During the stakeholder teleconference with FDA on September 13, 2012, Dr. Sandra Kweder said that FDA considers ME/CFS to be a serious or life-threatening condition. In the world of FDA regulations, this is a very important designation. Here’s the full quote from Dr. Kweder:

We consider your condition to be in the category of serious or life threatening diseases. Okay, so all of the measures to move things through rapidly, all of the tools that we have here at FDA to try and expedite reviews or expedite development and work with companies to try and encourage them along that would apply to, you know, immediately life threatening cancer, as far as we’re concerned they apply to this condition. This is a serious condition and I just want to make that clear. We consider it in the same category because there are no approved treatments for this condition and we understand how seriously and severely peoples’ lives are impacted by this disease – by this condition. (FDA Stakeholder Teleconference Transcript, pp. 13-14)

But what does this actually mean? How did FDA make this determination? Richard Klein, FDA Office of Special Health Issues, provided me with some background information.

FDA’s definitions of serious and life-threatening come from the Federal Regulations governing FDA. According to the regulations, a serious disease or condition “has substantial impact on day-to-day functioning.  . . . Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.” (21 CFR 312.300) It is patently obvious that CFS meets this definition because of its devastating impact on day-to-day functioning.

The definition of life-threatening is found in several regulations. In the section on investigational new drugs, “life-threatening” means “(1) Diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted; and (2) Diseases or conditions with potentially fatal outcomes, where the end point of clinical trial analysis is survival.” (21 CFR 312.81) Another section of the regulations says “Immediately life-threatening disease or condition means a stage of disease in which there is reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment.” (21 CFR 312.300)

So is FDA saying that CFS is a life-threatening condition? I know many patients believe that it is a life-threatening condition, and Dr. Lily Chu had made a strong case for why research should examine the issue. But I suspect FDA has not drawn this conclusion. Note that Dr. Kweder said “serious OR life-threatening,” according to the transcript. Several patients discussed the possibility that CFS is life-threatening, but no one from FDA said that it was. It is unclear to me whether FDA believes CFS is life-threatening.

Having said that, it is very clear that FDA believes CFS is a serious condition. This is a very important designation because serious (or life-threatening) conditions are eligible for several drug review programs intended to speed drugs to market. In my next post, I will attempt to explain what these programs are and how they might help those of us waiting for treatment.

 

Let’s play a game. Imagine you have a large puzzle that makes an Impressionist picture of a colorful cottage-style garden. You can put it together as long as you have the picture on the box. First you assemble the lower left corner, all lavender and yellow flowers. Another section of red roses sits somewhere in the middle. Near the upper right corner is a section of white and gray paving stones, and you also put together an area of green herbs although you are not sure where it goes yet. This puzzle will take a lot of time to solve, but with the finished image on the box you know that you’ll put it together eventually.

Now imagine the box is gone. All you have is a white/gray blob, and lavender/yellow section, the red rose section and another green blob. The rest of the pieces are all mixed up together, and while you can separate out some edge pieces and consolidate others by color, without the box you cannot even be certain what the final picture should look like. It’s frustrating, isn’t it, to have all those pieces on the table and not see how it fits together or even know for certain that you have all the pieces. That’s the feeling I got reading the American Family Physician’s article on Chronic Fatigue Syndrome: Diagnosis and Treatment. I dissected the AAFP patient information sheet on CFS in a recent post, but now I think it’s important to examine this review article by the same authors. The article attempts to present a finished picture of CFS for family practitioners, but so many pieces are missing that the paper bears little resemblance to the CFS I live with.

Generally Speaking

“Chronic Fatigue Syndrome: Diagnosis and Treatment” by Dr. Joseph Yancey and Dr. Sarah Thomas gives an overview of CFS for family physicians. They review the Oxford and Fukuda criteria, the basic lab workup recommended by CDC, and a list of exclusionary conditions. In a section on etiology of CFS, the authors quickly cover the immune system, genetics, psychosocial, adrenal system, and sleep/nutrition. Finally, the treatment section focuses on cognitive behavioral therapy (they say it works), graded exercise therapy (this works too), nonpharmacological (nothing really helps) and pharmacological treatments (these don’t work either).

In the authors’ defense, there are significant space limitations in the American Family Practitioner journal: 1,500 to 1,800 words in the case of clinical review articles like this one. There is no way to include all the information about CFS that family doctors need in such a limited space. It also appears that neither Yancey nor Thomas are CFS experts, based on the very limited information I could find online. I emailed Dr. Yancey, the corresponding author for the paper, on October 24th with a few questions but to date I have not received a response.

Method Madness

Drs. Yancey and Thomas describe their research methods as follows:

A PubMed search was completed using the MeSH term chronic fatigue syndrome. The search included randomized controlled trials and clinical trials in English from the past 10 years. We also searched the Cochrane database, Essential Evidence Plus, the National Institutes for Health and Clinical Excellence guidelines, and the Centers for Disease Control and Prevention Web site. Search date: August 26, 2011.

This methodology accounts for some of the missing pieces. First, anything published after August 26, 2011 was not captured in the search. That includes the IACFS/ME Primer, NCI’s paper on the risk of cancer among elderly CFS patients, the ME-ICC criteria, and the Rituximab trial. But before we forgive the authors’ oversight of these papers based on the date of their literature search, consider a curiosity I found in the paper references. The authors cite one paper published after August 26, 2011: The FITNET trial of internet based CBT for adolescents with CFS is included as reference Number 27. Does that strike you as odd? If the authors truly limited themselves to the references found on August 26, 2011 then this paper should not be included. Furthermore, of all the papers published after August 2011 to include in a review of CFS treatment and diagnosis, why was a CBT paper the one cherry-picked by the authors?

Even within the boundaries of the search methodology, the authors missed some papers that would have been helpful in their overview sketch of CFS. I attempted to recreate the authors’ search in PubMed, and found more than 1,300 clinical study papers alone. These include all of the letters critical of the PACE study and Tom Kindlon’s many letters and papers on the potential harms and inaccuracies in CBT/GET studies. Other important papers such as the spinal fluid proteome by Schutzer, et al., the differential gene expression post-exercise paper from Light, et al., and the cytokine network modeling by Broderick, et al. were captured in the PubMed search but did not make it into this review paper.

Finally, there are several seminal papers that are not returned in the PubMed search. The Journal of Chronic Fatigue Syndrome published the Canadian Consensus Criteria by Caruthers, et al., in 2003. This case definition is gaining broad acceptance among policy makers and researchers, but it does not show up in a PubMed search because the journal was never indexed in Medline. Another example is the Van Ness, et al. study showing the significance of two-day exercise testing in differentiating CFS patients from controls. This is a critical paper, suggesting a possible diagnostic test (albeit an extremely unpleasant one) for CFS. But because the journal was never indexed, these papers do not show up in a PubMed search and so non-experts like Yancey and Thomas never see them.

Cognitive Bias

I do not know what Dr. Yancey and Dr. Thomas believe about CFS, including whether they believe the illness is primarily psychological in origin. After reading this paper, however, I fear this may be the case. I can best illustrate this through examples.

In the opening paragraph of the article, the authors say “CFS is often mentally and emotionally debilitating, and persons with this diagnosis are twice as likely to be unemployed as persons with fatigue who do not meet formal criteria for CFS.” What about physically debilitating? If the authors recognized the physical disability experienced by many CFS patients, and the physical suffering of all of us, wouldn’t they mention it in this paragraph? This simple omission is a very subtle way to communicate that people with CFS are not physically ill.

There is a brief discussion of the case definition in the paper. According to the authors, the 1988 CDC definition focused on physical symptoms, and the 1991 Oxford definition “emphasize mental fatigue over physical symptoms.” But the criteria, printed as Table 1 in the article, require fatigue to be “severe, disabling, and affects physical and mental functioning.” I’m no fan of the Oxford definition, but even I can see the requirement of physical disability. Again, Yancey and Thomas gloss right over the fact that CFS has serious, physical symptoms.

In discussing the biopsychosocial model of CFS etiology, the authors say: “CFS is often associated with depression, which has led many physicians to believe that CFS is a purely psychosomatic illness. Evidence supporting this conclusion is lacking.” Fair enough. But then they say, “Strong evidence suggests that childhood trauma increases the risk of CFS by as much as sixfold.” Sigh. I covered this in my dissection of the patient information sheet. Childhood trauma may have physical systemic affects, but I am not aware of any evidence showing that CFS patients have higher rates of trauma compared to patients with other illnesses like MS or lupus or diabetes or cancer. In my opinion, it is misleading to single out childhood trauma as a risk factor for CFS in the absence of such evidence.

The authors devote space and attention to CBT and GET studies, and this is understandable given the fact that CBT and GET treatments have received the most study in CFS. CBT “can help persons with CFS recognize how their fears of activity lead to behaviors that ultimately cause them to feel more fatigued and disabled.” It is true that CBT can help patients correct activity avoidance behavior, but in my experience this is a very small minority of patients. Even the CDC, target of so much criticism, does not describe CBT this way. The CDC says: “CBT can be useful by helping them pace themselves and avoid the push-crash cycle in which a person does too much, crashes, rests, starts to feel a little better, and then does too much once again.” This is a more appropriate description of CBT that acknowledges the importance of self-management and the prevalence of the push-crash cycle, as opposed to the activity avoidance highlighted by Yancey and Thomas.

Graded exercise therapy is very controversial for CFS patients, mainly because traditional GET uses a scheduled increase process as opposed to a patient-driven increase process based on symptoms. Not surprisingly, this issue is not discussed in the paper. The authors do mention that a heart rate monitor can be used to avoid overexertion during exercise, but there is no mention of the body of evidence on CFS exercise testing and pacing methods. They even cite a study that suggests improvements in GET do not correlate with increases in exercise capacity, suggesting that GET may actually work by “decreasing symptom-focusing behavior in persons with CFS.” Pacing, the only behavioral technique that truly helps CFS patients, is not mentioned by name, although the authors do say:

Patients should be encouraged to take rest periods as necessary, and to practice relaxation techniques. Although there is no evidence these modalities are effective, they are unlikely to be harmful and may be helpful.

Neither CBT nor GET is curative because it does not target the underlying mechanism of illness. CBT is not curative for cancer or heart disease either, for the same reason. Drawing the conclusion that these therapies are not curative because of the patient is a fallacy, but this is the conclusion that Yancey and Thomas suggest:

Despite the positive results of CBT and graded exercise therapy, the effects are usually moderate and rarely lead to resolution of CFS. Patients with poor social adjustment, a strong belief in an organic cause for fatigue, or some sort of sickness benefit (i.e. financial incentive) tend to have worse responses to therapy. Unlike with many other illnesses, membership in a CFS support group was associated with worse outcomes.

The study cited by the authors in support of these statements is this one from 2002. That study points out its own limitations: it uses the Oxford definition, lost 17% of the patients to follow-up, and did not actually measure the exercise capacity of the patients. But this is the kind of evidence that is sufficient for Yancey and Thomas.

The overall tone, selective quotation, and reference choices give me the impression that the authors believe CFS to be a psychological condition, at least in part. I do not know this for a fact, but if I read only this article about CFS and nothing else, I would believe that it is an emotional problem. It’s not just the amount of space devoted to the psychosocial research. The authors focus on the psychological elements to the exclusion of discussion of physical disability, post-exertional malaise, and the well-documented physiological findings in this illness.

Missing Pieces

There are huge gaps in this paper. Orthostatic intolerance, an issue for most CFS patients, is not mentioned at all. Post-exertional malaise is not explained, and no CFS exercise studies are referenced. The importance of medications and other treatments in managing sleep and pain issues is ignored, and pain is barely discussed at all.

This article illustrates a few pieces of the puzzle, mainly CBT, GET and the psychosocial model of CFS. A family physician reading only this article would not be able to separate chronic fatigue from CFS patients, and would understand almost nothing about the complexity of CFS. I found the tone to be generally hopeless: try therapy and exercise but it probably won’t help you much. Maybe a motivated physician would visit the CDC website (and this illustrates the importance of fixing problems in those materials).

No one will be able to assemble the CFS puzzle using the pieces in this article. Too much evidence is ignored, too much emphasis is placed on the psychosocial pieces, and there is very little information about how to manage the other symptoms of the illness. I know the full picture exists and I can identify the gaps. But a family physician who does not have the picture of the box will not recognize all that is missing and will never be able to assemble the pieces in a way that will help CFS patients.

I fear that doctors will rely on this article to provide the same kind of advice I received from doctors in 1994: keep going to the gym, staying in bed is the worst thing you can do, get some counseling, there is nothing else we can do to help you. This bad advice and hopelessness did not help me, and may have even hurt me by keeping me much more active than my body could tolerate. It was years before I found and received adequate care for pain, sleep, and orthostatic intolerance, and even more years before I found expert help for pacing and activity management. This article will do nothing to change the way doctors treat CFS, and will reinforce the destructive pattern already in place.

I’m on the verge of tearing my hair out, and I suspect I’m not the only one. The American Academy of Family Physicians published a review article about CFS (paywall) on Monday, accompanied by a patient information sheet. From the very first sentence, this information sheet is a disaster. It packages harmful misinformation for family doctors to share with patients. Let’s take a look:

Chronic fatigue syndrome (CFS) is a disorder that causes you to be very tired.

NO! No it does not! A person with sleep apnea is tired. A nursing mother is tired. A perfectly healthy person studying for the bar exam is tired (ask me how I know). CFS does not make me tired. CFS causes prostration, a medical term that means a collapse from complete physical or mental exhaustion. Using the word “tired” is not only medically inaccurate, it falsely minimizes the severity of my disease and my experience.

People with CFS may have other symptoms, such as poor sleep, trouble with remembering things, pain, sore throat, tender lymph nodes, or headaches.

Can you spot what’s missing? Post-exertional malaise! The generally accepted hallmark symptom of this disease is not on the list. It is the first symptom on the Fukuda criteria list of accompanying symptoms. But it’s not listed here and not explained to the patient.

Not everyone with CFS has all of these symptoms.

I know hundreds of CFS patients. Every single one of us has experienced these symptoms for extended periods of time, if not daily, over the course of years. While it is technically correct that the Fukuda criteria do not require all of those symptoms, it is an oversimplification to simply say we don’t have all the symptoms. And of course all the other symptoms and overlapping conditions are not mentioned at all.

Childhood trauma (for example, physical or sexual abuse) may raise the risk of getting it.

I am aware of two studies that showed a higher prevalence of childhood trauma among CFS cases compared to healthy controls (this one and this one). Here’s the problem: childhood trauma may raise the risk of many disorders later in life. Without comparing the prevalence rate of trauma among other illness groups, there is no way to know if the association with CFS is unique. Are there studies comparing the incidence of childhood trauma among people who develop multiple sclerosis, rheumatoid arthritis, cancer, hepatitis, heart disease or  . . . oh, that’s right. Doing that kind of study in those illnesses might be offensive because those illnesses are real. But we can do those studies in CFS with no problem.

Two treatments can help with CFS: cognitive behavior therapy (CBT) and graded exercise therapy. With CBT, a therapist teaches you about how your thinking affects how you feel and act. With graded exercise therapy, you slowly increase your physical activity, which hopefully increases your function.

You know where this is going, right? Setting aside the arguments about whether CBT and GET studies actually show a benefit, and setting aside how this sort of statement plays right into the mental illness meme, let’s talk about GET. Will GET increase CFS patients’ functional ability? Maybe some patients, but it should be pursued with extreme caution and prejudice. As the work of the Pacific Fatigue Lab and my own exercise testing results show, the energy metabolism systems of CFS patients are severely impaired. We do not make or use energy, or recover from activity, the way other people (including other illness groups) do. Graded exercise must be undertaken very carefully because it takes very little activity to push a patient into a severe crash.

I shudder to think about how family doctors will use this information sheet, and what it will do to the patients who receive it. What is truly remarkable about it is that it bears only a passing resemblance to the full review article and the AAFP’s patient education page on CFS. But this watered down, oversimplified summary of misinformation about CFS will undoubtedly be used, and it is likely to make things worse for patients, not better.

So does anyone – journalists, doctors, policymakers, or other observers – wonder why the CFS Advisory Committee and patient advocates have been begging CDC to fully revise its website and remove the harmful content that filtered into this information sheet?

This is why.

Does anyone wonder why the CFSAC  recommended that the CDC remove its Toolkit from the CDC website?

This is why.

Does anyone wonder why an alliance of organizations and patients wrote a lengthy and heavily referenced position paper in support of that recommendation?

This is why.

Does anyone wonder why there was such vigorous disagreement at the CFSAC meeting about whether professional societies like the AAFP should be invited to participate in revising the CFS case definition?

THIS. IS. WHY.

 

 

Update November 2, 2012: Author Toni Bernhard published a great article about the AAFP patient information sheet.

Update October 31, 2012: I’ve also published a detailed analysis of the AAFP review article on CFS.

Pacing is . . . actually, my descriptions of pacing generally involve expletives that are not appropriate for this blog, so we’ll stick with “Pacing is challenging.” One positive side effect of my pacing efforts, though, is that I am still celebrating my birthday one month after the fact.

Last week, I went out for a birthday lunch with Friend K. We’ve been friends for 22 years now, and K knew me for four years before I got sick. We went to law school and took the bar exam together, and undertook a mammoth road trip together. When I started dating my husband, K was the first friend I asked to check him out. Hanging out with K is great because she really gets the illness, and so I don’t have to talk about it but I can if I want to. She told me the latest stories about her sons, and generally made me laugh my ass off. For a few hours, I felt like a normal person having lunch with her best friend, and it was glorious.

I also went out for a birthday dinner last week with Friend M. I met M soon after I got sick, and she is another rare gem: a friend who gets it. M and her husband read a prayer at our wedding, and she is one of the most loyal and giving people I know. For my birthday, M took me to one of my favorite local restaurants for dinner and we closed that place down. The meal was sublime, but having M’s undivided attention for four hours was even better. She told me some great stories about her eight year old daughter, including the “court proceedings” in which M has been accused of posing as the tooth fairy. I felt just like the women at the table next to ours, enjoying a girls’ night out with one of my closest friends. These moments of normalcy, of interacting with the world the way I used to, are so rare and precious.

And then there was the payback. The day after that dinner, I was crashed but I didn’t care. It was totally worth the pain and post-exertional relapse. I was still high on the joy of being with my friends. But then I was crashed for two more days, and I started to question the price of normalcy.

My attempts to implement stricter pacing techniques have challenged me far more deeply than I expected. I’m questioning everything now. Before the exercise testing, I was absolutely convinced that having occasional episodes of normalcy was worth the crash days. Outings like these feed my spirit and make me so happy. But now I wonder if it’s the right thing to do. Do I have to give up the last few remnants of my healthy life in order to cope with my sick life? How do I strike the right balance between accommodating my physical limitations and hanging on to who I am? What else do I have to give up in order to live crash free?

I feel like these are deep, existential questions. For 18 years, I have sacrificed my body in order to enjoy occasional outings with my friends, to participate in CFS advocacy, and to take care of my family. If pain and crashing was the price of continuing to participate in my life, I paid it gladly. But is this the right way to balance the equation? Is having dinner with a friend worth three days in bed? Facing that consequence is not fair, and I don’t want my life to be this way. But this is my reality. I need some kind of owner’s manual to tell me how to figure this out. Do I punish my body by exceeding my physical limits? Or do I punish my soul by living within those limits? It’s a no-win situation, and I don’t know how to answer these questions any more.

Dr. Lily Chu submitted these written comments to the CFS Advisory Committee for its June 2012 meeting. She has kindly given me permission to publish them here.

Dear Sirs and Mesdames,

Thank you for this opportunity to address official and ex-officio members of CFSAC.

In the early 1990s, it was a habit of mine to watch the newsmagazine show “20/20” every Friday. One evening, the show was about Dr. Jack Kevorkian and the controversy over physician-assisted suicide; as a pre-medical student, I was interested in anything medically related and  paid extra attention.  I learned that one of the persons he assisted was Judith Curren, a nurse affected by fibromyalgia and chronic fatigue syndrome (CFS), who had suffered from severe pain and other symptom prior to her death.  Later on, as a medical student and then a physician working with elderly patients, I remembered the case because of the ethical situation but not because of CFS.

Now, however, what stands out to me is that Ms. Curren suffered from CFS and was affected enough that she chose death over life. When I first encountered this illness six years ago, one of the first persons I spoke to was a good friend who also happened to be an excellent physician.  She told me she had taken care of a very sick man in his 30s with CFS, so sick that a short car ride to her office was hardly tolerated.  Not long after she had changed medical practices, she heard he had passed away.  She was particularly upset because she did not think people could die from this illness. It was a revelation to me too and I put it down to a rare incident.  However, since that time, I have known two young people personally that have passed away within the last year and have heard/ read of many others (1- 5) yet outside of the patient community and a few ME/CFS researchers and clinicians, the fact that people do die from ME/CFS is hardly acknowledged anywhere and rarely investigated.

My intention is not to cause anxiety, fear, or alarm – many people with CFS continue to live years to decades, albeit at much reduced function/ quality compared to their lives pre-CFS – but rather to encourage governmental agencies and researchers to take this illness seriously and urgently examine areas of ME/CFS that have been neglected.

1) Study the effects of  ME/CFS long-term through cross-sectional and longitudinal studies.

A few studies have looked at the effects of ME/ CFS superficially in people who have lived with this for more than a decade but there are practically no longitudinal studies beyond a few years. Just 2 weeks ago, Chang et al., utilizing a large national cancer registry and a case-control design, showed that there was a statistically significant increased risk of non-Hodgkin’s lymphoma in people with CFS over the age of 65. (6)  Since Paul Levine’s studies in the mid-1990s, this increased risk has been theorized to exist but there was no follow-up until recently. (7)

Furthermore, Chang or other researchers should consider replicating the study in a younger population.  In 2006, Jason et. al. studied a list of ME/CFS deaths and concluded that 20% of the deaths were not only related to cancer but that the cancer deaths occurred 15 years earlier on average than cancer deaths in the population (48 vs. 72). (8) Thus, Chang et al., confining their study to those over the age of 65, would have missed any findings from this younger group.

2) Encourage researchers to include homebound and bedbound subjects in their studies.

There have been no studies on how many or what percentage of US ME/CFS patients are homebound or bedbound but using figures from British studies, at least 25% of patients fall into this category. (9) Having done home visits in the past for the elderly, I know that this type of population is particularly vulnerable – they are some of the sickest patients yet receive the least amount of care. This is further compounded by the fact that these ME/CFS patients rarely show up in emergency rooms or hospitals, as very sick patients with other illnesses do, and thus continue to stay invisible to the medical/ scientific community. Part of this is that patients feel these places have very little to offer them but the other part is that medical staff may not believe that they could be so sick and not take patients’ symptoms seriously nor treat them appropriately.

Furthermore, there are only two studies that have been published including this population, both based in the UK. (10, 11) Yet, treatment goals and suggestions are routinely made for this group originating from clinic-based studies, which often involve less severely affected patients. In other areas of medicine, such as diabetes or hypertension, treatment suggestions, such as what should be the initial first drug of choice, are made based partly on severity of illness and goals may change based on the individual, not a one-size-fits-all paradigm. (12, 13) Why can’t the same concept be applied to ME/CFS?  At the same time, symptoms these patients DO suffer from including uncontrolled pain, inability to sit up without passing out, light/ noise sensitivity, difficulty swallowing/ eating, and severe cognitive dysfunction are neither studied nor treated appropriately to the best of medicine’s current ability. Thus, it is not surprising that many of the deaths I am aware of occurred in this group,  because of suffering/ despair/ hopelessness and/ or underlying biological processes the scientific/ medical community has yet to understand.

Over the last 2 decades, technology has advanced to the point where some tests and procedures that were once confined to the clinic or hospital are now able to be done during home visits. Aside from researchers visiting subjects, blood tests, certain x-rays, ultrasounds, and other portable diagnostic testing should be explored in investigating this group.

3) Consider autopsy and tissue sample studies and communicate with clinicians/ researchers involved in these studies.

Autopsy studies are a valuable method of gaining insight into the pathophysiology of illnesses.  In 2005, Sophie Mirza, a 32-year old woman from the United Kingdom, died of ME/CFS after having been bedridden for 6 years.  Before her death, Ms. Mirza was subjected to healthcare professionals who thought her illness was entirely psychological and who tried to have her placed in a psychiatric hospital. A preliminary autopsy revealed ME/CFS to be the main cause of death and the neuropathologist involved, Dr. Dominic O’Donovan, stated:

“the spinal chord [sic] looked normal but…4 out of 5 dorsal root ganglia were abnormal and showed disease. [I was unable] to find exactly what had caused this but the result was dorsal root ganglionitis – an inflammation.”

“dorsal root ganglionitis is a pathological condition….psychiatrists were baffled by her illness but… “It lies more in the realms of neurology than psychiatry, in my opinion.” (3)

Since then, Dr. O’Donovan and Dr. Abhijit Chaudhuri have performed at least 3 other autopsies with each individual consistently showing evidence of inflammation of the dorsal root ganglion and/or degenerative changes in the spinal cord or brain. (14, 15) Such inflammation may explain some of the severe pain and other neurologic symptoms some patients suffer from. They, along with other groups in the UK are currently working on establishing a post-mortem ME/CFS tissue bank to continue to study these unfortunate incidents systematically. (16)

In the United States, as far as I know, no such study is ongoing or has been proposed although I am aware that the CFIDS Association of America, Dr. Dan Peterson’s group, as well as possibly the Whittemore-Peterson Institute may have some tissue samples and have thought about this topic. I suggest that government officials and researchers communicate with these groups as well with Drs. O’Donovan and Chaudhuri.

Finally, it has been brought to my attention that governmental officials would not allow submission of photographs or short videos involving homebound/ bedbound people as a means of testimony although videos have been allowed in the past. (17)  Photographs and videos allow officials, researchers, clinicians, and the public a glimpse of the bedrooms that severely ill people are confined to for years to decades in a way that words on a page or a voice on the telephone do not. Would this not add to the picture of the illness the government needs to formulate an appropriate response to this illness? Are people afraid of seeing the truth?  I suggest officials see the film “Voices from the Shadows,” about severely ill ME/CFS patients, which is now available online and won the Audience Favorite award at the Mill Valley Film Festival in November of 2011. (18)

If some of what I have written sounds familiar, it is because some of the same ideas have been suggested in the past. Please take action on these issues soon. I hope to never hear about another preventable death nor to attend another funeral due to ME/CFS. Thank you for your attention.

Sincerely,

Lily Chu, MD, MSHS

 

References

1. ME/CFS Memorial. Blue Ribbon Campaign for ME/CFS. http://www.blueribboncampaignforme.org/ME_CFS_Memorial.html. Accessed June 2012.

2. Casey Fero ME-CFS Tissue and Blood Bank. Wisconsin ME/CFS Association, Inc. http://www.wicfs-me.org/casey_fero_blood_blank.htm. Accessed June 2012.

3. The story of Sophia and ME.  Invest in ME. http://www.investinme.org/Article-050%20Sophia%20Wilson%2001.htm.  Accessed June 2012.

4. Emily Collingridge, 1981-2012: such a short life, such a huge legacy. The ME Association.  http://www.meassociation.org.uk/?p=10880. Accessed June 2012.

5. Alison Hunter Memorial Foundation. http://www.ahmf.org/smh040502.html Accessed June  2012.

6. Chang CM, Warren JL, Engels, EA. (2012), Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults. Cancer. doi: 10.1002/cncr.27612

7.  Levine PH, Pilkington D, Strickland P. Chronic fatigue syndrome and cancer. Journal of Chronic Fatigue Syndrome, 2000, Vol. 7, No. 1 : Pages 29-38

8.  Jason LA, Corradi K, Gress S, Williams D, Torres-Harding S. Causes of death among patients with chronic fatigue syndrome. Health Care Women Int. 2006 Aug; 27(7): 615-26.

9.  The 25% ME Group. http://www.25megroup.org/home.html Accessed June 2012.

10.  Wiborg JF, van der Werf S, Prins JB, Bleijenberg G. Being homebound with chronic fatigue syndrome: A multidimensional comparison with outpatients. Psychiatry Res. 2010 May 15; 177 (1-2): 246-9. Epub 2010 Mar 5.

11.  Wearden AJ, Riste J, Dowrick C, et al. Fatigue Intervention by Nurses Evaluation – the FINE Trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol. [ISRCTN74156610]. BMC Med. 2006 Apr 7; 4:9.

12. Standard in medical care of diabetes – 2012. American Diabetes Association. http://care.diabetesjournals.org/content/35/Supplement 1/S11.full. Accessed June 2012.

13. JNC7 Express. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Hypertension. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. Accessed June 2012.

14.  Inflammation in chronic fatigue. The Naked Scientists, http://www.thenakedscientists.com/HTML/content/interviews/interview/2099/. Accessed June 2012.

15. O’Donovan DG. Pathology of chronic fatigue syndrome: pilot study of four autopsy cases. http://www.bond.edu.au/prod ext/groups/public/@pub-burcs gen/documents/genericwebdocument/bd3 016859.pdf. Accessed June 2012.

16.  Lacerda EM, Nacul L, Pheby D, Shepherd C, Spencer P. Exploring the feasibility of establishing a disease-specific post-mortem tissue bank in the UK: a case study in ME/CFS. J Clin Pathol. 2010 Nov; 63(11): 1032-4. Epub 2010 Oct 5.

17.  Testimony of Laurel Bertrand to Chronic Fatigue Syndrome Advisory Committee, October 30, 2009, http://www.hhs.gov/advcomcfs/meetings/presentations/bertrand1009.html. Accessed June 2012.

18.  Voices from the Shadows. Directed by Josh Biggs and Natalie Boulton. http://mubi.com/films/voices-from-the-shadows. Accessed June 2012.

 

I posted about the cancer and CFS study last week based on the abstract only. Now I have a copy of the full paper, and there is much more to discuss. Dr. Suzanne Vernon also wrote about the study, so you might want to check out her analysis too. I expressed concerns about two aspects of the study: whether the subjects actually had CFS and whether the odds ratio represented a significant risk of cancer. Reading the full paper, my concerns were justified.

Case Selection

The study began with the selection of 1.2 million cancer cases from the SEER cancer registry. These cases were all first cancers in people aged 66 to 99 between 1992 and 2005. Cases had to have Medicare coverage for at least 13 months prior to diagnosis with cancer, and people with HMO coverage were excluded. Controls (100,000) were selected at random from the Medicare database and matched by gender, age, and location to the cancer cases. Both the cancer cases and controls were then evaluated for CFS in the Medicare database.

The presence of CFS was evaluated based on the database only. No confirmation of the diagnosis was attempted. More importantly, two codes were counted as CFS. The CFS code (780.1) was introduced in 1998. For older cases, this study used the code for neurasthenia (300.5). Neurasthenia is a topic unto itself, but its definition should give you pause:

a condition that is characterized especially by physical and mental exhaustion usually with accompanying symptoms (as headaches, insomnia, and irritability), is believed to result from psychological factors (as depression or emotional stress or conflict), and is sometimes considered similar to or identical with chronic fatigue syndrome

In this study, the authors used two definitions of CFS. The first group was diagnosed with CFS or neurasthenia beginning in 1991, and the second group was diagnosed only with CFS after 1998. Neurasthenia is not the same as CFS, and is much more likely to be applied to people with chronic fatigue and other vague symptoms. Such a diagnosis is not the same as the 1994 Fukuda definition of CFS. And it should be quite obvious to readers that neither the neurasthenia nor the CFS diagnoses were made using anything like the Canadian Consensus Criteria.

The authors did attempt to apply stringent requirements to the CFS groups. The diagnosis had to be documented in at least 1 hospital claim or by at least two outpatient claims that were 30 days apart. They also did not consider CFS diagnoses made during the year prior to the diagnosis of cancer to avoid the possibility that undiagnosed cancer was the source of fatigue. Despite these conditions, the authors acknowledge, “We were unable to assess whether CFS was correctly diagnosed by physicians and reported in Medicare claims.” This is a major weakness of the study. The authors point to their overall prevalence rate of 0.5% as being consistent with community-based studies like Dr. Leonard Jason’s. But Dr. Jason’s study was not limited to diagnosed cases. If we assume that only 25% (a generous number) of CFS cases are diagnosed, then the prevalence rate of this population would be 2%. That’s a prevalence number approaching that of the CDC’s empiric definition, and we know that definition is highly likely to capture patients with depression and other sources of fatigue.

Based on all of this, I have little confidence that the prevalence rate and CFS case selection in this study is accurate. It would be very interesting to pull the CFS cases and use chart review to attempt to confirm the diagnosis.

Actual Cancer Risk

This study found higher odds that certain cancer cases had CFS (compared to controls) in non-Hodkin’s lymphoma, pancreatic and kidney cancers. The study found lower odds that cases of breast and oral cavity/pharynx cancers would have CFS compared to controls. However, the only association that held up after multiple comparison adjustment was non-Hodgkin’s lymphoma. Even when the neurasthenia cases are excluded, the odds ratio holds up (Table 2 of paper). This study was also able to examine sub-types of non-Hodgkin’s lymphoma, and three subtypes were significantly associated with CFS/neurasthenia: diffuse large B cell lymphoma, marginal zone lymphoma, and B cell non-Hodgkin’s lymphoma not otherwise specified.

There are more than a dozen subtypes of non-Hodgkin’s lymphoma, but interestingly the first two subtypes associated with CFS have a median age at diagnosis of 65 to 70 years of age. The authors note the significant limitation of their study, “because our study was limited to people aged 66 years and older, our results may not be generalizable to younger (nonelderly) populations.” The authors also note that neither CFS nor neurasthenia was associated with cancer overall. Only the odds ratio with non-Hodgkin’s lymphoma held up in the study.

The actual numbers should be noted. According to Table 2 in the paper, 500 controls had CFS/neurasthenia (.5% of 100,000). Of the almost 1.2 million cancer cases, 5,885 had CFS/neurasthenia (.5% of 1,176,950). Of the 57,632 cases with non-Hodgkin’s lymphoma, 403 people had CFS/neurasthenia. While this is probably the biggest statistical study of CFS and cancer, the actual numbers of cases are still quite small. Even so, the hypothesis that chronic immune activation or infection could play a role in the association of CFS and non-Hodgkin’s lymphoma is supported by this study. As the authors note, “Our study results support continued efforts to understand the biology of CFS.”

Abstract vs. Paper

The hype in the CFS community when this study was released can be summarized as “Ack! People with CFS have a higher risk of non-Hodgkin’s lymphoma!” Here is yet another illustration of the absolute peril of relying upon paper abstracts and media spin. The paper explicitly refuses to make such a claim:

We would also caution further against any direct interpretation or application of our results in a clinical setting. We could not estimate the absolute risk of NHL associated with CFS, but the risk is likely too small to affect the clinical management of patients with CFS.

Everyone got that? This paper does not say that people with CFS have a higher absolute risk of non-Hodgkin’s lymphoma. This paper did find some interesting statistical associations that should be investigated further, especially given the role of immune activation in CFS. But that’s all the paper found.

A study published online today found that CFS patients have a higher risk of developing certain kinds of cancer. I cannot get full access to the study (curse you, paywall!), so this post is based only on the abstract.

The study used the Medicare database to identify 1.2 million cancer cases and 100,000 controls between the ages of 66 and 99 years old. CFS was identified using linked Medicare claims at a prevalence in both groups of 0.5%. The association of CFS with cancer was calculated using odds ratio. An odds ratio is the ratio of the odds of an event occurring in the first group to the odds of it occurring in the second group. If the odds ratio is greater than one, then the condition or event is more likely to occur in the first group; an odds ratio of less than one, then the condition is less likely to occur in the first group.

The study reported the following odds ratios for cancer: non-Hodgkin’s lymphoma 1.29; pancreas 1.25; kidney 1.27; breast 0.85; and oral cavity and pharynx 0.70.  It is very important to note that only the non-Hodgkin’s lymphoma odds ratio withstood multiple comparison adjustment, which is why the study only draws a conclusion about the association of non-Hodgkin’s lymphoma with CFS. The study concludes that, “Chronic immune activation or an infection associated with CFS may play a role in explaining the increased risk of NHL.”

This is scary stuff. An increased association with or higher risk of cancer in people with CFS has long been reported by Dr. Dan Peterson and others. But based on reading the abstract, I have some serious questions about this study.

First, CFS was identified in these cohorts based on linked Medicare claims. That means that a doctor had to code the patient as having CFS. We know that CFS is under-diagnosed, with only 20% or fewer cases actually receiving a diagnosis. In this study, 0.5% of the cohorts had been coded as having CFS. But that prevalence of 0.5% is higher than the prevalence rate found by Leonard Jason’s community-based study. Jason’s study found a prevalence of 0.42%. That is not consistent with the maxim that CFS is under-diagnosed. Furthermore, there is no information provided about how CFS was diagnosed in these patients. It seems highly likely to me that an unknown number of these cases are actually cases of chronic fatigue, and not CFS.

Second, odds ratio is not the same thing as relative risk. By way of example, let’s assume that 90 out of 100 sixth grade boys laugh at fart jokes, but only 20 of 100 sixth grade girls laugh at fart jokes. The odds of a boy laughing at a fart joke are 9:1. The odds of a girl laughing at a fart joke are 1:4, or 0.25:1. The odds ratio is calculated 9/0.25, or an odds ratio of 36. But this does not mean that boys are 36 times more likely to laugh at fart jokes than girls. The relative position is calculated 90/20, or boys being 4.5 times more likely to laugh at fart jokes than girls. That’s still a huge disparity, but it’s nowhere near the odds ratio of 36.

In this study, the odds ratios are very small: 1.29 in non-Hodgkin’s lymphoma cases. And this number tells us nothing about the relative risk of a CFS patient developing non-Hodgkin’s lymphoma. Based on these numbers alone, and the uncertainty about how accurately CFS was diagnosed in any of these cases, I’m not sure this paper should be sending any of us to push the panic button.