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.
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.
