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.



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

(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

(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.

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