Tuesday, July 22, 2014

P2P: The Question They Will Not Ask

The P2P (Pathways to Prevention) Panel was originally convened to examine case definitions for ME/CFS and to address differences between ME and CFS.

The examination of differences relates directly to case definition. The CDC (Fukuda) definition, for example, is broad enough to encompass people with deconditioning and depression, as well as most early cases of MS.

The Canadian Consensus Criteria for ME, on the other hand, includes people with more neurological symptoms and physical impairment (e.g. PEM).

The disease that specialists in the US call "CFS" is actually ME. Whereas the condition that most non-specialists (and many researchers) call "CFS" could be just about anything.

The disease definition provides the foundation for diagnosis, research, and treatment. So, why was the question "How are ME and CFS different?" abandoned?

Reprinted with permission from Occupy CFS

P2P: The Question They Will Not Ask

by Mary Dimmock and Jennie Spotila

The most important question about ME/CFS – the question that is the cornerstone for every aspect of ME/CFS science – is the question that the P2P Workshop will not ask:

How do ME and CFS differ? Do these illnesses lie along the same continuum of severity or are they entirely separate with common symptoms? What makes them different, what makes them the same? What is lacking in each case definition – do the non-overlapping elements of each case definition identify a subset of the illness or do they encompass the entirety of the population?

Boiled down to its essence, this set of questions is asking whether all the “ME/CFS” definitions represent the same disease or set of related diseases. The failure to ask this question puts the entire effort at risk.

This fundamental question was posed in the 2012 application for the Office of Disease Prevention to hold the P2P meeting (which I obtained through FOIA). It was posed in the 2013 contract between AHRQ and the Oregon Health & Science University for the systematic evidence review (which I obtained through FOIA). It was posed to the P2P Working Group at its January 2014 meeting to refine the questions for the evidence review and Workshop (according to Dr. Susan Maier at the January 2014 Institute of Medicine meeting).

And then the question disappeared.

The systematic evidence review protocol does not include it. Dr. Beth Collins-Sharp said at the June 2014 CFSAC meeting that the Evidence Practice Center is not considering the question because there is “not enough evidence” in the literature to answer the question. However, she said that the P2P Workshop could still consider the question.

But the draft agenda for the Workshop does not include it. Furthermore, every aspect of the P2P Workshop treats “ME/CFS” as a single disease:

  • The P2P description of ME/CFS refers to it as a single disorder or illness throughout the meeting webpage.
  • The P2P website characterizes the names myalgic encephalomyelitis and chronic fatigue syndrome as synonymous.
  • Every section of the Workshop agenda lumps all the populations described by the multiple case definitions together, discussing prevalence, tools, subsets, outcomes, presentation, and diagnosis of this single entity.
A 20-minute presentation on “Case Definition Perspective” is the only lip service paid to this critical issue. This is completely inadequate, if for no other reason than because the presentation is isolated from discussions on the Workshop Key Questions and dependent topics like prevalence and natural history. As a result, it is unlikely to be thoroughly discussed unless one of the Panelists has a particular interest in it.

Why is this problematic? Because both the P2P Workshop and the evidence review are based on the assumption that the full set of “ME/CFS” case definitions describe the same disease. This assumption has been made without proof that it is correct and in the face of data that indicate otherwise, and therein lies the danger of failing to ask the question.

What if the case definitions do not actually describe a single disease? If there are disparate conditions like depression, deconditioning, non-specific chronic fatigue and a neuroimmune disease characterized by PEM encompassed by the full set of “ME/CFS” definitions, then lumping those together as one entity would be unscientific.

The most important part of designing scientific studies is to properly define the study subjects. One would not combine liver cancer and breast cancer patients into a single cohort to investigate cancer pathogenesis. The combination of those two groups would confound the results; such a study would be meaningful only if the two groups were separately defined and then compared to one another to identify similarities or differences. The same is true of the P2P evidence review of diagnostics and treatments: assuming that all “ME/CFS” definitions capture the same disease (or even a set of biologically related diseases) and attempting to compare studies on the combined patients will yield meaningless and confounded results if those definitions actually encompass disparate diseases.

There is a growing body of evidence that underscores the need to ask the fundamental question of whether “ME/CFS” definitions represent the same disease:

· The P2P Workshop is focused on “extreme fatigue” as the defining characteristic of “ME/CFS,” but fatigue is a common but ill-defined symptom across many diseases. Further, not all “ME/CFS” definitions require fatigue or define it in the same way. For instance, Oxford requires subjective fatigue, and specifically excludes patients with a physiological explanation for their fatigue. But the ME-ICC does not require fatigue; instead it requires PENE, which is defined to have a physiological basis.

- When FDA asked CFS and ME patients to describe their disease, we did not say “fatigue.” Patients told FDA that post-exertional malaise was the most significant symptom: “complete exhaustion, inability to get out of bed to eat, intense physical pain (including muscle soreness), incoherency, blacking out and memory loss, and flu-like symptoms.”

- Multiple studies by Jason, Brenu, Johnston and others have demonstrated significant differences in disease severity, functional impairment, levels of immunological markers and patient-reported symptoms among the different case definitions.

 - Multiple studies have demonstrated that patients with PEM have impairment in energy metabolism and lowered anaerobic threshold, and have shown that patients with depression, deconditioning and a number of other chronic illnesses do not have this kind of impairment.

 - Multiple studies have demonstrated differences in exercise-induced gene expression between Fukuda/CCC patients and both healthy and disease control groups.

- The wide variance in prevalence estimates shines a light on the case definition problem. Prevalence estimates for Oxford and Empirical populations are roughly six times higher than the most commonly accepted estimate for Fukuda. Even Fukuda prevalence estimates vary widely, from 0.07% to 2.6%, underscoring the non-specificity of the criteria. Nacul, et al., found that the prevalence using CCC was only 58% of the Fukuda prevalence. Vincent, et al., reported that 36% of Fukuda patients had PEM, representing a smaller population that would be eligible for diagnosis under CCC.

- The work of Dr. Jason highlights the danger of definitions that include patients with primary psychiatric illnesses, especially because such patients may respond very differently to treatments like CBT and GET.

By contrast, there have not been any published studies that demonstrate that the set of “ME/CFS” definitions being examined in P2P encompass a single entity or biologically related set of entities. From Oxford to Fukuda to ME-ICC, there are significant differences in the inclusion and exclusion criteria, including differences in the exclusion of primary psychiatric illness. The magnitude of these differences makes the lack of such proof problematic.

Given that treating all “ME/CFS” definitions as a single entity is based on an unproven assumption of the clinical equivalence of these definitions, and given that there is ample proof that these definitions do not represent the same disease or patient population, it is essential that the P2P “ME/CFS” study start by asking this question:

Does the set of “ME/CFS” definitions encompass the same disease, a spectrum of diseases, or separate, discrete conditions and diseases?

The failure to tackle this cornerstone question up-front in both the agenda and the evidence review puts the scientific validity of the entire P2P Workshop at risk. If this question is not explicitly posed, then the non-ME/CFS expert P2P Panel will swallow the assumption of a single disorder without question, if for no other reason than that they do not know the literature well enough to recognize that it is an assumption and not established fact.

Friday, July 18, 2014

The Diagnosis of Chronic Fatigue Syndrome: An Assertive Approach by Dr. Paul R. Cheney and Dr. Charles Lapp

This paper (below) by Dr. Paul Cheney and Dr. Charles Lapp was written more than two decades ago. It contains detailed descriptions of numerous test abnormalities found in ME/CFS patients, all which can be used for diagnosis.

In spite of the fact that these (and other) objective findings have been noted by specialists for decades, the CDC has not made any of these criteria available to the broader medical community. It is equally as incomprehensible that in spite of these findings - described in great detail in the Cheney/Lapp paper - we now have two federal initiatives involving the diagnosis of ME/CFS, neither of which has taken into account the numerous objective markers for the disease. 

Thirty years after the Incline Village outbreak, the myth still persists that ME/CFS cannot be diagnosed using objective measurements (which are still considered "controversial").  ME/CFS is still described as "mysterious." And it is still a waste-basket diagnosis.

Dr. Cheney and Dr. Lapp were not ahead of their time. The problem is that all of our institutions lag far behind.

The Diagnosis of Chronic Fatigue Syndrome: An Assertive Approach by Paul R. Cheney, MD, PhD and W. Charles Lapp, MD, FAAP

Introduction: The Case for Diagnosis by Objective Criteria

Over the past ten years, a considerable and diverse medical literature has arisen concerning the chronic fatigue syndrome (CFS). Like all medical literature written on an emerging disorder, these published findings include a range of views and some discrepancies.

Systematic errors exist among the tools used to discern differences between CFS cases and "healthy" controls. The central problem, however, is case selection. Many patients with CFS are excluded from studies because they seem "too sick" to have CFS and are perceived as having something else. CFS cases are mixed in with non-cases. Inappropriate controls are sometimes used. Some investigators, aware or unaware of a bias, attract or include in their studies the very patients who best fit their view of CFS. This so-called selection bias can markedly affect the observations of a study. Despite these discrepancies, a more or less consistent pattern of observable abnormalities has emerged and we believe a case definition using objective abnormalities can now be defended.

Having stated the inherent problems with CFS research, we will attempt to defend an assertive approach (i.e.,diagnosis by inclusion) to the diagnosis of CFS using the available medical literature to support it. This is a different approach from just applying the Centers for Disease Control (CDC) case definition, which in essence defines a sign-symptom complex in the absence of a "known medical illness" (i.e., diagnosis by exclusion). The medical evidence cited for CFS asserts that the following are present more or less in every patient during the course of his or her disease: T-cell activation, discrete immune defects, viral activation or re-activation, exercise-related dysfunction, and evidence of brain dysfunction or injury. While none of these tests can stand alone to "diagnose" the illness, an array of these tests can be used to support this diagnosis, given the proper clinical context derived through the application of the CDC case definition. The use of non-specific tests to defend or support a diagnosis is a time-honored tradition in medicine, and the concept is used to diagnose such disorders as multiple sclerosis, lupus erythematosus, acute infectious mononucleosis, and even AIDS.

There are a number of criticisms given for using nonspecific tests in the diagnosis of CFS. They include the following:

(1) We lack a gold standard for determining this disorder and therefore lack a means to test the relative value of certain tests (i.e., false positive and false negative rates).

This is certainly a valid point in confirming a diagnostic test, but it is not a valid criticism in using a non-specific test to support a clinical impression. If a test abnormality has been shown in the medical literature to be associated with a certain disease, such as a positive ANA in lupus, then it is valid test to be used in supporting a clinical diagnosis. Furthermore, as in the "diagnostic" tests for the hepatitis C virus and the Lyme agent, poor test performance may be ignored in the case where benefits, however defined, outweigh poor performance.

(2) Even if there are test abnormalities which can be associated with CFS there is no need to make a more definitive diagnosis because there is no treatment for the disease.

If this were a valid argument, then it would also apply to multiple sclerosis, many cancers, acute infectious mononucleosis, and even AIDS. Documentation of an illness by objective criteria is important not only to confirm the diagnosis, but also to reassure the patient about other disorders they may or may not have. Reassurance is itself therapeutic and proportional to the degree of objective support found for a diagnosis.

Though there may be no scientifically validated treatment options for CFS (a situation which may soon change with the recent conclusion of the Ampligen trials), there are many therapeutic rationales based on test abnormalities which can defend empiric therapy. Such rationale exist for T-cell activation, certain immune deficiency states, herpes-group virus reactivation and even nonspecific brain injury. In the everyday practice of medicine, empiric therapy is often warranted in severe or functionally devastating illness. It is common practice to use unproven but rational therapies to treat clinical diagnoses such as a migraine, PAS, atypical depression, and many other disorders. Finally, documentation of abnormalities associated with CFS can assist the patient in disability arguments.

Disability Law Judges almost never respond favorably to disabling disorders without objective findings. This is even more the case for emerging disorders. The ability to successfully argue for disability is an extremely important aspect of therapy for this disorder. We have several examples of patients coming off disability and returning to work in part because the disability concept can itself be therapeutic.

(3) CFS is a "self-limited illness" which nearly always responds to rest, good nutrition, and proper exercise. As such, little is gained from extensive testing other than to disprove the presence of other disorders.
This misperception of CFS patients is pervasive among many clinicians and the lay public. A debilitating illness lasting years or longer is in fact not self-limited, and it deserves considerable medical attention. Some patients appear to be permanently disabled by this disorder. It may not completely or permanently resolve even in most patients who do see improvement over time. There are theoretical reasons to be concerned and vigilant about long-term health issues in all CFS patients.

Also, and intuitively, it seems to us to be helpful to intervene early in the course of CFS, even if only to dispel the false idea that any exercise will help this disorder and to counsel patients on lifestyle adjustment and symptom relief, especially for sleep disorder. Good documentation of this disorder lays the groundwork for future empiric intervention should it be necessary and gives a baseline with which to compare future results.

The CDC Case Definition

A case definition for CFS proposed by researchers at the CDC and elsewhere was published in 1988 1 . This clinical case definition consists of both major (all must be met) and minor (some but not all must be met) criteria. Difficulties in the application of this case definition include: How does one define a 50 percent or greater reduction in activity? Exactly how far does one go to exclude other disorders? What does one do with patients with remote onset--say in childhood—of chronic fatigue who would be excluded by the current case definition? Should some minor criteria be moved to major criteria and others dropped entirely? What does one do with patients who have confounding medical and psychiatric problems which might explain some if not all of their symptoms? What does one do with patients who lack severity criteria or sufficient signs and symptoms? What signs or symptoms and what other objective tests should be added to sharpen the diagnosis?

While some of these questions have been partially addressed by the authors of the CDC case definition, most persist and are handled differently by different investigators. Despite the problems with the present case definition, we believe that it generally functions to separate most cases from possible or probable non-cases. We recommend continued use of the criteria but designate probable non-cases who meet criteria and probable cases who do not meet criteria as atypical cases or non-cases of CFS.

Further subdivision of atypical cases by severity and confounding medical or psychiatric issues is probably a worthwhile endeavor and has been adopted by the CDC in their surveillance studies.

Clinical Observations Helpful in the Diagnosis of CFS

We have had the opportunity to make a number of clinical observations in over 1,200 cases of CFS which we believe are helpful in the diagnosis of CFS. None of these findings can be used individually to diagnose a case, but they add collective weight to the final clinical judgment. Some patients will have a normal physical examination and many will have essentially normal routine laboratory values.

Physical Findings - Contrary to suggestions by some investigators, abnormalities on physical examination, although sometimes subtle, are usually present:
  1. Fever at or above 99.2 F in 38% of patients
  2. Subnormal temperatures
  3. Intermittent tachycardia
  4. Low blood pressures
  5. Abnormal oral pharynx exam, including: buccal mucosal ulcerations; posterior cobblestoning, erythema and "crimson crescents" over soft palate; tongue coatings or blisters; and rare thrush
  6. Fluctuating anisocoria over time in dim light
  7. Photophobia
  8. End gaze nystagmus
  9. Posterior cervical lymphadenia with slight, palpable enlargement, usually asymmetric
  10. Axillary lymphadenia with slight, palpable enlargement, usually asymmetric
  11. Tender points typical for fibromyalgia
  12. Mild to severe skin atrophy of distal finger tips, loss of fingerprints
  13. Diffuse abdominal tenderness
  14. Hyperreflexia is very common, worse in lower extremities, and with occasional unsustained clonus
  15. Mild tremulousness on drift testing
  16. Intention tremor
  17. Mitral valve prolapse
  18. Sallow skin tone
  19. Brittle, thinning hair with reddish tint
  20. Excessive titubation or actual inability to maintain Romberg or tandem stance and tandem walk (probably represents an apraxia or vestibular disturbance and very common in these patients)
  21. Tentativeness or inability to serial seven subtract, especially while attempting Romberg test, is very common
  22. Facial and torso rashes, mostly macular erythema and acneform eruptions
Routine Laboratory Tests - Findings may be subtle but are often present
  1. Low sedimentation rates in 40% (0-3 mm/hr); modestly elevated (20-40) in 10%, usually will fall over time
  2. Akaline urines are common (PH>7.0)
  3. Mild leukocytosis or leukopenia
  4. Macrocytosis with elevated MCV
  5. Mild LFT elevations, rarely persist
  6. Atypical lymphocytes
  7. Elevated blood lipids
  8. Low normal free T4 and TSH
  9. Low level ANAs, may not persist
  10. Rare positive Lyme antibodies - failure to respond to accepted therapy
Immunologic Dysfunction

Immunologic tests have been frequently applied to patients with CFS in part because they are frequently abnormal and in part because the signs and symptoms of CFS can be explained as a consequence of immunologic function or dysfunction. Fever, sore throat, swollen glands, aching muscles and joints, sleep disturbance, and even neuropsychological complaints can all be attributed to immunologic responses generally ascribed to T-cell activation with excess cytokine production (i.e., IL-1 alpha, IL-2, interferon-alpha). Whether this excessive immune response is itself the cause (auto-immune or neuroendocrine defects) of CFS or perhaps the effect of a chronic viral infection or even compensation, by whatever means, for an acquired immune deficiency remains uncertain.

We propose here a set of tests that look for evidence of T-cell activation along with discrete immune defects.  All of these tests are available from commercial laboratories and defended by published medical literature.2-20 Although specific immune tests do not always correlate with disease severity, nor is any single test always abnormal, they become more valuable when used as an array or set of tests used to determine a pattern of immune dysfunction.

Tests of Immunity T-cell activation

1. IL-2 receptor, T8-receptor -elevated
2. One and two-color flow cytometry
  • CD3/DR, CD8/DR - elevated
  • CDllb, CD8/CDllb - depressed
  • CD3 - elevated
  • CD56 - elevated
  • CD4/CD45R - depressed
  • CD20 elevated (3) 
  • Interferon-alpha, IL-1-alpha - elevated (4) 
  • Intracellular 2-5A, Rnase-L antiviral activity - elevated
Discrete Immune Defects
  1. Hypogammaglobulinemia (IgG)
  2. IgG subclass deficiencies
  3. Anergy and hypoergy by epicutaneous skin testing
  4. Mitogen stimulation deficiencies (T and B cell deficiencies)
  5. Natural Killer (NK) cytotoxic deficiencies
  6. Circulating immune complexes

Viral Activation or Re-activation

Viral activity or activation is suggested in CFS due in part to the abrupt onset of a flu-like, mono-like, or encephalitic-like illness which usually precedes the development of this disorder, its signs and symptoms over time, and the nature of the immune response observed. The common symptoms of debilitating fatigue, swollen glands, sore throat, and headache have suggested re-activation of mono-causing herpes viruses (EBV, HHV-6, or CMV), which are usually contracted much earlier in life. It is probable that these lymphotropic herpes viruses are involved in most cases of CFS but are not the cause of CFS. It is likely that they are merely reflecting T-cell activation itself or loss of immunologic control of these viruses due to a state of immune deficiency by whatever cause. It is conceivable that an as-yet-unknown virus has initiated CFS much as HIV initiates AIDS. Such a virus is likely to be subtle, immunotropic, and neurotropic. Retroviruses are all of these things, and attention has focused on them in recent years.

The following is a set of tests that look for evidence of re-activation of herpes-group viruses as well as evidence of a possible retrovirus infection. The retroviral assays include DNA amplification technology and evidence of non-specific cytopathic effects in cell culture consistent with a family of retroviruses recently associated with CFS. Again, more important than the results of a single test is the pattern of herpes-group virus re-activation, evidence of retroviral gene sequences, and evidence of retroviral cytopathology in nonspecific culture assays, all of which support the role of viral activation in CFS. Whether this activity is cause or effect, however, is still open to question. It should be noted that lymphotropic herpes viruses and retroviruses can activate or transactivate each other and are therefore synergistic.

Tests of Viral Activation or Re-activation Herpes-Group Virus Assays 21-26
  1. Antibody assays for EBV, HHV-6, CMV, HSV-1,2 & VZ looking for elevated titers consistent with recent activity.
  2. Viral DNA amplification for EBV, HHV-6, and CMV using the polymerase chain reaction (PCR), with positive results suggesting viral activity.
  3. Giant cell assays with monoclonal labeling for various herpes-group viruses, with positive results suggesting such viral activity.

Retrovirus Assays 27-30
  1. Cytopathology in fibroblast cell lines consistent with human foamy retroviruses or human intracisternal retroviruses
  2. HTLV-II gag probes, run using low-stringency PCR to detect retroviral gene sequences present in CFS patients which are HTLV-II-like but not HTLV-II. This test will likely give way to specific probes based on conserved sequences of actual retroviral isolates of whatever family cultured from CFS patients.
Exercise-Related Dysfunction

Patients with CFS describe characteristic worsening of their symptoms following exercise as well as exercise limitations. Exercise ergometry with gas analysis has proven useful in CFS to document defects in functional capacity; a functional consequence of debilitating fatigue. Several reports have attracted further interest in this technology as a diagnostic instrument for showing neuroendocrine defects in response to exercise, 31 as well as defects in respiratory control mechanisms within the central nervous system in CFS patients.

Bicycle ergometry with gas analysis has proven useful to document disability in CFS and will likely prove useful to document deep brain dysfunction characteristic of CFS patients.

Tests of Exercise-Related Dysfunction Important measurements using bicycle ergometry with gas analysis
  1. Peak oxygen consumption at maximum exertion
  2. Work rate at anaerobic threshold as against peak work rate.
  3. Oxygen consumption at anaerobic threshold
  4. Work efficiency - independent of conditioning
  5. Breath-to-breath tidal volume variance at peak exercise
Brain Dysfunction

Perhaps no set of symptoms is more disturbing to CFS patients nor more striking to clinicians than the neurocognitive complaints seen in CFS. They characteristically evolve slowly over time and often grow to dominate the clinical scene. At first there is only the mental "fog" of a viral syndrome, but this slowly gives way to the more worrisome complaints of memory disturbance, word searching, processing speed, and spatial disorganization. There also may be neuropsychological complaints including panic attacks, depression, and mood swings. Evidence of characteristic abnormalities on neuropsychometric tests and characteristic profiles on the MMPI have been reported.32,33 Defects on structural34,35 (MRI) and functional scans (SPECT and Topographic Computer EEC) of the brain have also been reported.36,37 As mentioned above, soft neurologic findings are also frequently demonstrated under physical examination. We have proposed a number of approaches to document evidence of brain dysfunction in CFS.

Tests to Document Brain Dysfunction

Structural Scans - MRI is recommended for any patient with an abnormal neurologic examination or significant neurologic symptoms. This is done primarily to rule out structural abnormalities which might mimic CFS signs and symptoms. Many CFS patients (50 percent or more) will exhibit small punctate areas of increased signal, usually in subcortical white matter areas.

Functional Scans - SPECT scans, which primarily measure blood flow, are frequently abnormal (80 to 85 percent), showing areas of decreased perfusion primarily in the temporal and frontal lobes.

Topographic computer EEC brain mapping has shown increased slow-wave activity usually in the anterior leads and especially when patients are engaged in certain cognitive tasks. This usually diffuse slow-wave activity strongly suggests metabolic or toxic encephalopathy.

Neuropsychometric Testing - A complete Halstead Reitan battery or subsets of this battery form the basis of determining the nature and extent of cognitive impairment in CFS. Patients will exhibit characteristic focal and multifocal deficits in which performance on certain subtests will be normal or even well above normal while performance on certain other subtests will be substantially below normal. Performance deficits appear to occur more frequently in particular subtests of this battery.

Knowledge Is Power

CFS clinical and bench researchers are developing an array of tests which are increasingly sensitive and specific for CFS — particularly when used in combination. When patients present with symptoms that suggest CFS, we believe it is in their best interest to selectively employ these tests to confirm the diagnosis and to document the nature and extent of each case. This information: increases both the physician's and patient's confidence in the diagnosis and their ability to track the course of the disease; enables the patient to make appropriate lifestyle adjustments (including defense of disability claims when necessary); and provides the physician with a basis for therapeutic intervention.


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33. Iger, LM. Changes on the CFS profile with the MMPI-2. The Third Annual Conference - Chronic Fatigue Syndrome and the Brain, Bel-Air, California, April 24-26, 1992
34. Daugherty SA, Henry BE, Peterson DL, Swarts RL, Bastien S, Thomas RS. Chronic fatigue syndrome in northern Nevada. Rev Infect Dis, 13{Supp l):S39-44, 1991 (MRI Scans)
35. Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Abalashi DV, Salahuddin Z, Saxinger C, Biddle R, Kikinis R, Jolesz FA, Folks T, Balachandran N, Peter JB, Gallo RC, Komaroff AL. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus-6. Ann Int Med, Vol.116,(2), pp.103-113, January 15, 1992
36. Mena I. Study of cerebral perfusion by NeuroSpect in patients with chronic fatigue syndrome. Symposium on Myalgic Encephalomyelitis, p.21, Cambridge, England, April 1990 (SPECT Scans)
37. Cheney PR, et al. CFS: A clinical perspective on the use of MEG and EEC brain mapping. The Third Annual Conference - Chronic Fatigue Syndrome and the Brain, Bel-Air, California, April 24-26, 1992

Tuesday, July 15, 2014

Hydrotherapy for ME/CFS - Dr. Cheney's Protocol

The DAR state forest in Goshen, MA - my "swimming hole"
In the 1990s, Dr. Cheney proposed the idea of cool-water hydrotherapy for ME/CFS patients. The idea behind the treatment was that vertical immersion in cool (not cold) water would help down-regulate immune system activation, which Dr. Cheney believed was an integral part of ME/CFS symptoms. 

Allergies, flu-like symptoms, and food sensitivities are all signs of immune activation, as are autoimmune comorbidities (e.g. Hashimoto's disease). Because I had all of these, as well as heat intolerance, I decided to put Dr. Cheney's theories to the test. I immersed myself in cool water (see photo), twice a day for roughly 15 minutes. The water was too cool to simply stand, so I swam very slowly using a modified breaststroke - head above water, body at roughly a 45-degree angle - for about 15 minutes.

The first thing I noticed was that my head cleared. All my cognitive problems disappeared for a few hours after getting out of the lake. My energy levels also improved, as did my stamina.

It turned out that there was more to Dr. Cheney's theory than lymph fluid reversal. Immersion in cool water shunts blood to vital organs - specifically to the heart and brain. (Heat has the reverse effect.) Swimming in cool water for a short period of time helped clear my  head simply because my brain was getting more blood, and, as a consequence, more oxygen.

For those who are interested, I have pasted Dr. Cheney's original hydrotherapy program below. While Dr. Cheney recommended working up to an hour or more, I found that 10-30 minutes was more than sufficient.



Patients with Chronic Fatigue Syndrome (CFS) have evidence of immune activation. Many of the symptoms associated with CFS may in fact be the result of or indirectly related to an overactive immune response. A substantial reduction in these symptoms may therefore occur with the down-regulation or re-regulation of this overactive immune system.

There are two methods of interest to us which are both inexpensive and have low side effects which can conceivably provoke immune down-regulation in CFS. A low temperature method and perhaps the more powerful pressure gradient method used to accelerate lymphatic flow. These methods could obviously be merged.

Clinicians in Germany have recently used low temperature water baths to treat both Multiple Sclerosis (MS) and Chronic Fatigue Syndrome both of which have evidence of immune activation. It has been observed that Multiple Sclerosis patients worsen when they are overheated by vigorous exercise or after Jacuzzi hot water bathing. MS patients, however, seem to do better after swimming, perhaps because there is much less overheating during this type of exercise.

Several CFS patients treated at The Cheney Clinic using the German cold-water treatment method have reported "windows" or short time periods of improvement following this treatment. As in MS, it has been observed that CFS patients also worsen after being overheated, whether by exercise or by hot water bathing. The two disorders are, of course, immunologically similar in terms of immune activation.

With respect to pressure gradient therapy, there have been two double blind placebo controlled trials documenting at least partial efficacy in CFS of IV gammaglobulin infusion at high dose.

Gammaglobulin is an immune modulator and in addition to being a source of antibodies, possesses a number of immunomodulatory proteins which are known to down-regulate or re-regulate immune system function. 

Tissue lymph fluid bears some resemblance to gammaglobulin as it also contains antibodies and immunomodulatory proteins. The tissue lymph in Chronic Fatigue Syndrome patients is likely to contain immune activation proteins or cytokines in excess. Given evidence in CFS of lymphadenitis and tenderness along lymph node channels, especially in the lower left base of the neck, it is likely that there is increased production of tissue lymph related to their immune activation state.

This excess lymph flow would be expected to back up from the thoracic duct and provoke tenderness in the
Virchow's node area above the left clavicle and extend up into the left middle and posterior cervical node chains and/or into the left axillary (armpit) node chain. In our experience, this is exactly what is seen in most cases of Chronic Fatigue Syndrome. Lymphatic congestion could provoke pain in the left shoulder, left arm and down into the anterior chest. Severe lymphatic congestion would produce tissue edema or fluid retention and perhaps more extensive pain and gastrointestinal complaints, all common in CFS.

Vertical immersion in water creates a significant pressure gradient which can enhance lymphatic flow up the body and torso and into the thoracic duct which lies below the left clavicle The pressure gradient effects would act to autotransfuse tissue lymph back into the blood stream at the level of the left subclavian vein. 

This autotransfusion of excess immunoreactive lymph fluid would likely provoke a down-regulatory immune response which with time could result in a significant improvement in symptoms. Factors which may enhance this lymphatic flow and its effects include water temperature, length of vertical immersion, and the number of days per week in which therapy takes place.

Temperature may be a particularly important variable. Lower temperatures may be better as noted above by the Germans; however, low temperatures may also mitigate against prolonged immersion since as the patient's body cools down, a greater proportion of their energy will be shifted to maintain body temperature, and they then may become more fatigued. On the other hand, higher temperatures accelerate immune activation states and may be counter productive.

It is likely that a temperature somewhere between 80 and 86° is the best compromise between these two issues. It is also felt that length of time per session may be important. At least an hour to an hour and a half per session will likely be required to provoke sufficient lymphatic flow in most patients. The number of sessions per week could also be important and from preliminary studies, it would appear that a minimum of three sessions per week will be necessary.

Factors which may inhibit improvement include lymphatic blockage especially at the Virchow's node area which would be suggested by discomfort in that area following total body immersion. It is also possible that sicker patients may lack sufficient ability to down-regulate against tissue lymph, and, therefore, no significant improvement will be seen. There is also an outside chance that in some patients this therapy could actually exacerbate their condition in the early stages of therapy since the tissue lymph is rich in immune augmenting cytokines.

Finally, it is possible that good hydration will also aid tissue lymph flow, and we would recommend that patients on this protocol drink at least eight glasses of water per day and that sicker patients even consider an infusion of a full liter of IV fluids prior to immersion.

Instructions: Sixteen Week Treatment Protocol

It is important that the pool have water temperatures between 80° and 86°.

Patients will float and occasionally "water walk" primarily in the deep end of the pool and are encouraged to socialize while in the water. Water resistant, head-mounted tape or radio players to listen to audio tapes of books, music or radio can be used to help pass the time. Patients must remain as vertical as possible and submerged to the neck while in the water. The ideal time each patient should stay in the water and the ideal number of sessions per week may vary from individual to individual.

The Cheney Clinic recommends that patients attempt to reach a minimum immersion time of one hour per session for three sessions per week. Longer times per session or more sessions per week may be helpful for some and not for others. Each person will need to determine what is ideal for them. Please note that "water walking" or water exercising is not necessary and can be detrimental in the early phases of treatment. With time, however, water walking may be the ideal exercise for CFS patients. Remember that 30 minutes of water walking is equal to two hours of land walking. CFS patients should be very cautious about overextending in the pool.

Most patients report at first feeling more fatigued or tired after their Hydrotherapy sessions. With time, however, they will typically better tolerate the sessions.

The length of time spent in the water should be increased gradually over the first three weeks starting at 15 minutes per session at a frequency of three times per week. Add 5 to 10 minutes to each successive session over the first three weeks. Never jump ahead to longer times as this has provoked worsening of symptoms in some patients. Session length may need to be abbreviated if you are feeling worse over time and sessions should be omitted on a down-day or if you have a fever above 100 degrees. No session should extend beyond one and one-half hours and a session should be cut short if you become cold or shiver.

Patients will take care to drink at least eight, 8-ounce glasses of water or juice per day. They are particularly encouraged to drink at least twelve ounces of water or non-citrus juice up to but not beyond one hour prior to water immersion. Non-citrus juices include apple, pineapple, papaya and cranberry juices.

Care must be taken to not use hot water showers before or after immersion. This could activate the immune system, especially after immersion. Prior to and following immersion a warm but comfortable shower should be taken. A warm but comfortable then five minutes of cool but comfortable shower method should be used at all other times. No hot water Jacuzzis, saunas, or hot water bathing should be used during this program nor at any other time by CFS patients.

Patients who are cold intolerant or get too cold in the pool should invest in a wet suit. We recommend the O'Neil, full or partial length wet suit as it is relatively easy to get into and out of and can be worn to the pool. Torso thickness should be a three and limb thickness a two. (ie. a 3/2 thickness wet suit). A wet suit can greatly increase the comfort level of longer times in the pool. A wet suit will also increase buoyancy.

Patients who are improving on this therapy must guard against physical, emotional, or cognitive overextension. Patients remain brittle for some time and subject to relapse even as they improve on Hydrotherapy. What you chose to do with your improved functional status may well dictate how successful this program will be for you.

Wednesday, July 9, 2014

Shake-up at HHS - Koh Resigns

Hot on the heels of Secretary of Health and Human Service Kathleen Sebelius' resignation comes the resignation of Howard Koh, Assistant Secretary for Health (see below).

The ongoing turmoil at HHS is beyond a doubt due to the messy roll-out of the Affordable Care Act (Obamacare). Sebelius was described at numerous press conferences as being "clueless," which, as someone who was supposed to be the "face of the ACA," was unforgivable.

Given the inoperability of the federal website, the plethora of legal challenges (right up to the Supreme Court), and near constant attempts to undermine Obamacare through threatened lawsuits (which can't actually make it to court, but which get huge play in the press), is it any wonder that the top officials at HHS have "resigned"?

Adding fuel to the fire that is burning HHS's house down, was the dramatic departure of David Wright, head of the Office of Research Integrity, last March. In a detailed letter of resignation, Wright described HHS as "dysfunctional" and characterized Koh's office as “seriously flawed ...  secretive, autocratic and unaccountable.” Wright's letter got gleeful coverage from the media, which is always happy to jump at the chance of reporting a scandal. Once Sylvia Burwell took over as head of HHS, it was predicable that Koh would follow in the wake of Sebelius' hasty retreat.

What does this mean for the ME/CFS community? Very little, actually. It means HHS will be paying very little attention to this illness, while it tries to salvage Obamacare. It will be devoting very little of its resources, energy and time to our concerns. Very little money will be provided for scientific research. And people with very little interest in making necessary updates on the CDC's website, or including biomarkers in the CDC's multi-site study, or relying on the experience of experts to define the illness will continue to hold sway.

From: Burwell, Sylvia M. (HHS/OS)
Sent: Wednesday, July 02, 2014 03:53 PM
To: OS - Political Staff; OS - OPHS - All Employees
Subject: Important Staff Announcement


After more than five years of distinguished service, Dr. Howard Koh has informed me that he will step down as the Assistant Secretary for Health to assume a new position at the Harvard School of Public Health as Professor of the Practice of Public Health Leadership.

As Assistant Secretary for Health, Howard has been at the forefront of confronting the leading public health issues of our time.  And as one of our top physicians at HHS and in federal government, he has been a trusted and respected voice in implementing and communicating the critical public health dimensions of the Affordable Care Act.

Howard’s broad range of accomplishments at HHS reflects his deep passion for promoting public health in so many arenas. He was the primary architect of landmark HHS strategic plans on tobacco control, health disparities, and chronic viral hepatitis that will leave a legacy for many years. He has led the HHS implementation of the President’s National HIV/AIDS Strategy, and the President’s Climate Action Plan as it relates to public health.  Through his work, he has promoted efforts in areas such as behavioral health, cancer control, adult immunization, physical activity and obesity prevention, health literacy, multiple chronic conditions, organ donation and epilepsy.  Additionally, he was actively engaged in matters related to the modernization of the Commissioned Corps, and oversaw the unveiling of Healthy People 2020.

Throughout his tenure, Howard has leveraged his decades of unique experience as a clinician, educator, researcher, advocate and former state public health commissioner to bring better understanding and empathy to underserved populations.  Please join me in thanking him for his tireless commitment and wishing him all the best in his new position.


Sylvia Burwell

Friday, July 4, 2014

CFS, FM, and Fraud - How the Mythology of "Faking It" is Perpetuated in the Media

On January 29, 2014 CBS re-aired a segment on disability fraud. In this segment, reporter Steve Kroft characterized SSDI as a "secret welfare system" with its own "disability industrial complex," namely lawyers who charge a percentage of back disability payments to assist people with their applications.

There is no government program that does not suffer from fraud, all the way from social security benefits, disability, and food stamps, to multi-million dollar grants given to researchers at prestigious universities who fake test results.

Fraud is simply a fact of life. But for some reason, it is only the programs that offer assistance to people who are impoverished, ill, disabled, or elderly that are "ravaged by waste and fraud."

How exactly do disability applicants defraud the government? According to Jenna Fliszar, attorney at Binder & Binder, the largest disability firm in the country, applicants claim to be disabled by illnesses that are "subjective."
Jenna Fliszar: Many of the cases they [Binder & Binder] handled involved ailments with subjective symptoms like backache, depression and fibromyalgia, which is joint and muscle pain along with chronic fatigue. 
Steve Kroft: Hard to prove you've got it? 
Jenna Fliszar: Yes. And there's really no diagnostic testing for it. 
Steve Kroft: Hard to deny you don't have it. 
Jenna Fliszar: Correct.
Because Fliszar claims that half of her cases were not deserving of disability, and most of these were "subjective," the implication is that people with FM (and CFS) are not really disabled, and are committing fraud by applying for disability benefits.

The public has now heard the words "fibromyalgia," "chronic fatigue" and "fraud" linked together on national media - twice. Is it any wonder that people with FM and CFS are constantly accused of "faking it"?

You can view the segment here.

You can send a comment to CBS here.

Monday, June 30, 2014

“Justina’s Law” Introduced in Congress - Is This the Beginning of the End for Voodoo Medicine?

Justina's father carries her home after her 16-month incarceration
The saying that politics makes strange bedfellows has gained a new dimension today. In a rare bipartisan effort, two staunchly conservative congressmen, Michele Bachmann and Tom Marino, have joined forces with liberals Karen Bass and Jim McDermott to propose "Justina's Law."

Justina's Law would bar federal funding of any institution that uses wards of the state for medical experimentation. On the surface, this appears to be a law fraught with loopholes. It is possible that mental hospitals could justify forced psychiatric treatment on the grounds that it is usual and customary.

Usual and customary treatment for all mental illnesses (other than schizophrenia, bipolar disorder, and psychosis) consists of therapy (e.g. CBT), sedatives, and/or antidepressants. These are not actually treatments, because there are no objective tests for mental disorders. That is because the majority of mental disorders are not illnesses; they are simply reflections of social conventions and cultural norms of the time. Given the lack of any scientific evidence for the existence of somatoform disorder - an antiquated diagnosis left over from Freudian psychiatry -  it would be a stretch to claim that its treatment is anything but experimental.

The treatment Justina was given throughout her stay as a ward of the state was not approved by Justina's parents, who have consistently maintained that the state of Massachusetts experimented on their daughter. Justina's previous diagnosis of mitochondrial disease (an inherited condition also suffered by her sister) was disputed by a neurologist at Boston Children's Hospital. The neurologist re-diagnosed Justina with "somatoform disorder." Her parents were then accused of "medicalizing" her illness. Over the next year, Justina was refused medication for mitochondrial disease, and placed in a locked mental ward. Eventually, the state moved her to foster care. During the 16 months she was a ward of the state, Justina's condition deteriorated until she could no longer walk or stand.

Justina's Law, if passed, could have profound ramifications for the ME/CFS community. Hundreds of children with ME/CFS have been taken from their homes on the basis of psychiatric diagnoses that are just as unsubstantial as somatoform disorder. This law would give legal grounds to parents suing to get their children back. It might even help get some of these pseudo-psychiatric "diagnoses" relegated to the dustbin of history, which is where they belong.

Please ask your representatives to support H.R. 4989, "Justina's Law."

Find your representatives here.

You may use this letter as a template.

Please support H. R. 4989, "Justina's Law." Justina Pelletier was incarcerated by the state of Massachusetts for over a year based on a psychiatric diagnosis for which there is not one shred of scientific evidence (somatoform disorder). As a result, Justina's disease (mitochondrial disease, a rare inherited disorder) has progressed, and she is no longer able to walk. Justina is not the only child to have suffered this fate. In 2009, Ryan Baldwin, a boy with myalgic encephalomyelitis (aka chronic fatigue syndrome) was taken away from his family in North Carolina and placed in foster care, where he grew steadily worse.

Please prevent more cases like Justina's and Ryan's. Support "Justina's Law."

Reps. Bachmann, Bass, Marino, and McDermott Introduce “Justina’s Law”

Michele Bachmann, Jun 27, 2014

Washington, D.C. -- Rep. Michele Bachmann (R-MN) joined with Reps. Karen Bass (D-CA), Tom Marino (R-PA), and Jim McDermott (D-WA), the co-chairs of the Foster Youth Caucus, to introduce bipartisan legislation that prohibits federal funding for medical experimentation on a ward of the State.

The bill, H.R. 4989, nicknamed “Justina’s Law”, is a response to the recent case of 16-year-old Justina Pelletier, who was finally released from Boston Children’s Hospital (BCH) back to the care of her family after a 16-month custody battle between the Commonwealth of Massachusetts and Justina’s parents.

BCH and many other hospitals have an internal policy that allows for children who are deemed “wards of the State”, including foster children, to receive treatment or be involved in research that presents great risk even if there is no prospect of any benefit to the child.

“Whether it is one child or thousands, it is our duty to guarantee that children are kept safe from harm while in the custody of their respective states. Not all these children have families like the Pelletiers willing or able to advocate on their behalf. Sixteen months ago, Justina was a figure skater. Today, she cannot stand, sit, or walk on her own. It is unconscionable what happened to Justina, and we must do all we can to prevent it from ever happening again. Removing federal funding from such experimentation is an important first step.” – Rep. Michele Bachmann (MN-06)

"Children need to be loved and cared for, not treated as something to be experimented on. Foster children are particularly vulnerable because they may not have parents to advocate for them. This bill will make it clear that children are blessings, not guinea pigs." – Rep. Karen Bass (CA-37)

“The bonds between children and parents is sacred. The closeness and level of intimate understanding between them transcends our societal constructs. In Justina’s case, she was kept from her loved ones and essentially detained by the hospital and the state. She was lucky to have parents that fought for her and leveraged the support of the media and public officials. Yet too many children do not have parents to speak for them and look out for their health and best interests during times of physical and emotional vulnerability. That fact saddens me. It would sadden any person who knows the power of love and affection. That is why I am proud to support Reps. Bachmann, Bass, and McDermott on this legislation because no child, with parents or not, should be subject to medical experimentation under the legal designation as ward of the state.” – Rep. Tom Marino (PA-10)

“The strength and bravery that Justina Pelletier and her family have shown in the face of incredible hardship is a guidestar for us all. We must act to protect and cherish children in the care of a state and make sure that they are not the subject of risky medical experimentation. I look forward to working with Reps Bachman, Bass, Marino and countless other colleagues from both sides of the aisle to pass Justina’s law as quickly as possible.” – Rep. Jim McDermott (WA-07)

Click here to view the full text of H.R. 4989.

Tuesday, June 24, 2014

The Big Lie

There have been several attempts to gain access to the full results of the Queen Mary University of London's PACE trial under the Freedom of Information Act.

All of these attempts have been quashed. Nonetheless, Mr. Matthees continues to make his case, and make it well. [See below]

There are many reasons to demand that the PACE trial submit its full results, not the least of which is that the published results of the PACE trial are misleading (if not outright tweaked). Bad science is one thing, but the wholesale acceptance of bad science is something else entirely.

With the spate of publicity surrounding the trial, doctors, clinics, and health agencies have uncritically embraced CBT and graded exercise as legitimate treatments for ME/CFS. Here are just a few examples in the US:

Mayo Clinic
"The most effective treatment for chronic fatigue syndrome appears to be a two-pronged approach that combines psychological counseling with a gentle exercise program.
  • Graded exercise. A physical therapist can help determine what types of exercise are best for you. Inactive people often begin with range-of-motion and stretching exercises for just a few minutes a day. If you're exhausted the next day, you're doing too much. Your strength and endurance will improve as you gradually increase the intensity of your exercise over time.
  • Psychological counseling. Talking with a counselor can help you figure out options to work around some of the limitations that chronic fatigue syndrome imposes on you. Feeling more in control of your life can improve your outlook dramatically."
CDC Toolkit
"Cognitive behavioral therapy, or CBT, is an individualized, structured, goal-oriented form of therapy often prescribed to help chronically ill patients cope with illness and develop behaviors and strategies that help improve symptoms. CBT has been shown to be effective for some patients with CFS, but it must be paced, personalized, and tailored to the individual’s level.
Graded exercise therapy (GET) has shown to be very helpful to some CFS patients. Graded activity and exercise is defined as starting from a very low, basic level of exercise and/or activity and gradually increasing it to a level where people can go about their daily life." 
University of Maryland Medical Center
"Seeing a therapist who is trained in cognitive-behavioral therapy (CBT) can help CFS patients regain a sense of control over their lives. A number of studies [it added] have reported the benefits of a graded exercise program, in which patients gradually perform more intense exercises as their abilities improve. Research has found that most CFS patients who are able to engage in exercise, particularly aerobic exercise, report less fatigue and better daily functioning and fitness. Exercise works best for CFS when combined with CBT and education."
With our most respected agencies and clinics recommending CBT and GET it is no wonder that virtually all of the treatment information found online reflects the results of the PACE trial.

Dr. Roach (syndicated health columnist)
"If, after a thorough evaluation, your diagnosis turns out to be chronic fatigue syndrome, the most effective therapies are cognitive behavioral therapy and a graded exercise program."
"Two types of therapy appear to benefit CFS patients. One is psychological counseling to help you cope with CFS and improve your mindset. The other is physical therapy. A physical therapist can evaluate you and create an exercise routine for you that gradually increases in intensity. This is known as graded exercise therapy, or GET."
"In general the therapy will be a combination of psychological counseling (to help with the day-to-day burden CFS imposes on the patient's life) and mild, guided exercise..."

In short, the PACE trial is more than bad science. It is a piece of propaganda that is directly modeled after the Big Lie: “If you tell a lie big enough and keep repeating it, people will eventually come to believe it." (Joseph Goebbels)

The lie that cognitive behavioral therapy and GET are "the most effective therapies," "appear to help," "are very helpful" for ME/CFS is one that will continue to inform physicians and harm patients as long as the actual results of the PACE trial remain under wraps.

[Please see below for Mr. Matthees' argument for why full disclosure is in the public interest.]

Dear Mr Smallcombe / QMUL,

Thankyou for the response to FOI 2014/F73, which was refused as
exempt under s.40(2) and s.41(1) of the Freedom of Information Act
2000 (FOIA), drawing upon the the Data Protection Act 1998 (DPA),
and with references to GMC and MRC guidance: "as the information
consists of sensitive medical data provided in confidence by
participants in the PACE trial" and cannot be fairly processed by
the data controller for purposes other than what it was explicitly
collected for. Unfortunately, I am dissatisfied with the response
and would like to request an internal review and further
clarification with reference to the following:

• It is entirely possible to disclose anonymised trial data without
breaching the DPA or fairness of the FOIA, the DPA's definition of
personal data cannot be extended to cover situations where the
disclosed data does not identify any individual, the disclosure of
anonymised data is not a disclosure of personal data even when the
data controller holds the key to re-identification, consent is not
necessary to release anonymised data when it is unlikely to lead to
re-identification, and the DPA does not require anonymisation to be
completely risk free but mitigated until the risk of
re-identification is remote. [1] This FOI request involves a
heavily redacted dataset with most variables removed, or a
selection of trial data which has undergone de-identification /
anonymisation, and ceases to be personal data at the point of
disclosure so the DPA does not apply. [2]

• QMUL have claimed that re-identification from the requested
(pseudo)anonymised data is a significant risk. However, there is no
obvious or plausible method for a member of the public to do this
without additional data that is held securely at QMUL and highly
unlikely ever to come into the possession of myself or other
members of the public. According to the ICO's Knowledge Base on FOI
Policy with reference to the Data Protection Act, the onus is on
public authorities to explain how re-identification would occur.
[3] Speculative assertions about alleged 'extremists' may reflect
the potential existence of a 'motivated intruder', but if such
people exist they are highly unlikely to succeed in
re-identification and therefore such speculation is irrelevant. In
a previous unrelated ICO ruling, the Commissioner attempted to play
the role of 'motivated intruder' and was unsuccessful. [4] Any fair
attempts to play the role of 'motivated intruder' for the purposes
of assessing this FOI request would also fail. The selected data
being requested was chosen so that the results could be calculated
from the bare minimum of data required (except without the optional
criteria for recovery from a clinical perspective, and with the
addition of 6MWD data).

• It is also the responsibility of the public authority to
establish how disclosure would lead to adverse consequences. QMUL
have stated that disclosure without explicit consent is unfair and
"very likely" to cause "great distress" to participants to their
obvious detriment, with adverse consequences such as revealing that
an individual suffers from a certain health condition, and
therefore constitutes a probable actionable legal offense. These
assertions appear to be based primarily on the assumption that the
requested data is strictly personal data that can identity trial
participants when disclosed. As the requested data would not
plausibly lead to identification of any individuals, the given
hypothetical examples of adverse consequences do not apply, and it
remains unclear how disclosure would constitute a serious invasion
of privacy causing considerable distress if no individuals can be
identified. The fairness test can be satisfied by removing
identifiable information about individuals and/or by anonymising
the data, "for example, by removing the name but leaving the rest
of the information". [5]

• Much of the requested data is already one step removed from the
information directly provided by trial participants e.g. fatigue
and physical function numerical scores are calculated from multiple
answers to different questions on a paper questionnaire, the
specific answers of which cannot be reliably extrapolated from the
summed numerical scores. The requested data consists of either
dichotomous or continuous values which are common and/or
fluctuating (it is not comparable to genetic information or a
National Insurance Number). The data is quantitative not
qualitative; it is not for example the written accounts of personal
opinions, identifiable contextual experiences about personal lives,
or the handwriting of living individuals.

• QMUL stated that explicit consent will not be requested from
trial participants for this particular FOI request. Assuming that
such consent is actually necessary for the release of
non-identifiable anonymised trial data (which according to multiple
references no longer qualifies to be classified as personal data),
the Ministry of Justice guidance on s.40 also points out that "a
public authority should not be able to engineer a situation in
which data cannot be disclosed by failing to notify the data
subjects". [5]

• QMUL stated that "Principle 2 of the Data Protection Act 1998
also does not allow data controllers to process personal data for
further incompatible purposes." However, other public authorities
tried to use this argument to refuse the disclosure of anonymised
data and failed, because anonymisation and/or redaction did not
count as a form of processing. [6]

• The GMC's guidance on confidentiality and MRC's guidance on data
sharing, cited by QMUL, did not appear to prohibit the disclosure
of non-identifiable anonymised data to members of the public.
Obviously this does not mean unrestricted access to all data
collected, but it certainly opens up the possibility of releasing
selected non-identifiable anonymised data.

• The implications of anonymisation on confidentiality is somewhat
less clear, but the s.41 exemption can only be applied if there is
a good chance of a successful actionable breach of confidence, [7]
which QMUL believes is the case. However, at least 2 expert
commentaries suggest that anonymisation of confidential data can
replace the need for consent, and can change the nature of the data
so that in most contexts it is no longer 'personal data' and thus
not subject to the legal duties of data protection. [8][9] It it
also appears that the public interest can override the requirement
for confidentiality. [10][11]

• The public interest strongly favours disclosure, but the argument
is complex and involves specific details about the trial which
cannot be easily summarised into a paragraph. Therefore I will add
an additional annotation below describing the public interest
argument in about 2800 words and providing appropriate
references. Patients and clinical commissioners have a right to
accurate information about treatments promoted to them as
rehabilitative or potentially curative, but it can be demonstrated
that the (apparently post hoc and possibly unapproved)
redefinitions of improvement and recovery in the PACE trial were
too lax (e.g. recovery thresholds overlapping with the trial
eligibility criteria for severe chronic disabling fatigue and not
guaranteeing no longer having CFS), that these outcomes were
inaccurately presented as based on strict or conservative
thresholds, and that the most controversial change to the physical
function criteria was erroneously based on a misinterpretation of
summary statistics from a population study. The FOIA appears to be
most plausible method for finding out the results as promised in
the original stricter PACE trial protocol. It is doubtful whether
disclosure would actually deter future research. Conversely, it
could be counter-argued that research candidates may feel
discouraged from participating in controversial research topics if
previous trials have involved major, questionable, and possibly
unapproved, deviations from the pre-approved original protocol.

Yours sincerely, Mr Matthees.

References (abbreviated to save space):

6. http://www.cloudlegal.ccls.qmul.ac.uk/Re...
8. http://www.apira.co.uk/userfiles/files/C...

From: Mr Matthees

Reasons why the public interest strongly favours disclosure of the
requested data:

(FOI 2014/F73) 18th June 2014

Assertions about complete recovery and/or functional remission from
any chronic debilitating illness with a poor prognosis that is
regarded as difficult to treat should be taken seriously and be
based on reasonably stringent definitions. However, a recent 2014
systematic review of studies on recovery from CFS (including the
PACE trial) concluded that in general what the literature defined
as 'recovery' is better described as modest clinical improvement
only. There was no guarantee of 'recovery' per se, as
classification was based on limited assessments, less than a full
restoration of health, and self-reports lacking objective measures
in function which when used in behavioural intervention studies
suggested no changes (prompting the authors to conclude that these
therapies for CFS were not rehabilitative as often claimed). [1] An
earlier 2012 systematic review concluded that a "comprehensive
rehabilitation programme only rarely results in full recovery". [2]

The PACE trial has been repeatedly presented as offering
'definitive' answers on the controversial issue of 'rehabilitative'
treatments for CFS (e.g. in the official website FAQ, [3] in the
trial statistical analysis plan, [4] by the Science Media Centre,
[5] and on ABC radio [6]). The published definition of
recovery/remission was presented by the principal investigators
White et al. as 'comprehensive and conservative' and purported to
use stricter thresholds than a previous study on recovery from CFS
by Knoop et al. published in 2007. [7] However, multiple
significant issues have been identified with the recovery criteria
which strongly challenge or contradict these presentations and have
not been adequately addressed by the authors. [1,8,9] Disclosure of
the requested data will greatly help the resolution of these

The thresholds used for the 'normal range' score of fatigue and
physical function inappropriately overlapped with the trial
eligibility criteria for 'severe fatigue' and 'significant
disability'. The recovery definition allowed participants to be
classified as 'recovered' without reporting clinically significant
improvements to fatigue and physical function, as such improvements
were not required and allowed a 5 point decline in physical
function. No longer meeting Oxford criteria for CFS in the trial
did not necessarily mean no longer meeting Oxford criteria or
suffering from CFS in the clinic, because additional criteria for
fatigue and physical function were required, and participants were
classified as 'no longer meeting Oxford criteria' if they failed to
meet a single one of these thresholds e.g. moving from a score of
65 to 70 points in physical function but remaining unwell. 11% of
excluded candidates failed to meet these additional criteria
despite otherwise meeting Oxford criteria, which itself also
requires fatigue to be the only principal symptom (which is not a
requirement of any other CFS case definition. [10] and 80% of
candidates who were definitely or provisionally diagnosed with CFS
before the trial were excluded from participation, with the most
common reason being not meeting Oxford criteria for CFS).
Improvement on the clinical global impression scale does not
guarantee a recovery from CFS or any improvement in the primary
outcome measures of fatigue and physical function. The optional
requirements of not meeting CDC criteria for CFS or London criteria
for ME were superfluous because these were not an entry
requirement, tend to be more difficult to meet than the Oxford
criteria in the first place, and were not applied properly in the
trial. [7,11]

The relevant trial oversight bodies approved the original 2007
protocol published in BioMed Central, which included a much more
stringent definition of clinically significant improvement
('positive outcome') and complete 'recovery'. [12] According to
BioMed Central, "publishing study protocols will help to improve
the standard of medical research by ... enabling readers to compare
what was originally intended with what was actually done, thus
preventing both 'data dredging' and post-hoc revisions of study
aims". [13] The purpose of pre-publishing a protocol is to avoid
accusations of cherry picking the results, but when the protocol is
ignored this clearly cannot be guaranteed. The thresholds for
clinical improvement on an individual patient level for the primary
measures of fatigue and physical function were abandoned and
replaced with weaker thresholds which have been criticized for
being minimal. [14,15] Similarly, all components of the recovery
definition were significantly modified in a manner which made them
substantially less stringent and easier to qualify. Of particular
note, the threshold for normal physical function was dropped from
85 to 60 out of 100 points, a score low enough that 13% of
participants were already within the 'normal range' at baseline
despite meeting trial eligibility criteria for 'significant
disability' (65 points or less). [16] In contrast, participants
originally had to improve a minimum of 20 to 25 points to physical
function to be classified as recovered. Other researchers of CBT
for CFS have even classified a score of 60 to 70 points as
indicative of 'severe' impairments in physical function. [17,18]

Professor White previously requested that the threshold for a
'positive outcome' in physical function (later abandoned) be raised
from 70 to 75 points, because the entry criteria had been raised
from 60 to 65 to increase recruitment, so a 10 point gap between
entry criteria and 'positive outcome' scores was needed to avoid a
'trivial' difference. [19,20] Now there is a 5 point gap in the
opposite direction, which cannot not be described as a strict or
'conservative' threshold. Although it has been argued that
protocols can change in light of new information, it is unclear how
any of these changes could "more accurately reflect recovery" as
asserted in the paper by White et al. [7] Furthermore, as the
changes to the definition of recovery published in 2013 appear to
be largely based on controversial post hoc analyses conducted for a
previous paper on the trial results published in 2011, [21] it is
unclear whether these major deviations from the protocol were
approved by the relevant trial oversight bodies, and this confusion
surrounding the timing of changes has reached the level of
parliamentary debate in the House of Lords. [22]

As a previous claim made in the Lancet paper about the normative
dataset used from a population study had turned out to incorrect,
[23] it seemed prudent to examine the justification behind the most
controversial change to the recovery criteria. White et al.
asserted that the change to the threshold of normal physical
function was justified because a score of ≥85 "would mean that
approximately half the general working age population would fall
outside the normal range". [7] However this is incorrect, as
independent analyses of the English normative dataset cited by
White et al. revealed that over half score the maximum of 100
points. The median(IQR) score for the general working age
population sample is 100(90-100) not about 85 as implied (which
suggested an erroneous assumption that the mean and median were
equivalent), and only about 18% of the general working age
population sample had a score under 85. [24] The original threshold
of >=85 points appears to be reasonable and appropriate, as it
"represents the ability to carry out moderate activities, such as
lifting a table, carrying purchases, or bowling, without
limitations". [25] 92% of the healthy working age population score
85 points or more, and 61% score the maximum of 100 points. The
mean(SD) and median(IQR) scores for this population are 95.0(10.2)
and 100(95-100) respectively, with scores under 80 appearing to be
extreme outliers when defined as more than 3 x IQR below the
median. [24] It is highly unlikely that the PACE trial participants
classified as 'recovered' have a similar distribution of scores
compared to a healthy working age population.

White et al. stated that "we derived a mean (S.D.) score of 84 (24)
for the whole sample, giving a normal range of 60 or above for
physical function" and asserted that this sample was
"demographically representative". [7] However, the 'whole sample'
was a general population which included the elderly and chronically
disabled, [26] with age and illness having a major impact on
physical function scores in a way which decreases the mean and
increases the standard deviation, therefore lowering the threshold
of 'normal'. The mean(SD) age was 48.3(19.0) years, 32% were aged
60 years or more, and 22% reported chronic debilitating illnesses
(many of which would have medically excluded candidates from
participating in the PACE trial). [24][26] Whereas PACE trial
participants had a mean(SD) age of about 38(12) years at baseline,
only 3% were aged 60 years or more, [27] and were previously
screened for common chronic debilitating illnesses in the
population which would have excluded them from a CFS diagnosis.
Although described as a 'conventional' method, [23] White et el.
have applied a simple parametric statistical method to a dataset
without any apparent consideration for what the authors of the
cited paper (Bowling et al.) described as a heavily skewed
distribution, [26] which was specifically warned against in a paper
previously co-authored by Professor White [28] and has been
described elsewhere as a "fundamental misuse of statistics". [29]
Furthermore, the use of normative data from a general population
sample with important demographic differences to PACE trial
participants (age distribution and presence of common debilitating
illnesses) has never been justified in any of the publicly
available PACE trial literature. It is unclear why the authors did
not stop and think twice before using a 'recovery' threshold that
was unusually low and overlapped with their own trial criteria for
'significant disability'. A score of 60 points means reporting
significant limitations in multiple domains (somewhere between
minor limitations for 8/10 questions or major limitations in 4/10
questions), [30] which is unusual for healthy people of working age
and an unsuitable threshold for a genuine recovery. White et al.
[7] incorrectly claimed that their threshold was more
"conservative" i.e. stricter than the previous work of Knoop et al.
[28] The latter paper actually used the same mean plus or minus 1
SD formula as PACE did (not mean plus or minus 2 SD as claimed by
White et al.), and relied on a healthy population instead of a
general population to calculate a higher threshold of 80 points in
physical function as the normal threshold for recovered. Similarly,
serious questions have also been raised about the suitability of
the threshold for normal fatigue and the population used to derive
it. [8,31-33]

In response to the paper on 'recovery', Dr Esther Crawley from the
University of Bristol said that "Every patient with CFS/ME wants to
know how likely they are to recover." [34] Yet, many patients were
rather unsatisfied with the major deviations from the previously
established protocol, questioned the 'normal range' in particular,
and wanted to know the 'positive outcomes' and more importantly the
recovery rates as previously defined more stringently. A collection
of patient charities made a FOI request for this information in
2011, which included the results according to the original recovery
criteria [35] but were refused on the grounds that this information
was exempt under s.22 of the FOIA i.e. due for future publication.
[36] A similar FOI request in 2012 was refused on the grounds that
the information was not held in final form because the definition
of recovery had changed with a pending paper and there was no
intention on publishing the requested information in the future
(the refusal notice also incorrectly claimed that some of the
changes made the definition more stringent). [37] Another FOI
request in 2013 was refused on the grounds that the raw data
required to calculate these outcomes does exist but would require
over 18 hours to do so. [38] Therefore, this FOI request is for
selected raw data so that these calculations can be done without

ME/CFS is regarded as a controversial subject, but this controversy
is only further fuelled by the lack of transparency over trial
results presented as 'definitive' and the failure to publish the
measures specified in the original approved protocol. Given that
the published recovery thresholds appear to be fundamentally based
on previous post hoc analyses, coincide with less than expected
clinical improvements, and are generally at or below the level of
the trial entry criteria, it is difficult to believe that the
accusations of cherry picking or intentionally misleading
vulnerable patients and clinical commissioners (irrespective of
whether it is true or not) will simply go away without the
publication of these stricter outcomes. It is critical that
sufficient data is placed in the public domain to allow patients
and clinical commissioners to accurately assess recovery and the
sensitivity to any particular threshold.

There have been recent calls for medical research to be more
transparent and accessible and accountable, as per the AllTrials
campaign (www.alltrials.net). Although this does not necessarily
mean unrestricted public access to all the data of a trial,
AllTrials calls for "All trials past and present should be
registered, and the full methods and the results reported." The
Wellcome Trust takes a step further and calls for the full release
of all trial data. [39] The public interest in transparency around
drug trials has been well established by the European Medicines
Agency and the same principles should apply to psychotherapy and/or
behavioural interventions. [40] The PACE trial was publicly funded
research and the (anonymised) data should be openly available to
the maximum practical extent. Answers to remaining questions in
science are generally gained from further replication, but the PACE
trial cost taxpayers £5m, and due to its high cost and large size,
it is highly unlikely that another similar trial will be conducted
anytime soon. Therefore, the collected data should be explored to
the maximum extent possible. Without voluntary transparency, the
task of finding out the results as promised in the original PACE
trial protocol depends on members of the public, and the FOIA
appears to be most plausible method for seeing this happen in the
foreseeable future.

The ongoing confusion and controversy is adding to the suffering of
patients, and getting to the bottom of this issue is important
whatever the outcome may be. The results and interpretations do not
just affect those who are curious about research, but have national
and perhaps even global ramifications. Patients and clinical
commissioners of this chronic debilitating illness have a right to
accurate information about treatments which are promoted to them as
rehabilitative and potentially curative. This is required for them
to assess and give informed consent for treatments, or make
informed decisions about health care. Lax definitions of
recovery/remission and clinical improvement lead to unreasonable
expectations from patients by those who provide their care. In a
similar study known as the FINE trial [41] (which released the
results according to its own published protocol and failed to show
significant improvements with therapies similar to and sharing
elements with CBT/GET tested in the PACE trial), some participants
had doubts about the (overly optimistic) treatment rationales, and
therapists reported becoming angry and blaming participants as "the
bastards don't want to get better". [42]

It is doubtful whether disclosure would actually deter future
research. Conversely, it could be counter-argued that research
candidates may feel discouraged from participating in controversial
research if previous trials have involved major, questionable, and
possibly unapproved, deviations from the pre-approved original
protocol which made it much easier for the tested therapies to
appear successful, coincided with less impressive than expected
results, and led to the results being exaggerated. For example, the
published rates of trial participants within the 'normal range' for
fatigue and physical function (which overlapped with trial
eligibility criteria for severe chronic fatigue and significant
disability) was presented in 2011 at a Lancet press conference with
the principal investigators as returning back to normal, [43] and
this was then widely misinterpreted as a complete recovery or cure
in the national news media e.g. [44,45] and medical journals e.g.
[46,47] The Lancet editorial which accompanied the 2011 paper on
the PACE trial results inaccurately claimed that the 'normal range'
was a strict criterion for recovery based on scores from healthy
people, [48] but the Press Complaints Commission later ruled that
this comment was misleading and breached Clause 1 (Accuracy) of the
Code. [49] Such repeated misstatements of fact have negative
implications for how patients are treated by doctors, how funding
decisions are made, and for scientific accuracy concerning recovery
from ME/CFS. A poll conducted on the ME Association website during
March 2011 revealed that 89% of 751 respondents were significantly
concerned that the PACE trial results would adversely affect
treatment within the NHS. [50]

Unless the PACE group themselves promptly publish the original
protocol-defined 'positive outcomes', the original protocol-defined
'recovery' rates, and summary statistics on those classified as
recovered (both versions) compared with appropriate summary
statistics of healthy populations with a similar age distribution
as trial participants, then the disclosure of the requested data
allowing others to do the necessary calculations is certainly in
the public interest. Given that the lax definition of 'recovery'
fundamentally depends on a threshold for 'normal' physical function
which appears to be seriously flawed and inaccurately presented as
strict or conservative, with the reason for abandoning the original
protocol-defined threshold found to be erroneously based on a
misinterpretation of summary statistics from a population study,
the requested data will be important to help the public (patients,
carers, research community, healthcare staff, et cetera) further
assess the degree and nature of improvements in the PACE trial.
Please help resolve this controversy once and for all by granting
this FOI request.

References (abbreviated to save space):

1. http://www.ncbi.nlm.nih.gov/pubmed/24791...
2. http://www.ncbi.nlm.nih.gov/pubmed/22725...
3. http://www.pacetrial.org/faq/faq2.html
4. http://www.trialsjournal.com/content/14/...
7. http://www.ncbi.nlm.nih.gov/pmc/articles...
8. http://www.ncbi.nlm.nih.gov/pubmed/23363...
11. http://www.ncbi.nlm.nih.gov/pubmed/21334...
12. http://www.biomedcentral.com/1471-2377/7/6
13. http://www.biomedcentral.com/authors/pro...
17. http://www.ncbi.nlm.nih.gov/pubmed/22354...
18. http://eurpub.oxfordjournals.org/content...
21. http://www.ncbi.nlm.nih.gov/pmc/articles...
24. http://dx.doi.org/10.5255/UKDA-SN-3660-1
25. http://www.ncbi.nlm.nih.gov/pubmed/9054791
26. http://www.ncbi.nlm.nih.gov/pubmed/10528...
27. http://www.bmj.com/content/347/bmj.f5963...
28. http://www.ncbi.nlm.nih.gov/pubmed/17426...
29. http://www.bmj.com/content/347/bmj.f5963...
32. http://evaluatingpace.phoenixrising.me/a...
33. http://www.meactionuk.org.uk/Normal-fati...
35. http://www.meassociation.org.uk/?p=6171
40. http://www.ema.europa.eu
41. http://www.ncbi.nlm.nih.gov/pmc/articles...
42. http://www.ncbi.nlm.nih.gov/pmc/articles...
43. http://www.meactionuk.org.uk/pacepressco...
44. http://www.ncbi.nlm.nih.gov/pmc/articles...
45. http://www.bmj.com/content/342/bmj.d1168...
49. http://www.pcc.org.uk/news/index.html?ar...
50. http://www.meassociation.org.uk/archive-...

Mr Matthees left an annotation ()

Clarifications for the public interest argument above:

• If there is any doubt about the ease of which some trial participants could be disqualified from meeting Oxford criteria at followup (for failing any additional ad hoc criteria bolted onto the Oxford criteria for the purposes of the trial), QMUL previously stated: "A score of 70 or more on the SF-36 sub-scale would mean that the participant did not meet Oxford criteria. Similarly having a score of 5 or less on the Chalder fatigue questionnaire would mean that the participant did not meet Oxford criteria." [1] This is not usually part of the Oxford criteria and means that no longer meeting Oxford criteria at followup in the trial could be achieved by borderline cases improving a single increment on either scale but who could still be significantly affected by CFS and still otherwise meet Oxford criteria outside the trial setting. In the original trial protocol, a fatigue score of 5/11 on the CFQ (bimodal scoring) and a score of 70/100 on the physical function sub-scale of the SF-36 were still both regarded as abnormal scores, and required a fatigue score of 3/11 and a physical function score of 85/100 to be classified as recovered. [2]

• Re: "11% of excluded candidates failed to meet these additional criteria despite otherwise meeting Oxford criteria". This was based on Figure 1 of the 2011 Lancet paper, [3] but it is not entirely clear how many excluded candidates failed to meet each stated reason for exclusion, as only one reason is given for each exclusion but it is plausible that excluded candidates failed more than one. Out of the 2517 candidates who were excluded (all of which had previously been definitely or provisionally diagnosed with CFS), 43% were excluded for not meeting Oxford criteria, 10% were excluded for scoring over 65/100 points in physical function, and 1% were excluded for scoring under 6/11 points in fatigue, suggesting that some excluded candidates still had CFS.

• A video has been made demonstrating how a trial participant could improve a single increment in fatigue, decline a single increment in physical function, report feeling significantly better e.g. due to pain medication, and then be classified as 'recovered' despite remaining significantly unwell with CFS. [4] Some participants would have to improve more to cross the thresholds, but it demonstrates a problem with the lax recovery criteria and that combining multiple recovery criteria does not necessary negate the weaknesses of each individual criteria. The definition of 'recovery' is simply too lax to justify the use of the word 'recovered', particularly without objective measures (which when used have generally shown a lack of clinically significant improvement).

• Re: "The thresholds for clinical improvements on an individual patient level for the primary measures of fatigue and physical function were abandoned and replaced with weaker thresholds...". To further clarify in context with the sentence which preceded it about BioMed Central's statement on post hoc revisions, the latter thresholds were the 'clinically useful difference' i.e. 2/33 points in fatigue (Likert scoring) and 8/100 points in physical function, which did not appear in the final version of the statistical analysis plan, [5] and were described as post hoc in the 2011 Lancet paper. [3] It is unclear when these were introduced and whether they were approved by the relevant trial oversight bodies (see below for why doubts have been raised).

• Re: "as the changes to the definition of recovery published in 2013 appear to be largely based on controversial post hoc analyses conducted for a previous paper on the trial results published in 2011". To further clarify, the methods and thresholds for the normal range for fatigue and physical function used in the revised definition of recovery did not appear in the final version of the statistical analysis plan [5] and are exactly the same as the post hoc analyses that were introduced during the peer review stage [6] of the fast tracked 2011 Lancet publication [3] (i.e. not introduced by the authors themselves). This is why doubts have been understandably raised over whether the changes to the recovery thresholds were approved by the relevant trial oversight bodies and whether the recovery definition was revised after rather than before these post hoc analyses were conducted, which would contradict the published impression that the changes were made to the recovery criteria before analysing any data. [7,8]

1. https://listserv.nodak.edu/cgi-bin/wa.ex...
2. http://www.biomedcentral.com/1471-2377/7/6
3. http://www.ncbi.nlm.nih.gov/pmc/articles...
4. http://www.youtube.com/watch?v=d_7J5ELjArU
5. http://www.trialsjournal.com/content/14/...
6. http://www.meactionuk.org.uk/whitereply....
7. http://www.ncbi.nlm.nih.gov/pmc/articles...
8. https://www.whatdotheyknow.com/request/t...