Myalgic Encephalomyelitis: A Baffling Syndrome With a Tragic Aftermath by A. Melvin Ramsay

Dr. Melvin Ramsay was a consulting physician at the Infectious Diseases Department of the Royal Free Hospital when an epidemic of what he would later call myalgic encephalomyelitits struck over 200 members of the staff in 1955.

Like Drs. Peterson and Cheney during the Incline Village outbreak, Dr. Ramsay was convinced from the start that the Royal Free epidemic was caused by a pathogen, and that it was infectious. His meticulous observations, as well as decades of clinical experience, formed the basis for his book, Post-viral fatigue: The saga of the Royal Free Disease (reprinted by the MEAssociation).

Dr. Ramsay's understanding of the disease was profound. Many of the discoveries that were later to inform a new generation of ME physicians were presaged by Dr. Ramsay. In a letter published in the Postgraduate Medical Journal in 1978, Dr. Ramsay suggested that the muscle fatigability in ME patients might be due to mitochondrial impairment. He never doubted that the disease was primarily neurological. Nor did he underestimate its severity.

While there are many reasons to discard the trivializing name CFS in favor of ME, Ramsay's Disease has always been my preferred name for the illness that Dr. Ramsay so accurately described nearly 60 years ago.

For a complete list of Dr. Ramsay's publications click here. 

________________________________________________________

Myalgic Encephalomyelitis: A Baffling Syndrome With a Tragic Aftermath

By A. Melvin Ramsay M.D., Hon Consultant Physician Infectious Diseases Dept., Royal Free Hospital (Pub. 1986)

The syndrome which is currently known as Myalgic Encephalomyelitis in the UK and Epidemic Neuromyasthenia in the USA leaves a chronic aftermath of debility in a large number of cases. The degree of physical incapacity varies greatly, but the dominant clinical feature of profound fatigue is directly related to the length of time the patient persists in physical effort after its onset; put in another way, those patients who are given a period of enforced rest from the onset have the best prognosis.

Although the onset of the disease may be sudden and without apparent cause, as in those whose first intimation of illness is an alarming attack of acute vertigo, there is practically always a history of recent virus infection associated with upper respiratory tract symptoms though occasionally there is gastro-intestinal upset with nausea and vomiting. Instead of making a normal recovery, the patient is dogged by persistent profound fatigue accompanied by a medley of symptoms such as headache, attacks of giddiness, neck pain, muscle weakness, parasthesiae, frequency of micturition or retention, blurred vision and/or diplopia and a general sense of 'feeling awful'. Many patients report the occurrence of fainting attacks which abate after a small meal or even a biscuit, and in an outbreak in Finchley, London, in 1964 three patients were admitted to hospital in an unconscious state presumably as a result of acute hypoglycaemia. There is usually a low-grade pyrexia [fever] which quickly subsides. Respiratory symptoms such as sore throat tend to persist or recur at intervals. Routine physical examination and the ordinary run of laboratory investigations usually prove negative and the patient is then often referred for psychiatric opinion. In my experience this seldom proves helpful is often harmful; it is a fact that a few psychiatrists have referred the patient back with a note saying 'this patient's problem does not come within my field'. Nevertheless, by this time the unfortunate patient has acquired the label of 'neurosis' or 'personality disorder' and may be regarded by both doctor and relatives as a chronic nuisance. We have records of three patients in whom the disbelief of their doctors and relatives led to suicide; one of these was a young man of 22 years of age.

The too facile assumption that such an entity - despite a long series of cases extending over several decades - can be attributed to psychological stress is simply untenable. Although the aetiological factor or factors have yet to be established, there are good grounds for postulating that persistent virus infection could be responsible. It is fully accepted that viruses such as herpes simplex and varicella-zoster remain in the tissues from the time of the initial invasion and can be isolated from nerve ganglia post-mortem; to these may be added measles virus, the persistence of which is responsible for subacute sclerosing panencephalitis that may appear several years after the attack and there is a considerable body of circumstantial evidence associating the virus with multiple sclerosis. There should surely be no difficulty in considering the possibility that other viruses may also persist in the tissues. In recent years routine antibody tests on patients suffering from myalgic encephalomyelitis have shown raised titres to Cocksackie B Group viruses. It is fully established that these viruses are the aetiological agents of 'Epidemic Myalgia' or 'Bornholm's Disease' and that, together with ECHO viruses, they comprise the commonest known virus invaders of the central nervous system. This must not be taken to imply that Cocksackie viruses are the sole agents of myalgic encephalomyelitis since any generalised virus infection may be followed by a period of post-viral debility. Indeed, the particular invading microbial agent is probably not the most important factor. Recent work suggests that the key to the problem is likely to be found in the abnormal immunological response of the patient to the organism.

A second group of clinical features found in patients suffering from myalgic encephalomyelitis would seem to indicate circulatory disorder. Practically without exception they complain of coldness in the extremities and many are found to have abnormally low temperatures of 94 or 95 degrees F. In a few, these are accompanied by bouts of severe sweating even to the extent of waking during the night lying in a pool of water. A ghostly facial pallor is a well known phenomenon and this has often been detected by relatives some 30 minutes before the patient complains of being ill.

The third component of the diagnostic triad of myalgic encephalomyelitis relates to cerebral activity. Impairment of memory and inability to concentrate are features in every case. Many report difficulty in saying the right word and are conscious of the fact that they continue to say the wrong one, for example 'cold' when they mean 'hot'. Others find that they start a sentence but cannot complete it, while some others have difficulty comprehending the written or spoken word. A complaint of acute hyperacusis is not infrequent; this can be quite intolerable but alternates with periods of normal hearing or actual deafness. Vivid dreams generally in colour are reported by persons with no previous experience of such a phenomenon. Emotional lability is often a feature in a person of previous stable personality, while sudden bouts of uncontrollable weeping may occur. Impairment of judgement and insight in severe cases completes the 'encephalitic' component of the syndrome.

I would like to suggest that in all patients suffering from chronic debility for which a satisfactory explanation is not forthcoming a renewed and much closer appraisal of their symptoms should be made. This applies particularly to the dominant clinical feature of profound fatigue. While it is true that there is considerable variation in degree from one day to the next or from one time of the day to another, nevertheless in those patients whose dynamic or conscientious temperaments urge them to continue effort despite profound malaise or in those who, on the false assumption of 'neurosis', have been exhorted to 'snap out of it' and 'take plenty of excercise' the condition finally results in a state of constant exhaustion. This has been amply borne out by a series of painstaking and meticulous studies carried out by a consultant in physical medicine, himself an ME sufferer for 25 years. These show clearly that recovery of muscle power after exertion is unduly prolonged. After moderate excercise, from which a normal person would recover with nothing more than a good night's rest, an ME patient will require at least 2 to 3 days while after more strenuous excercise the period can be prolonged to 2 or 3 weeks or more. Moreover, if during this recovery phase, there is a further expenditure of energy the effect is cumulative and this is responsible for the unrelieved sense of exhaustion and depression which characterises the chronic case. The greatest degree of muscle weakness is likely to be found in those muscles which are most in use; thus in right- handed persons the muscles of the left hand and arm are found to be stronger than those on the right. Muscle weakness is almost certainly responsible for the delay in accommodation which gives rise to blurred vision and for the characteristic feature of all chronic cases, namely a proneness to drop articles altogether with clumsiness in performing quite simple manoeuvres; the constant dribbling of saliva which is also a feature of chronic cases is due to weakness of the masseter muscles. In some cases, the myalgic element is obvious but in others a careful palpitation of all muscles will often reveal unsuspected minute foci of acute tenderness; these are to be found particularly in the trapezii, gastrocnemii and abdominal rectii muscles.

The clinical picture of myalgic encephalomyelitis has much in common with that of multiple sclerosis but, unlike the latter, the disease is not progressive and the prognosis should therefore be relatively good. However, this is largely dependent on the management of the patient in the early stages of the illness. Those who are given complete rest from the onset do well and this was illustrated by the aforementioned three patients admitted to hospital in an unconscious state; all three recovered completely. Those whose circumstances make adequate rest periods impossible are at a distinct disadvantage, but no effort should be spared to give them the all-essential basis for successful treatment. Since the limitations which the disease imposes vary considerably from case to case, the responsibility for determining these rests upon the patient. Once these are ascertained the patient is advised to fashion a pattern of living that comes well within them. Any excessive physical or mental stress is likely to precipitate a relapse.

It can be said that a long-term research project into the cause of this disease has been launched and there are good grounds for believing that this will demonstrate beyond doubt that this condition is organically determined.

Kindling, Chemical Sensitivities, and ME/CFS

Dr. Jay Streastrunk (now deceased) was a pediatric and adolescent psychiatrist who had a clinical practice in Texas and California. He was known for his explanation of the primary mechanism of multiple chemical sensitivities - "kindling" - and for his willingness to treat patients with an illness that most doctors still don't believe is "real."

Kindling is a neurological mechanism through which repeated exposures to a stimulus can sensitize an individual so that even a small stimulus produces a reaction. In neurological circles, kindling has been linked to seizures. Among allergists, kindling is known as "sensitization." It accounts for why even a hint of peanut can cause anaphylactic shock in an allergic individual. Kindling also is involved in FM and other pain syndromes.

In 2009, Jason et al. proposed that kindling was part of the etiology of ME/CFS. In a paper titled, "Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome", the authors state:

"Viral exposure early in life could trigger an immunologic cascade with significant effects on kindling. The release of TNF-alpha and other mediators could contribute to immunologic sensitization through inflammation and corticosteroid mediation. This then might leave an individual primed to respond in an adverse fashion to a future stressor event through amygdala and hippocampal kindling. The response to a stressor event then might reintroduce an inflammatory response that could contribute to the development of lesions and symptomatology. This could help explain why viral exposure does not necessarily trigger immediate symptomatology."

This model is in keeping with the theory of occult infection - an infection which remains latent, or asymptomatic, until a second stressor is introduced. However, Jason et al. took the model one step further by proposing that the repetition of the exposure over time leads not only to an increasingly sensitive nervous system (which is why relapses often manifest differently from the initial illness), but to a prolonged inflammatory cycle.

Below is Dr. Seastrunk's excellent explanation of kindling. The treatment he recommended for kindling was Neurontin (gabapentin), a neuro-inhibitory drug also favored by Dr. Jay Goldstein. Some ME/CFS patients have reported benefits from gabapentin, however, as with all treatments, responses to gabapentin are mixed.

_____________________________________________________

KINDLING , FOCAL BRAIN INJURY AND CHEMICAL and ELECTRICAL SENSITIVITY in the production of "Environmental Disease"

by Jay Seastrunk

Kindling

In the 1960's while doing research at Tulane Medical School, I became interested in the correlation between the electrical manifestation of brain activity and behavior. I was fortunate enough to be able to participate in deep electrode long term implant studies in non-psychotic and psychotic individuals. This experience strongly imprinted in me the connection between brain activity and behavior. In reviewing the literature for Dr. R. G. Heath, my department chairman, I came across the "mirror focus" literature.

In 1949, Pope et.al., described the "mirror focus" phenomenon, while working with Penfield on man and monkeys. In "mirror focus" development, an epileptic focus (a mirror focus) is found to develop in the hemisphere opposite to an original epileptic focus, even though there has never been an injury in that hemisphere. This developed focus takes ten to fifteen years to emerge in humans. In 1969, Goddard and two other researchers in the field of epilepsy published an article entitled, "A Permanent Change in Brain Function Resulting from Daily Electrical Stimulation". They were curious as to why an incubation period often elapsed between a traumatic brain injury, and the occurrence of a first seizure, months to years after the injury.

What they discovered was that repeated applications of either chemical or electrical irritants to the brains of animals eventually produce intense seizure discharges, even if each one of the irritating stimulation themselves is incapable of producing a seizure. They discovered that a stimulus to the brain, that ordinarily would produce no change in either the animal's behavior or in the electrical activity of its brain, did produce significant changes in both behavior and electrical activity, if it were repeated and repeated. They called the repeated stimulus "a chronic irritant", and the resulting effect "kindling." In Vietnam veterans, psychosis took fifteen years to emerge following brain injury illustrating that the limbic and/or more subtle behavioral manifestations of brain injury take a long time to emerge perhaps related to the "kindling" phenomena.

In 1992, Bell and her co-workers applied this reasoning to chemical sensitivity. They pointed out that the olfactory system of animals and humans permits access (via the nose) of environmental chemicals directly into the brain. These molecules pass into the entry point of the smell system, called the olfactory bulb. Numerous projections from this part of the brain are present in the upper regions of the nose and permit aromas, perfumes, aromatic hydrocarbons, and solvents to pass into the brain. Even more remarkable than the fact that these molecules pass directly into the brain, is the fact that they can progress neuron by neuron to the furthest reaches of the emotional portion of the brain, called the limbic system.

The limbic system, located primarily in the temporal lobe, serves not only as the location of our emotions, but even more interestingly, it is the location where we organize our information into understandable categories. This is because in animals, smeil has great significance. An odor can mean the difference between food or poison, and friend or foe, so it is reasonable that odors and their significance would be closely linked in the animal brain.

The limbic system, located partially in the temporal lobe, serves, not only as the location of our emotional system, but even more interestingly, as an information organizer, where we process information into understandable perceptions, wheather they are olfactory, visual, tactile, or auditory. Memory with its emotional conections is stored here However, it is tuned into many more inputs than just a single sensory perception. In fact, it seems to be tuned into all possible inputs, whether sensory, imaginative, verbal, or motor. This is why odors, movements, sights, sounds, ideas, or a combination of these can rapidly trigger memories, emotions, and behaviors.

When the limbic temporal lobe is injured, the individual cannot always recall memories at will, even though the memory is still in the brain. Individuals affected with chemical injuries frequently report that they are having memory problems, yet are surprised when psychological tests show no memory damage. This is because the system where the memories are stored, which is analogous to the bookshelves in a library is intact; it is the memory organization and retrieval system or the card catalogue of the library that has been injured.

How does the kindling and the mirror focus phenomenon fit into this? Researchers into epilepsy have long known that the olfactory and limbic systems are particularly susceptible to kindling. In fact, two limbic structures, the amygdala and the hippocampus are frequently used in animals to study epilepsy, because of the ease with which they can be kindled.

This means that individuals whose brains have been injured can be kindled by either repeated low level stimulation of a chemical or electrical irritant, or by a single peak exposure. Thus, an individual will continue to experience more and more effects from exposures too weak to affect a previously unaffected person and possibly become more and more sensitive to weaker and weaker exposures.

Time-Dependent Sensitization

A second mechanism, called time-dependent sensitization, is almost identical to kindling. According to Bell et al. (1992), time-dependent sensitization is very similar to kindling in that an external substance, e.g. a chemical, that has no effect at first on an animal's brain will later produce a major reaction. This sounds almost like kindling, except for a few minor differences. By definition, kindling eventually leads to seizures, whereas time-dependent sensitization does not necessarily lead to seizures. Instead, it can lead to changes in the animal's behavior, its sensations, cognitions, autonomic nervous system responses, vestibuiar (balance) responses, motion responses, and/or or in hs immune or hormonal function.

Another difference is that time-dependent sensitization can occur after a single intense exposure, rather than a few small, repeated ones. After the passage of time, and without further exposure, a new exposure will suddenly produce the altered experience and/or behavior, or alter the immune function.

Finally, time-dependent sensitization shows cross-sensitization, which means that after a given individual is sensitized, other substances, different from the one causing the initial exposure, will now produce the altered experience, and/or behavior or function in a stereotyped way for each individual.

Kindling and time-dependent sensitization answer one of the most mysterious aspects of chemical and electrical sensitivity i.e. who gets affected and why? Another phenomenon, known as cacosmia, must be introduced to understand this

RISK FACTORS FOR CHEMICAL NEUROTOXICITY

On November 13, 1993, over 400 affected workers, health care professionals, and interested labor and management representatives listened to Dr. Bell present her latest findings to a conference hosted by the Washington Toxics Coalition in Seattle, WA. What she and her co-workers suggested is that there is an identifiable group of people more at risk for the development of chemical brain injury than other more resistant individuals.

To be able to identify these individuals, it is first necessary to understand a new term. The new term is cacosmia (ca-COS'-mi-a), which means "an altered sense of smell, accompanied by a tendency to feel ill i.e. nausea, headache, and dizziness from the odor of chemicals at low levels (that have no effect on normals." In other words, cacosmic individuals are the ones who first notice and are affected by the chemical odors in an environment. Six per cent of college students report cacosmia when asked if they develop illness when exposed to pesticides, car exhaust, paint, perfumes, or new carpet. Among the individuals that were studied, women represented 79% of those identified as the most cacosmic.

Among both women and men who were identified as strongly cacosmic, there was a much higher incidence of reported food allergies, self-reported memory loss, and somatic symptoms in general, when compared with noncacosmic subjects.

For electromagnetically sensitive patients, a similar recruitment, sometimes by subliminal visual, or auditory inputs, or by electromagnetic waves themselves, activate a kindled brain focus, causing it to fire, producing the characteristic, stereotyped, repetitive symptoms of that individual's "reaction".

A second risk factor appears to be stress. Ester Stemberg described how the central nervous system affects the immune system through endocrine, paracrine, and neuronal mechanisms. Bell, also, points out that one of the stress hormones in the brain, CRH, cannot only itself produce kindling, but when present in above normal amounts, makes it more likely that other external stimuli will induce kindling. Stress and sleep deprivation have long been known to increase epileptic seizures.

I feel that a third necessary factor is focal brain injury related to trauma, infection, or toxic insult. The location of this injury determines the scope of the repetitive, stereotyped symptoms, which becomes the "reaction" kindled by the external stimulus whether chemical, electrical, and/or stress and sleep deprived related.

Conclusions

1 It appears that perhaps some of the mystery of chemical sensitivity syndrome is beginning to disappear. Repeated small exposures to inhaled toxins, chemical or visual kindling, auditory, and/or electrical stimulation, or single overwhelming exposures, acting on focal injuries can bring about sensitization of the brain's limbic system injury.

2. Because the brain's limbic system modulates emotions and memory organization systems, emotional and memory symptoms will be common features of the disease. This area of the brain also controls balance, gastrointestinal motility, the autonomic nervous system, and auditory and visual integration of stimuli as well as memory

3. Repeated exposures after the kindling or sensitization of the focus has occurred will produce effects out of proportion to the intensity of the exposure.

4 Cacosmic people seem more at risk than non-cacsomic people; but this has not yet been proved by a prospective study.

5. Stress may play some role in who becomes affected, but how big a role is still uncertain. Stress definitely increases the occurrence of "reactions", as does sleep deprivation due to its effect on focal brain irritability.

6. Because a fundamental brain mechanism is involved in the production of chemical sensitivity, continued exposure of individuals without protection or treatment is sure to increase the number of affected individuals and the severity of the symptoms in any particular individual.

TREATMENT

To be effective, treatment must interrupt these processes. Certainly avoidance of the stimuli can stop the setting off of the focal firing either directly or by stopping the kindling. Medications that stabilize the irritated cell decreasing its sensitivity to the kindling stimulus would be helpful. In this approach the amino acid anticonvulsant gabapentin has been very promising in our experience. Decreasing stress and improving sleep will also be beneficial. Removing any toxin that is still present in the brain should also decrease cell irritability. Desensitizations of all types, allergic, and behavioral, seem to provide benefit.

References

Bell, I., Miller, C., & Schwartz, G. An olfactory-limbic model of multiple chemical sensitivity syndrome, possible relationships to kindling and affective spectrum disorders. Biol. Psychiatry. 1992, 32: 218-242.

Bell L Schwartz C, Peterson A, et al. Possible time dependent sensitization to Xenobiotics: Self-reported illness from chemical odors, foods, and opiate drugs in an older population. Archives of Environmental Health. 1993, 48:315-327, 60p cit #4 p. 316.

Goddard G., Mclntyre D, Leech C. A permanent change in brain function resulting from daily electrical stimulation Exp Neurology 1969,25:295-330

Heath R Correlation of brain function with emotional behavior. Biol Pychiatry. 1976:11 463-480

McNamara J, Bonhaus D, Shin C, et al. The kindling model of epilepsy: a critical review CR Clin Neurobiol 1985;l:341-391

Monroe R. Limbic Ictus and Atypical Psychoses. Jwr of Nervous and Mental Disease 1982;170 #12:711-716.

Morrell F. Experimental epilepsy in animals. Arch Neural 1959,1:141-147. Morrell F Secondary epileptic lesions Epilepsia 1960,1538-560.

Pope A. Morris AA, Jasper H. et al. Histochemical and action potential studies on epileptogenic areas of cerebral cortex in man and the monkey. Res Publ Assoc Res Nerv Mem Dis 1946:26:218-233.

Schwartzkroin, P. A. Epilepsy: Models. Mechanisms, and Concepts Cambridge University Press 1993,27-47;40p Cit #2 pg.221.

Stemberg EM The role of the hypothalamic-pituitary-adrenal axis in susceptibility to autoimmune/inflammatory disease Immunomethods Aug. 1994 5(1): 73-8

Sutula T Experimental models of temporal lobe epilepsy, new insights from the study of kindling and synaptic reorganization Epilepsia 1990;31 (suppl. 3): S45-S5Q.

P2P: The Question They Will Not Ask

The P2P (Pathways to Prevention) Panel was originally convened to examine case definitions for ME/CFS and to address differences between ME and CFS.

The examination of differences relates directly to case definition. The CDC (Fukuda) definition, for example, is broad enough to encompass people with deconditioning and depression, as well as most early cases of MS.

The Canadian Consensus Criteria for ME, on the other hand, includes people with more neurological symptoms and physical impairment (e.g. PEM).

The disease that specialists in the US call "CFS" is actually ME. Whereas the condition that most non-specialists (and many researchers) call "CFS" could be just about anything.

The disease definition provides the foundation for diagnosis, research, and treatment. So, why was the question "How are ME and CFS different?" abandoned?
___________________________________________

Reprinted with permission from Occupy CFS

P2P: The Question They Will Not Ask

by Mary Dimmock and Jennie Spotila

The most important question about ME/CFS – the question that is the cornerstone for every aspect of ME/CFS science – is the question that the P2P Workshop will not ask:

How do ME and CFS differ? Do these illnesses lie along the same continuum of severity or are they entirely separate with common symptoms? What makes them different, what makes them the same? What is lacking in each case definition – do the non-overlapping elements of each case definition identify a subset of the illness or do they encompass the entirety of the population?

Boiled down to its essence, this set of questions is asking whether all the “ME/CFS” definitions represent the same disease or set of related diseases. The failure to ask this question puts the entire effort at risk.

This fundamental question was posed in the 2012 application for the Office of Disease Prevention to hold the P2P meeting (which I obtained through FOIA). It was posed in the 2013 contract between AHRQ and the Oregon Health & Science University for the systematic evidence review (which I obtained through FOIA). It was posed to the P2P Working Group at its January 2014 meeting to refine the questions for the evidence review and Workshop (according to Dr. Susan Maier at the January 2014 Institute of Medicine meeting).

And then the question disappeared.

The systematic evidence review protocol does not include it. Dr. Beth Collins-Sharp said at the June 2014 CFSAC meeting that the Evidence Practice Center is not considering the question because there is “not enough evidence” in the literature to answer the question. However, she said that the P2P Workshop could still consider the question.

But the draft agenda for the Workshop does not include it. Furthermore, every aspect of the P2P Workshop treats “ME/CFS” as a single disease:

• The P2P description of ME/CFS refers to it as a single disorder or illness throughout the meeting webpage.
• The P2P website characterizes the names myalgic encephalomyelitis and chronic fatigue syndrome as synonymous.
• Every section of the Workshop agenda lumps all the populations described by the multiple case definitions together, discussing prevalence, tools, subsets, outcomes, presentation, and diagnosis of this single entity.

A 20-minute presentation on “Case Definition Perspective” is the only lip service paid to this critical issue. This is completely inadequate, if for no other reason than because the presentation is isolated from discussions on the Workshop Key Questions and dependent topics like prevalence and natural history. As a result, it is unlikely to be thoroughly discussed unless one of the Panelists has a particular interest in it.

Why is this problematic? Because both the P2P Workshop and the evidence review are based on the assumption that the full set of “ME/CFS” case definitions describe the same disease. This assumption has been made without proof that it is correct and in the face of data that indicate otherwise, and therein lies the danger of failing to ask the question.

What if the case definitions do not actually describe a single disease? If there are disparate conditions like depression, deconditioning, non-specific chronic fatigue and a neuroimmune disease characterized by PEM encompassed by the full set of “ME/CFS” definitions, then lumping those together as one entity would be unscientific.

The most important part of designing scientific studies is to properly define the study subjects. One would not combine liver cancer and breast cancer patients into a single cohort to investigate cancer pathogenesis. The combination of those two groups would confound the results; such a study would be meaningful only if the two groups were separately defined and then compared to one another to identify similarities or differences. The same is true of the P2P evidence review of diagnostics and treatments: assuming that all “ME/CFS” definitions capture the same disease (or even a set of biologically related diseases) and attempting to compare studies on the combined patients will yield meaningless and confounded results if those definitions actually encompass disparate diseases.

There is a growing body of evidence that underscores the need to ask the fundamental question of whether “ME/CFS” definitions represent the same disease:

· The P2P Workshop is focused on “extreme fatigue” as the defining characteristic of “ME/CFS,” but fatigue is a common but ill-defined symptom across many diseases. Further, not all “ME/CFS” definitions require fatigue or define it in the same way. For instance, Oxford requires subjective fatigue, and specifically excludes patients with a physiological explanation for their fatigue. But the ME-ICC does not require fatigue; instead it requires PENE, which is defined to have a physiological basis.

- When FDA asked CFS and ME patients to describe their disease, we did not say “fatigue.” Patients told FDA that post-exertional malaise was the most significant symptom: “complete exhaustion, inability to get out of bed to eat, intense physical pain (including muscle soreness), incoherency, blacking out and memory loss, and flu-like symptoms.”

- Multiple studies by Jason, Brenu, Johnston and others have demonstrated significant differences in disease severity, functional impairment, levels of immunological markers and patient-reported symptoms among the different case definitions.

 - Multiple studies have demonstrated that patients with PEM have impairment in energy metabolism and lowered anaerobic threshold, and have shown that patients with depression, deconditioning and a number of other chronic illnesses do not have this kind of impairment.

 - Multiple studies have demonstrated differences in exercise-induced gene expression between Fukuda/CCC patients and both healthy and disease control groups.

- The wide variance in prevalence estimates shines a light on the case definition problem. Prevalence estimates for Oxford and Empirical populations are roughly six times higher than the most commonly accepted estimate for Fukuda. Even Fukuda prevalence estimates vary widely, from 0.07% to 2.6%, underscoring the non-specificity of the criteria. Nacul, et al., found that the prevalence using CCC was only 58% of the Fukuda prevalence. Vincent, et al., reported that 36% of Fukuda patients had PEM, representing a smaller population that would be eligible for diagnosis under CCC.

- The work of Dr. Jason highlights the danger of definitions that include patients with primary psychiatric illnesses, especially because such patients may respond very differently to treatments like CBT and GET.

By contrast, there have not been any published studies that demonstrate that the set of “ME/CFS” definitions being examined in P2P encompass a single entity or biologically related set of entities. From Oxford to Fukuda to ME-ICC, there are significant differences in the inclusion and exclusion criteria, including differences in the exclusion of primary psychiatric illness. The magnitude of these differences makes the lack of such proof problematic.

Given that treating all “ME/CFS” definitions as a single entity is based on an unproven assumption of the clinical equivalence of these definitions, and given that there is ample proof that these definitions do not represent the same disease or patient population, it is essential that the P2P “ME/CFS” study start by asking this question:

Does the set of “ME/CFS” definitions encompass the same disease, a spectrum of diseases, or separate, discrete conditions and diseases?

The failure to tackle this cornerstone question up-front in both the agenda and the evidence review puts the scientific validity of the entire P2P Workshop at risk. If this question is not explicitly posed, then the non-ME/CFS expert P2P Panel will swallow the assumption of a single disorder without question, if for no other reason than that they do not know the literature well enough to recognize that it is an assumption and not established fact.

The Diagnosis of Chronic Fatigue Syndrome: An Assertive Approach by Dr. Paul R. Cheney and Dr. Charles Lapp

This paper (below) by Dr. Paul Cheney and Dr. Charles Lapp was written more than two decades ago. It contains detailed descriptions of numerous test abnormalities found in ME/CFS patients, all which can be used for diagnosis.

In spite of the fact that these (and other) objective findings have been noted by specialists for decades, the CDC has not made any of these criteria available to the broader medical community. It is equally as incomprehensible that in spite of these findings - described in great detail in the Cheney/Lapp paper - we now have two federal initiatives involving the diagnosis of ME/CFS, neither of which has taken into account the numerous objective markers for the disease. 

Thirty years after the Incline Village outbreak, the myth still persists that ME/CFS cannot be diagnosed using objective measurements (which are still considered "controversial").  ME/CFS is still described as "mysterious." And it is still a waste-basket diagnosis.

Dr. Cheney and Dr. Lapp were not ahead of their time. The problem is that all of our institutions lag far behind.

___________________________________

The Diagnosis of Chronic Fatigue Syndrome: An Assertive Approach by Paul R. Cheney, MD, PhD and W. Charles Lapp, MD, FAAP

Introduction: The Case for Diagnosis by Objective Criteria

Over the past ten years, a considerable and diverse medical literature has arisen concerning the chronic fatigue syndrome (CFS). Like all medical literature written on an emerging disorder, these published findings include a range of views and some discrepancies.

Systematic errors exist among the tools used to discern differences between CFS cases and "healthy" controls. The central problem, however, is case selection. Many patients with CFS are excluded from studies because they seem "too sick" to have CFS and are perceived as having something else. CFS cases are mixed in with non-cases. Inappropriate controls are sometimes used. Some investigators, aware or unaware of a bias, attract or include in their studies the very patients who best fit their view of CFS. This so-called selection bias can markedly affect the observations of a study. Despite these discrepancies, a more or less consistent pattern of observable abnormalities has emerged and we believe a case definition using objective abnormalities can now be defended.

Having stated the inherent problems with CFS research, we will attempt to defend an assertive approach (i.e.,diagnosis by inclusion) to the diagnosis of CFS using the available medical literature to support it. This is a different approach from just applying the Centers for Disease Control (CDC) case definition, which in essence defines a sign-symptom complex in the absence of a "known medical illness" (i.e., diagnosis by exclusion). The medical evidence cited for CFS asserts that the following are present more or less in every patient during the course of his or her disease: T-cell activation, discrete immune defects, viral activation or re-activation, exercise-related dysfunction, and evidence of brain dysfunction or injury. While none of these tests can stand alone to "diagnose" the illness, an array of these tests can be used to support this diagnosis, given the proper clinical context derived through the application of the CDC case definition. The use of non-specific tests to defend or support a diagnosis is a time-honored tradition in medicine, and the concept is used to diagnose such disorders as multiple sclerosis, lupus erythematosus, acute infectious mononucleosis, and even AIDS.

There are a number of criticisms given for using nonspecific tests in the diagnosis of CFS. They include the following:

(1) We lack a gold standard for determining this disorder and therefore lack a means to test the relative value of certain tests (i.e., false positive and false negative rates).

This is certainly a valid point in confirming a diagnostic test, but it is not a valid criticism in using a non-specific test to support a clinical impression. If a test abnormality has been shown in the medical literature to be associated with a certain disease, such as a positive ANA in lupus, then it is valid test to be used in supporting a clinical diagnosis. Furthermore, as in the "diagnostic" tests for the hepatitis C virus and the Lyme agent, poor test performance may be ignored in the case where benefits, however defined, outweigh poor performance.

(2) Even if there are test abnormalities which can be associated with CFS there is no need to make a more definitive diagnosis because there is no treatment for the disease.

If this were a valid argument, then it would also apply to multiple sclerosis, many cancers, acute infectious mononucleosis, and even AIDS. Documentation of an illness by objective criteria is important not only to confirm the diagnosis, but also to reassure the patient about other disorders they may or may not have. Reassurance is itself therapeutic and proportional to the degree of objective support found for a diagnosis.

Though there may be no scientifically validated treatment options for CFS (a situation which may soon change with the recent conclusion of the Ampligen trials), there are many therapeutic rationales based on test abnormalities which can defend empiric therapy. Such rationale exist for T-cell activation, certain immune deficiency states, herpes-group virus reactivation and even nonspecific brain injury. In the everyday practice of medicine, empiric therapy is often warranted in severe or functionally devastating illness. It is common practice to use unproven but rational therapies to treat clinical diagnoses such as a migraine, PAS, atypical depression, and many other disorders. Finally, documentation of abnormalities associated with CFS can assist the patient in disability arguments.

Disability Law Judges almost never respond favorably to disabling disorders without objective findings. This is even more the case for emerging disorders. The ability to successfully argue for disability is an extremely important aspect of therapy for this disorder. We have several examples of patients coming off disability and returning to work in part because the disability concept can itself be therapeutic.

(3) CFS is a "self-limited illness" which nearly always responds to rest, good nutrition, and proper exercise. As such, little is gained from extensive testing other than to disprove the presence of other disorders.

This misperception of CFS patients is pervasive among many clinicians and the lay public. A debilitating illness lasting years or longer is in fact not self-limited, and it deserves considerable medical attention. Some patients appear to be permanently disabled by this disorder. It may not completely or permanently resolve even in most patients who do see improvement over time. There are theoretical reasons to be concerned and vigilant about long-term health issues in all CFS patients.

Also, and intuitively, it seems to us to be helpful to intervene early in the course of CFS, even if only to dispel the false idea that any exercise will help this disorder and to counsel patients on lifestyle adjustment and symptom relief, especially for sleep disorder. Good documentation of this disorder lays the groundwork for future empiric intervention should it be necessary and gives a baseline with which to compare future results.

The CDC Case Definition

A case definition for CFS proposed by researchers at the CDC and elsewhere was published in 1988 1 . This clinical case definition consists of both major (all must be met) and minor (some but not all must be met) criteria. Difficulties in the application of this case definition include: How does one define a 50 percent or greater reduction in activity? Exactly how far does one go to exclude other disorders? What does one do with patients with remote onset--say in childhood—of chronic fatigue who would be excluded by the current case definition? Should some minor criteria be moved to major criteria and others dropped entirely? What does one do with patients who have confounding medical and psychiatric problems which might explain some if not all of their symptoms? What does one do with patients who lack severity criteria or sufficient signs and symptoms? What signs or symptoms and what other objective tests should be added to sharpen the diagnosis?

While some of these questions have been partially addressed by the authors of the CDC case definition, most persist and are handled differently by different investigators. Despite the problems with the present case definition, we believe that it generally functions to separate most cases from possible or probable non-cases. We recommend continued use of the criteria but designate probable non-cases who meet criteria and probable cases who do not meet criteria as atypical cases or non-cases of CFS.

Further subdivision of atypical cases by severity and confounding medical or psychiatric issues is probably a worthwhile endeavor and has been adopted by the CDC in their surveillance studies.

Clinical Observations Helpful in the Diagnosis of CFS

We have had the opportunity to make a number of clinical observations in over 1,200 cases of CFS which we believe are helpful in the diagnosis of CFS. None of these findings can be used individually to diagnose a case, but they add collective weight to the final clinical judgment. Some patients will have a normal physical examination and many will have essentially normal routine laboratory values.

Physical Findings - Contrary to suggestions by some investigators, abnormalities on physical examination, although sometimes subtle, are usually present:

1. Fever at or above 99.2 F in 38% of patients
2. Subnormal temperatures
3. Intermittent tachycardia
4. Low blood pressures
5. Abnormal oral pharynx exam, including: buccal mucosal ulcerations; posterior cobblestoning, erythema and "crimson crescents" over soft palate; tongue coatings or blisters; and rare thrush
6. Fluctuating anisocoria over time in dim light
7. Photophobia
8. End gaze nystagmus
9. Posterior cervical lymphadenia with slight, palpable enlargement, usually asymmetric
10. Axillary lymphadenia with slight, palpable enlargement, usually asymmetric
11. Tender points typical for fibromyalgia
12. Mild to severe skin atrophy of distal finger tips, loss of fingerprints
13. Diffuse abdominal tenderness
14. Hyperreflexia is very common, worse in lower extremities, and with occasional unsustained clonus
15. Mild tremulousness on drift testing
16. Intention tremor
17. Mitral valve prolapse
18. Sallow skin tone
19. Brittle, thinning hair with reddish tint
20. Excessive titubation or actual inability to maintain Romberg or tandem stance and tandem walk (probably represents an apraxia or vestibular disturbance and very common in these patients)
21. Tentativeness or inability to serial seven subtract, especially while attempting Romberg test, is very common
22. Facial and torso rashes, mostly macular erythema and acneform eruptions

Routine Laboratory Tests - Findings may be subtle but are often present

1. Low sedimentation rates in 40% (0-3 mm/hr); modestly elevated (20-40) in 10%, usually will fall over time
2. Akaline urines are common (PH>7.0)
3. Mild leukocytosis or leukopenia
4. Macrocytosis with elevated MCV
5. Mild LFT elevations, rarely persist
6. Atypical lymphocytes
7. Elevated blood lipids
8. Low normal free T4 and TSH
9. Low level ANAs, may not persist
10. Rare positive Lyme antibodies - failure to respond to accepted therapy

Immunologic Dysfunction

Immunologic tests have been frequently applied to patients with CFS in part because they are frequently abnormal and in part because the signs and symptoms of CFS can be explained as a consequence of immunologic function or dysfunction. Fever, sore throat, swollen glands, aching muscles and joints, sleep disturbance, and even neuropsychological complaints can all be attributed to immunologic responses generally ascribed to T-cell activation with excess cytokine production (i.e., IL-1 alpha, IL-2, interferon-alpha). Whether this excessive immune response is itself the cause (auto-immune or neuroendocrine defects) of CFS or perhaps the effect of a chronic viral infection or even compensation, by whatever means, for an acquired immune deficiency remains uncertain.

We propose here a set of tests that look for evidence of T-cell activation along with discrete immune defects.  All of these tests are available from commercial laboratories and defended by published medical literature.2-20 Although specific immune tests do not always correlate with disease severity, nor is any single test always abnormal, they become more valuable when used as an array or set of tests used to determine a pattern of immune dysfunction.

Tests of Immunity T-cell activation

1. IL-2 receptor, T8-receptor -elevated

2. One and two-color flow cytometry

• CD3/DR, CD8/DR - elevated
• CDllb, CD8/CDllb - depressed
• CD3 - elevated
• CD56 - elevated
• CD4/CD45R - depressed
• CD20 elevated (3) 
• Interferon-alpha, IL-1-alpha - elevated (4) 
• Intracellular 2-5A, Rnase-L antiviral activity - elevated

Discrete Immune Defects

1. Hypogammaglobulinemia (IgG)
2. IgG subclass deficiencies
3. Anergy and hypoergy by epicutaneous skin testing
4. Mitogen stimulation deficiencies (T and B cell deficiencies)
5. Natural Killer (NK) cytotoxic deficiencies
6. Circulating immune complexes

Viral Activation or Re-activation

Viral activity or activation is suggested in CFS due in part to the abrupt onset of a flu-like, mono-like, or encephalitic-like illness which usually precedes the development of this disorder, its signs and symptoms over time, and the nature of the immune response observed. The common symptoms of debilitating fatigue, swollen glands, sore throat, and headache have suggested re-activation of mono-causing herpes viruses (EBV, HHV-6, or CMV), which are usually contracted much earlier in life. It is probable that these lymphotropic herpes viruses are involved in most cases of CFS but are not the cause of CFS. It is likely that they are merely reflecting T-cell activation itself or loss of immunologic control of these viruses due to a state of immune deficiency by whatever cause. It is conceivable that an as-yet-unknown virus has initiated CFS much as HIV initiates AIDS. Such a virus is likely to be subtle, immunotropic, and neurotropic. Retroviruses are all of these things, and attention has focused on them in recent years.

The following is a set of tests that look for evidence of re-activation of herpes-group viruses as well as evidence of a possible retrovirus infection. The retroviral assays include DNA amplification technology and evidence of non-specific cytopathic effects in cell culture consistent with a family of retroviruses recently associated with CFS. Again, more important than the results of a single test is the pattern of herpes-group virus re-activation, evidence of retroviral gene sequences, and evidence of retroviral cytopathology in nonspecific culture assays, all of which support the role of viral activation in CFS. Whether this activity is cause or effect, however, is still open to question. It should be noted that lymphotropic herpes viruses and retroviruses can activate or transactivate each other and are therefore synergistic.

Tests of Viral Activation or Re-activation Herpes-Group Virus Assays 21-26

1. Antibody assays for EBV, HHV-6, CMV, HSV-1,2 & VZ looking for elevated titers consistent with recent activity.
2. Viral DNA amplification for EBV, HHV-6, and CMV using the polymerase chain reaction (PCR), with positive results suggesting viral activity.
3. Giant cell assays with monoclonal labeling for various herpes-group viruses, with positive results suggesting such viral activity.

Retrovirus Assays 27-30

1. Cytopathology in fibroblast cell lines consistent with human foamy retroviruses or human intracisternal retroviruses
2. HTLV-II gag probes, run using low-stringency PCR to detect retroviral gene sequences present in CFS patients which are HTLV-II-like but not HTLV-II. This test will likely give way to specific probes based on conserved sequences of actual retroviral isolates of whatever family cultured from CFS patients.

Exercise-Related Dysfunction

Patients with CFS describe characteristic worsening of their symptoms following exercise as well as exercise limitations. Exercise ergometry with gas analysis has proven useful in CFS to document defects in functional capacity; a functional consequence of debilitating fatigue. Several reports have attracted further interest in this technology as a diagnostic instrument for showing neuroendocrine defects in response to exercise, 31 as well as defects in respiratory control mechanisms within the central nervous system in CFS patients.

Bicycle ergometry with gas analysis has proven useful to document disability in CFS and will likely prove useful to document deep brain dysfunction characteristic of CFS patients.

Tests of Exercise-Related Dysfunction Important measurements using bicycle ergometry with gas analysis

1. Peak oxygen consumption at maximum exertion
2. Work rate at anaerobic threshold as against peak work rate.
3. Oxygen consumption at anaerobic threshold
4. Work efficiency - independent of conditioning
5. Breath-to-breath tidal volume variance at peak exercise

Brain Dysfunction

Perhaps no set of symptoms is more disturbing to CFS patients nor more striking to clinicians than the neurocognitive complaints seen in CFS. They characteristically evolve slowly over time and often grow to dominate the clinical scene. At first there is only the mental "fog" of a viral syndrome, but this slowly gives way to the more worrisome complaints of memory disturbance, word searching, processing speed, and spatial disorganization. There also may be neuropsychological complaints including panic attacks, depression, and mood swings. Evidence of characteristic abnormalities on neuropsychometric tests and characteristic profiles on the MMPI have been reported.32,33 Defects on structural34,35 (MRI) and functional scans (SPECT and Topographic Computer EEC) of the brain have also been reported.36,37 As mentioned above, soft neurologic findings are also frequently demonstrated under physical examination. We have proposed a number of approaches to document evidence of brain dysfunction in CFS.

Tests to Document Brain Dysfunction

Structural Scans - MRI is recommended for any patient with an abnormal neurologic examination or significant neurologic symptoms. This is done primarily to rule out structural abnormalities which might mimic CFS signs and symptoms. Many CFS patients (50 percent or more) will exhibit small punctate areas of increased signal, usually in subcortical white matter areas.

Functional Scans - SPECT scans, which primarily measure blood flow, are frequently abnormal (80 to 85 percent), showing areas of decreased perfusion primarily in the temporal and frontal lobes.

Topographic computer EEC brain mapping has shown increased slow-wave activity usually in the anterior leads and especially when patients are engaged in certain cognitive tasks. This usually diffuse slow-wave activity strongly suggests metabolic or toxic encephalopathy.

Neuropsychometric Testing - A complete Halstead Reitan battery or subsets of this battery form the basis of determining the nature and extent of cognitive impairment in CFS. Patients will exhibit characteristic focal and multifocal deficits in which performance on certain subtests will be normal or even well above normal while performance on certain other subtests will be substantially below normal. Performance deficits appear to occur more frequently in particular subtests of this battery.

Knowledge Is Power

CFS clinical and bench researchers are developing an array of tests which are increasingly sensitive and specific for CFS — particularly when used in combination. When patients present with symptoms that suggest CFS, we believe it is in their best interest to selectively employ these tests to confirm the diagnosis and to document the nature and extent of each case. This information: increases both the physician's and patient's confidence in the diagnosis and their ability to track the course of the disease; enables the patient to make appropriate lifestyle adjustments (including defense of disability claims when necessary); and provides the physician with a basis for therapeutic intervention.

References

1. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S, Tosato G, Zegan SLS, Purtilo DT, Brown N, Schooley RT, Brus I. Chronic fatigue syndrome: a working case definition. Ann of Int Med, 108:387-9, 1988

2. Klimas N, Salvato F, Morgan R, abnormalities in chronic fatigue syndrome. J of Clin Micro, 28:1403-10, 1990

3. Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Immunological abnormalities in the chronic fatigue syndrome. M J of Australia, 151(3):122-4, 1989

4. Caligiuri M, Murray C, Buchwald D, Levine H, Cheney PR, Peterson D, Komaroff AL, Ritz J. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immun 139:3306-13, 1987

5. Aoki T, Usuda Y, Miyakoshi H, Tamura K, Herberman RB. Low natural killer syndrome: clinical and immunologic features. Cat Immun Cell Growth Regul, 6:116-128, 1987

6. Tosato G, Straus S, Henle W, Pike SE, Blaese RM. Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection (chronic infectious mononucleosis). J Immunol 134:3082-8, 1985

7. Prieto J, Subir'a ML, Castilla A, Serrano M. Naloxone reversible monocyte dysfunction in patients with chronic fatigue syndrome. Scan J Immunol. 30(1)-.13-20, 1989

8. Salvato F, Fletcher M, Ashman M, Klimas N. Immune dysfunction among chronic fatigue syndrome (CFS) patients with clear evidence of Epstein-Barr virus (EBV) reactivation. J Exp Clin Cancer Res, (sup)7:89, 1988

9. Linde A, Hammarstrom L, Smith C. IgG subclass deficiency and chronic fatigue syndrome. Lancet i:885-6, 1988

10. Komaroff AL, Geiger AM, Wormseley S. IgG subclass deficiencies in chronic fatigue syndrome. Lancet i(8597):1288-9, 1988

JL1. Read R, Spickett G, Harvey J, Edwards AJ, Larson HE. IgG 1 subclass deficiency in patients with chronic fatigue syndrome. Lancet, i:241-2, 1988

12. Franco E, Kawa-ha K, Doi S, Yumura K, Murata M, Ishihara S, Tawa A, Yabuuchi H. Remarkable depression of CD4+2H4+T cells in severe chronic active Epstein-Barr virus infection. Scan J Immunol 26:769-73, 1987

13. Cheney PR, Rozovsky I. The relationship of soluble IL-2 receptor to functional capacity in CFS. The CFIDS Association 1990 CFIDS Research Conference, "Unravelling the Mystery," Nov. 17-18, 1990, Charlotte, NC.

14. Subira ML, Castilla A, Civeira MP. Deficient display of CD3 on lymphocytes of patients with chronic fatigue syndrome [Letter] J Infect Dis 60(l):165-6, July,1989.

15. Levy J, et al. Chronic fatigue syndrome: clinical condition associated with immune activation. Lancet Vol.338, No.8769, Sept. 1991

16. Biron, et al. Severe herpesvirus infections in an adolescent without natural killer cells. NE J Med 320: 1731-5, June 29, 1989

17. Morte S, Castilla A, Iveira MP, Serrano M, Prieto J. Production of interleukin-1 by peripheral blood mononuclear cells in patients with chronic fatigue syndrome [Letter]. J Infect Dis, 159:362, 1989

18. Straus SE, Dale JK, Peter JB, Dinarello CA. Circulating lymphokine levels in the chronic fatigue syndrome [Letter]. J Infect Dis, 160(6):1085-6 1989

19. Cheney PR, Dorman SE, Bell DS. Interleukin-2 and the chronic fatigue syndrome [Letter]. Ann Int Med 110:321 1989

20. Linde A, Anderson B, Svenson SB, Ahrne H, Carlsson M, Forsberg P, Hugo H, Karstop A, Lenkei R, Lindwall A, Loftenius A, Sail C, Anderson J. Serum levels of lymphokines and soluble cellular receptors in primary Epstein-Barr virus infection and in patients with chronic fatigue syndrome. J Infect Dis, 165:994-1000, 1992

21. Buchwald D, Freedman A, Ablashi D, Sullivan J, Caliguiguri M, Weinberg D, Hall C, Ashley R, Saxinger C, Balachandran N, Ritz J, Nadler L, Komaroff AL. A chronic postinfectious fatigue syndrome associated with benign lymphoproliferation, B-cell proliferation, and active replication of human herpesvirus-6. J Clin Immun, 10(6):335-344, 1990

22. Komaroff AL. Human herpesvirus-6 and human disease. Am J Clin Pathol, 93:836-7, 1990

23. Steeper TA, Horwitz CA, Ablashi DV, et al. The spectrum of clinical and laboratory findings due to human herpesvirus-6 (HHV-6) in patients with mononucleosis-like illnesses not due to EBV or CMV. Am J Clin Pathol, 93:836-7, 1990

24. Tobi M, Moraq A, Ravid Z, Chowers I, Feldman-Weiss V, Mitchell Y, Chetrit E Ben, Shalit M, Knobler H. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet, 1:61-4, 1982

25. Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses; elevated anti-early antigen antibodies. Ann Int Med 102:1-7, 1985

26. Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, Davey R, Pearson G, Epstein J, Brus I, Blaese RM. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Int Med, 102:7-16, 1985

27. DeFreitas E, Billiard B, Cheney PR, Bell DS, Kiggundu E, Sankey D, Wroblewska Z, Palladino M, Woodward JP, Koprowski H. Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA, Vol.88, mpp.2922-26, April 1991

28. Bothe K, Aguzzi A, Lassmann H, Rethwilm A, Horak I. Progressive encephalopathy and myopathy in transgenic mice expressing human foamy virus genes. Science, Vol.253, pp. 555-567, August, 1991

29. Cameron KR, Bircham SM. Moss MA. Isolation of foamy virus from patient with dialysis encephalopathy: Lancet p. 796, October 7, 1978

30. Weiss RA. A virus in search of a disease. Nature, Vol.333, June 9, 1988

31. Daly J. The ventilatory response to exercise in CFS. The Third Annual Conference - Chronic Fatigue Syndrome and the Brain, Bel-Air, California, April 24-26, 1992

32. Onischenko T. It's all in your head - well, indeed it is... The Third Annual Conference - Chronic Fatigue Syndrome and the Brain, Bel-Air, California, April 24-26, 1992

33. Iger, LM. Changes on the CFS profile with the MMPI-2. The Third Annual Conference - Chronic Fatigue Syndrome and the Brain, Bel-Air, California, April 24-26, 1992

34. Daugherty SA, Henry BE, Peterson DL, Swarts RL, Bastien S, Thomas RS. Chronic fatigue syndrome in northern Nevada. Rev Infect Dis, 13{Supp l):S39-44, 1991 (MRI Scans)

35. Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Abalashi DV, Salahuddin Z, Saxinger C, Biddle R, Kikinis R, Jolesz FA, Folks T, Balachandran N, Peter JB, Gallo RC, Komaroff AL. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus-6. Ann Int Med, Vol.116,(2), pp.103-113, January 15, 1992

36. Mena I. Study of cerebral perfusion by NeuroSpect in patients with chronic fatigue syndrome. Symposium on Myalgic Encephalomyelitis, p.21, Cambridge, England, April 1990 (SPECT Scans)

37. Cheney PR, et al. CFS: A clinical perspective on the use of MEG and EEC brain mapping. The Third Annual Conference - Chronic Fatigue Syndrome and the Brain, Bel-Air, California, April 24-26, 1992

Hydrotherapy for ME/CFS - Dr. Cheney's Protocol

The DAR state forest in Goshen, MA - my "swimming hole"

In the 1990s, Dr. Cheney proposed the idea of cool-water hydrotherapy for ME/CFS patients. The idea behind the treatment was that vertical immersion in cool (not cold) water would help down-regulate immune system activation, which Dr. Cheney believed was an integral part of ME/CFS symptoms. 

Allergies, flu-like symptoms, and food sensitivities are all signs of immune activation, as are autoimmune comorbidities (e.g. Hashimoto's disease). Because I had all of these, as well as heat intolerance, I decided to put Dr. Cheney's theories to the test. I immersed myself in cool water (see photo), twice a day for roughly 15 minutes. The water was too cool to simply stand, so I swam very slowly using a modified breaststroke - head above water, body at roughly a 45-degree angle - for about 15 minutes.

The first thing I noticed was that my head cleared. All my cognitive problems disappeared for a few hours after getting out of the lake. My energy levels also improved, as did my stamina.

It turned out that there was more to Dr. Cheney's theory than lymph fluid reversal. Immersion in cool water shunts blood to vital organs - specifically to the heart and brain. (Heat has the reverse effect.) Swimming in cool water for a short period of time helped clear my  head simply because my brain was getting more blood, and, as a consequence, more oxygen.

For those who are interested, I have pasted Dr. Cheney's original hydrotherapy program below. While Dr. Cheney recommended working up to an hour or more, I found that 10-30 minutes was more than sufficient.

____________________

CHRONIC FATIGUE SYNDROME TREATMENT PROGRAM USING HYDROTHERAPY

Introduction

Patients with Chronic Fatigue Syndrome (CFS) have evidence of immune activation. Many of the symptoms associated with CFS may in fact be the result of or indirectly related to an overactive immune response. A substantial reduction in these symptoms may therefore occur with the down-regulation or re-regulation of this overactive immune system.

There are two methods of interest to us which are both inexpensive and have low side effects which can conceivably provoke immune down-regulation in CFS. A low temperature method and perhaps the more powerful pressure gradient method used to accelerate lymphatic flow. These methods could obviously be merged.

Clinicians in Germany have recently used low temperature water baths to treat both Multiple Sclerosis (MS) and Chronic Fatigue Syndrome both of which have evidence of immune activation. It has been observed that Multiple Sclerosis patients worsen when they are overheated by vigorous exercise or after Jacuzzi hot water bathing. MS patients, however, seem to do better after swimming, perhaps because there is much less overheating during this type of exercise.

Several CFS patients treated at The Cheney Clinic using the German cold-water treatment method have reported "windows" or short time periods of improvement following this treatment. As in MS, it has been observed that CFS patients also worsen after being overheated, whether by exercise or by hot water bathing. The two disorders are, of course, immunologically similar in terms of immune activation.

With respect to pressure gradient therapy, there have been two double blind placebo controlled trials documenting at least partial efficacy in CFS of IV gammaglobulin infusion at high dose.

Gammaglobulin is an immune modulator and in addition to being a source of antibodies, possesses a number of immunomodulatory proteins which are known to down-regulate or re-regulate immune system function. 

Tissue lymph fluid bears some resemblance to gammaglobulin as it also contains antibodies and immunomodulatory proteins. The tissue lymph in Chronic Fatigue Syndrome patients is likely to contain immune activation proteins or cytokines in excess. Given evidence in CFS of lymphadenitis and tenderness along lymph node channels, especially in the lower left base of the neck, it is likely that there is increased production of tissue lymph related to their immune activation state.

This excess lymph flow would be expected to back up from the thoracic duct and provoke tenderness in the

Virchow's node area above the left clavicle and extend up into the left middle and posterior cervical node chains and/or into the left axillary (armpit) node chain. In our experience, this is exactly what is seen in most cases of Chronic Fatigue Syndrome. Lymphatic congestion could provoke pain in the left shoulder, left arm and down into the anterior chest. Severe lymphatic congestion would produce tissue edema or fluid retention and perhaps more extensive pain and gastrointestinal complaints, all common in CFS.

Vertical immersion in water creates a significant pressure gradient which can enhance lymphatic flow up the body and torso and into the thoracic duct which lies below the left clavicle The pressure gradient effects would act to autotransfuse tissue lymph back into the blood stream at the level of the left subclavian vein. 

This autotransfusion of excess immunoreactive lymph fluid would likely provoke a down-regulatory immune response which with time could result in a significant improvement in symptoms. Factors which may enhance this lymphatic flow and its effects include water temperature, length of vertical immersion, and the number of days per week in which therapy takes place.

Temperature may be a particularly important variable. Lower temperatures may be better as noted above by the Germans; however, low temperatures may also mitigate against prolonged immersion since as the patient's body cools down, a greater proportion of their energy will be shifted to maintain body temperature, and they then may become more fatigued. On the other hand, higher temperatures accelerate immune activation states and may be counter productive.

It is likely that a temperature somewhere between 80 and 86° is the best compromise between these two issues. It is also felt that length of time per session may be important. At least an hour to an hour and a half per session will likely be required to provoke sufficient lymphatic flow in most patients. The number of sessions per week could also be important and from preliminary studies, it would appear that a minimum of three sessions per week will be necessary.

Factors which may inhibit improvement include lymphatic blockage especially at the Virchow's node area which would be suggested by discomfort in that area following total body immersion. It is also possible that sicker patients may lack sufficient ability to down-regulate against tissue lymph, and, therefore, no significant improvement will be seen. There is also an outside chance that in some patients this therapy could actually exacerbate their condition in the early stages of therapy since the tissue lymph is rich in immune augmenting cytokines.

Finally, it is possible that good hydration will also aid tissue lymph flow, and we would recommend that patients on this protocol drink at least eight glasses of water per day and that sicker patients even consider an infusion of a full liter of IV fluids prior to immersion.

Instructions: Sixteen Week Treatment Protocol

It is important that the pool have water temperatures between 80° and 86°.

Patients will float and occasionally "water walk" primarily in the deep end of the pool and are encouraged to socialize while in the water. Water resistant, head-mounted tape or radio players to listen to audio tapes of books, music or radio can be used to help pass the time. Patients must remain as vertical as possible and submerged to the neck while in the water. The ideal time each patient should stay in the water and the ideal number of sessions per week may vary from individual to individual.

The Cheney Clinic recommends that patients attempt to reach a minimum immersion time of one hour per session for three sessions per week. Longer times per session or more sessions per week may be helpful for some and not for others. Each person will need to determine what is ideal for them. Please note that "water walking" or water exercising is not necessary and can be detrimental in the early phases of treatment. With time, however, water walking may be the ideal exercise for CFS patients. Remember that 30 minutes of water walking is equal to two hours of land walking. CFS patients should be very cautious about overextending in the pool.

Most patients report at first feeling more fatigued or tired after their Hydrotherapy sessions. With time, however, they will typically better tolerate the sessions.

The length of time spent in the water should be increased gradually over the first three weeks starting at 15 minutes per session at a frequency of three times per week. Add 5 to 10 minutes to each successive session over the first three weeks. Never jump ahead to longer times as this has provoked worsening of symptoms in some patients. Session length may need to be abbreviated if you are feeling worse over time and sessions should be omitted on a down-day or if you have a fever above 100 degrees. No session should extend beyond one and one-half hours and a session should be cut short if you become cold or shiver.

Patients will take care to drink at least eight, 8-ounce glasses of water or juice per day. They are particularly encouraged to drink at least twelve ounces of water or non-citrus juice up to but not beyond one hour prior to water immersion. Non-citrus juices include apple, pineapple, papaya and cranberry juices.

Care must be taken to not use hot water showers before or after immersion. This could activate the immune system, especially after immersion. Prior to and following immersion a warm but comfortable shower should be taken. A warm but comfortable then five minutes of cool but comfortable shower method should be used at all other times. No hot water Jacuzzis, saunas, or hot water bathing should be used during this program nor at any other time by CFS patients.

Patients who are cold intolerant or get too cold in the pool should invest in a wet suit. We recommend the O'Neil, full or partial length wet suit as it is relatively easy to get into and out of and can be worn to the pool. Torso thickness should be a three and limb thickness a two. (ie. a 3/2 thickness wet suit). A wet suit can greatly increase the comfort level of longer times in the pool. A wet suit will also increase buoyancy.

Patients who are improving on this therapy must guard against physical, emotional, or cognitive overextension. Patients remain brittle for some time and subject to relapse even as they improve on Hydrotherapy. What you chose to do with your improved functional status may well dictate how successful this program will be for you.

Shake-up at HHS - Koh Resigns

Hot on the heels of Secretary of Health and Human Service Kathleen Sebelius' resignation comes the resignation of Howard Koh, Assistant Secretary for Health (see below).

The ongoing turmoil at HHS is beyond a doubt due to the messy roll-out of the Affordable Care Act (Obamacare). Sebelius was described at numerous press conferences as being "clueless," which, as someone who was supposed to be the "face of the ACA," was unforgivable.

Given the inoperability of the federal website, the plethora of legal challenges (right up to the Supreme Court), and near constant attempts to undermine Obamacare through threatened lawsuits (which can't actually make it to court, but which get huge play in the press), is it any wonder that the top officials at HHS have "resigned"?

Adding fuel to the fire that is burning HHS's house down, was the dramatic departure of David Wright, head of the Office of Research Integrity, last March. In a detailed letter of resignation, Wright described HHS as "dysfunctional" and characterized Koh's office as “seriously flawed ...  secretive, autocratic and unaccountable.” Wright's letter got gleeful coverage from the media, which is always happy to jump at the chance of reporting a scandal. Once Sylvia Burwell took over as head of HHS, it was predicable that Koh would follow in the wake of Sebelius' hasty retreat.

What does this mean for the ME/CFS community? Very little, actually. It means HHS will be paying very little attention to this illness, while it tries to salvage Obamacare. It will be devoting very little of its resources, energy and time to our concerns. Very little money will be provided for scientific research. And people with very little interest in making necessary updates on the CDC's website, or including biomarkers in the CDC's multi-site study, or relying on the experience of experts to define the illness will continue to hold sway.
______________________________________

From: Burwell, Sylvia M. (HHS/OS)
Sent: Wednesday, July 02, 2014 03:53 PM
To: OS - Political Staff; OS - OPHS - All Employees
Subject: Important Staff Announcement

Colleagues,

After more than five years of distinguished service, Dr. Howard Koh has informed me that he will step down as the Assistant Secretary for Health to assume a new position at the Harvard School of Public Health as Professor of the Practice of Public Health Leadership.

As Assistant Secretary for Health, Howard has been at the forefront of confronting the leading public health issues of our time.  And as one of our top physicians at HHS and in federal government, he has been a trusted and respected voice in implementing and communicating the critical public health dimensions of the Affordable Care Act.

Howard’s broad range of accomplishments at HHS reflects his deep passion for promoting public health in so many arenas. He was the primary architect of landmark HHS strategic plans on tobacco control, health disparities, and chronic viral hepatitis that will leave a legacy for many years. He has led the HHS implementation of the President’s National HIV/AIDS Strategy, and the President’s Climate Action Plan as it relates to public health.  Through his work, he has promoted efforts in areas such as behavioral health, cancer control, adult immunization, physical activity and obesity prevention, health literacy, multiple chronic conditions, organ donation and epilepsy.  Additionally, he was actively engaged in matters related to the modernization of the Commissioned Corps, and oversaw the unveiling of Healthy People 2020.

Throughout his tenure, Howard has leveraged his decades of unique experience as a clinician, educator, researcher, advocate and former state public health commissioner to bring better understanding and empathy to underserved populations.  Please join me in thanking him for his tireless commitment and wishing him all the best in his new position.

Best,

Sylvia Burwell