Wednesday, August 20, 2014

Do Gut Bacteria Rule Our Minds? Cravings, Weight Gain, and Bugs in ME/CFS

Feed me, Seymour. Feed me!
Every once in a while, I come across an article that inspires an "Aha!" moment. The article below is one of them.

Researchers from UC San Francisco have discovered that not only do those trillions of bacteria that live in our guts influence our mood, they can choose what we eat.

Food cravings, especially for sugar, are common in ME/CFS. Formerly, this was chalked up to an overgrowth of Candida, a yeast that thrives on sugar. Dr. Carol Jessop found that after putting her CFS patients on anti-yeast medication, as well as an anti-Candida diet, they made considerable improvement. John Rutter, a well-known composer and ME patient, reported that an anti-Candida regimen was the turning point in his illness.

But, what if the picture is more complicated? What if gut bacteria also play a role in the symptomology of ME/CFS?

Nearly 20 years ago, Lauren Gellman (co-author of Chronic Fatigue Syndrome: A Treatment Guide), and I conducted a survey. Among the questions we asked ME/CFS patients was whether they had recently been treated for infections. Every single one of the respondents answered that they had taken long-term antibiotics prior to contracting ME/CFS.

Antibiotics have saved millions of lives, but, as Oakland, CA gastroentrologist and fecal transplant proponent Dr. Neil Stollman points out, "antibiotics are a scourge." By altering the microbiome with antibiotics, the body's immune system is compromised. And with the proliferation of unhealthy bacteria in our guts, we are prone to inflammation, which can lead to autoimmune disease and colitis. We are also prone to an overgrowth of bacteria in the small intestines known as SIBO, or small intestine bacterial overgrowth. 

Dr. Cheney has proposed that the majority of patients with ME/CFS suffer from SIBO. The symptoms of SIBO include every GI symptom you can think of -  including IBS - as well as exhaustion, insomnia, night sweats, brain fog, muscle weakness, flu-like symptoms, muscle aches, and a horrible night-time malaise. Among gastroenterologists, the cause of SIBO is recognized as antibiotics, which, like the hair of the dog that bit you, are also used to treat SIBO (Xifaxan is preferred).

The test for SIBO is the lactulose breath test. After refraining from eating sugar and milk products, both of which feed the overgrowth, a small amount of lactulose (a synthetic sugar which acts as a mild laxative) is administered. The gases that are produced - methane and hydrogen - are then measured. In simple terms, the more gas produced, the more severe the infection. (You can order this test without a prescription, and administer it yourself.)

So, the question is, what do you crave? Do you crave ice cream, sweets? And, is it you craving those foods, or is it the overgrowth in your small intestine? Nearly all physicians who treat ME/CFS recommend the elimination of sweets. Perhaps the bugs in your gut provide an explanation for why sweets make patients feel worse - and why we crave them.

Even if the elimination of sweets and milk products from your diet doesn't cure you of ME/CFS, there are definitely a few trillion good reasons to refrain from eating them.
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Do gut bacteria rule our minds? In an ecosystem within us, microbes evolved to sway food choices

By Jeffrey Norris 

Press Release: UCSF, August 15, 2014. It sounds like science fiction, but it seems that bacteria within us -- which outnumber our own cells about 100-fold -- may very well be affecting both our cravings and moods to get us to eat what they want, and often are driving us toward obesity.

In an article published this week in the journal BioEssays, researchers from UC San Francisco, Arizona State University and University of New Mexico concluded from a review of the recent scientific literature that microbes influence human eating behavior and dietary choices to favor consumption of the particular nutrients they grow best on, rather than simply passively living off whatever nutrients we choose to send their way.

Bacterial species vary in the nutrients they need. Some prefer fat, and others sugar, for instance. But they not only vie with each other for food and to retain a niche within their ecosystem -- our digestive tracts -- they also often have different aims than we do when it comes to our own actions, according to senior author Athena Aktipis, PhD, co-founder of the Center for Evolution and Cancer with the Helen Diller Family Comprehensive Cancer Center at UCSF.

While it is unclear exactly how this occurs, the authors believe this diverse community of microbes, collectively known as the gut microbiome, may influence our decisions by releasing signaling molecules into our gut. Because the gut is linked to the immune system, the endocrine system and the nervous system, those signals could influence our physiologic and behavioral responses.

"Bacteria within the gut are manipulative," said Carlo Maley, PhD, director of the UCSF Center for Evolution and Cancer and corresponding author on the paper." "There is a diversity of interests represented in the microbiome, some aligned with our own dietary goals, and others not."

Fortunately, it's a two-way street. We can influence the compatibility of these microscopic, single-celled houseguests by deliberating altering what we ingest, Maley said, with measurable changes in the microbiome within 24 hours of diet change.

"Our diets have a huge impact on microbial populations in the gut," Maley said. "It's a whole ecosystem, and it's evolving on the time scale of minutes."

There are even specialized bacteria that digest seaweed, found in humans in Japan, where seaweed is popular in the diet.

Research suggests that gut bacteria may be affecting our eating decisions in part by acting through the vagus nerve, which connects 100 million nerve cells from the digestive tract to the base of the brain.

"Microbes have the capacity to manipulate behavior and mood through altering the neural signals in the vagus nerve, changing taste receptors, producing toxins to make us feel bad, and releasing chemical rewards to make us feel good," said Aktipis, who is currently in the Arizona State University Department of Psychology.
In mice, certain strains of bacteria increase anxious behavior. In humans, one clinical trial found that drinking a probiotic containing Lactobacillus casei improved mood in those who were feeling the lowest.

Maley, Aktipis and first author Joe Alcock, MD, from the Department of Emergency Medicine at the University of New Mexico, proposed further research to test the sway microbes hold over us. For example, would transplantation into the gut of the bacteria requiring a nutrient from seaweed lead the human host to eat more seaweed?

The speed with which the microbiome can change may be encouraging to those who seek to improve health by altering microbial populations. This may be accomplished through food and supplement choices, by ingesting specific bacterial species in the form of probiotics, or by killing targeted species with antibiotics. Optimizing the balance of power among bacterial species in our gut might allow us to lead less obese and healthier lives, according to the authors.

"Because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating," the authors wrote.

The authors met and first discussed the ideas in the BioEssays paper at a summer school conference on evolutionary medicine two years ago. Aktipis, who is an evolutionary biologist and a psychologist, was drawn to the opportunity to investigate the complex interaction of the different fitness interests of microbes and their hosts and how those play out in our daily lives. Maley, a computer scientist and evolutionary biologist, had established a career studying how tumor cells arise from normal cells and evolve over time through natural selection within the body as cancer progresses.

In fact, the evolution of tumors and of bacterial communities are linked, points out Aktipis, who said some of the bacteria that normally live within us cause stomach cancer and perhaps other cancers.

"Targeting the microbiome could open up possibilities for preventing a variety of disease from obesity and diabetes to cancers of the gastro-intestinal tract. We are only beginning to scratch the surface of the importance of the microbiome for human health," she said.

The co-authors' BioEssays study was funded by the National Institutes of Health, the American Cancer Society, the Bonnie D. Addario Lung Cancer Foundation and the Institute for Advanced Study, in Berlin.

Journal Reference: Joe Alcock, Carlo C. Maley, C. Athena Aktipis. Is eating behavior manipulated by the gastrointestinalmicrobiota? Evolutionary pressures and potential mechanisms. BioEssays, 2014; DOI: 10.1002/bies.201400071

Friday, August 15, 2014

ME/CFS - Dr. John Richardson and the Enterovirus Connection

The late Dr. John Richardson was a family physician who practiced in Newcastle, UK. For more than 40 years, Dr. Richardson tracked his patients, taking detailed histories, documenting their illnesses, and performing autopsies on those who died. These records provided the basis for his book, Enteroviral and Toxin Mediated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Other Organ Pathologies, which is regarded as one of the most valuable medical compilations in the field of ME/CFS.

Early in his practice, Dr. Richardson realized that enteroviral infections were endemic among his patients, and that not only did they spread from one family to another, they were transmitted from one generation to the next. Out of 7000 patients who contracted viral illnesses, 1780 went on to develop pathologies - 894 had subsequent organ pathology and 111 died. The causes of death were cardiac failure, carcinomas, and other organ failure.

While all of these deaths were attributed to their proximate causes (heart attack, cancer, etc.) Dr. Richardson showed, through autopsy results, that the underlying pathology was caused by enteroviruses, which were still live and replicating in the affected organs years after the initial infection had resolved.

Dr. Richardson noted that roughly 20% of those affected by enteroviral infections (primarily coxsakie virus) developed ME. Because of his diligence, knowledge, and powers of observation, Dr. Richardson soon became one of the world's foremost experts in the disease.

Dr. Richardson's book is not designed for the layperson, which makes for difficult reading. But the information it contains is worth the effort.  Below is the section on diagnosing ME, excerpted from Enteroviral and Toxin Mediated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Other Organ Pathologies, CRC Press; 1st edition (August 15, 2001).

One can only hope that Drs. Cheney, Peterson, Bell and other physicians who have assembled years of data from thousands of ME/CFS patients will undertake to make their observations and clinical data available to the public, as Dr. Richardson has done. 

You can find links to Dr. Richardson's papers and presentations here.

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MYALG1C ENCEPHALOMYELITIS

Nowhere is a variety of systemic symptoms seen more often than in myalgic encephalomyelitis. While it is a defined entity, other organ pathology is not infrequent and can obscure the picture. In this series about 25 percent also developed other antibodies, and antithyroid an­tibodies occurred in about 20 percent of cases. A lecture given at Cambridge in 1990 summarizes this syndrome (Nightingale Re­search Foundation, 1991).

Much has been written on the subject. It has been treated as a myth, or as a single entity that was then claimed by some to be psychiatric or by others to be organic in origin. In the first group, labels were ap­plied ranging from depression to hysteria while in the second, valid observation as well as vague hypotheses are still the order of the day. This merely illustrates the limitations of the medical mind in fully ex­plaining the fundamental pathology of all illness.

The observations in the following sections are the result of contin­uous follow-up and analysis of sequential illness in patients varying in situation and time over a period of forty years.

Prevalence and Clinical Diagnosis

As with poliomyelitis, surveys have shown ME to be epidemic, endemic, and also sporadic. It may follow an acute viral illness such as Bornholm disease, pericarditis, labyrinthitis, or meningoencephalitis. A more vague flulike illness with chest or bowel disturbance may be the harbinger of a more insidious onset. Apparent malaise not only fails to end but becomes more defined, developing symptoms such as anomia or severe concentration difficulty in a previously highly accomplished person who now cannot recall a paragraph even after reading it several times. Muscle power may not appear to be affected, but if examined carefully, softened and very tender areas may be demonstrated. Muscle jitter is a feature in 25 percent of these cases. 

This can be shown by seating the patient on the examination table and asking him or her to raise and lower the lower leg, whereby the jitter is easily seen. Concomitant myocardial or endocrine gland dysfunction also occurs, but if these resolve, the physician may be very frustrated to find that the patient is still ill. The graphs in Figure 3.12 show relative prevalence, and it is apparent that females do not predominate as some have thought, given the overall CNS sequelae to viral illness. Since these graphs were developed, the absolute number of cases being considered has risen, but the percentages have remained unchanged.

I devised the scoring chart shown in Table 3.3 in the early 1960s to summarize the symptoms that were recorded by patients in their own written histories of this illness. There were approximately 300 such written histories, and the symptoms that form the basis of this chart occurred in 80 percent of the cases.

If the patient qualifies for the diagnosis for each question, then the score indicated in the third column is recorded in the fourth column. The sum of the values in this fourth column then represents the patient's overall score.

Table 3.3 ME scoring chart

1. Has there ever been any evidence, either illness or titer, of past viral infection? 1

2. FATIGUE: (a) Are you less than 33% efficient per full day (including hobbies after work, etc.) 2
(b) Do you need a period of bed or settee rest: during each day, or 3 on 2 or 3 days a week? 2

3. Have you excessive fatigue after work effort? 2

4. Do you have nocturnal sweats or cold feelings? 2

5. EVIDENCE OF DISTURBED MENTAL ACTIVITY
(a) Do you have difficulty finding the correct words? 1
(b) Can you write a long letter without your handwriting deteriorating? 1
(c) Do you tire if you have to talk for long? 1

6. FAINT ATTACKS (VASOMOTOR CNS INSTABILITY)
(a) Do you tend to have faint attacks:
and lose consciousness? 3
or: without loss of consciousness but have to sit down or lie down? 2

7. Do you feel fatigued on waking? 1

8. Can you stand a lot of “chatter” (hyperacusis)? 1

9. Do you have cold or numb feelings in your extremities of face? 2

10. Is your gait consistent with your age or is it that of a person much older or unsteady? 1

Answering these questions, therefore, yields a global view of the symptoms that occur in ME. An overall score of fifteen or more is highly suggestive of the condition and can be broken down into four sections:

1. Fatigue. This can be either central fatigue or muscle fatigue. Central fatigue is probed in question 7 while peripheral fatigue is indicated by questions 3 and 10. The resulting combination would be suggested by question 2 (a) and (b). Muscle fatigue is known to be related to an excess of lactic acid after work effort. In this condition, however, excessive activity is usually reflected the following day, and it may take days for the patient to recover.

2. Mental Activity. Question 5(a) indicates anomia, which is a very well recognized symptom in this condition, while question 5(b) reflects the motor fatigue involved in transposing verbal to written language. This may indicate the involvement of supra- and infrasensorial mechanisms within the brain and may also be evidenced by a positive response to question 5(c).

3. CNS Instability. This is seen in varying degrees of severity in 80 percent of the cases, hence the two grades of response to question 6(a). The test for the former is performed by placing the patient prone on the examination couch and performing serial ECGs and carefully monitoring blood pressure. The backrest is then raised to 45° and blood pressure recorded at two-minute intervals. If any change in heart rate is detected, then further ECGs are performed. After five minutes the patient is asked to stand upright, and further blood pressures are recorded. In only 10 percent of cases is there a significant change in heart rate, but changes in blood pressure as indicated usually occur. In the supine position, the blood pressure normally is quite low but in the 45° position often rises by 50 mm systolic and 20 mm diastolic. When the patient assumes the erect position it again falls to levels either equal to or below those recorded for the supine position. Only in the small minority of cases with a concomitant bradycardia did a collapse occur, but, as indicated, many of the other patients felt weak and had to sit down.

Question 8 again alludes to the central fatigue in which the patient has a limited ability to absorb information. On occasion, certain tones become extremely painful, constituting the "tensor tympani" syndrome.

Question 9 relates to vasomotor instability reflected in temperature or sensory changes, which again may reflect abnormal reception in the hypothalamic nuclei.

4. Overall Result. Finally, question 10 is obviously the result of a conglomeration of the other symptoms.

The Differential Diagnosis of Myalgic Encephalomyelitis

Obviously the history obtained is of first importance. In the cases so far, it is striking how consistent the symptoms are that characterize this condition. Moreover, when the cases are studied in retrospect, the following fact emerges. Approximately 7,000 cases of viral illness over four decades have been listed and broken down into five groups. The first contained over 5,000 cases who had had quite a severe ill­ness but recovered without sequelae within six months. However, just under 20 percent of this group did have a recurrence of enteroviral or­igin at a future date but not always with the same syndrome, e.g., one case had Bornholm disease and the second attack was viral meningi­tis. These were chiefly enteroviral cases, and it is interesting that no one in Group 1 progressed to postviral illness, be it ME or another syndrome. However, of all 7,000 cases, 1,670 did have postviral syn­dromes, some from the original attack and some who had a recurrent illness (Group 2).

It is of interest to note that some of the initial illnesses appeared to clear completely (e.g., meningitis or Bornholm disease), while others (e.g., pericarditis, myocarditis, nephritis, etc.), could remit or pursue a more chronic course. A lifelong syndrome (e.g., diabetes) might en­sue in a small minority. Yet again, in a small minority with acute on­set there are those who do not make a recovery and develop ME. The difficulty of diagnosis is compounded by the fact that in many cases, none of the severe initial syndromes may have presented. In fact it might be assumed that a severe, acute illness provoked a host re­sponse with complete remission, while a subacute illness did not. However, there is an overlap, and as usual it is probably too facile to be dogmatic.

Thus, for the purpose of differential diagnosis two main conditions should be considered, namely, the pathogenic agent and the organ af­fected. The host response should also be seen as a third condition that vitally affects these two factors. Considered separately in the context of the condition studied here, this can be summarized as follows.

Pathogenic Agent

Pathogenic agents may be organic or inorganic. In the present con­text most organic pathogens are viral, but, as shown later, this is not exclusive of other agents. Most of the inorganic agents are varying chemical toxins, and of these the insecticides used on farms for crops or animals, or in the home for insects on plants and occasionally for lice on children or pets, together with wood preservatives used in the home or at work, are the most common in the United Kingdom. This is not exclusive and could be extended to the ingestion of toxins on food or in water, etc. We have recorded such cases, which have caused profound paresis in some cases and in others subclinical weakness that could be classified as ME.

Organs Affected

It is obvious that either organic or inorganic toxins may have an ef­fect on varying organs and thus give rise to varying syndromes de­scribed under various titles. This depends not only on the toxin but also on the host.

Host Response

Host response is a crucial consideration relating to the previous considerations. In the case of organisms, be they virus or others, it can be shown that the host response may determine the degree as well as the site of infection. Some patients may be immune to certain or­ganisms while others may be susceptible. The degree of immunity may vary over months or years and also be suppressed by varying fac­tors (e.g., toxins), which then act as cofactors. While we are aware of this, other host factors that appear to influence organ susceptibility are not so well understood. It is interesting that antibodies may be general and circulating in serum or they may be purely local.

I showed this thirty years ago while investigating cases of infertil­ity, where sperm subjected to only one minute of contact with cervi­cal mucin died, but would survive a whole night in the female's serum. When a viral infection occurs in a family, one member may have cardiac and another CNS involvement, while the others remain free of illness. Thus a single agent may be responsible for differing syndromes. This may be explained by "local cell surface" acting anti­bodies with specific organ-protective qualities, but these antibodies also can vary over the years. Taking this into account, the differential diagnosis should not be taken to imply a different etiology. Another corollary is that identical causes, with differing syndromes, would re­spond to the same treatment. However, bearing this in mind, it is also important to see that multiorgan involvement may occur due to infec­tion; also, the involvement of one organ may have effects on other organs. 

This is well demonstrated in the hypothalamic region, which has a wide supervisory role, operated via neuronal and humeral mecha­nisms. Examples of these mechanisms can be seen more centrally in pituitary regulation, with its further effects from the thyroid, adre­nals, etc. to the apparently more distant regulation of bowel motility.

These factors make an exclusive title for an illness difficult. In dia­betes there is not just pancreatic involvement, because the Kimmel-stiel-Wilson syndrome, which involves multiorgan sequelae, shows how diffuse the effects may be. Also in anterior poliomyelitis other neurological involvement takes place apart from that in the motor system. Autonomic disturbance is perhaps the most frequent, and hy­per- or hypohidrosis, systemic hypertension, and gastric hypomotility or atony with constipation, as well as sensory loss due to the posterior roots of the cord being affected, have all been recorded (Plum, 1956). In my series, cerebellar ataxia, papilloedema due to increased intra-cranial pressure, and Reye's syndrome have also occurred in the acute infective stage of viral illness, and these conditions were also reported by Curnen and colleagues (1961) and Brunberg and col­leagues. The progression from the acute to the more chronic stage in all these diseases may not follow an orderly pattern either in time or organ location, which may be diffuse, and this is reflected in the ME syndrome.

We can briefly consider some of the factors involved in virus-host in­terchange. Viruses are intracellular obligate parasites, and the host mechanism has to recognize this if it is to deal effectively with the virus. The T cell population only recognizes antigen when it is displayed on cell membranes along with a cell marker. These markers belong to the major histocompatibility group (MHC). The T cells, if thus primed to the viral antigen, recognize and bind to it and the MHC molecule and commence to produce interferons (IFNs). Anti­bodies, complement, and polymorphonuclear leukocyte deal with circulating extracellular infection, while T cells, IFNs, macrophages, and NK cells deal with intracellular infection—in this case viral. This mechanism can be thwarted by so-called antigenic shift or drift. In the first, there is movement of genomic material, while in the second, there is a swapping of genetic material from reservoirs of different viruses. This could explain the way in which one infection reactivates a latent strain.

However, both local and systemic antibodies attempt to block the rep­lication and spread of viruses, either circulating or being shed from a cell that has been infected and killed. IgG is the most prevalent anti­body of the immunoglobulin system and is a potent opsonizing agent. The complement system of serum proteins is activated by IgM and later by IgG. They opsonize target cells for the phagocytes, which are then bound by IgM or IgG, and this is the classical pathway. Cells synthesize interferon when infected by virus; it is secreted into extracellular fluid and binds to adjacent cells. Interferon-alpha is de­rived from lymphocytes and interferon-beta from fibroblasts and other cell types. The IFNs acton certain cell genes that either catalyse or retard factors responsible for protein synthesis, which in turn re­duces mRNA translation, while another factor results in the degrada­tion of host and viral mRNA. The total result is to establish a sort of cordon of uninfectable cells around the virus. Thus, viral replication is inhibited. In mice if interferon is inactivated by an antiserum, they succumb to a small viral dose. IFNs have at least three roles—to kill vi­rus, to inhibit host cell division, and to modulate the activity of NK cells.

In ME, as with certain other viral illness, T cell dysfunction occurs, and Hamblin showed an increase in suppressor activity with T cell sup­pression of in vitro synthesis by normal B cells. Also, Caligiuri (1987) found 73 percent of ME cases had a decrease in the number of NK cells, and the T3 negative subset was reduced in 50 percent. This is in­teresting in the light of the foregoing remarks, and CD4 T cells migrate from blood to tissues in virus-induced disease as viruses are intra-cellular obligate parasites. The persistent viral infection cycle is com­plex.

There may be a primary acute illness that would qualify for a defi­nition, or it may be followed by a series of other symptoms that would require further definition. In some initial infections the primary stage may not be evident, including diseases as diverse as TB and even AIDS, among many others. All of this is true of ME. Thus a search for the origin may not be helpful and the continuing multiorgan effects may be confusing. Investigations for the continuing reason for this are a challenge. In considering these problems, the differential diag­nosis of the primary illness is obviously important, and in my series some of the final diagnoses arrived at are discussed here.

Acute illness may be as follows: Bornholm disease; viral meningi­tis or encephalitis; labyrinthitis; cerebellar syndrome; hand-foot-and-mouth disease; GI syndromes; pancreatitis; viral pneumonitis; spinal radiculopathies; nonspecific influenza-type febrile illness. In consid­ering the differential diagnosis, the following section is a brief and in­complete survey of variables.

Acute Presentations
• Bornholm disease, which may mimic gallstone or renal colic, torsion of bowel and pleurisy, or even myocardial infarction.
• Meningitis and encephalitis, which may be bacterial.
• Labyrinthitis is viral in most cases, but may mimic a basilar ar­tery insufficiency syndrome.
• Cerebellar syndrome may again mimic a vascular-mediated syn­drome.
• Hand-foot-and-mouth disease, with or without iritis, is usually viral, but erythema chronicum migrans (ECM) must be kept in mind as Lyme disease can closely mimic ME. Ixodes dammini, I have been told, exist in deer as near my area as Sherwood Forest. I have had one case.
• G.I. syndromes, e.g., gastroenteritis and also pancreatitis, may also be bacterial, toxic, or viral. Radiculopathies also occur and may have varied etiologies, but a viral cause should always be considered.
• Flulike illnesses may have varied and obscure causes. Serological titers often are not performed, although it may well be wise to do so for future reference, in case chronic sequelae occur.

Chronic Sequelae

The more challenging task involves chronic sequelae, which is particularly true in ME as the effects may be neurological, hormonal, autoimmune, or myalgic in varying degrees, and the latter may in­volve the myocardium. All of these may be discrete but also may oc­cur as an additive in ME, which of course tends to cause problems. Moreover, the difficulty lies in the fact that the pathogenesis of the acute stage might not have been accurately defined. Because of my interest, serological titers were usually performed on more than one occasion in those presenting with a well-defined illness as shown in the previous list, but some patients with a flulike illness did not pres­ent until secondary effects developed. In these, the definitive liters may have fallen and culture was often negative, but the VP1 test de­veloped by Professor Mowbray has proved of considerable value for suggesting ongoing enteroviral infection.

Conditions considered in this work, which again are not exclusive:

Brucellosis—This may be difficult to define, and only one was proven in this series. However, it can produce all the acute and chronic symptoms alluded to in this work. In the CNS, diverse spinal and cerebral syndromes occur, sometimes with paranoid delusions. Endocarditis may cause emboli with remote effects. 

As with toxins, this should be considered in those who work with animals. However, the ESR is high, and lesions may de­velop that mimic sarcoidosis. The ELISA IgM in the acute stage or IgG in the chronic stage should be assayed. Lyme disease—As with brucellosis, it is difficult to prove in the chronic stage, and I have only seen one, which was considered but never proven. Lyme disease causes ECM skin lesions in the acute stage, which may be confused with hand-foot-and-mouth (HFM) disease. In the later stage neurological, cardiac, and arthritic condi­tions may follow, as with viruses. Lyme disease, however, is due to a spirochete transmitted by ixodid ticks.

Tuberculosis—One was referred as ME but had a very high ESR, which is most unusual in ME. TB may have an obscure location, as was the case here, which was eventually shown to be renal. Carcinomas—Again, they usually have a high ESR. This is dealt with in another context in Chapter 8 and may be primary or se­quential.

Endocrine—This is dealt with in Chapter 5, but thyroid antibod­ies as well as diabetes can develop in these patients and be a complication in the ME syndrome.

CVS—Pericarditis, perimyocarditis, and myocarditis have all been noted in this series as discrete or additive. The additive cases still manifest the symptoms of ME after the cardiac condition resolves. CNS—A list of other syndromes that have followed well-docu­mented viral illness has been listed, but most, in my experience, can be excluded by careful examination, using MRI scans, etc.

Auto-immune—This is a difficult area, and autoimmune sequelae are well recognized following viral infection. However, they should be differentiated clinically as a separate entity or as an additive factor in ME.

Toxins—A small number have been seen and serologically proven. They can give rise to serious illness and should be borne in mind. They do have a depressive effect on bone marrow, which also occurs with viral infections. Jacobson and colleagues published the results of a good study in 1987. In these cases the serum folate was low, below 3 ug/L, which is the lower limit of normal. They reported that in half to three-quarters of all such patients, an unexpectedly low serum folate was found. In twenty-nine patients it was as low as 1.6 ug/L. Patients with nor­mal values had on average 5.8 ug/L. Folate is required for hemopoiesis and for the conversion of uridylate to thymidylate of DNA and for all other cells and tissues. It is necessary for the synthesis of purine rings and of RNA and proteins. All infection causes a bimodal response of the immune system in cellular multiplication and synthesis of immunoglobulins, both of which are folate dependent. Repair in pulmonary and skin lesions makes demands on folates also.

A high incidence of folate deficiency was found in those who had viral skin rashes. Also, Behan and colleagues (1985) noted this folate lack in cases of ME. However, thirty or more years ago I noted the association between folate levels and fetal abnor­mality, particularly in tissues deriving from ectoderm. Not infre­quently, this was also linked with a viral infection at or just before the time of conception. It is also relevant that insecticides have been incriminated in fetal abnormality. The question then arises as to whether virus or toxin lowers the folate to danger lev­els, or whether a low folate level allows the body to be suscepti­ble to infection. I suspect the former, but it still begs the question—Is it the virus or the low folate that actually mediates the neonatal pathology or adult illness?

The question is sometimes asked, "Do women with ME have an in­creased risk of bearing children with an abnormality?" The simplistic answer is "No." However, I did a study in a group of women of child-bearing age (seventeen to thirty-seven years) who had a viral illness with at least an eightfold rise in Coxsackievirus titer and had become pregnant or had developed the illness during the last trimester. In that study, 68.2 percent had normal children, but there was a rather high number, 31.8 percent, which were abnormal. 

Broken down, the abnor­mal cases included: two aborted (3.0 percent); six stillbirths (9.1 per­cent); eleven fetal abnormalities (16.7 percent); and two babies who died from cardiac complications (3.0 percent). However, I emphasize that this is not related to ME but does relate to the pathogenicity of the enteroviral group of viruses.

The important consideration, however, is that the syndromes out­lined may all cause chronic illness, and some may actually coexist with ME and have the same etiology, while others may mimic the condition. A very careful history written by the patient, which both saves time and is much more reliable than question and answer (which may be bi­ased), should, in most cases, define the issue. The exercise can alert us to the possibility of occult infection in conditions that may cause chronic malaise. The persistence of spirochetes and viruses should by now be well recognized, but the investigatory proceedings needed in some cases, in my opinion, require more intensive laboratory investiga­tions.

It may be helpful to review the "response to stress" and see the inter­play of neurological and hormonal activity, which can be seen as an "efferent" response by the host. By the same token, there is an "affer­ent" result from the response of the immune system. This integrated function determines the whole pathological scenario, felt by the patient and perhaps perceived by the medical investigator, but this depends upon signs, which are often less obvious than symptoms.

Friday, August 8, 2014

Sophia Mirza and Severe ME/CFS




August 8 is the birthday of Sophia Mirza, a British woman who died of ME at the age of 32.

Sophia contracted ME in 1999 after a "flu."  She never recovered her health, and by June 2000 was bedbound. Like many patients with severe ME, Sophia could not tolerate light, touch, or sound. She developed sensitivities to foods, and was unable to read, write, or even bathe herself. In response to her mother Criona's request for help, Sophia's GP, Dr. Firth, suggested that Sophia had made herself ill so she could "get attention."

Over the course of the next three years, Criona's attempts to have her daughter treated for ME were repeatedly thwarted. Dr. Firth referred Sophia to a psychiatrist, Dr. Baginski, who recommended a clinic that supposedly treated ME. When Sophia discovered that the treatment consisted of Graded Exercise Therapy, she declined.

At that point, the physicians involved with Sophia's case began to threaten Criona.
"I was told that if Sophia refused to go to Oldchurch Hospital in Romford, or if she did not recover within the following 6 months, that she would be sectioned under the Mental Health Act, then added that if I tried to stop this, then he, Dr. Baginski, would go to the courts to have me removed as the nearest relative. Furthermore, if I did not open the door when they would come to take Sophia away, that the police would be called to “smash the door down”. When I asked how much better Sophia would get by these proposed actions, the reply was given that it was “none of your business, that it was for the courts to decide”. The psychiatrist wanted to arrange for me to see a psychologist so that I could understand the good, that he, Dr. Baginski, was doing to Sophia. I refused." (Sophia and ME)
In July 2003, Dr. Baginski made good on his threat. The police smashed down the door and took Sophia to a local mental hospital, where she was placed in a locked room within a locked ward. During the weeks she was confined to the mental ward, Sophia did not receive even the most basic care. Her sheets were not changed, her blood pressure was not taken; she was never washed, and her bathroom was never cleaned. By the time Sophia was  released, the damage had been done. Sophia descended into a "hell-hole" from which she never recovered.

On November 25, 2005, Sophia Mirza died. The official cause of death was listed as acute aneuric renal failure (failure to produce urine) due to dehydration as a result of Chronic Fatigue Syndrome. A subsequent autopsy revealed that 80 % of the dorsal root ganglia of Sophia's spine were damaged. (This is consistent with active herpes infection.) The dorsal root ganglia are responsible for conveying sensory information to the brain, so damage to the ganglia would produce pain, sensitivity to sound, light, touch - all the hallmark symptoms of severe ME.

Other Sophias

Sadly, Sophia's case is not unique. Many patients diagnosed with ME or CFS are not only labeled as psychiatric cases, but are forcibly removed from their families to undergo "treatments" that only make them worse.

In 1986, Ean Proctor, a 12-year-old boy living on the Isle of Man, fell ill with severe ME. By 1988 he was confined to a wheelchair and could no longer speak. In spite of his diagnosis of ME, Ean was removed from his home after Dr. Simon Wessely decided that Ean was mentally ill. He was taken to a psychiatric ward in a hospital, where the staff told the boy that his parents were" letting him die." Because they did not believe he was unable to get out of his wheelchair, they let him soil himself rather than take him to the bathroom. Then they pushed him into a swimming pool, in the belief that he was faking his paralysis. Ean promptly sank to the bottom. After five months of legal battles, the Proctors finally got their son back, but not until they had nearly bankrupted themselves with legal costs.

Karina Hansen, a Danish woman, is still locked in a mental ward in Denmark. After more than a year of "treatment" her health is worsening, but the state will not release her, in spite of concerted national and international efforts.

David, a German boy who was struck with severe ME at the age of 15, was taken to a mental ward after his physician determined that his sensitivities to noise and light were psychogenic. At the clinic, he was forced to exercise. David was "traumatised" by the experience, and never recovered. At age 17 David died of a brain hemorrhage.

And on the home front, the recent case of Justina Pelletier's incarceration in a mental ward made national news. Her physical deterioration while locked in the ward could be documented, because the press got involved. Justina became a cause célèbre, to the point that two Congressmen have introduced a law that would prevent medical experimentation on children in hospitals.

These cases, while striking, are not isolated. How many ill children - and adults - have been stuck away in locked mental wards, to be abused, drugged, and ignored? And how many people have died, after years of medical neglect, from complications due to their illnesses?

What Really Killed Sophia Mirza

When doctors are unable to make a diagnosis they almost always place the blame on their patients. Perhaps in a society in which doctors were less arrogant, this would not be the case. But in our society - which has given almost god-like status to physicians - if a patient does not get well, it is because the patient does not want to get well. The subsequent psychiatric diagnoses saddled on these patients are numerous - somatoform disorder, factious disorder, Munchausen's - but they all amount to "I cannot figure out how to fix you, therefore you are to blame."

Once people are branded with a psychiatric disorder, they cease to be human beings. Their civil and legal rights are revoked, and they can expect no compassion. Psychiatric patients are isolated from friends and family, who are almost universally considered "enablers." They are drugged into a state of compliance. And rather than attend to their needs, which are considered part of their "illness," staff members can, on doctor's orders, legitimately engage in active abuse, which is justified by relabeling it as "therapy."

Cases like Sophia's, or Ean's, or Karina's, or David's, or Justina's raise some very important questions, one of which is "Should anybody, under any circumstances, be treated like that?"

Another question is "Who decides what is real?" What special training qualifies social workers, school nurses, and petty bureaucrats to determine what is and is not real? For that matter, which course in medical school trains physicians in the finer points of reality?

Sophia's decline can be directly attributed to active medical neglect. But as long anyone in an official capacity is allowed to make the determination of what is real and what isn't, the physicians and bureaucrats responsible for contributing to Sophia's demise will never be held accountable.

Who Decides What is Real?

The idea that an illness is not "real" arises from the concept that people whose illnesses cannot be easily diagnosed by physicians must be faking it. There is an inherent problem with this line of reasoning.

With a few exceptions, mental illnesses are "all in your head." There is no identifiable physical cause for the majority of them. They cannot be confirmed by a medical test, and there is no cure. The treatments are, at best, palliative, and, at worst, fatal.

Yet, insurance companies pay for treatments for mental illness. Why do they spend money on illnesses that are imaginary? And why do therapists have a 991-page manual describing these "not real" illnesses? If all one has to do is convince the patient that he or she does not have a real illness, why are there hospitals, clinics, hefty fees, and a pharmaceutical industry built around these illnesses?

Furthermore, if these illnesses are "all in your head" then why aren't evil eye and spirit possession included in the DSM V as well? If physicians actually believe that physical symptoms can somehow be created by the mind, why isn't there a diagnostic code for voodoo? Are there levels of unreality in which some unreal illnesses are more unreal than others?

Even more bizarre is the notion that if you believe that you have an organic (real) illness, but the doctor can't find a test to confirm it, then your belief that your illness is organic proves that it isn't.

That brings us back to Sophia Mirza. Sophia was diagnosed with ME, a neurological illness her doctors did not believe was "real." Eventually, Sophia's "unreal" illness killed her. Her autopsy revealed that there had been a real problem all along. Yet nearly ten years after Sophia's death, doctors still don't believe in the reality of ME/CFS. Nor will they ever as long as cultural myopia is permitted as an acceptable basis for medical opinion.


Tuesday, July 29, 2014

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. 
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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.

Friday, July 25, 2014

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.
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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.


Tuesday, July 22, 2014

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?
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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.

Friday, July 18, 2014

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.
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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.

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