Wednesday, October 29, 2014

Stanford study finds brain abnormalities in ME/CFS patients

Image courtesy Pixabay
Press Release: Eurekalert, October 29, 2014. An imaging study by Stanford University School of Medicine investigators has found distinct differences between the brains of patients with chronic fatigue syndrome and those of healthy people.

The findings could lead to more definitive diagnoses of the syndrome and may also point to an underlying mechanism in the disease process.

It's not uncommon for CFS patients to face several mischaracterizations of their condition, or even suspicions of hypochondria, before receiving a diagnosis of CFS. The abnormalities identified in the study, to be published Oct. 29 in Radiology, may help to resolve those ambiguities, said lead author Michael Zeineh, MD, PhD, assistant professor of radiology.

"Using a trio of sophisticated imaging methodologies, we found that CFS patients' brains diverge from those of healthy subjects in at least three distinct ways," Zeineh said.

CFS affects between 1 million and 4 million individuals in the United States and millions more worldwide. Coming up with a more precise number of cases is tough because it's difficult to actually diagnose the disease. While all CFS patients share a common symptom — crushing, unremitting fatigue that persists for six months or longer — the additional symptoms can vary from one patient to the next, and they often overlap with those of other conditions.

Scientific Challenge

"CFS is one of the greatest scientific and medical challenges of our time," said the study's senior author, Jose Montoya, MD, professor of infectious diseases and geographic medicine. "Its symptoms often include not only overwhelming fatigue but also joint and muscle pain, incapacitating headaches, food intolerance, sore throat, enlargement of the lymph nodes, gastrointestinal problems, abnormal blood-pressure and heart-rate events, and hypersensitivity to light, noise or other sensations."

The combination of symptoms can devastate a patient's life for 10, 20 or even 30 years, said Montoya, who has been following 200 CFS patients for several years in an effort to identify the syndrome's underlying mechanisms. He hopes to accelerate the development of more-effective treatments than now exist. (A new Stanford Medicine magazine story describes the study in more detail.)

"In addition to potentially providing the CFS-specific diagnostic biomarker we've been desperately seeking for decades, these findings hold the promise of identifying the area or areas of the brain where the disease has hijacked the central nervous system," Montoya said.

"If you don't understand the disease, you're throwing darts blindfolded," said Zeineh. "We asked ourselves whether brain imaging could turn up something concrete that differs between CFS patients' and healthy people's brains. And, interestingly, it did."

The Stanford investigators compared brain images of 15 CFS patients chosen from the group Montoya has been following to those of 14 age- and sex-matched healthy volunteers with no history of fatigue or other conditions causing symptoms similar to those of CFS.

Three Key Findings

The analysis yielded three noteworthy results, the researchers said. First, an MRI showed that overall white-matter content of CFS patients' brains, compared with that of healthy subjects' brains, was reduced. The term "white matter" largely denotes the long, cablelike nerve tracts carrying signals among broadly dispersed concentrations of "gray matter." The latter areas specialize in processing information, and the former in conveying the information from one part of the brain to another.

That finding wasn't entirely unexpected, Zeineh said. CFS is thought to involve chronic inflammation, quite possibly as a protracted immunological response to an as-yet unspecified viral infection. Inflammation, meanwhile, is known to take a particular toll on white matter.

But a second finding was entirely unexpected. Using an advanced imaging technique — diffusion-tensor imaging, which is especially suited to assessing the integrity of white matter — Zeineh and his colleagues identified a consistent abnormality in a particular part of a nerve tract in the right hemisphere of CFS patients' brains. This tract, which connects two parts of the brain called the frontal lobe and temporal lobe, is called the right arcuate fasciculus, and in CFS patients it assumed an abnormal appearance.

Furthermore, there was a fairly strong correlation between the degree of abnormality in a CFS patient's right arcuate fasciculus and the severity of the patient's condition, as assessed by performance on a standard psychometric test used to evaluate fatigue.

Right vs. Left

Although the right arcuate fasciculus's function is still somewhat mysterious, its counterpart in the brain's left hemisphere has been extensively explored. The left arcuate fasciculus connects two critical language areas of the left side of the brain termed Wernicke's and Broca's areas, which are gray-matter structures several centimeters apart. These two structures are important to understanding and generating speech, respectively. Right-handed people almost always have language organized in this fashion exclusively in the left side of the brain, but the precise side (left or right) and location of speech production and comprehension are not so clear-cut in left-handed people. (It's sometimes said that every left-hander's brain is a natural experiment.) So, pooling left- and right-handed people's brain images can be misleading. And, sure enough, the finding of an abnormality in the right arcuate fasciculus, pronounced among right-handers, was murky until the two left-handed patients and four left-handed control subjects' images were exempted from the analysis.

Bolstering these observations was the third finding: a thickening of the gray matter at the two areas of the brain connected by the right arcuate fasciculus in CFS patients, compared with controls. Its correspondence with the observed abnormality in the white matter joining them makes it unlikely that the two were chance findings, Zeineh said.

Although these results were quite robust, he said, they will need to be confirmed. "This study was a start," he said. "It shows us where to look." The Stanford scientists are in the planning stages of a substantially larger study.


Additional Stanford co-authors are former medical fellow James Kang, MD, now a neuroradiologist in Hawaii; former professor of radiology and chief of neuroradiology Scott Atlas, MD, now a senior fellow at the Stanford-affiliated Hoover Institution; professor of radiology and of psychiatry and behavioral sciences Allan Reiss, MD; lead scientific programmer Mira Raman; physician assistant Jane Norris; and social-science research assistant Ian Valencia.

The study was supported by GE Healthcare and by the CFS Fund, which is housed in the Stanford Department of Medicine's Division of Infectious Diseases. Information about Stanford's Department of Radiology, which also supported this work, is available at

Thursday, October 16, 2014

AHRQ Evidence Review - Comments From the Advocates

This post comes via Mary Dimmock, Claudia Goodell, Denise Lopez-Majano, and Jennie Spotila. You are welcome to publish it on your site with attribution and a link back to Jennie's post. You are also welcome to use this (and other material they’ve gathered) as a framework for your own comments on the draft evidence review - due October 20th.

Evidence Review Comments Preview

From Occupy CFS, October 15, 2014

By Jennie Spotila

It’s been a challenging few weeks, digesting and analyzing the AHRQ Draft Systematic Evidence Review on Diagnosis and Treatment of ME/CFS. We continue to be deeply concerned about the many flaws in the review, in terms of both the approach it took and how it applied the study protocol.

Our comments on the Review will reflect our significant concerns about how the Evidence Review was conducted, the diagnostic, subgroup, and harms treatment conclusions drawn by this report, and the risk of undue harm that this report creates for patients with ME. We believe a final version should not be published until these scientific issues are resolved.

Most fundamentally, the Evidence Review is grounded in the flawed assumption that eight CFS and ME definitions all represent the same group of patients that are appropriately studied and treated as a single entity or group of closely related entities. Guided by that assumption, this Evidence Review draws conclusions on subgroups, diagnostics, treatments and harms for all CFS and ME patients based on studies done in any of these eight definitions. In doing so, the Evidence Review disregards its own concerns, as well as the substantial body of evidence that these definitions do not all represent the same disease and that the ME definitions are associated with distinguishing biological pathologies. It is unscientific, illogical and risky to lump disparate patients together without regard to substantive differences in their underlying conditions.

Compounding this flawed assumption are the a priori choices in the Review Protocol that focused on a more narrow set of questions than originally planned and that applied restrictive inclusion and exclusion criteria. As a result, evidence that would have refuted the flawed starting assumption or that was required to accurately answer the questions was never considered. Some examples of how these assumptions and protocol choices negatively impacted this Evidence Review include:
  • Evidence about the significant differences in patient populations and in the unreliability and inaccuracy of some of these definitions was ignored and/or dismissed. This includes: Dr. Leonard Jason’s work undermining the Reeves Empirical definition; a study that shows the instability of the Fukuda definition over time in the same patients; studies demonstrating that Fukuda and Reeves encompass different populations; and differences in inclusion and exclusion criteria, especially regarding PEM and psychological disorders.
  • Diagnostic methods were assessed without first establishing a valid reference standard. Since there is no gold reference standard, each definition was allowed to stand as its own reference standard without demonstrating it was a valid reference.
  • Critical biomarker and cardiopulmonary studies, some of which are in clinical use today, were ignored because they were judged to be intended to address etiology, regardless of the importance of the data. This included most of Dr. Snell’s and Dr. Keller’s work on two day CPET, Dr. Cook’s functional imaging studies, Dr. Gordon Broderick’s systems networking studies, Dr. Klimas’s and Dr. Fletcher’s work on NK cells and immune function, and all of the autonomic tests. None of it was considered.
  • Treatment outcomes associated with all symptoms except fatigue were disregarded, potentially resulting in a slanted view of treatment effectiveness and harm. This decision excluded Dr. Lerner’s antiviral work, as well as entire classes of pain medications, antidepressants, anti-inflammatories, immune modulators, sleep treatments and more. If the treatment study looked at changes in objective measures like cardiac function or viral titers, it was excluded. If the treatment study looked at outcomes for a symptom other than fatigue, it was excluded.
  • Treatment trials that were shorter than 12 weeks were excluded, even if the treatment duration was therapeutically appropriate. The big exclusion here was the rituximab trial; despite following patients for 12 months, it was excluded because administration of rituximab was not continuous for 12 weeks (even though rituximab is not approved for 12 weeks continuous administration in ANY disease). Many other medication trials were also excluded for not meeting the 12 week mark.
  • Counseling and CBT treatment trials were inappropriately pooled without regard for the vast differences in therapeutic intent across these trials. This meant that CBT treatments aimed at correcting false illness beliefs were lumped together with pacing and supportive counseling studies, and treated as equivalent.
  • Conclusions about treatment effects and harms failed to consider what is known about ME and its likely response to the therapies being recommended. This means that the PACE (an Oxford study) results for CBT and GET were not only accepted (despite the many flaws in those data), but were determined to be broadly applicable to people meeting any of the case definitions. Data on the abnormal physiological response to exercise in ME patients were excluded, and so the Review did not conclude that CBT and GET could be harmful to these patients (although it did allow it might be possible).
  • The Evidence Review states that its findings are applicable to all patients meeting any CFS or ME definition, regardless of the case definition used in a particular study.
The problems with this Evidence Review are substantial in number, magnitude and extent. At its root is the assumption that any case definition is as good as the rest, and that studies done on one patient population are applicable to every other patient population, despite the significant and objective differences among these patients. The failure to differentiate between patients with the symptom of subjective unexplained fatigue on the one hand, and objective immunological, neurological and metabolic dysfunction on the other, calls into question the entire Evidence Review and all conclusions made about diagnostic methods, the nature of this disease and its subgroups, the benefits and harms of treatment, and the future directions for research.

As the Evidence Review states, the final version of this report may be used in the development of clinical practice guidelines or as a basis for reimbursement and coverage policies. It will also be used in the P2P Workshop and in driving NIH’s research strategy. Given the likelihood of those uses and the Evidence Review’s claim of broad applicability to all CFS and ME patients, the flaws within this report create an undue risk of significant harm to patients with ME and will likely confound research for years to come. These issues must be addressed before this Evidence Review is issued in its final form.

Thursday, October 2, 2014

How to Oppose the P2P (Without Chaining Yourself to the White House Fence)

Disability rights activists chained themselves to the White House fence in 2009
There is no doubt in the minds of those who have been following the various means by which the HHS has consistently and callously acted against the interests of patients with ME/CFS over the last thirty years that the latest government initiatives - the P2P and IOM - do not bode well for us.

In spite of its seeming interest in our welfare, we should keep in mind who saddled us with a vague, inaccurate case definition, and a demeaning name, to start with.

The P2P is potentially the more damaging of the two initiatives, because it was sponsored by the NIH, which controls all major funding for medical research. (Find out more ... click HERE.)

ME/CFS is already grossly underfunded. Once this group of non-experts is done with their review, we will most certainly follow in the footsteps of Great Britain in its wholesale and uncritical adoption of CBT and GET as the only effective treatments for the disease. We will, in fact, no longer have a disease, but will be permanently and irrevocably reduced to having a mental condition that can be cured with a better attitude and a little fresh air.

There is no single right way to oppose the P2P. But there is a wrong way.

Saying nothing at all.

Silence on this important matter equals agreement. If we don't weigh in, nobody will do it for us. Even if you believe that resistance is futile, you will feel better if you express yourself than if you don't.

Does protesting really make a difference?

During my anti-war activist days, we were told repeatedly that nobody was paying attention to us. Years later we learned that public outcry - our public outcry - had prevented Nixon from dropping an A-bomb on Vietnam. History has demonstrated time and time again that protest can topple even the most entrenched institutions.

People with ME/CFS often feel as if nobody listens because physicians, friends, and even family members dismiss us. Government officials and representatives don't know that. They only know that an issue is important enough for you to tweet or send an email - and that you vote. They realize that for every citizen who bothers to communicate with them, there are a hundred who haven't. Sending a thousand tweets can have a huge effect.

Each of us may only be a single drop in an ocean - but an ocean is made up of nothing but drops. The important thing is to continue gathering those drops together until we've made a wave.

What we can do

Here are four things we can do that don't require much effort (see template below), and take up very little time.

1) Comment. The P2P has invited comments on its draft report. I really love it when people on these committees ask for comments. It gives me an opportunity to put my opposition on record, and to tell them all the ways in which they are wrong. Comments will be closed after October 20.  CLICK HERE to make a comment.
Need ammunition for your comment? Jennie Spotila has posted a critique of the review stressing three main problems. Feel free to use her points in your comments: 
A Review of the P2P Systematic Review 
You can also use any part - or all - of my critiqueThe AHRQ Draft Report
2) Tweet. Every Saturday there is a "Stop P2P for ME" tweetstorm. Tweeting is fast, and it's fun. Use the hashtag: #StopP2P4ME. CLICK HERE for sample tweets that you can copy and paste, along with @ targets.

3) Email your representatives. This is still a democracy, and our representatives are supposed to represent us. That means they must listen to what we have to say. Even if you get a form letter in reply, somebody had to read your email to send it. Remind your representative that you vote.
Find your representatives hereYou can get their phone numbers here.

4) Boycott. Boycotting the process is fine, but boycotts are useless unless you tell people about it. You need to explain why you aren't participating - otherwise you are simply remaining silent, which is not constructive. You can email Dr. Francis Collins letting him know that the entire P2P Workshop on ME/CFS needs to be canceled.

Below is a template for a letter to your representative, and/or to Dr. Francis Collins (head of the NIH):

Feel free to copy and paste, and to add anything else you have to say.

I am writing to request the cancellation of the P2P Workshop on ME/CFS. I believe that the P2P Workshop will not advance us towards the much needed ME/CFS research case definition or strategy, for the following reasons:
  • ME/CFS experts have already adopted the Canadian Case Definition for research. No new definition is needed.
  • The Workshop is examining the wrong illness. They are examining "medically unexplained fatigue," not ME/CFS.
  • NIH has not engaged or involved stakeholders in a substantive way.
  • The Workshop panel consists of non-ME/CFS experts.
  • HHS has made numerous contradictory statements about the purpose of the Workshop, so its goal is unclear.
  • The recent draft report from AHRQ is inaccurate, self-contradictory, and reflects a poor understanding of ME/CFS research
Careful consideration of the above issues raises legitimate concerns about whether the P2P Workshop will produce good science and sound recommendations.

I hope you will give my concerns a fair hearing, and that you will cancel the P2P Workshop.


[Your name]

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