This is difficult if not impossibe to answer. Firstly 'fatigue' is a common and normal human experience, think of exercise then feeling fatigue, thus most humans will feel fatigued on a regular basis. The more important question is what makes a person suffer a 'chronic fatigue syndrome'. We must then differentiate between chronic fatigue states and chronic fatigue syndrome as a discrete illness. For example suffering anaemia might make you chronically fatigued but this is not CFS. CFS if one accepts this term (and I do not) is an illness in its own right caused by a pathogen of unknown origin (in my view) and by psychological factors if you accept somatisation as aetiology. To understand the mechanism that pushes a person into CFS, one would need to know the pathogen and its pathogenesis. We would then need to know how different hosts (different people in this case) react. EBV is implicated in CFS - we know that most people have antibodies to EBV yet only a small fraction suffer illness lasting more than say 6 months, thus it is not just the potential pathogen but the interaction bewtween the pathogen and the host's immune response, as well as other factors, genetics and so on. We do know however that girls suffer CFS at a rate of 2:1 from males, thus being female is a risk factor. Also age, with common onset at 16-30. So there are some clues but my general opinion is that we will never know for sure why one person develops CFS while another does not, even if exposed to the same pathogen.

Thanks, Keith. I agree that CFS is a misnomer. I also doubt that its pathogen(s), even when discovered with confidence, will explain but a small fraction of variability in symptoms. I suspect it'll be more dependent on things like perception of effort or decision criterion - as distinct from d' in signal detection. And these things are purely mental. This is not to say that they can't be affected by a pathogen (possibly of a very different kind - e.g., not a virus but a lack of exposure to exertion-recovery cycles during critical periods of early development, similar to the "use it or loose it" in sensory and immune development). I also wonder if there is any parallel between individual dynamics of CFS and chronic fatigue trajectories in "normal" folk when their work-rest cycles get screwed (e.g., shiftworkers, young parents with bulging sleep debts, etc)?

Hi Eugene,

I agree it is not a viral trigger. To answer your acute to chronic question, I think it is interesting that CFS is often relapsing remitting. If therapies such as graded excercise are effective the patient can build up strength and increasingly return to near normal. Unfortunately another flare often comes along. This suggests there is some sort of threshold that pushes the sufferer between complete exhaustion and something more manageable.

I want to stress CFS is not just depression, but I wonder if a similar question could be asked about what triggers the shift from down moods to clinical depression? Genetic susceptibility, environmental factors, tipping the chemical balance in the brain?

This research came out this week about a possible cause of hypersomnia, you may find it relevant. I attached the press release so it is a quick read. http://www.sciencedaily.com/releases/2012/11/121121145613.htm

GET and CBT have been shown to be largely ineffective - see recent Spanish RCT 2011 "Health Related Quality of Life in Chronic Fatigue Syndrome:". This is supported by other work that shows that exercise induces an immune response and cellular level stress. This stress within cells is most likely caused by an immune response to a pathogen or some shift in immunity in response to a previous pathogen, thus some auto-immune state. read up on RNase L pathway -

In 2006, in combination with Australian researchers, the United States CDC found that the acuteness of the triggering infection was the key variable in who contracted CFS and who did not. Psychological factors or which specific pathogen was involved were not.

Psychiatrist Dr. Mady Hornig at the Columbia University Mailman School of Public Health and the Center for Infection and Immunity states, "“It’s very difficult in my mind to make this a psychological disorder,” said Dr. Hornig,“We do patients a disservice if we focus solely on secondary phenomena of being disabled or being unable to carry on life to your capacity – that shouldn’t ever be viewed as being the primary problem.”

Dr. Hornig most recently oversaw a NIH sponsored study on XMRV. People with psychological disorders were excluded from the cohort. Hundreds of blood samples and other bodily fluid samples remain available to research groups. Currently underway is a very large metagenomics study using cutting edge deep sequencing in the same patient cohort, the results of which should be published in 2013. More information here: http://chronicfatigue.stanford.edu/about/projects.html

There is a significant body of research regarding the role of pathogens in multi-system diseases including this area. Experts theorize, and have research showing, that it is a combination of genetics, immune system dysfunction and pathogens. However because some researchers use definitions that exclude

psychological disorders and some do not, both using the same term, researchers must be very careful about extrapolating results between completely different patient groups.

Back to exercise, probably best to look at the research of exercise physiologists and ME /CFS experts at the University of the Pacfic Fatigue Lab who specialise in research into the post exertional exhaustion that is one of the key components of myalgic encephalomyelitis/chronic fatigue syndrome. They have developed the Steven's Protocol to measure this dysfunction. (VanNess JM , Davenport TE, Snell CR, Stevens SR).

Other researchers are looking at mitochondrial dysfunction in such patients which could also influence the exercise intolerance found in these groups. Other researchers at the University of Utah examine gene expression abnormalities triggered by exercise. Check Light et al.

Juliet, whether depression is a normal psychosocial overlay in response to being severely ill or even stigma and whether it is an integral physiological component in subgroups could be related to pathogens in part.

Some pathogens such as herpes viruses have an affinity for the brain and nervous system. It could be postulated that pathogens in some patients may cause damage in those regions of the brain affecting emotion for example. Same thing with toxins.

And Keith, have a little faith in the process of science. Answers often require advances in technology not to mention research money, but eventually questions are answered. Centuries ago, people thought disease was a process of humoral fluids or bad air. The answers didn't come in their lifetime perhaps, but they did come.

I have had the Chronic Fatigue Syndrome/ME since getting the 1957 Asian flu. I was six years old at the time. It was relapsing/remitting the first twenty years (except for some muscle problems that showed up in Oct 1957 that have been with me ever since) . It has been permanent the last 35 years. It is definitely NOT a psychological disorder. The type of fatigue is different from a normal person's experience of it. In fact, I have felt as many as six or seven types of fatigue simultaneously. I can give very plausible physiological causes for all of them--they have absolutely nothing to do with state of mind. NOTHING!

In fact, had a I not been a very creative, stubborn person with a great deal of psychological resilience, I never would have finished school, let alone got a PhD in mathematics and have a career as a university professor. I was lucky to be in remission for graduate school.I was also lucky that the worst of the neurocognitive problems didn't start to show up until 22 years ago. I got another infection which set off the usual symptoms permanently shortly after I started teaching in 1978. Over decades, the illness has definitely turned into some type of degenerative neurological/neuromuscular illness. In 1998 I was sent to a mitochondrial specialist. A series of blood test over time on the same day established as fact what I could tell physiologically. Lactic acid builds up and doesn't break down for a day or more afterwards. For me, this has been a major component of the fatigue. No amount of mind over matter will cause lactic acid to break down. You have to wait it out. The specialist ultimately took my view of the mitochondrial dysfunction--it was the result of damage from chronic viral infections in certain muscles. But only certain muscles. We both agreed I don't have typical mitochondrial disease. Also muscle biopsies have established my mitochondria LOOK fine. They just don't work right. The specialist also explained that the reason I feel prostrated, especially the day after doing something, is because my body is reacting to the high levels of reactive oxygen species (ROS) and my body is telling me to go to bed and not move because a great deal of damage is going on that it wants to limit. He also explained the peculiar pain I experience then is from that, too.

A neurologist at MASS General went outside his area of expertise and figured out that high levels of biotin, B-1 and B-2 would speed up the recovery process. He was right. They have. So I've been able to teach several days in a row, if I'm careful of my recovery periods being long enough. I gained another 14 years of my career thanks to his insight.

Recent papers have established mitochondrial dysfunction as a common component of CFS. This is now a well-established scientific medical fact. For more information on this, you can see my paper on mitochondrial dysfunction in CFS posted on the Massachusetts CFIDS-ME & FM Association website http://masscfids.org/resource-library/13/302.

In addition I've had another type of muscle dysfunction problem consistently since Oct 1957. That I haven't found in any other person and I can't find any specialist who has the slightest clue about it. I can't find anything in the medical literature about it, either. It does respond temporarily to bananas and potatoes (for about an hour) and for a while it did to metformin. But that response has faded after the last infection I got and as my insulin-resistance has grown.It is getting worse and worse over time. I'm sure I'm not the only person in the world with the problem, but it clearly isn't anything the medical community has investigated yet. It has been established that it isn't a known genetic illness. As far as I can see, it is from some type of potassium channel dysfunction in my arm and leg muscles combined with something to do with insulin receptors, especially in the muscles that were infected at various times. It does get permanently worse after every infection of muscles or nerves. I decided I have to live to over one hundred in order to find out what is wrong. I hope I do find out before I die. I would really like to know what is going on, even if it is too late to help.

I do strongly recommend that most of you start reading the well-established medical literature on CFS/ME. There are many things wrong with the immune system as well as other components of the body in CFS/ME. This is a very complicated illness with changes in the body that are hard to measure--which is why it is taking so long to understand it.

As for cause--I've been convinced for decades that many different viral and bacterial triggers exist. Certainly in my case, influenza has been a consistent one, but there have been other types--including Coxsackie virus and West Nile virus. I have felt for the last twenty years or so that the defective RNAse-L found in many CFS/ME patients explains a great deal of the causes of the illness. I also have found that excessive response to histamine's effects on the immune system were a major cause of my chronic fever and other immune-system symptoms. I've stopped the chronic fever and other problems since 1985 by taking a H-1 and H-2 blocker. But I can't fix anything else. At least I haven't been smart enough to think of anything.

Lucy,

Thanks for your closely reasoned post and your extensively researched article on mitochondrial dysfunction posted on the Massachusetts CF site. I've read both plus your supplement on supplements plus a number of the papers you cited. I'm a physiologist/electrical engineer working as a volunteer systems biologist with a dedicated CFS research group at Stanford. What you've written prompted several questions in my mind, which I hope you will have time to address.

First, I was surprised to see that "many CFS patients have a low-grade fever." I don't know of a paper on this subject (if you do, please tell me), but I know two CFS patients personally, one moderate, one very severe, and both consistently have LOW resting body temperature. If there are CFS subgroups based on body temperature, I'd like to know it because mitochondrial UCP function might well be involved.

Second, the prescription suggested by your neurologist friend (riboflavin, thiamine, and biotin) fascinated me because it parallels my own intuition about CFS. Parenthetically, a colleague has told me of a single CFS patient who reports significant and ongoing improvement in symptoms as a result of sublingual FMN, which, as you know, is the product of the first step on the pathway from riboflavin to FAD. Presumably, the sublingual route delivers FMN directly to the blood, but I was still surprised it was effective because I did not think FMN could cross cell membranes. Still, there are plenty of carrier proteins whose functions are not known, and, as you point out, FMN and its metabolic successor, FAD, are critical for the function of complex I and complex II, respectively. 

Initially, I had been focused on NAD, rather than FAD, but it seems reasonable that any vitamin whose active form has a role in ETC function (riboflavin, niacin) or TCA cycle function (thiamine, biotin) is a natural candidate in the etiology of CFS. So I was surprised that your neurologist's insight did not include niacin given its role as the precursor to NAD, which links the TCA cycle and beta-oxidation to complex I.  I'd value your thoughts on this, and his too if you are still in touch with him.

You also mentioned a unique type of fatigue associated with some skeletal muscles, but not all skeletal muscles. This prompted the general question about which of the body's 200+ cell types express a CFS phenotype. Some research groups (ours included) are exploring questions about CFS using peripheral blood mononuclear cells (PBMCs) because they can more readily be obtained from patients and healthy controls than, say, skeletal muscle cells. I've been concerned that PBMCs may not express a CFS phenotype and that defects in their function may be due to the molecular components of CFS blood plasma in which they have spent their lives. Again, I'd value your thoughts on this.

One question I ask every CFS patient who has a scientific bent: If you think back, given all you know now, to the beginning of your CFS (and I realize you were only 6) can you identify the first non-flu symptom and where you felt it?

There is no rush in providing your responses. I promise to work through them whenever you have time and energy to reply. If you'd prefer to respond privately, that is fine with me. 

Regards,

Rob

Hello, I have found the following webtrail provides lots of material on this illness and research being conducted to uncover possibilities for those afflicted, and their carer's/supporters, Please accept mycontribution as a non-medical person who is caring for a daughter who succumbed to ME/CFS aged 12 and who now struggles along aged 17, living a life which is a shadow of her former vitality. I have found the STORK site delivers current research regularly to my email: Contact - [email protected]  

e.g. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. by Yamano, Sugimoto, …, Kataoka (2016) Sci Rep (impact factor: 5.1) 

AND

Calcium mobilisation in natural killer cells from Chronic fatigue syndrome/Myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels. by Nguyen, Johnston, …, Marshall-Gradisnik (2016) Clin. Exp. Immunol. (impact factor: 3.3)

AND a study in 2016 discovering interesting information about the blood and DAUER state [things].  This all provides hope of something helpful .....soon, we hope.

Kind Regards - Jenny

I have a brother inlaw who became exhausted ["burnt-out", they called it in those days] studying smultaneously with financial hardship and two infants to care for. A bout of winter influenza left him with exhaustion that is very definately ME/CFS. That started for him 21 years ago and now, aged 49, he has had to relinquish the final one day per week of his job that he had clung to over those years.Foggy head, physical activity leads to exhaustion that sleep won't refresh, frequent use of PawPaw lip balm for the ring of fire around the lips, regular sore but not pustuled or infected throats, sits in freezing winter with a singlet and jeans when all others are wrapped in woolies/wears sunglasses inside due to light hurting eyes, etc etc. Apparently the younger brother also had the same illness but when he was 11-13 years old....and a herbalist of Indian cultural background apparently mixed up medicine for him and he improved overa few motnhs and recovered.  I knew the younger brother inlaw had been very ill when young, nothing more, and we knew brother in law 2, [living in another country for the last 18 years] seemed to not ever recover fully from [burn-out]. But it wasn't until my daughter aged 12 wore out and kept taking days off school when 11, then stopped school altogether aged 12, sore throats, gave up beloved sports, etc, that we found no GP's with clear knowledge of the problem.

We booked her with ENT specialist to see if family tonsilitis weakness would provide improvement but the surgeon ENT specialist suggested ME/CFS simply because he recognised the symptoms from his own extended family member's situation.  Now, five years later, our daughter is 17 and bedroom-bound for 20 hours or more every single day. I am so pleased to see some recent work in this field. I am not medically qualified but have experience of this dis-ablility-causing problem for people. All the best with tracking things down. I think if we had known what to pay more attention to when our girl had influenza, or sore throats, antibiotics, etc pushing self in winter sports whils t slightly unwell,perhaps we could have avoided inviting ME/CFS....ahh one lives in hope.

My contribution is now to offer carers and sufferers dealing with this illness, Narrative Therapy and a place to have their voice heard. Finding wonderfulness amongst their frustrations, having ears to hear their new emerging story of living within a landscape where the freedoms of engaging in life are sometimes  fenced off., For my family - we follow the fencelines, hope and search for the gates, the stiles, the hillside slips where you can wriggle through for an hour, or a day, until the ME/CFS symptoms herd you back and shut the gate on you...until next time! (Yes, graduated exercise and CBT became an inolerable restriction in the end, it seemed to serve the purpose of enabling the medical persons' to "apply a treatment" but did nothing to actually improve the young person's life or physical experience.)

"following the fencelines" ... I find strength in your poetry and we will not cease our efforts at stile and gate-building.

Aah, Robert - what's the science behind this sweet medicine of giving me this "high-five?"