The Puzzle of Chronic Fatigue Syndrome

By Dov Michaeli

First published 2/21/11 on The Doctor Weighs In

A study in the Feb. 18 online issue of Lancet on different therapeutic modalities of Chronic Fatigue Syndrome (CFS) is bound to raise howls with the “CFS community”, meaning their advocacy groups. So let’s take a dispassionate look at the issue.

What is CFS?

Here is the major problem: nobody knows. The CDC definition of CFS:

  1. A new onset (not lifelong) of unexplained, persistent fatigue unrelated to exertion and not substantially relieved by rest, that causes a significant reduction in previous activity levels.
  2. Four or more of the following symptoms that last six months or longer:
    • Impaired memory or concentration
    • Post-exertional malaise, where physical or mental exertions bring on “extreme, prolonged exhaustion and sickness”
    • Unrefreshing sleep
    • Muscle pain (myalgia)
    • Pain in multiple joints (arthralgia)
    • Headaches of a new kind or greater severity
    • Sore throat, frequent or recurring
    • Tender lymph nodes(cervical or axillary)

A bewildering set of symptoms that defies any rational analysis as to etiology (cause). It is a diagnosis of exclusion, after you rule out sleep disorders, depression, alcohol/drug abuse, diabetes, hypothyroidism, mononucleosis(mono), lupus, multiple sclerosis(MS), chronic hepatitis and various malignancies. Medications can also cause side effects that mimic symptoms of CFS.

Now, this is not to say that CFS is not real –it probably is. But a definition based on symptoms and a long list of conditions that masquerade as CFS makes it hard to pin down with any degree of certainty.

To compound the problem of diagnostic  vagueness, physicians who specialize in treating these patients, aided and abetted by advocacy groups, made it their mission to lend “scientific” credibility to the condition by trying to rid it of the vague “fatigue” term and substitute it with respectable – sounding names such as benign myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic myalgic encephalomyelitis, epidemic neuromyasthenia, Iceland disease, myalgic encephalomyelitis, myalgic encephalitis, myalgic encephalopathy, postviral fatigue syndrome, raphe nucleus encephalopathy.

Trouble is, there is not a shred of evidence for any of those. No muscle pathology, no central nervous system pathology, no immune deficiency evidence, no trace of mononucleosis. It was sheer semantic invention.  A 1999 review in  Journal of Internal medicine advocated the use of chronic fatigue syndrome instead of myalgic encephalomyelitis or ME which was in wide use in the United Kingdom, “because there is, so far, no recognized pathology in muscles and in the central nervous system as is implied by the term ME.” But the power of patient advocacy is not to be discounted; aLancet commentary in 2002 noted that the recent report by the “Working Group on CFS/ME” used the compromise name CFS/ME stating, “The fact that both names for the illness were used symbolises (British spelling) respect for different viewpoints whilst acknowledging the continuing lack of consensus on a universally acceptable name.” Speaking of political correctness…I thought the Brits had little patience for this sort of nonsense.

XMRV to the rescue?

XMRV is a mouse virus that causes leukemia in mice. XMRV was first identified in 2006 in patients with prostate cancer.  A study published by Lombardi and colleagues (Science, 2009;326:585) reported finding evidence of XMRV DNA and antibodies in about two-thirds of CFS patients and nearly 4% of healthy persons. Hopes were high the finally, at long last a “real” causative agent for this ill-defined disease was found. Not so fast; a bunch of other papers found no trace of the virus DNA either in patients’ or control blood. So what is the source of the discrepancy? It turns out that it was a simple case of contamination. DNA assay, called PCR, used kits that were contaminated with mouse DNA. Also, the most popular animal in biological laboratories is the mouse, and its DNA is literally everywhere. Consequently, incredible measures need to be taken to ensure lack of contamination. But, we are only human and sometimes we screw up.

The Lombardi paper in Science reports also on anti XMRV antibodies in the patients’ sera, and this assay does not depend on DNA, but on protein. However, a report published by CDC investigators and colleagues in July 2010 found no evidence of antibodies. I cannot think of an easy explanation for this discrepancy.

Push the envelope

Back to the latest Feb.18 Lancet article. The investigators evaluated 3 different treatment modalities currently in use:

  • Cognitive behavior Therapy (CBT)  tries to help patients understand their individual symptoms and beliefs and develop strategies to improve day-to-day functioning
  • Graded exercise therapy (GET) is a form of physical therapy that starts very slowly and gradually increases over time, basically pushing gently to exceed what had been accomplished in previous sessions.
  • Adaptive pacing acknowledges the patients’ limitations and helps them live within their limits.

The 641 patients in the study — the largest ever in the treatment of chronic fatigue — were randomly assigned to different treatments, got six months of therapy, and then were evaluated for fatigue and level of function six months after that.

The two therapies that proved superior in the study were:

  • Twice-a-week cognitive behavior therapy to change the way CFS patients think about their devastating fatigue, or to reduce their fear of exertion; or
  • Similarly frequent sessions that gradually increase a patient’s activity level, within the patient’s ability.

Between the two, psychotherapy coupled with exercise therapy was the most effective.

Adaptive pacing, favored by many CFS specialists, was no better than doing nothing.

The message is clear: “When a therapist worked with the patient to help them do better over time, it produced better function and less fatigue” according to Dr. Sharpe, the paper’s senior author.

So what’s no to like?

Great paper. But wait for the predictable pushback from the advocacy groups, as if any acknowledgment that there is a psychological component to CFS is a threat to the quest for its biological cause. The first volley has already been fired: ”The issue with cognitive behavior therapy and graded exercise therapy…have to do with the impression that if these things are effective then it must mean that the condition is all in my head, “stated Kim McCleary to NPR. She is president of the Chronic Fatigue and Immunodeficiency Association of America.”If you can make it better by changing my illness beliefs, what you’re saying to me is that I don’t have a real illness or a physical illness”.

Really? Nobody doubted Michelle Akers’ diagnosis or severity of her CFS. Yet she was a leading American association football player, who starred in the historic 1991 and 1999 Women’s World Cup victory by the U.S. She won the Golden Boot as the top scorer in the 1991 tournament. She is a member of the National Soccer Hall of Fame. All of those feats while heroically battling her disease.

C’mon…Can’t we just say “great job” and “thank you” Dr. Sharpe?

Dov Michaeli MD, PhD writes at The Doctor Weighs In.

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