stress response. These presumably include the HPA axis dysfunction, high rates of oxidative stress/inflammation, metabolic syndrome, NK cell dysfunction, autonomic nervous system abnormalities, etc. found in ME/CFS.

Given his belief that ME/CFS constitutes a failure by the brain to adapt it’s not surprising to see Dr. Jones propose that studies which challenge the different systems of the body are best suited to ME/CFS. He proposes that challenge experiments using brain imaging technology should, in particular, examine the areas of the brain involved in interpreting signals from the body and producing a response.

This is an intriguing idea because stress tests (fMRI’s, HPA axis stress tests. etc) have, in fact, generally been more successful at uncovering abnormalities than studies of the body when its at rest.

Treatment Dr. Jones targets two parts of the brain; the higher brain areas (prefrontal cortex) where the behavioral responses to the interoceptive picture of the body are generated, and the lower parts of the brain where the unconscious aspects of the interoceptive response (heart rate, breathing, blood chemistry, etc.) are regulated. He proposes that the

“the term ‘altered self’..constitutes in the case of a prolonged illness, a failure to adapt to a different state”.

therapy of choice should depend on which parts of the brain that brain imaging experiments indicate are impaired.

Abnormalities found in higher brain functioning would be meet with behavior therapies designed to challenge the maladaptive thoughts generated by the ‘wrong’ picture of the body. Abnormalities found in lower brain functioning that regulate breathing, heart rate, blood chemistry, etc. would be met with drugs, biofeedback or meditation. The ultimate goal would be to ‘break the ‘circle’ of chronic sickness behavior’ with all the connotations that the medical interpretation of behavior implies. The ultimate goal is to ‘return (the ME/CFS patient) to a functional self state’.

Editorial. Some chronic fatigue syndrome (ME/CFS) patients have questioned how Dr. Jones, a virologist by training, could be speaking on a field like interoception. The CDC’s original focus on chronic fatigue syndrome (ME/CFS) was on identifying the pathogen causing it and its program was placed in the viral division under the direction of several virologists (Dr. Reeves, Vernon, Jones). These researchers presumably would have loved to find a virus at the heart of this disorder. Rightly or wrongly at least Dr. Reeves and Dr. Jones no longer appear to believe this is true and they are looking elsewhere.

The senior members of CDC’s CFS research team are ending up spending a good deal of their careers on this disease. Like researchers everywhere their reputations will rise and fall on the strength of their ideas. While their conception may be disturbing to some patients they should be examined in the context of a group of researchers who’ve taken a long look at this disease. They may be right or they may wrong but their ideas should never be discarded out of hand.

Dr. Reeves Report to the Chronic Fatigue Syndrome Advisory Panel on the CDC’s CFS Research Program. Nov, 2007

Dr. Reeves report suggests that the CDC’s understanding of chronic fatigue syndrome (ME/CFS) is in congruence with many of Dr. Jones ideas. He reports that ME/CFS, for instance, is highly associated with increased stress. The markers of ‘allostatic load’ which measures the body’s ability to adapt to stress, are six times higher in ME/CFS patients than in the general population.

How ME/CFS occurs is unclear but Dr. Reeves believes it is an ‘adaptation disorder’ that is associated with ‘early adverse experiences’ which can range from childhood abuse, infections, malnutrition and surgery. Whatever the initiating problem the focus is on ‘early’; this is presumably a necessary corollary of the allostatic load concept which requires that an accumulation of insults occur over time. This is possibly why the rates of CFS – as do many chronic systemic diseases – rise over time; incidence is lowest in childhood, higher in adolescents and appears to peak in middle age. “People with CFS are six times more likely…to have suffered severe childhood trauma…People with CFS also have about a six-fold excess of allostatic load – a physiologic marker of accumulated stress”

The allostatic stress paradigm also suggests why Dr. Reeves believes that chronic fatigue syndrome (ME/CFS) is the type of illness that leads to disease. These diseases (metabolic syndrome ???) presumably occur when after years of a dysfunctional stress response different facets of the body finally break down. The CDC’s detailed documentation of their study populations has revealed ME/CFS patients have a high incidence of other (usually untreated) physical problems.

The pattern of cognitive problems in ME/CFS suggests damage has occurred to the parts of the brain Dr. Jones referred to; the circuits that link the frontal cortex and the basal ganglia. Abnormalities in brain wave patterns during sleep suggest problems with ‘sleep homeostasis’ or attaining normal sleep are present. The faster heart rates, lower heart rate variability,

• Hot Links:
• Allostatic stress in ME/CFS
• The Autonomic Nervous System in ME/CFS

lower plasma aldosterone and higher plasma norepinephrine are all suggestive of increased sympathetic nervous system (fight or flight) and reduced parasympathetic nervous system (rest and digest) activity.

This suggests the bodies of ME/CFS patients are ‘on alert’ – a status, as was just noted, that could over time lead to problems with well-being. Low cortisol levels suggest abnormalities in the other main stress response system; the HPA axis. The underperformance of the HPA axis could conceivably be caused by earlier over activation of that system.

Dr. Reeves noted that two different kinds of stress are handled somewhat differently; one (anticipation, fear of getting beaten, etc.) is perceived through the frontal lobes while the other (infection, hypothermia, etc.) comes up through the brainstem. They both meet, however, at the top of the HPA axis in the hypothalamus, which then affects the immune system, etc. The CDC is currently examining how the brains of ME/CFS function during mental activities. They are honing in the basal ganglia; an area governing movement, cognition and emotion.
“There are reproducible changes in the brain during stress testing, which we believe…may differentiate CFS from non-CFS. We’re particularly interested in the basal ganglia..”
Thus the CDC’s paradigm appears, at least indirectly, to include the possibility of immune dysfunction but puts its source in the brain not in an infection. This immune dysfunction could, of course, increase the risk for infection. Given this it’s intriguing that ME/CFS researchers typically focus on opportunistic pathogens present in our everyday environment or latent in our bodies (EBV, HHV-6, enteroviruses).

The CDC’s current research efforts include (1) identifying brain regions using fMRI’s associated with fatigue, cognitive function and autonomic nervous system functioning in ME/CFS patients. (2) Using brain imaging to characterize how ME/CFS patients brains function during tests measuring reaction times, sustained attention and memory. (3) Continue to characterize the functioning of the stress response by measuring cortisol, the autonomic nervous system, cytokines and gene expression during stress tests.

Takeaway Points

Dr. Jones believes ME/CFS patients brains are reacting to their bodies as if they still have the infection that triggered their illness.

This causes their brains to produce an illness state in ME/CFS (called sickness behavior) very similar to that found in infection.

This chronic state of brain-driven ‘sickness behavior’ results in the stress response being constantly turned on, which, in turn, causes the HPA axis, natural killer cell and other abnormalities seen.

Over time these chronically activated systems lead to numerous (mostly undiagnosed) health problems in the ME/CFS population.

Depending on which parts of the brain are effected behavioral therapies, meditation or drugs are suggested as treatments.

The CDC is testing its theory by using brain imaging to determine if the parts of the brain that analyze signals coming from the body are responding normally in ME/CFS patients.