PHOENIX RISING

Rating The Months Research - The thesis of this newsletter is that the most important studies deal with the pathophysiology of CFS. Each month is graded according to the following criteria;

A – several difference making papers on CFS pathophysiology

B – a difference making paper on CFS pathophysiology plus several important ones

C - several important papers on CFS pathophysiology

The problem with subsets is their ability to mess up CFS research efforts. If, for instance, CFS patients with primarily immune or primarily neurological problems are combined in a study, then elucidating either group will be difficult if not impossible. The recognition that subsets may pose a problem in CFS is not new. The authors of the CDC ‘Fukuda’ definition of CFS in 1994 noted that the ‘looseness’ of definition would probably result in the inclusion of different kinds of CFS patients. Indeed it is the vague definition of CFS that makes the subset problem possible.

Researchers have never been clear on what constitutes CFS. The 1994 definition was promulgated to produce a more or less consistent baseline for research studies. A consensus definition created by a panel of experts based on anecdotal reports; i.e. their conception of what constituted CFS, it seemed more like a stopgap measure that a permanent entity.

Now the standard criteria in CFS research studies, this rather vague definition (severe fatigue of at least six months duration and 4/8 symptoms; post-exertional fatigue, sore throat, tender lymph nodes, headaches of a new type, unrefreshing sleep, muscle pain, multi-joint pain, impaired concentration) has certainly brought consistency to the field but at a cost of reduced precision. It seems unrealistic to expect that this definition would not evolve over time, yet it has remained unchanged for over 10 years now, and the CDC, the agency that created it – and the only organization with the standing to alter it – has, until recently, been committed to it. A paper on the CDC’s efforts to create a new definition for CFS will appear shortly.

The types of subsets in CFS and the negative effects they may have on research findings are hot topics right now. Jason presented a major paper last year that argued that differentiating subsets is absolutely critical if we are to make further progress in CFS. Likewise, Vance Spence, a researcher associated with CFS research group MERGE, stated in his recent presentation that there was no more critical problem in CFS than identifying subsets. Spence talked of how strange patterns of data seen in CFS studies often leave CFS researchers, as he put it, ‘scratching their heads.

Given the problems subsets can cause for CFS research and the potential for their occurrence it is remarkable how little work has been done to ferret them out. Most attempts to do so have used symptom and clinical data rather than laboratory data. The two studies before us are amongst the first to use both clinical and physiological data

Either process could lead to increased levels of the pro-inflammatory cytokines (immune messengers) that are believed responsible for creating what has come to be called ‘sickness behavior’.

These researchers theorized that a subset of CFS patients with decreased NK cell activity would display greater ‘sickness behavior", i.e. greater fatigue and cognitive problems, etc. than CFS patients with normal NK cell activity.

Since NK cells are involved in down regulating the cytokine response once an infection has been resolved the authors posited that low NK cell activity could result in prolonged cytokine activity and therefore prolonged periods of ‘sickness behavior’. Alternatively the inability of NK cells to clear an infection could result in a chronic state of ‘sickness behavior’ This theory is attractive because it does not require that a specific virus be present but suggests that NKC dysfunctional CFS patients as a group will display increased rates of viral infection (which they seem to do).

This study was a great start but it’s only a start. Note that the title of the paper is in the form of question and contains the word ‘preliminary’. NK cell test results (and CFS) can be quite variable over time and this variability has apparently prompted the authors to embark on a follow study to determine how consistent their results are. If they turn out to be consistent, the authors will presumably attempt to fully characterize an immune subset in CFS using tests of viral/bacterial activation, cytokine abundance and other markers of immune activation. That would be big, big, big news in CFS. This could be one of the most important papers of the year.

Note that the title of this paper says chronic fatigue not chronic fatigue syndrome. Like many of the other Pharmacogenomics studies this study contained three study groups, only one of which contained chronic fatigue patients; a CFS group (n=55), an idiopathic fatigue group (n=53), and an un-fatigued group that had been age, sex, race and BMI matched to the CFS group. These groups contained only women. The study was aimed not specifically at CFS but at states of unexplained fatigue in general.

This group took all the data points gathered by the CDC (~500) and winnowed them down to 38 measures that best explained the variability found in the data set. They included clinical (3), symptom (15) and lab data (21). The lab data consisted of the following categories; sleep (6), endocrine (6), immune (3), red blood cell (3) and tilt data (1).

The researchers hoped to use statistical programs to differentiate the different groups from each and to uncover subsets within each group.

Findings - The basic questions one asks about such studies are a) did they find subsets and b) did the subsets make sense? The answer in this case was a qualified yes.

Of the six classes developed three were dominated by CFS patients (1, 5, 6), two by idiopathic fatigue patients (3, 4), and one was dominated by the healthy controls (2). This study then appeared to differentiate three subsets in CFS.

The correlation between obesity and markers of inflammation (CRP, IL-6) and insulin and the problems with sleep in classes 1 and 3 prompted the researchers to state that obesity in itself plays a ‘prominent role in the production and maintenance of fatigue and other symptoms latent classes 1 (CFS) and 3 (idiopathic fatigue)’.

The most important symptoms in differentiating the different groups were.

• Post-exertional fatigue – was the first and third most important differentiating variables in the two statistical analyses done (principal components analysis (PCA, Latent Class Analyses). Its discriminatory prowess was highlighted by the fact that it and concentration difficulties were the only variables not found at all in the Well Group (class 2). The very high levels of post exertional fatigue in the three classes dominated by CFS patients (78-91%) and the low to moderate levels of it in the classes dominated by idiopathic fatigue patients (33-41%) indicate that it plays, as Dr. Jason has suggested, a special role in CFS. CFS is often described as being an amalgam of very common symptoms but this study indicates that post-exertional fatigue is not common in the population nor in other unexplained fatiguing diseases.
• Sore throat, shortness of breath, concentration and sleep problems were all found in much higher rates in the CFS subsets than in the others. (See complete paper for more detail).

Post –exertional fatigue, in particular, plus sore throat, shortness of breath and concentration and sleep problems appear to much more prevalent in CFS patients than in fatigued patients who do not meet the critieria for CFS or in healthy controls. This is another indication that a unique disease process is occurring in CFS.

Glutamate is the chief excitatory neurotransmitter in the brain. The function of the gene upregulated in this study is to reduce extracellular glutamate levels before they become ‘excitotoxic’ i.e. before they start to damage or kill neurons. The presence of this gene therefore suggests that increased glutamate levels are found in idiopathic fatigue and CFS.

I was born in the United States in 1952. My husband, who is Bermudian by birth, and I live in Bermuda. Many people confuse Bermuda with the Bahamas, but if you look at an atlas, you will see that Bermuda is 600 miles off the coast of North Carolina, and Bermuda has the most northern coral reef in the world. This is a tiny island (20 miles long and in certain areas less than one mile wide.) The island is just beautiful and tourism is flourishing. During cruise ship season from April through October, we see cruise ships in the harbor.

I have a sister two years older and a sister three years younger. All of us were born premature. We all had the usual childhood diseases, but all three of us somehow escaped mumps. Nothing unusual there. But I was the only one who contracted scarlet fever, and I was so young at the time, I don’t have any memory of this at all. My mother was sick a lot with stomach problems and back problems, which would result in several failed back fusion surgeries, that orthopedic doctors were quick to perform then. I can only guess that perhaps she may have had FM then.

When I was in elementary school I do recall bouts of sinus feeling like a sock was stuffed up my nose. This condition is called rhinitis, and can be allergic or non allergic. Dr. Baraniuk has been doing research on rhinitis and CFS. IBS was apparent by the time I was maybe around the age of ten or so, and there would be times of constipation, followed by sharp abdominal pain and diarrhea.

At 14 Mono hit me (neither of my siblings had any health problems that I would experience) and I was diagnosed by my family doctor. I seemed to have the typical "recovery" pattern and I went back to school and everything seemed OK. But the summer before my senior year, I got hit with pneumonia, along with a soaring temperature, I landed at the hospital where I stayed for one week. The diagnosis was "viral pneumonia" and I wonder if that Mono had something to do with this. Today some scientists are again relooking at EBV, and CMV and their role in CFS. It hasn’t been either proved or disproved, while the current fashion is to declare that EBV or CMV don’t "cause" CFS. Dr. Huber from Tufts school of Medicine is doing research on EBV transactivating endogenous HERV-K18 as a risk factor in CFS. Some groups are suggesting that childhood vaccines are the vector for the mass introduction of these viruses, which reactivate and then the host can spread contagion to others when the virus reactivates.

After the viral pneumonia, my family doctor sent me to a highly respected allergist in Boston, and I tested positive for numerous food and pollen type allergies as well as asthma. I started the desentisation weekly injection therapy. I don’t think that this cured my allergies at all. About age 20, I experienced migraine with aura, and I NEVER had this before. I would then experience this several times yearly and I just went on with my life. I studied, and worked, but in my 20’s I noticed peculiar, nagging bouts of feeling tired after normal exertion. On the several attempts to get any medical answers for this, I got none. In my 30’s. I passed 2 kidney stones, but have never done so since. IBS continued.

I dated my husband, whom I met on a trip here, and after several years we got married (almost 20 years now) and I moved to Bermuda. I work as a graphic designer and also do my own artwork. Then in January of 2005 CFS hit hard! Right after the holidays, I noticed that the gland in my left neck felt swollen and I could feel a lump the size of a pea and I did not feel well. I also had several bouts with vertigo and more and more disequllibrium. A full day at work left me totally wasted and I could hardly move along with upper back and neck pain. I went to my local GP, he informed me that I had "arthritis" and gave me ibuprofen. No help at all. I went back to him and with his dismissive attitude, this doctor gave me an antidepressant prescription (which I threw out after 5 days)……..

It seems that nothing is ever simple in CFS. Even as I felt my muscles relax and strengthen things began to go haywire elsewhere. As my body got stronger my brain seemed to collapse. First I became really jittery. It was odd to be feeling so much stronger only to collapse into a bundle of nerves every time I tried talk to somebody. My chemical sensitivities also increased. I cut down my massages to a few points on my abdomen and legs but this seemed to make little difference – I had become so hypersensitive that even rubbing a few points lead to substantial jitteriness. Things really reached a head when my old ‘friend’ nausea retuned to the scene. I could handle jitteriness but nausea was a different story. I had spent years recovering from chronic nausea after a bad exposure to chemicals. I was not going down that road again. I ramped the massaging down further – and then as the nausea continued and even strengthened I had to quit it altogether. As I stopped massaging these tender/trigger points I could feel the stiffness and tightness return, my shoulders narrow, chest contract.

Was that the end of the tender point massages? No it wasn’t. A few weeks later I started the massaging again. I was surprised to find that the massaging had stuck for a few points; they were either gone or much diminished. Many never showed any change but the several important ones on my hips were gone. I’ll continue to work on these since this area seems to influence a large number of muscles. I don’t forsee the really big changes but I do see some real help over time – probably a lot of time.

In the meantime we’ve gotten another book suggestion for this tender/trigger point problem.