The ME/CFS Zoo Hypothesis

A constant question regarding ME/CFS (and fibromyalgia) goes something like this:

Is it one disease, or is it a "spectrum", or is it multiple (distinct) diseases that look the same?

I that regard: I find the "Blind men and an elephant" parable helpful – and would like to expand it.

First of all, let me recount from the Wikipedia page a slightly modified summary of the parable:

In various versions of the tale, a group of blind men touch an elephant to learn what it is like. Each blind men feels a different part, but only one part, such as the trunk, or an foot, or the tusk.

A Jain version of the story says that six blind men were asked to determine what an elephant looked like by feeling different parts of the elephant's body. The blind man who feels a leg says the elephant is like a pillar; the one who feels the tail says the elephant is like a rope; the one who feels the trunk says the elephant is like a tree branch; the one who feels the ear says the elephant is like a hand fan; the one who feels the belly says the elephant is like a wall; and the one who feels the tusk says the elephant is like a solid pipe.

Afterwards the blind men talk to each other and learn that they are in complete disagreement. Some of the stories differ in how violent the conflict becomes, and how (or if) the conflict among the men and their perspectives is resolved.

In some versions, they stop talking, start listening and collaborate to "see" the full elephant. When a sighted man walks by and sees the entire elephant all at once, they also learn they are blind. While one's subjective experience is true, it may not be the totality of truth.

My impression is that many in the ME/CFS "community" think that most of the studies are equally "true" – I think that is the first mistake. To stay in the parable: Some of the blind men have never touched an elephant (or any other animal, for that matter) and simply make things up. Here you have blind men who describe not an elephant, but maybe an park bench, or an found umbrella, or maybe an object that exists only in their fantasy (and even describing that they suck). Yes Virginia, I'm talking about Lombardi, Mikovits and Ruscetti. There are others. Like those blind men trying to describe the color of the elephant. Somehow, now I have to think of the names Meirleir, Maes and Gerwyn.

And even if you sieve out all the blind men describing inanimate objects (or worse, make-believe objects), you get some who grabbed some random animal in the zoo and tried to described it. Now if they can describe two (or more) of those animals, and the differences between them, and if they do not try to make you believe that they describe the whole animal, I think they are much more trustworthy than those who want to make you believe they describe only an elephant, and that they know the entire elephant.

If you have someone who says "Here I found two animals with distinctly different tusk, one has leather like skin, the others is furry", well then we are on to something. Currently I have seen few people who would fit that bill: Alan Light (et al.), and maybe Julia Newton (come to my mind).

But one thing should be clear, all those harping about how we need better criteria to "sieve out all non-elephants" (to stay within the parable) should know that:
a) Your are an "blind men" yourself
b) You might be an "non-elephant" yourself
c) The studies you trust might describe non-elephants
d) The studies you trust might describe non-elephant animals that are different from you

Yes, better (and more stringent) criteria might be helpful, but what we need are ways to look at "a collection of zoo animals" (parable again), and learn to differentiate them properly, both in a research setting, and in a clinical setting.

"One Diagnosis - Several Fatigue Diseases"

Via the CO-CURE.org maillist (emphasis mine, and I corrected a few sentences that seem to be roughly translated):

A diagnosis - several diseases Fatigue.

Prejudice among many in the medical profession scares away most people who are interested in researching the ME's biological basis.

Lars Th. Narvestad- earlier Ass. Director of Hydro, now bedridden patient Published: 10.okt. 2012

Fatigue comes in many shapes and forms, and is one of the most common symptoms associated with the disease. It is associated with a variety of physical and mental disorders. Because it is so common and associated with so many different diseases, fatigue isolated symptom, not suitable as a basis for a medical diagnosis.

In spite of this it is prevailing practice in health-Norway that patients with some form of fatigue lasting more than four months (plus one additional symptom of a list of ten) are diagnosed with Chronic Fatigue Syndrome (Chronic Fatigue Syndrome - CFS), so while other known disease can not be detected with blood tests or other objective tests (NICE criteria).

One need not be a doctor to understand that such a diagnosis, which more or less exclusively based on the symptom of fatigue, will accommodate several different diseases and conditions.

One of the populations that have ended up in this bag diagnosis, patients with a distinct neuro-immune disease that historically only had the name Myalgic Encephamyelitis (ME). Under unfavorable circumstances, the term CFS introduced in the mid 1980's and is now used CFS and ME interchangeably when patients with this diagnosis should be described (CFS / ME), although prevalence studies show that there may be as few as one in five patients actually ME using broad diagnostic criteria for CFS.

Different patients - different forecasts

Mixing of disease descriptions with different patient groups has created great confusion and skepticism to these patients in the medical community and the public. Who what's wrong, and is it really any of those patients who have a severe physical illness? The impression is reinforced by the health authorities' experts argue that most with this diagnosis are cured, and some patients are presented in the media and declares himself fully with various forms of alternative therapy.

This picture is in stark contrast to the clinical experience of physicians who follow ME patients over time doing it. One of them, Professor of Medicine Anthony Komaroff of Harvard Medical School, who has followed over 400 patients over 25 years, says that very few of his patients recover. Almost all [live with the] disease [for] the rest of [their lives], often with a gradual deterioration. Many are very crippled, the sickest in an almost vegetative state.

Questionable Research

This experience, and all the studies that point to biological causes of disease, have been overlooked by health authorities with regard to the research conducted by a group of British psychiatrists and their allies. These researchers argue that their study provides evidence that cognitive behavior therapy (CBT) and graded exercise (GET) is a safe and curative treatment for patients with this diagnosis, despite the fact that research shows that the vast majority of ME patients whatsoever not noticed any effect of this kind of treatment. Then the seriously ill patients, who are worse by minimal effort, not included.

Weak results and strong criticism of criteria that include different patient groups, has not stopped these researchers from getting a steady stream of studies with the same topic for the past 20 years. The need to repeat itself, coupled with the constant attack from all studies that indicate biological causes of ME, memories suspicious about the research and propaganda tobacco industry sponsored to inactivate, dilute and disguise the damage to health caused by smoking.

Unexplained illness

Unfortunately, one of these methods succeeds in spreading a perception in the medical community that ME is a psychosomatic disorder, and research on MES biological basis and reason has as a consequence been virtually eradicated from public budgets for decades.

It is therefore no coincidence that […] ME is still an unexplained illness. If the biopsychosocial school [has their way, then ME] remains mysterious. Then they periodically go on the podium and continue their guesses, and theorizing about ME. For patients and relatives whose lives are ruined by this disease, it is a sickening thought. However, there is evidence to suggest that it might be the idea.

Over Diagnosis

Health Directorate works fortunately now to have realized that they have long relied on incorrect information and that it is necessary with the introduction of new and more stringent diagnostic criteria for ME. This is an important step in stopping the overdiagnostiseringen which unfortunately taking place, and with it form the basis for the right patient gets the right treatment.

When Haukeland GPs Fluge and Mella published their study on the effects of the cancer drug Rituximab in ME last fall, it was given its great hope for ME sufferers. In a small, but very well done study experienced two thirds of patients clear improvement after treatment. The results attracted attention around the world and received great attention because discovery could potentially change the lives of hundreds of thousands of ME patients while providing an understanding of disease biological mechanisms.

Conspiracy Theories

In response to these brilliant news managed Journal of the Norwegian Medical Association for two leaders in quick succession to put forward conspiracy theories and more strange comparisons that seemed to have intended to ask the authorities, patients and Rituximab study in a bad light. It was given the impression that CFS patients as a group scares scientists and clinicians away from the disease. The reality is unfortunately that there are prejudices of many in the medical profession that scares away most people who are interested in researching the MES biological basis. There is nothing patients want more than biomedical research. There, however, they do not want is doctors who are researching various forms of fatigue and presents it as ME research.

The media's lack of critical attention on the dilution of diagnostic criteria contributes to blurring and polarize public debate on ME. This leads to a deep despair and frustration for thousands of Norwegians living with a life-long disease.

Political responsibility

Last year's report from SINTEF and the two leaders of the Medical Association Journal has exposed attitudes and beliefs that dominate in the medical community about ME. When you also know that ME / CFS costs the Norwegian society in excess of $ 1 billion annually in lost income, benefits, and nursing and care costs, a Norwegian politicians no longer leave important decisions about health care in this patient group to traditional agencies. One must ensure that the necessary resources and influence given to the academic communities who want and are able to differentiate ME patients from patients with other disorders.

Cancer doctors at Haukeland need 11 million to complete a large multicenter trial of Rituximab, and it is successfully write medical history. Should Council, contrary to expectations, reject the application for funding this world leading research, the patient wilderness continue.

Well, I disagree that there is one "distinct neuro-immune disease that historically only had the name Myalgic Encephamyelitis (ME)" – I think there are a few distinct diseases that will be found under the label ME. But otherwise it is

Is Myalgic Encephalomyelitis (ME) an Neurological Disease?

First of all, let me say that Myalgic Encephalomyelitis (ME) is classified as a Neurological Disease (ICD 10 G93.3, or F286).

And I don't want to change that.

At least not now. Not until we know whether ME is one disease, or several distinct diseases, and until we know what the pathological processes at the root of ME are.

So regardless how ME is classified, what is the reality of ME? About that I want to speculate a bit.

Personally, I think it will turn out that the ME patient population, very much like CFS, will be composed of several diseases. Maybe there are, compared to CFS, less people who are (mis-)diagnosed with ME but have actually something else – but I doubt that ME is only one disease.

From the Norwegian Rituxan study by Fluge and Melle we know that a sizable portion of ME/CFS patients may have an autoimmune condition – which may or may not exclude neurologic problems to be the root cause. We can't tell from the Norwegian study one way or the other.

From the studies by Christopher Snell we know that VO2 max and exercise tolerance are reduced in a CFS patient population, which would point to cardiovascular causes, lung causes, or muscle-metabolic causes – a neurological root cause seems IMHO unlikely in the sub-group characterized by Dr. Snell, but still possible. The results from Dr. Snell are not particular specific and can be caused by different pathological processes, so there could be several diseases out there having the same VO2 max presentation (as seems already to be the case with other known non-CFS diseases).

From the studies by Kathleen and Alan Light we know that there are at least two sub-groups in the ME/CFS (and FM) patient population:

• People with a specific presentation of POTS like gene-expression
• People with a nonspecific presentation of fatigue and pain gene-expression

The specific POTS presentation may be indicative of a cardiovascular orgin, possibly with the involvement of endocrine system (beta-receptors seem to be implicated in a sub-group in the Lights studies). So the POTS sub-group IMHO may be one distinct disease, and I think it is unlikely to be several diseases.

The later sub-group (fatigue/pain) may IMHO most likely originate from metabolic problems in the muscle. It could be possibly caused by several pathways, which would possibly mean several distinct diseases.

These problems could in turn affect the brain in a negative way, showing up as neurological symptoms ("brain fatigue" or "brain fog", etc.)

So in conclusion, at the moment a sizable portion of patients seem to have a non-neurological root cause, especially hinted by the work of Kathleen and Alan Light.

Still, a minority of ME/CFS patients may be suffering from one (or more) – as of now – unknown and/or poorly understood neurological diseases – though it seems unlikely to me that a majority of ME/CFS patients have a neurological problem as root cause.

Of course, this does not preclude an neurological involvement in ME/CFS patients with non-neurological root causes.

This picture may change when more research brings us more data, until then we have to consider non-neurolgical etiologies for a majority of ME/CFS patients – I would not cling on to the neurological label forever.

Some Speculation on Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME)

There was recently a paper by an Israeli group about the question whether Fibromyalgia (FM) and ME/CFS are same. This was followed by some speculation in the ME/CFS community. The general assumption seems to be that some consider FM a distinct illness/disease, and ME an different distinct illness/disease, and that CFS is some sort of "catch all" category.

I recently speculated how the "landscape" for ME/CFS might look like. I came to the conclusion that once proper biomedical tests (like done in the currently running Lipkin study) yield results, that ME/CFS will be shown to consist of several discrete illnesses/diseases.

I think a similar picture will emerge for FM.

Furthermore I think some (but not all) of the illnesses/diseases that will be found to cause FM will be the same as will be found to cause ME/CFS.

And on a related note: Some people want to get rid of the "CFS" label – to which I say bravo! Alas, I have the impression these advocates consider ME one distinct illness/disease (which I think is wrong), and they think that CFS is some sort of hodgepodge. Well assuming it so, then there are still many people (and I mean many people) who have an diagnosis of CFS, but actually have this "distinct ME" illness/disease. By cutting off these ME patients, that have been misdiagnosed as CFS patients, what do you accomplish?

Furthermore, these advocates seem to have no problem that people with the diagnosis "CFS" get slandered as psycho(somatic) cases, as long as "their ME" illness/disease is taken seriously. To which I say: If you don't fight for protection of CFS patients from psychobabblers, then why should ME patients be protected from psychobabblers?

A prediction for ME/CFS

Here's my prediction for what Lipkin will find in ME/CFS patients (take it with some grains of salt):

• He will find two dominant distinct diseases in roughly 60% of patients: One disease will have an share of about 40% of patients, while the other will be about 20%.
  
  The two dominant diseases he will find will be either: in the form of an "new" autoimmune disease (as of now undocumented autoimmune-antibody/antigen and target tissue), or an undocumented presentation of a known virus (e.g. one of the HHVs or Enteroviruses), or an combination thereof.
  
  An unknown virus is possible, but seems to me unlikely.
• About 25% of patients will be comprised of patients with on of about 10 diseases. Diseases will be e.g. atypical presentations of known common diseases, and possibly some novel diseases.
• The remaining 15% of patients will have a multitude of diseases, some common and some rare, some known and some currently unknown.

The great unknown seems to be the role of HHVs. Interesting will be whether the majority of patients have an "simple" disease (e.g. with one autoimmune-antibody targeting one tissue type as prime cause) that "simply" causes the complex "multi-organ" disease presentation, or whether there is actually multi-organ involvement as prime cause.

Let's see – I'm not taking bets.

"The phenomenon of 'chronic Lyme'; an observational study."

The phenomenon of 'chronic Lyme'; an observational study.
Ljøstad U, Mygland A.

Department of Neurology, Sørlandet Hospital, Kristiansand, Norway Institute of Clinical Medicine, University of Bergen, Bergen, Norway Department of Habilitation, Sørlandet Hospital, Kristiansand, Norway

Abstract

Purposes:
To chart clinical, laboratory, and psychometric profiles in patients who attribute their complaints to chronic Lyme disease.

Methods:
We assessed the patients by clinical examination, laboratory tests, and questionnaires measuring fatigue, depression, anxiety, health-related quality of life, hypochondriasis, and illness perceptions.

Results:
We found no evidence of ongoing Borrelia burgdorferi (Bb) infection in any of the 29 included patients using current diagnostic guidelines and an extended array of tests.

Eight (28%) had other well-defined illnesses.

Twenty-one (72%) had symptoms of unknown cause, of those six met the suggested criteria for post-Lyme disease syndrome.

Fourteen (48%) had presence of anti-Bb antibodies.

The patients had more fatigue and poorer health-related quality of life as compared to normative data, but were not more depressed, anxious, or hypochondriacal.

Their beliefs about the illness were characterized by negative expectations.

Conclusion:
Our patients, who all attributed their symptoms to chronic Lyme disease, were heterogeneous.

None had evidences of persistent Bb infection, but whether current diagnostic criteria are functional in patients with longstanding complaints is controversial.

Other well-defined illnesses or sequelae from earlier Lyme disease were probable as main explanatory factor in some cases.

The patients were not more depressed, anxious, or hypochondriacal than the normal population, but they had poorer health-related quality of life, more fatigue, and negative expectations about their illness.

Unforutnatly only the abstract is available. The other "well-defined illnesses" would be interesting to collect.

And about half(!) of the patients who were seen by these doctors supposedly with "chronic Lyme" did actually not have anti-bodies against Borrelia Burgdorferi - and none had evidences of persistent infection! There are certainly some Quacks out there diagnosing people with "Chronic Lyme". And only "six met the suggested criteria for post-Lyme disease syndrome".

NIAID on Chronic Lyme and long-term Antibiotic use

NIAID on Chronic Lyme:

The first clinical trial, which included two studies conducted at multiple research sites, provided no evidence that extended antibiotic treatment is beneficial (New Engl J Med 345: 85-92, 2001). In those studies, physicians examined long-term antibiotic therapy in patients with a well-documented history of previous Lyme disease, but who reported persistent pain, fatigue, impaired cognitive function, or unexplained numbness. Patients were treated with 30 days of an intravenous antibiotic followed by 60 days of treatment with an oral antibiotic.

These studies did reinforce the evidence that patients reporting PLDS symptoms have a severe impairment in overall physical health and quality of life. However, prolonged antibiotic therapy showed no benefit when compared with groups who received placebo.

In another study, published in 2003, researchers examined the effect of 28 days of intravenous antibiotic compared with placebo in 55 patients reporting persistent, severe fatigue at least 6 months following treatment for laboratory-diagnosed Lyme disease. Patients were assessed for improvements in self-reported fatigue and cognitive function (Neurology 60: 1923-30, 2003).

In that study, people receiving antibiotics did report a greater improvement in fatigue than those on placebo. However, no benefit to cognitive function was observed. In addition, six of the study participants had serious adverse events associated with intravenous antibiotic use, and four patients required hospitalization. Overall, the study authors concluded that additional antibiotic therapy for PLDS was not supported by the evidence.

More recently, a study supported by the National Institute of Neurological Disorders and Stroke (NINDS), also a part of the National Institutes of Health, again showed that long-term antibiotic use for Lyme disease is not an effective strategy for cognitive improvement (Neurology 70(13): 992-1003, 2008). Researchers compared clinical improvement following 10 weeks of intravenous ceftriaxone versus intravenous placebo. The patients were treated for Lyme disease and presented with objective memory impairment tests. In a complicated statistical model, the ceftriaxone group showed a slightly greater improvement at 12 weeks, but at 24 weeks, both the ceftriaxone and the placebo groups had improved similarly from baseline. In addition, adverse effects attributed to intravenous ceftriaxone occurred in 26 percent of patients. The authors concluded that because of the limited duration of the cognitive improvement and the risks involved, 10 weeks of intravenous ceftriaxone was not an effective strategy for cognitive improvement in these patients, and more durable and safer treatment strategies are still needed.

To recap:

• The people are ill 
• Long-term antibiotics do most certainly not cure
• Long-term antibiotics have dangers
• Diagnose is done through "a well-documented history of previous Lyme disease"

As far as I am concerned, there is no evidence that "Chronic Lyme" or "post-Lyme disease syndrome" (PLDS) is anything else then just another pathogen that can cause CF(S) or PVFS.

"Multiple Chemical Sensitivity (MCS): A Spurious Diagnosis"

Stephen Barrett, M.D. at Quackwatch on Multiple Chemical Sensitivity ("MCS"):

…
Psychologist Herman Staudenmayer, Ph.D., of Denver, Colorado, has treated "MCS" patients for more than 30 years. He believes that although some people are very sensitive to various microorganisms, noxious chemicals, and common foods, there is no scientific evidence that an immunologic basis exists for generalized allergy to environmental substances. During the 1990s, like Rea, Staudenmayer and his colleague—the late John C. Selner, M.D. (an allergist)—used an environmental chamber to test sensitivity to airborne chemicals. However, they rejected clinical ecology theories and practices. Using well-designed double-blind tests, they demonstrated that "universal reactors" may develop multiple symptoms in response to the testing process without being allergic to any of the individual substances administered. One of their reports describes how they used an environmental chamber to evaluate 20 patients with multiple symptoms attributed to chemical hypersensitivity. These patients believed that they were reactive or hypersensitive to low-level exposure to many chemicals. Some had previously been evaluated and managed by clinical ecologists and diagnosed with "MCS." During nonblinded tests, these patients consistently reported symptoms they had associated with exposure at work, at home, or elsewhere. The environmental chamber enabled the patients to encounter measured amounts of purified air, compressed gasses, and air containing specific chemical concentrations, without knowing which situation was which. None of the patients demonstrated a response pattern implicating the chemicals supposedly responsible for their symptoms. Eighteen reported no symptoms at least once when the suspect chemical was present. Fifteen reported symptoms at least once when the suspect chemical was absent [10]. In other words, patients reacted to their feelings and beliefs about the test, rather than to the substance in question [11].

In 1999, the American Health Foundation's Environmental Health and Safety Council reached a similar conclusion. After reviewing the evidence for various alleged mechanisms though which odor-bearing chemicals might cause MCS symptoms, the council concluded:

In no case was there persuasive evidence that any olfactory mechanism involving fragrance underlies either induction of a sensitized state or the triggering of MCS symptoms. Fragrances and other odorants could, however, be associated with symptoms as claimed by MCS symptomatics, because they are recognizable stimuli, but fragrance has not been demonstrated to be causal in the usual sense. [12]

A more recent study tested whether "MCS" patients could reliably distinguish between airborne solvents and placebo and whether there were significant differences in measurable biological and neuropsychological parameters between solvent and placebo exposures. During the study, 20 MCS patients and 17 controls underwent six sessions in a challenge chamber in which they were exposed to solvent fumes and clean air in random order. Neither the patients nor the experimentors knew which exposures were which at the time they took place. No differences accuracy in identifying chemical exposure were found between the two groups. Nor was cognitive performance influenced by solvent exposure or different between the groups. Nor was there any difference between the groups in serum cortisol levels measured before and after exposures [13].

So probably no MCS, but other illnesses.

So what about the symptoms? They are interesting:

… The complaints associated with these labels include depression, irritability, mood swings, inability to concentrate or think clearly, poor memory, fatigue, drowsiness, diarrhea, constipation, dizziness, mental exhaustion (also called "brain fog" or "brain fag"), lightheadedness, sneezing, runny or stuffy nose, wheezing, itching eyes and nose, skin rashes, headache, chest pain, muscle and joint pain, urinary frequency, pounding heart, muscle incoordination, swelling of various parts of the body, upset stomach, tingling of the fingers and toes, and psychotic experiences associated with schizophrenia.

Well, some of it sounds like from ME/CFS, Fibromyalgia and POTS…

William J. Rea, M.D., who says he has treated more than 20,000 environmentally ill patients, states that they "may manifest any symptom in the textbook of medicine."

Oh my. If someone can diagnose literally anyone with MCS for having "any symptom in the textbook of medicine", then MCS is a worthless diagnose. And most certainly one will miss many other diagnoses, of real illnesses and diseases.

"40% of CFS patients seen by the Newcastle Service could in fact be diagnosed with other conditions"

Breakthrough magazine Autumn 2011

The correct diagnosis
Are we getting better at diagnosing ME/CFS?

At present, there are many ways of diagnosing ME, CFS, CFIDS, CFS/ME and ME/CFS – and just listing these acronyms illustrates the confusion that besets the field. Yet each new definition delivers only a “diagnosis of exclusion” of other conditions, based on clusters of vaguely defined symptoms shared with other illnesses. How valid a diagnosis of ME/CFS really is depends critically on the rigour of the initial clinical assessment, and the efforts expended to exclude other treatable conditions that might be causing the collection of symptoms.

The clinical guideline produced by the UK’s National Institute for Health and Clinical Excellence (NICE) in 2007 came up with its own variant of diagnostic criteria for “CFS/ ME” – new, unexplained, persistent/recurrent fatigue with a post-exercise component plus one or more of a range of common symptoms such as difficulty with sleeping, muscle and/or joint pain and headaches. …

The most important finding was that 103 (40%) of patients seen by the Newcastle Service could in fact be diagnosed with other conditions. As the Figure opposite shows, the most common alternative diagnosis in these patients was fatigue associated with a chronic disease (47% of all alternative diagnoses …). The next common alternative diagnosis was primary sleep disorder (20%), including 8 patients with obstructive sleep apnoea and 12 with another primary sleep disorder – an important finding since sleep disorders form a significant and potentially treatable diagnostic group. Furthermore, 15% of all alternative diagnoses were psychological/psychiatric illnesses (most commonly, depression, anxiety and post-traumatic stress disorder); 13% were “unexplained” but not ME/CFS (5.2% of total referrals); and 4% were cardiovascular disorders (vasovagal syncope in patients with fatigue symptoms, who also had a history of episodes of loss of consciousness, with the diagnosis made after a reproduction of symptoms in head-up tilt testing). [Other conditions included metabolic syndrome and coeliac disease.]

Prof. Newton’s results concur with those from two smaller service audits (Dundee 1993; Newcastle 2007), and reiterate that a significant minority of UK patients referred from primary care with a diagnosis of ME/ CFS can receive alternative, exclusionary diagnoses if investigated at a specialist clinic. And they illustrate that in the absence of a full clinical assessment (which most patients in the community have either never undergone, or last had many years ago), the diagnosis of ME/CFS can easily become a stopping-off point for clinically complex patients with a variety of different illnesses.

This problem is encountered not only in the UK. A fascinating commentary in 2008 in Minnesota Medicine (available online) described the difficulties experienced at a clinic in the USA for patients with fatigue, exercise intolerance and weakness (i.e., patients very like ME/CFS patients in the UK). After reporting on three paediatric cases (all of whom received serious, new diagnoses), the authors commented that, “a thoughtful and thorough physical exam can sometimes reveal otherwise hidden diagnoses”. Commentaries like this, and investigations like this one at Newcastle, certainly raise the question of which treatable diagnoses might be uncovered if all patients currently parked in the ME/CFS diagnostic layby were examined intensively at a specialist Centre of Excellence by thoughtful and thorough physicians.

The ideal would be for ME/CFS or the subtypes within to be diagnosed objectively with criteria based on clinical or laboratory measurements. …

Amen to the last.

CFS, ME and PVFS share "more similarities between the three entities than there are differences"

CFSAC November 2011 recommendation:

…
We feel that the interests of patients, the scientific and medical communities, continuity and logic are best served by keeping CFS, (B)ME (Benign Myalgic Encephalomyelitis) and PVFS (Post Viral Fatigue Syndrome) in the same broad grouping category. Current scientific evidence would indicate there are more similarities between the three entities than there are differences. Whether they are synonyms for the same underlying concept, disease entities and sub-entities, or merely the best coding guess is unclear. In reality, any or all of the above may be correct. While the relationship between CFS, B(ME) and PVFS is not stated, that they are grouped together in ICD 10 (WHO) would indicate some rationale for a connection. Our understanding is that this association will be maintained in the ICD 11, which may also include further description of the relationship. …

Different pathogens can cause CFS-like illness

After two studies popped up recently (Naess et al. 2012 and Morroy et al. 2012), I thought I'll collect here some of the studies implicating different pathogens. Interesting is that the finding of Hickie et al. 2006 (to paraphrase: "Initial illness severity predicts duration of chronic fatigue") was found in Morroy et al. 2012, albeit reported inversely (as paraphrased: "the majority of persons with mild illness recover spontaneously within a few weeks"). The report of David Bell on patients of the Lyndonville outbreak after 25 years seem to go in a similar direction, that those who got hit the hardest, stayed the most ill.

Some things are missing. First of all, I have no measure of the quality of most of these studies. Hickie 2006 seems solid. John Chia's finding of Enterovirus seems intriguing (and jives well with previous findings of researchers on the British Isles), yet I'm cautious. If half of the people presenting with CF(S) at John Chia's office have persistent Enterovirus infections, then Ian Lipkin will find a comparable number.

Then another thing that is missing is (Chronic) Lyme and other pathogens like Mycoplasma.

And the third thing to keep in mind is that local outbreaks can skew any numbers, as obviously an outbreak increases the number of people who have the same pathogen in that region. Giardia cases may or may not be common now in Haukland, Norway – the incidence of Giardia in CF(S) cases in e.g. California may or may not be neglectable.

So here we go:

Hickie et al. 2006: a prospective cohort study on Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis) in Australia:

Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study

Ian Hickie 1, Tracey Davenport 1, Denis Wakefield 2, Ute Vollmer-Conna 3, Barbara Cameron 2, Suzanne D Vernon 4, William C Reeves 4, Andrew Lloyd 2

Cite this as: BMJ 2006;333:575
Degenerative joint disease Drugs: CNS (not psychiatric) Epidemiologic studies

1 Brain and Mind Research Institute, Sydney University, Sydney, NSW 2050, Australia,
2 School of Medical Sciences, University of New South Wales, Sydney, NSW 2052,
3 School of Psychiatry, University of New South Wales,
4 Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, GA 31033, USA

Correspondence to: A Lloyd

Abstract
Objective To delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections.

Design
Prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis).

Setting
The region surrounding the township of Dubbo in rural Australia, encompassing a 200 km geographical radius and 104 400 residents.

Participants
253 patients enrolled and followed at regular intervals over 12 months by self report, structured interview, and clinical assessment.

Outcome measures
Detailed medical, psychiatric, and laboratory evaluations at six months to apply diagnostic criteria for chronic fatigue syndrome. Premorbid and intercurrent illness characteristics recorded to define risk factors for chronic fatigue syndrome. Self reported illness phenotypes compared between infective groups.

Results
Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors.

Conclusions
A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome.

Naess et al. 2012 on Giardia in Norway:

Chronic fatigue syndrome after Giardia enteritis: clinical characteristics, disability and long-term sickness absence.
Halvor Naess, Morten Nyland, Trygve Hausken, Inghild Follestad and Harald I Nyland

Institute of Clinical Medicine, Department of Neurology, and Unit for Gastroenterology, Department for Medicine, Haukeland University Hospital, N-5021 Bergen, Norway

BMC Gastroenterology 2012, 12:13 doi:10.1186/1471-230X-12-13

Abstract (provisional)
Background
A waterborne outbreak of Giardia lamblia gastroenteritis led to a high prevalance of long-lasting fatigue and abdominal symptoms.

The aim was to describe the clinical characteristics, disability and employmentloss in a case series of patients with Chronic Fatigue Syndrome (CFS) after the infection.

Methods
Patients who reported persistent fatigue, lowered functional capacity and sickness leave or delayed education after a large community outbreak of giardiasis enteritis in the city of Bergen, Norway were evaluated with the established Centers for Disease Control and Prevention criteria for CFS.

Fatigue was self-rated by the Fatigue Severity Scale (FSS).

Physical and mental health status and functional impairment was measured by the Medical Outcome Severity Scale-short Form-36 (SF-36).

The Hospital Anxiety and Depression Scale (HADS) was used to measure co-morbid anxiety and depression.

Inability to work or study because of fatigue was determined by sickness absence certified by a doctor.

Results
A total of 58 (60%) out of 96 patients with long-lasting post-infectious fatigue after laboratory confirmed giardiasis were diagnosed with CFS.

In all, 1262 patients had laboratory confirmed giardiasis.

At the time of referral (mean illness duration 2.7 years) 16 % reported improvement, 28 % reported no change, and 57 % reported progressive course with gradual worsening.

Mean FSS score was 6.6. A distinctive pattern of impairment was documented with the SF-36.

The physical functioning, vitality (energy/fatigue) and social functioning were especially reduced.

Long-term sickness absence from studies and work was noted in all patients.

Conclusion
After giardiasis enteritis at least 5% developed clinical characteristics and functional impairment comparable to previously described post-infectious fatigue syndrome.

Morroy et al. 2012 Q-fever (Coxiella burnetii) in The Netherlands:

Self-reported sick leave and long-term health symptoms of Q-fever patients

Gabriella Morroy 1,2, Hans H. J. Bor 2, Johan Polder 3, Jeannine L. A. Hautvast 2, Wim van der Hoek 4, Peter M. Schneeberger5 and Clementine J. Wijkmans 1,2

1 Department of Infectious Disease Control, Municipal Health Service Hart voor Brabant, ‘s-Hertogenbosch, The Netherlands
2 Academic Collaborative Centre AMPHI, Department of Primary and Community Care, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
3 Department Tranzo, Tilburg University, Tilburg, The Netherlands
4 Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
5 Laboratory of Medical Microbiology, Jeroen Bosch Hospital, ‘s-Hertogenbosch, The Netherlands

Abstract

Background:
In The Netherlands, 1168 Q-fever patients were notified in 2007 and 2008.

Patients and general practitioners (GPs) regularly reported persisting symptoms after acute Q-fever, especially fatigue and long periods of sick leave, to the public health authorities.

International studies on smaller Q-fever outbreaks demonstrate that symptoms may persist years after acute illness. Data for the Dutch outbreaks were unavailable.

The aim of this study is to quantify sick leave after acute Q-fever and long-term symptoms.

Methods:
Our study targeted 898 acute Q-fever patients, notified in 2007 and 2008 residing in the Province Noord-Brabant.

Patients from the 2008 cohort were mailed a questionnaire at 12 months and those of the 2007 cohort at 12–26 months after onset of illness.

Patients reported underlying illness, Q-fever-related symptoms and sick leave.

Results:
The response rate was 64%.

Forty percent of the working patients reported long-term (>1 month) sick leave.

Pre-existent heart disease odds ratio (OR) 4.50; confidence interval (CI) 1.27–16.09), hospitalization in the acute phase (OR 3.99; 95% CI 2.15–7.43) and smoking (OR 1.69; 95% CI 1.01–2.84) were significant predictors for long-term absence.

Of the patients who resumed work, 9% were—at the time of completing the questionnaire—still unable to function at pre-infection levels due to fatigue or concentration problems.

Of the respondents, 40% reported persisting physical symptoms at the time of follow-up.

Fatigue (20%) was most frequently reported. Daily activities were affected in 30% of cases.

Conclusions:
Q-fever poses a serious persisting long-term burden on patients and society.

In 2007, the Netherlands began a large, drawn-out outbreak of Q fever, which resulted in thousands being infected and a dozen or so fatalities.

In a study just released in the European Journal of Public Health, Dutch researchers show that many of those infected with Coxiella burnetti previously, now face chronic fatigue syndrome and other physical symptoms.

1,168 Q-fever patients were notified in 2007 and 2008 in the Netherlands. The study targeted 898 acute Q-fever patients, notified in 2007 and 2008 residing in the Province Noord-Brabant. Patients from the 2008 cohort were mailed a questionnaire at 12 months and those of the 2007 cohort at 12-26 months after onset of illness. In the questionnaire, patients reported underlying illness, Q-fever-related symptoms and sick leave.

Some of the key results found in the study include:

• Forty percent of the working patients reported long-term (greater than 1 month) sick leave.
• Daily activities were affected in 30% of cases.
• 20% of respondents reported issues with fatigue.
• 9% of those who did return to work reported they were (up to 2 years post-Q fever infection) still unable to function at pre-infection levels due to fatigue or concentration problems.

Based on the results of the study, the authors conclude that Q-fever poses a serious persisting long-term burden on patients and society.

Q fever is caused by the obligate intracellular pathogen, Coxiella burnetii. The disease is usually transmitted to people through either infected milk or through aerosols.

This disease is found on most continents with the reported incidence probably much lower than the actual because so many cases are so mild.

Animal reservoirs of C. burnetii include sheep, cattle, goats, dogs and cats. In areas where these animals are present, Q fever affects veterinarians, meatpacking workers, and farmers.
…

The mortality rate for acute Q fever is low (1–2%), and the majority of persons with mild illness recover spontaneously within a few weeks although antibiotic treatment will shorten the duration of illness and lessen the risk of complications.

John Chia 1999 about Chronic Chlamydia Pneumoniae:

Chronic Chlamydia pneumoniae infection: a treatable cause of chronic fatigue syndrome.

John K. S. Chia and Laura Y. Chia

Torrance Memorial Medical Center, Torrance, California

…
Over the past 3 years, we encountered 10 of 171 patients with symptoms of chronic fatigue who had elevated titers of antibody to C. pneumoniae long after initial respiratory infection. Most pa- tients had favorable clinical and serological responses to a 1- to 2-months course of azithromycin therapy, although relapse was common. The clinical symptoms of and titers of antibody to C. pneumoniae for our 10 patients over the course of treatment are summarized in table 1.
…

The spontaneous rise of titers for several patients correlated with an increased severity of fatigue and a concomitant increase in respiratory symptoms. This observation suggests that relapses of symptoms could be due to persistent infection with periodic reac- tivation rather than reinfection. All of the patients with relapses responded to additional azithromycin treatment.
…

Collectively, these results suggest that C. pneumoniae is an uncommon yet treatable cause of chronic fatigue. The sensitivity, specificity, and interlaboratory variability of the DNA test will need to be better defined.…

And John Chia 2003 again, this time with his son, about many different pathogens, but obviously implicating Enteroviruses:

Diverse Etiologies for Chronic Fatigue Syndrome

John K. S. Chia and Andrew Chia

I D Med, Torrance, California

Clinical Infectious Diseases 2003;36:671–2
…

Probable cause	Criteria for inclusion	No. of patients (n = 200)
Chlamydia pneumoniae infection	High antibody titer compared with control subjects from the community; response to macrolide therapy	18
Epstein-Barr virus infection	Whole blood (at 1:1000 dilution) or urine sample positive for EBV DNA; response to Val or iv Cid therapya	6
Cytomegalovirus infection	Surveillance of acute infection for a period 16 months; positive culture results; response to iv Cid or IVIG therapy	3
Recurrent VZV infection	Recurrent lesions; response to antiviral drugs	6
Recurrent HHV6-like disease	Recurrent roseola-like illness for a period of 3 years; response to iv Cid therapy	1
Parvovirus B19 infection	Test results positive for IgM or viral DNA	3
Hepatitis C	Resolution of symptoms after interferon/ribavirin therapy	3
Neurocardiogenic hypotension	Initial flulike illness; tilt test positive for NMS; response to midodrine therapy	2
Toxic mold exposure	Documented cultures of environmental samples positive for toxic mold; 11 household member was affected; symptoms improved after leaving the house	2
Postvaccination	Received pneumovax, MMR, or influenza vaccine	3
Enterovirus infection	Persistent, significantly elevated levels of neutralizing antibody for coxsackievirus B or high echovirus titer compared with controls from the community; PBMC sample positive for enteroviral RNAb	109
Unknown	—	44

Chia's study is surely not made to gold standards and any numbers should be taken not to be poured in concrete. Chia claims here to have found enteroviral RNAb in PBMCs, while later he opted to search for enteroviral protein VP1 in gut biopsies - something that seems to me to be unnecessarily complicated. If there is actual enteroviral RNAb in PBMCs in the majority of CFS patients, then Ian Lipkin will find it.

Taken together, it looks like there is a clear indication that different pathogens are likely invovled in different CF(S) subgroups and that there is not one single cause involved in all nor even most CF(S) cases – and though the group of likely pathogens is small, it is not exhaustive. While I am hopeful that it is possible to establish the etiology for a considerable portion of CF(S) cases within the next years, I am pessimistic and think that in the foreseeable future a substantial part of CF(S) patients will remain without a established etiology.

Broderick delivers a slap to Van Der Meer and Lloyd

We believe that a prime cause of inconsistent and confusing research findings in this heterogeneous patient population has been the use of overly inclusive criteria for CFS such as the Oxford and Reeves criteria, because each study may include very different patient sets. This dilutes the results, makes them difficult to confirm, leads to scepticism and thus inhibits progress. Jason et al. found the Reeves empirical criteria to be flawed because it was possible to meet the CFS criteria without any physical symptoms, only 10% actually had ME/CFS and 38% of patients with Major Depressive Disorder were misclassified as having CFS. The increased estimates of CFS from 0.24% (Fukuda) to 2.54% (Reeves, USA) and 2.6% (UK) confirm that the Reeves and Oxford criteria select patient sets that are approximately ten times larger and more inclusive than those selected by the Fukuda criteria. Whilst some general information about fatigue may be ascertained using these inclusive criteria, it is not productive to try to study the mechanisms of ME if up to 90% of the research patient set do not meet the criteria for ME. …

… If the same symptoms consistently flare in response to exertion, they are more likely to share a common cause. For example, if a patient consistently experiences flu-like symptoms, sore throat and tender lymph nodes in response to exertion, it suggests that immune activation is a component of their underlying pathophysiology, which then can be studied scientifically. Given that the Oxford criteria are based on general chronic fatigue and it is possible to meet the Reeves criteria without having any physical symptoms, it is surprising that the ICC was admonished for its use of subjective symptoms. Symptoms by definition are subjective; however, the clinician can observe visible signs that accompany symptoms such as swollen lymph nodes, crimson crescents in tonsillar fossae, abnormal accommodation responses of the pupils, abnormal body temperature or blood pressure, abnormal tandem gait and positive Romberg test, thus confirming symptoms. …

The ICC identify patients who have measurable and reproducible pathophysiological abnormalities in response to exertion, which people with general fatigue or depression do not have. In contrast, the Reeves and Oxford criteria do not require postexertional malaise or exhaustion in their definitions, and it is optional in the Fukuda criteria. The more general and stereotypic the criteria, the less useful they become because lumping together patients whose chronic fatigue is an integral part of many other diseases skews both clinical and research findings. It is prudent to study patients who have various kinds of adverse pathophysiological reactions to exertion to isolate various pathogeneses responsible for them and determine appropriate treatments. The use of patient sets selected by relevant, well-defined and consistent ICC for ME in research will thus advance science, provide greater clarity of understanding and elicit more reproducible scientific results. This will also allow a selection of more homogeneous sets of ME patients, given the current knowledge, which can then be compared with other populations. Whether patients with less severe conditions represent a continuum, faulty diagnosis or different disease entities can only be determined by future studies.

One cause, different effects

If you have two faulty copies of this gene, your brain won't be normal, but what goes wrong varies widely amongst different people. Although the 9 cases had some features in common, such as microcephaly (small head and brain), in other respects they differed greatly.

As the authors put it, mutations in WDR62 cause
a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients... had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities.

These are distinct entities, in the sense that you can have any one of them, without having the others. And they are different brain changes. What the authors mean is that everyone assumed that, because they're different, they must have different genetic causes. They've just shown that this is wrong.

So what is WDR62 "for"? Experiments in mice showed it to be involved in the migration of new neurons from their origin to their final location in the brain. So it's "for" correct neuronal placement, although how it works remains unclear.

WDR62 ought to remind us that there's a long and winding road from gene to phenotype, and that the same gene can, when mutated, cause very different symptoms. This is especially interesting in the light of recent evidence showing that the same mutations can cause a range of behavioural disorders from autism to ADHD to schizophrenia.

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