Chronic Fatigue Syndrome and its Connection to ADD/ADHD
delays, and revisions, this manuscript represents an attempt to
summarize much of the background and current literature to date
regarding this confusing phenomenon we call CFS/CFIDS and its
potential connection to ADHD in children (and adults).
this, I am attempting to help physicians, patients, educators
and others further understand this complex phenomenon. I have
attempted to separate what is "accepted" and/or verified
by literature publications, versus my "opinions" and
To all of
you reading this, I hope this helps add some insight and understanding
of the complex epiphenomena. To all of you who may have and are
suffering with this illness, I hope you will soon see an acceleration
of our clinical knowledge, such that successful treatment protocols
are available in the near future for all.
is often asked, "What can be done as patients." With
recognition by our medical establishment of the legitimacy of
this problem, they are encouragingly on a path to find answers
to verify or disprove clinical opinions and further basic science,
with an attitude significantly different from even a year ago.
This author believes the critical need for patients (via hopefully
corporate or private funding sources) is to accelerate steps that
will "jump-start" controlled therapies, while our medical
establishment searches for all the scientific answers.
I have said
too many times over the years, that in spite of the complexities
and uncertainties, there is an underlying logic that provides
for common sense and potential treatments in the near future,
providing for optimism rather than the ongoing pessimism one encounters.
There are good reasons to be optimistic, we all have to make things
happen - NOW.
Note: I wish
to thank my wife and family. While I would never wish this illness/syndrome
on any individuals, many times my wife and I have "kidded"
about the involvement and progress I have made thanks to her developing
this illness. Without my wife's participation and help, most of
my clinical research (in the midst of an ongoing Pediatric practice)
would have been impossible. My children, have been more than understanding
of the time required, along with helping edit and transcribe various
projects and papers along the way.
For the purpose
of this paper, the terms CFS or CFIDS (Chronic Fatigue Immune
Dysfunction Syndrome), the currently used and accepted nomenclature,
will be employed. However, it is the fervent hope of this writer
that in the near future the existence of an immune dysfunctional/dysregulatory
state will be commonly accepted, whether exhibiting fatigue or
not, especially in the case of juvenile patients. Perhaps we will
come to recognize that an immune dysregulatory state is a generalized
condition which may include many inner related phenomena, such
as CFS/CFIDS, atypical and/or typical rheumatoid disease, and
probably, parts of ADHD, Autism (particularly in high-functioning
or atypical patients), as well as other learning disabilities.
At the time
of this writing, what we call "Chronic Fatigue Syndrome"
is characterized primarily by chronic or recurrent debilitating
fatigue combined with other symptoms. These symptoms include,
but are not limited to, sore throat, lymph node pain and tenderness,
headache, myalgia, arthralgias, and an impaired ability to concentrate,
associated with short term memory loss. Sleep disruption, particularly
a non-restorative sleep, has frequently been associated with this
syndrome, as reported by other health professionals, as well as
my personal clinical experience. Non-restorative sleep and cognitive
dysfunction are frequently seen symptoms in children. During the
last century this syndrome has had many different names (figure
1). Since 1985, the Division of Viral Diseases, Centers for Disease
Control has responded to pronounced increases in requests for
information about Chronic Fatigue Syndrome.
single diagnostic test exists to define CFS/CFIDS, the current
definition is based upon a combination of signs and symptoms only.
According to the CDC's "original" 1988 definition (figure
2), Chronic Fatigue Syndrome is an operational concept designed
for research purposes. , Physicians and patients alike must recognize
it is not necessarily a single disease, but rather a group of
varying symptoms, comprising a "heterogeneous" mixture
of dysregulatory syndromes. As this goes to press, the new 1994
criteriahas just been released. In it (figure 3), CFS is defined
by "the presence of the following: 1) clinically evaluated,
unexplained persistent or relapsing chronic fatigue that is of
new or definite onset (has not been lifelong); is not the result
of ongoing exertion; is not substantially alleviated by rest;
and results in substantial reduction in previous levels of occupational,
educational, social or personal activities; and 2) the concurrent
occurrence of four or more of the following symptoms, all of which
must have persisted or recurred during 6 or more consecutive months
of illness and
must not have predated the fatigue: self-reported impairment in
short term memory or
concentration severe enough to cause substantial reduction in
previous levels of occupational, educational, social or personal
activities; sore throat; tender cervical or axillary lymph nodes;
muscle pain; multi-joint pain without joint swelling or redness;
headaches of a new type, pattern or severity; unrefreshing sleep;
and post exertion malaise lasting more than 24 hours."
to this day no single diagnostic blood test (or other test) to
diagnosis. One is left excluding other reasonable medical probabilities,
and without recovery over at least a six month period. Newer reports
at the AACFS/NIH (American Association for Chronic Fatigue Syndrome/National
Institute of Health) conference in Ft. Lauderdale, Oct. 1994,
are showing that as little as one month of abnormal fatigue or
prolonged illness may be
significant and suspicious. In this author's opinion, what initially
appears to be a confusing mixture of symptoms, is understandable,
when explained in terms of an immune-dysregulatory /CNS-dysfunctional
state. One must remain open to a variety of possible causes or
etiologies, perhaps expressed via common "end" pathways
in the body. For example, a patient who may present as psychological
or create physician "skepticism," may be understood
physiologically when analyzed in the context of an dysfunctional/dysregulatory
state. Specifically, one means an immune system that, for whatever
reason(s), is not returning the body to its normal homeostasis.
Fortunately, as more physicians have become familiar with this
syndrome, one sees that in spite of its unique qualities, CFS/CFIDS
has much in common with other immune-related diseases. Likewise,
Psychiatrists and Psychologists are beginning to recognize the
complex neuro-physiologic component in what has been labeled "
dysfunction before. (Note: There is and will likely always be
a "blurring" of "psychologic" vs. "physiologic"
dysfunction in medicine). Rather than the negative connotations
of the past, the interconnections and their further understanding
should help patients from whichever side of the spectrum they
diagnosis by the primary care physician is unlikely without knowledge
familiarity with CFS. In the absence of a single, definitive diagnostic
tool (figure 4), the
physician must always investigate the possibility of an underlying
disease. Routine laboratory studies, including a complete blood
count, sedimentation rate, urinalysis, basic chemistry panel (electrolytes,
kidney and liver function), thyroid screen (TSH and T4), autoimmune
disease screen (pursue further if indicated), and tests of muscle
enzymes (if indicated) should be performed to rule out other possible/probable
causes of fatigue. Patient history and a physical exam may indicate
that further studies are needed, such as sinus and chest x-rays,
pulmonary function tests, CT or MRI of the head, allergy skin
tests, B 12 levels or other metabolic markers, urine studies for
heavy metals, cardiac evaluation, or further neurologic testing.
It is very important for the physician to choose tests that eliminate
"probable" or "likely" derlying causes of
CFS/CFIDS, while striving to limit tests in number and expense
based on a logical
evaluation of the signs and symptoms presented by the patient.
definition" of CFS developed by Holmes et al.(figure2) in
1988 represented information gathered by investigators directly
from their own practices, as well as field research on the initial
outbreaks of this disease. But this has been in dispute and in
need of revision since its publication. As noted above, the new
1994 "revision" has just been published. It has been
the opinion of this author, and others, that there was potential
bias on the part of the researchers using the 1988 definition,
as perhaps as many as 50% or more of these cases cannot be traced
to an acute, epidemic out-break (this has been corrected in the
new edition). The CDC's definition was set up to initiate a basis
of scientific research, but it automatically overlooked all the
people who have had this syndrome for less than six months (although
fatigue may be the problem, it is acknowledged by many that symptoms
month, may be an abnormal state). It ignored the possibility that
some sufferers may continue to function in spite of the debilitating
symptoms they may bexperiencing (perhaps more
common in those one might define as gradual or insidious onset,
mildly immune dysregulatory, etc. . . acknowledge by dropping
of a specific amount of disability in the new version). And it
excluded most children, who seem to have different patterns, varying
with age ranges and immune system maturity (still a problem with
the 1994 revision). In fact, children generally start off healthier
and with more physical reserve than adults, a factor that may
logically explain some of the clinical variations we see in these
younger patients and even among adults themselves. In referring
to the 1988 CDC criteria, many authors often overlook the essential
"preamble". The CDC itself acknowledged that "this
definition is intended to serve as the basis for epidemeologic
and clinical studies of the Chronic Fatigue Syndrome." Although
it may be a
useful guide for the evaluation of a patient with a suggestive
illness, the definition remains sufficiently non-specific that
it cannot confirm or denthe diagnosis of Chronic Fatigue Syndrome
in an individual patient. Chronic Fatigue Syndrome remains a diagnosis
of exclusion, and physicians must continue to maintain a high
level of suspicion throughout the course of the illness for the
possibility that other more occult conditions may be causing the
symptoms. We will continue to search in vain for many occult conditions
until we are able to define and characterize this phenomenon further.
at the recent AACFS Conference in Ft. Lauderdale, Fl., many peer
reviewed surveys showed that the "strict" 1988 CDC guideline
might truly be only "the tip of an iceberg," and noted
many similarities between patients with fatigue or other immune
dysfunctional/dysregulatory/auto-immune illnesses, and those defined
as "CFS" by the CDC criteria. The new revision may be
much more practical overall, but there will likely still be controversies
definitions, flawed or otherwise, have helped lend credibility
to the concept of
Chronic Fatigue Syndrome. It's limitations and subsequent study
design faults have resulted in an acknowledged under-reporting
of its incidence in our society. In fact, it is likely that an
underestimation of the significance of the illness and dysfunction
caused by this syndrome has been occurring all along. The definition
implies such a heterogeneous group of patients, that refinements
are clearly necessary to distinguish potential sub-groups for
further evaluation and study, as well as treatment protocols.
It is unlikely that any study of treatments or treatment protocols
for "CFS/CFIDS" patients will yield "statistically
valid" results without first defining more pointedly the
population we intend to study. This factor of heterogeneity probably
explains many of the conflicting results in the published studies
of this syndrome to date.
has gone by different names, in different outbreaks dating back
to the 1500s. Many authors, have published books and articles
that consider the interlinking of various "outbreaks."
The most recent occurrence of groupings probably started some
time in the early 1980s in New Zealand (figure 1). In 1984, what
was called the "NK syndrome" was defined in Japan.,Many
physicians recall the major medical announcements at that time.
It was believed that researchers in Japan had detected a "new"
syndrome with no known viral or
bacterial cause. The primary characteristic present was low NK
cells,along with a general dullness of the patients, with loss
of interest in both physical and mental activities. Subsequently,
epidemics of CFS/CFIDS/Myalgic Encephalomyelitis were reported
in Australia and New Zealand. An outbreak in Lake Tahoe fostered
recognition of CFIDS in the United States, followed by outbreaks
in Philadelphia, Canada, England and Lyndonville, New York, among
others. This world-wide phenomenon seems to be continuing, rather
than subsiding as in the past.
As a clinician,
I have witnessed this phenomenon evolve within my own office practice.
Prior to 1988, I was not familiar with the terms Chronic Fatigue
Syndrome, CFIDS, or any such names. I recognized the presence
of an illness pattern, appearing in my pediatric patients and/or
their families in varying numbers that was unpredictable from
past experience. The symptoms affected my spouse, as well as parents
and children within my practice. The recognized epidemics are
significant as they have raised the question of whether specific
triggering agent(s) may exist in any given group of similarly
affected patients. However, as noted, large numbers of patients
have developed this illness independent of any epidemic and without
a specific recognizable triggering agent or cause. Many patients
seem to have a long-term insidious onset, which may finally lead
to an acute exacerbation or flare-up. However, other patients
report that they were totally well before an acute, often flu-like
illness, from which they uld not recover, suddenly overtook them.
At the recent AACFS conference in Ft. Lauderdale, it was noted
that we may be looking at different morbidity patterns and different
clinical patterns/courses between "acute" vs. "chronic"
onset patients. Prognosis and long term outcome may differ between
these two groups, emphasizing further the need to better define
this "heterogeneous" mixture we call CFS/CFIDS.
We have been
perhaps the last "academic" country in the world to
finally accept the existence of this syndrome. The amount of suffering
and morbidity associated with this syndrome is probably enormous.
Newsweek, back in 1990, quoted estimates of at least five to ten
million people in the U.S. affected by this disorder, with an
estimated one million in Los Angeles alone. Researchers familiar
with this syndrome quote a possible clinical occurrence rate at
3% - 5% of our population (or higher !). Currently epidemiologists
are finding incidents of 1 - 1.5%, acknowledging probable under-reporting.
We urgently need to implement a "controlled" database
and research tools to help define and control this disorder as
rapidly as possible.
many reports, particularly in the British literature,suggesting
a connection to the coxsackie/enteroviruses. While in the USA
it has been suggested that many cases may be linked to the Herpes
family of viruses (i.e., EBV, HHV6, HHV7, CMV, etc.)., , , , Neither
theory has been conclusively proven, nor has any contagability
been demonstrated, although some have inferred it based upon the
incidents of epidemic outbreaks., If an infectious etiology indeed
exists, it may be as ordinary as the common cold, or so rare that
we have not yet developed the tools to either identify or study
it. Based on my twelve years of office
observation and clinical experience, if there is indeed a period
of contagability, this author doubts that it occurs during the
chronic state, or even during the "acute" period, after
2 weeks to 2 months, if at all. Having once been triggered by
an illness, agent, trauma, combination of stresses, etc., irrespective
of any underlying cause, it is the inability of the immune system
and/or CNS (Central Nervous System) to return to a normal homeostasis
that probably best explains the clinical duration and variability
of this syndrome. Whether any agent remains or is ongoing is subject
to clinical speculation. This author tends to believe there will
be some patients in which a background virus, retro-virus, or
"stealth" virus may play a role, but there
are likely to be many patients in an immune dysfunction/dysgulatory
state in which no specific agent (or factor) continues to affect
seem likely is that we are confronted with an illness that has
multiple etiologies, multiple origins, and various clinical manifestations.
Genetic predisposition to this syndrome may have a great deal
to do with why certain individuals suffer these symptoms. What
we recognize to be heterogeneous expressions may be linked, or
even treatable, via the common pathway of an immune dysregulatory
/ CNS dysfunctional state. Outbreaks of this syndrome have been
observed as occurring in clusters larger than those reasonably
explained as chance, therefore compatible with the notion of a
transmissible etiology. Current research suggests the
probability of a retro-viral like agent, or another new, unknown
virus, that possibly
predisposes (or acts in "predisposed" individuals) some
people to this syndrome, and/or
simultaneously functioning as part of the ongoing illness in others?
An alarmingly rapid and sustained increase in cases over the last
ten to twelve years strongly infers a common environmental cause
or possible co-factor. Perhaps the decreased protection of the
ozone layer is creating new viral mutations and/or a generally
altered immune state. The concept of a world-wide onslaught of
immune compromised/dysregulatory state is quite plausible, as
evidenced by multiple incidents affecting humans as well as other
species that have been reported over the last decade.
this could be a primary psycho neurosis are defeated by several
factors: the similarity in the patients' descriptions of their
illness, the increased clinical associations of signs and symptoms
as a group consistent only with this type of illness, and in "acute"
onset patients, the similarity in how their symptoms first appeared.
Patients, particularly adults, tend to give similar descriptions
of the onset of their illness. A majority of these patients express
the suddenness with which they were overtaken by the symptoms,
having felt perfectly healthy before then. However, it should
be noted that sudden onset does not seem to be the most common
initial presentation in children. This "previous state of
wellness" should be scrutinized with a detailed medical history.
The concept of "well" may be a particularly difficult
term to apply to children, who may lack prospective as to what
is normal. In fact, as noted above, upon further investigation,
a large number of adults, adolescents, and chdren report recurrent
minor illness, a childhood history of significant allergies, particularly
to food or obvious
environmental factors and/or a degree of fatigue or "laziness"
when compared to their friends or siblings. None-the-less, in
what might be termed the more acute onset or "activation"
patients often remember the exact day they developed a simple
"cold" or "flu", accompanied by a sore throat,
cervical adenopathy, myalgia, fever, recurrent gastrointestinal
symptoms and profound fatigue which then developed into this syndrome.
By now a predictable
pattern has emerged within my own practice, and that of others.
This pattern includes increased allergies, ear infections, pharyngitis,
bronchitis, and recurrent minor illnesses. In this author's opinion,
the agent that triggers this in acute cases may be infectious,
but is probably one of thirty or forty different agents. Some
people who are predisposed to this syndrome may go into a CFIDS
like state, while many people may be adversely affected by exposure
to a particular agent for a finite period of time, usually a few
weeks, then return to "normal".
It seems probable
that this disease has an element of genetic predisposition (confirmed
in emerging epidemiologic studies). In following a number of families
in my practice, not all members of the same family become ill.
Often one child and/or one parent alone is affected. This likely
implies a lack of ongoing contagion, if any, associated with this
syndrome, suggesting genetic predisposition with probable multiple
triggering agents or events. These can include viruses, stress,
various traumas, etc., setting off a state in the body in which
the immune system, the CNS, or both, do not come back to a normal
What is the
origin of this illness? We may find thirty or forty different
factors can be involved. This writer wonders if CFIDS is not an
actual virus, but rather an altered response to a changing environment
or agents, which are probably acting as cofactors. Are we reacting
to ozone layer depletion? Is there some other environmental condition
creating or bringing out a genetic disposition for this phenomenon
in an increasing percentage of the population? There certainly
appears to be reason for great concern. Why are we experiencing
such high levels of this syndrome? Why did we start with an epidemic
some time in the late '70s, early '80s that, unlike past epidemics,
has never stopped?
At an International
Conference on PVFS (Post Viral Fatigue Syndrome, before name
change) years ago, Dr. Byron Hyde from Ottawa, Canada, identified
this syndrome as an overlooked epidemic in children. He noted
that children generally have been excluded from documented studies.
Dr. Hyde said, "It is evident we are not recognizing these
children: they are there. They are there in large numbers. Depression,
loss of energy, retardation of thought process, impairment of
concentration, etc. These may be dyslexics, children that were
getting good marks in grades six and seven, come down with a minor
viral infection, and then become school problems. They sometimes
get kicked out of school, sometimes sent off to psychologists.
Parents do not believe these kids, the doctors definitely don't.
Frequently physicians may start blaming the parents for harassing
or injuring the child in some way. Impairment of memory, disorders
of sleep, the behavioral disorders are typical of the changes
you see in children." Theurrent rise in attention to Munchausen
Syndrome or Munchausen Syndrome by proxy in the Pediatric literature
lends credibility to Dr. Hyde's worst fears. How many of these
parents are being falsely accused? How many of the children themselves
are labeled as malingerers or hypochondriacs? One can only wonder
with dread how many suffering from a very real physiologic dysfunction
are not receiving any treatment or support from their families
or the medical community.
physician, educator, or counselor should be suspicious about the
active child who has lately become a couch potato (figure 5).
It is often a child who has
recurrent illnesses, sinusitis, ear infections, bronchitis, and
who does not feel well on
weekends, as well as school days. These children will complain
every day and lose the time they should be devoting to valuable
play activities. Frequently in my practice a parent does not recognize
a decrease in play stamina, but rather the increase after treatment.
In retrospect, it seems evident that these children were not functioning
at their full potential, but it is a very difficult judgment to
make in children. How can the average parent know what is their
child's "full" potential?
problems may be a primary symptom of CFS, particularly in children.
children frequently experience difficulties in the school environment.
They are typically unable to concentrate and demonstrate lack
of memory skills. A common presentation is a child who is able
to read a book, but cannot recall what was read, or a child who
cannot remember what was said immediately after the teacher has
delivered a lesson. One can appreciate what this has done to a
child's self-image when applying the descriptions of this syndrome
we have heard from its adult victims. Imagine a child who knows
he is doing poorly in school, but has no basis for understanding
why. It is a very frustrating situation because CFS/CFIDS children
truly want to succeed. They want to go out and play and do all
of the things they see their peers doing. Eventually, they lose
hope in doing well and may even become behavior problems. As Dr.
Hyde has noted, they become difficult kids and may eventually
turn to drugs, and evesuicide (Perhaps we will come to learn that
this syndrome partly underlies the increased adolescent drug use
and suicide we are experiencing today). If their physiologic dysfunction
remains undetected and untreated, it is unlikely counseling or
therapy alone will be
very successful. One must always be suspicious regarding any change
in physical or behavioral patterns that fall outside the range
of what we accept as "normal". These children tend be
very anxious and clinging. They typically have poor self-esteem
and have an understandable reluctance to attend school as a result
of the constant failure they have suffered there. These children
will often adopt an attitude of lassitude as a facade. They frequently
have a disturbed sleep pattern and experience nightmares, restless
sleep, and/or a "non-restorative" sleep. Sometimes a
change in body weight is observed. They have, in the past, been
diagnosed as depressed, lazy, or under-achievers. Often parental
"over-involvement" has been blamed. As noted ove, how
many of the cases being referred to in the Pediatric literature
Syndrome (or Munchausen Syndrome by proxy), may truly be undiagnosed
history may suggest signs of cognitive dysfunction, particularly
lack of focus,
inability to concentrate on school work, perhaps the label of
"quiet" ADD/ADHD (Attention Deficit Disorder). Almost
all recent academic pediatric articles have focused on the high
incidence of school dysfunction, school absenteeism, and need
for home tutoring; often defining these problems as secondary
to the physical dysfunction, rather than arising from a primary
cognitive dysfunction. Fortunately, the majority of recent articles,
while they do not understand this phenomenon in children, have
generally noted the probable legitimacy of many of the patients
followed, and ruled out other diagnoses (including psychological)
over time. It is worth noting that over time, very few of these
patients go on to "another" diagnosis or explanation.
A past history
of allergies might actually be an indication of the early dysfunctional
stages of CFS (as discussed here in terms of an immune dysregulatory
state/epiphenoma), or at least a reason for increased suspicion.
Allergic patients often experience decreased host defenses to
an infectious agent, with increased immunologic responsiveness,
which is sometimes genetically rooted. Because allergic patients
have T-cell abnormalities, an inference can be made that a propensity
toward immune dysfunction may be involved with the pathogenesis
of CFS. CFS/CFIDS is quite possibly linked to "The Allergic-Fatigue
Syndrome" that is currently ascribed to environmental agents
or factors. The concept of a common expression of an
immune dysregulatory / CNS dysfunctional state may promote greater
understanding of this strange epiphenomena called CFIDS. It certainly
seems to be the only logical interpretation available to us given
our current information. When viewed in this context, CFIDS' multiplicity
of symptoms a clinical progression can be put into a logical pattern.
Perhaps it will overlap to many "idiopathic" or "auto-immune"
processes discussed in the medical literature of today, linking
many otherwise conflicting reports.
symptoms may also be significant in the history of the CFIDS sufferer.
Not the typical "growing" pains, but limb/joint pains
not classifiable into any of the established or typical Rheumatoid
patterns. This is especially significant when these symptoms are
present following a known viral URI (Upper Respiratory Infection),
flu, or mono-like illness.
children with various expressions of this syndrome, fatigue may
not be the
primary complaint. Children in general have much more physical
reserve than adults. There may be no obvious physical limitation,
or often, one that may become obvious only when the child improves
with therapy. This is a very key issue to understanding this syndrome,
especially in children. If looked upon as a stressful state or
ongoing immune/metabolic dysfunction, there will be different
expressions of this stress and in general, children will tolerate
the "physical" manifestations better than adults. Normal,
healthy children are generally active. They want to be active
and they have lots of the necessary energy. One characteristic
of the differentiation of this syndrome in children versus adults
is that the affected adult usually has a very clear lack of energy.
The child who may be a little slower, a little less active, but
still almost always has sufficient reserve to keep up with their
peers, because, on the average, their
younger bodies may be viewed as healthier than their adult counterparts.
In fact as severity increases and a child or adolescent cannot
keep up with their peers, maintain normal attendance at school,
etc., there may be secondary esteem and ego issues compounding
the intellectual dysfunction caused by CFIDS, sleep disturbance
appears to be a major indicator. Common complaints are very restless
sleep, absence of dreams or strange dreams, and awakening tired.
One can sleep 6, 8, 10, or even 12 hours yet awaken feeling tired
due to what is called "non-restorative" sleep. Researchers
have shown that patients with Chronic Fatigue Syndrome do not
go into a normal stage IV or REM sleep cycle. Such a patient will
experience difficulty in forming memories and in other "restorative
functions" due to this loss.
It is critical
that we learn to define and recognize this phenomenon in children.
In spite of my familiarity with this illness, even I thought Dr.
Hyde must have been exaggerating when I first heard him speak
on this subject. Initially, I found some of his conclusions almost
"far-fetched". But, as time has passed, it has become
obvious that Dr. Hyde was not overstating the case in the slightest.
The potential cost to children suffering from this dysfunction
is staggering, and is quite likely the culprit underlying many
scholastic problems and social failures.
may reveal no obvious or remarkable evidence of classical illness.
A common presentation is recurrent swollen lymph nodes with or
without a low-grade
temperature elevation or depression. Patients may have abdominal
pain, muscular or skeletal pain or discomfort, and/or tender points
such as that associated with fibromyalgia (it remains this author's
opinion that fibromyalgia and CFIDS are disorders reflecting varying
clinical expressions of similar or even the same epiphenomena).
An abnormal oropharyngeal exam is quite typical, frequently described
as a "red crescent". Lately there is increased reporting
of dental gingival disease, likely representing a chronic, low-grade,
gingivitis, stomatitis in many of the more chronic patients. Oral
thrush can be a marker for Candida in some of the patients. One
may observe frequent incidences of atypical rashes. There may
be occasional balance problems, and patients may exhibit fine
motor signs or "soft" neurological signs. Usually no
siificant neuro-muscular pathology is uncovered by standard exams.
be signs of recurrent allergies (boggy nasal turminate, nasal
mucosal redness, "allergic shiners," etc.) or mild/moderate
bronchospam, restrictive airway disease. This airway dysfunction
may be secondary to recurrent infections or secondary to reactive
titers to EBV, CMV, Herpes VI or VII, and abnormal lymphocyte
surface markers for T cells, B cells, and NK cells are frequent
findings in CFS patients.
Immunoglobulins and IgG subclasses are abnormal in 40% to 70%
antibodies to a retro-virus have been reported in 41% of CFS patients
compared with 6% of healthy controls in one study. The "contribution"
of a retro-virus is disputed by other authors,and remains an area
for technology and appropriate studies to further define. If one
observes an elevated titer of antibody to a particular virus (or
retro-virus) at the time of diagnosis of CFS, it is not possible
to identify which factor appeared first nor which of the two,
if either, might play a causal role. The scattering of reports
and lab results has contributed to the confusion surrounding this
syndrome. If examined within the context of an immune-dysregulatory
state, with potentially varying degrees of expression and different
possible origins in various patient cohorts, one can begin to
make sense of these different reports. It seems more and more
likely that we will be able to understand these variables only
under the auspices of a controlled database.
about adults, one finds reports of low and/or elevated natural
killer cell activity., There may be a change in T-4/T-8 ratio.
Patients may exhibit activated/abnormal T-cell subsets, abnormal
immunoglobulin levels, IgG subclass abnormalitie, altered Interleukin-2
activity (generally assuming an elevated Interleukin 2 soluble
receptor), and various other interleukin/cytokine abnormalities
which have been reported. There may or may not be elevated alpha-interferon
levels, plus or minus elevated rogi cell assays, possibly a weakly
positive ANA. There have been reports of a decrease or anergy
in skin testing for delayed hypersensitivity (the part of the
immune system responsible for dealing with fungi and similar pathogens).
Atopy ("hypersensitivity " due to hereditary influence)
may be a predisposing
factor, as it appears to be present in up to 80% of patients with
CFS. The salient feature that is repeatedly seen throughout this
process is that of a dysfunctional/dysregulated system, operating
with various degrees of activation or impaired reception, or inactivation
with decreased functi. The wide range of results may be explained
by the changing status of the patient and at which stage of the
disease process they are tested. Work is underway by Dr. Nancy
Klimas, to define "patterns" of cytokine abnormalities,
as a means to further define and understand various patient groups.
findings in children generally seem to be similar to those found
However, there remains significantly less clinical experience
with children in grouping of
immune patterns. The physician may observe low natural killer
cells and low Immunoglobulins (particularly IgG, IgG subclasses,
and/or IgA). As noted, various viral titers have shown mixed results.
Testing may show activation or inactivation of the immune system
(figure 4): It has been this author's observation to find some
patients with elevated IgM (a possible marker of viral/immune
activation) or elevated IgE (perhaps reflective in some patients
of increased allergies).
tests on adults and children vary. Looking at routine lab tests
in children and
adults, one may show elevated Cholesterol, a sign of mitochondrial
elevated liver functions, a possible indication of viral irritation,
inflammation, or other liver dysfunction. Abnormal elevated TSH
or low T4, reflecting thyroid dysfunction (often assumed to be
present clinically but difficult to measure peripherally), and/or
thyroid antibodies, a sign of auto-immune thyroiditis, may be
seen. Overall, one looks for "soft" signs of metabolic
dysfunction, but we still lack a diagnostic or classical pattern
to define a patient with this illness. There have been reports
of abnormal viral DNA particles identifiable by PCR probe technique
and abnormal muscle biopsies,, , although these are somewhat limited
tools surrounded by controversy.
existence of CFS/CFIDS appears best supported objectively by evidence
abnormal NeuroSPECT scans in sufferers, (author's work with children,
pending publication). Pathways with decreased blood flow apparently
have decreased function. A study by Dr. Jay Goldstein and Dr.
Ismael Mena, has shown, using a controlled population of normal
adults and adults with CFIDS, that they are clearly not the same
as adults with depression. CFIDS is not depression, although patients
with CFIDS can obviously have a reason to be depressed, and may
have some overlap of areas on NeuroSPECT. There is a quantifiable,
statistically significant difference that is physiologic, not
psychologic, in origin.
findings on NeuroSPECT scans help to confirm dysfunction and show
patient's CNS/brain is not functioning properly. What is very
promising is that the results can be altered with intervention.
So far, most brain malfunction seems to be reactive, and the SPECT
scans improve when the body becomes healthier. None-the-less,
there is preliminary evidence that permanent damage may result
from prolonged malfunctioning, confirming this author's belief
that this is not a benign process. There is a potentially significant
loss to adults and children who are afflicted by this disease
that only an accelerated research effort can mitigate.
an increasing number of psychologists and psychiatrists now recognize
CFS/CFIDS does not have a psychological origin as it does not
reflect the typical
presentations of classic fatigue or depression, confirming the
likelihood of an organic basis for the disease. Additionally,
children are less frequently known to present with psycho-somatic
illness than are adults.
It is this
author's opinion, that unless one wished to hypothesize a "mass
psychosis", the similarity of presentation in many patients
cannot be conceived as psychologic in onset. This is being supported
by research projects (works in process, presentations at the Ft.
Lauderdale, AACFS conference) confirming the differences between
patients with CFIDS, normals, patients with major depression,
and some patients with other immune related illnesses.
PLAY A ROLE?
between CFS/CFIDS and Candida, or other yeast, is not yet understood
in the medical community. There is no standardized test to date
for verifying or confirming the notion of a yeast overgrowth and
its potential adverse side-effects. As with CFIDS itself, the
general medical approach to this area has been a reluctance to
consider any possible explanations that cannot be measured. While
it has yet to be proven, it seems none-the-less logical to this
author that the presence of Candida or other opportunistic organisms
in CFIDS patients, while not likely the cause, may certainly contribute
to the dysfunction experienced by the patient. Yeast-like breath
or a distinct sour milk breath smell may be a clue in a child
or adult that a yeast over-growth has occurred. While it has been
correctly argued that yeast is abnormal G I pathogen in most humans,
this author strongly suspects that Candida/yeast may
take the form of a pathogenic overgrowth in a patient who is in
an immune dysrulatory state, specifically in the case of CFIDS.
there have been numerous reports of decreases in delayed-hypersensitivity
CFIDS adult patients. Significantly, this is the part of the immune
system responsible for
controlling yeast and other such pathogens. Assuming then, that
Candida may be a part of the CFIDS syndrome in some patients,
it is most likely a secondary opportunistic infection and not
a primary cause of illness. It is very doubtful that a patient
with CFIDS is compromised enough to allow disseminated fungal
conditions. Instead, in some cases, one may observe a G I or chronic
vaginal overgrowth. The GI overgrowth could potentially interfere
with a patients normal flora, GI function, and absorption of nutrients;
and/or as some researchers hypothesize, there may be a release
of toxic metabolic products, with direct effect on a patients
CNS. The later theories are receiving some support by the early
reports of abnormal metabolic products in the urine of CFS/CFIDS
patients. Regardless of the theory, treating Candida often does
seem helpful in returning the body to a normal state. Final answers
will await appropriately
controlled studies, and the techniques and measurements to perform
At this point
in time any discussion of therapies must be deemed antedotal.
Currently, there are no agents that have shown success consistently
in trials. None-the-less, there is an emerging base of clinical
experience that can serve as a rational approach to therapy as
we await more definitive conclusions. Ultimately, depending on
evolving physiology and ultimate etiologies, we will one day likely
have various immune-modulators at our disposal. Possibly they
will include direct anti-viral agents or other specific agents
to use as therapy for this condition. Progress will only occur
in the context of a clinical database and controlled trials using
defined patients. The rapid establishment of a clinically- oriented
database is critical to enable true evaluation of therapeutic
agents. It is important to note that the discrepancies among patient
samples will likely be resolved and understood only as we develop
tools to define similarities or common patterns within this heterogeneous
syndrome. Build in upon principles applied recently in approaching
HIV and other illness, an essential goal must be to inspire clinical
cooperation among health professionals. By working together via
inter-relational database, it should be possible to accelerate
the development of methods or patterns for identification and
separation of patient groups. This will be made possible the application
of "controlled" therapy trials for the benefit of sufferers
of this syndrome/epiphenomena.
a therapeutic approach, the physician should start with the easily
identifiable issues and proceed further as indicated. It is logical
to deal with the areas of dysfunction in which we are experienced
and then "see what is left over". This author would
emphasize the need for
treating the overall "well-being" of a patient, rather
than just the symptoms. My experiences have guided me to formulate
a treatment approach wherein I address whatever dysfunction(s)
I possibly can. The goal is to maintain maximum function until
the body, with or without medication, can return to normal.
When one or
more family members are affected with this syndrome, it is a primary
requisite that they receive understanding and support from the
rest of the family system. As noted previously, the medical system's
resistance to respond to this condition, through lack of understanding,
has caused untold amounts of family problems. This is especially
stinging when the strife results from the incorrect advice of
the primary health care-giver or a specialist who lacks knowledge
about this syndrome. This author has seen repeated examples of
children and adults who have shown dramatic improvement with the
recognition of their condition and some "supportive"
therapy, both medical and social.
modalities of what might be called "supportive" therapy,
we have antibacterials, antifungals, antivirals, antidepressants,
antihistamines, anti-inflammatories , vitamins, minerals, and
other "nutritional" supplements. Any or all of these
may aid the effort to bring about a return to normal functioning.
The concept of trying to "normalize" and improve body
functioning in an orderly, logical manner, has served this author
well over the years. While specific/directed modes of therapy
are on the near horizon, many patients can be helped while awaiting
ultimate answers. In many cases, children and adults have become
"well" as their immune system was able to "stabilize"
itself, after some "help". It remains this authors overall
optimism that successful therapy is currently possible, and can
become simpler and likely more
specific in the near future.
very likely that allergies have a major effect on adults and children
symptoms. Patients frequently present with a history of allergies
and/or recent allergy
exacerbation's as part of their symptomatology. My experience
and that of many other
physicians suggests that vigorous effort be made in the direction
of supportive therapies
involving allergies. The less the body's immune system is triggered
negatively, the easier it may be to return to a state of normalcy
or balance. Elimination diets have served as a major role in therapies
used in my practice over the years. A patient with a turned-on,
dysregulated immune system may be sensitive to any number of environmental
or nutritional antigens. While one cannot always control a sufferer's
environment, we can exercise control over foods ingested. Immediate
and intense attention to eliminating food irritants cannot be
stressed too much. In tandem, I recommend the aggressive use of
low-dose, overnight antihistamines (to control PND - st Nasal
Drip), and inhaled nasal or bronchial sprays when indicated. By
course of action, one can frequently minimize recurrent episodes
of sinusitis, otitis, bronchitis that frequently plague these
patients. Antihistamines used thus become allergy mediators. Taking
a low-dose antihistamine at bedtime will often stop postnasal
drip. If postnasal drip can be stopped, and/or other sources of
congestion controlled, sinus and ear infections and their symptomatic
headaches may be reduced. It has been my experience that much
of the shortness of breath patients experience can be controlled
by judicious allergy avoidance and appropriate bronchial sprays,
and by treating secondary bronchitis/infections when indicated.
particularly Prozac, Zoloft, Paxil, and Wellbutrin, have been
used for a
number of years by clinicians working with CFIDS patients. Antidepressants
can and do play a role, but not because people afflicted with
this are depressed or "depression" in origin as has
been so often falsely assumed. At low doses, Prozac, Zoloft, Paxil,
and very possibly Wellbutrin or BuSpar work on those areas of
the brain that are decreased in function as shown by NeuroSPECT
scan (clinical reports). Contrary to those physicians who have
tried to imply that their use indicates that CFIDS is a depressive
disorder, we actually find that most patients were normal (or
high functioning) adults and/or children prior to the onslaught
of their illness. Certainly, as acknowledged by even the CDC and
NIH over the last few years, and confirmed by reports looking
at different "populations" of patients, patients have
a basis for developing depression as a result of this illness.
As long as the depression is not "preexisti" (open to
interpretation), it is not very likely the cause of the illness.
Nor does its presence exclude a patient from the new CDC definition.
physicians have used Sinequan (Doxepin hydrochloride), Desyrel
(Trazodone HCL), Tofranil (Imipramine HCL), Elavil (Amitriptyline
HCl), etc. to induce sleep at night with various degrees of success,
there were clinical reports years ago about "success"
using low dosages of Prozac in the morning to help sleep problems.
Prozac, Zoloft, and Paxil may help to stabilize/normalize a part
of the central nervous system dysfunction associated with this
illness. Prozac has been demonstrated to actually increase blood
flow in areas that have been noted to be under-perfused on NeuroSPECT
scans. While not widely publicized, Prozac was reported to be
an immune-modulator at low dosages in its early days of use. When
of this several years ago, I became much more comfortable about
prescribing Prozac, both with children and adults, since it appears
to have a directly beneficial effect, and does not imply "medicate"
the symptom. Addressing the issue of sleep dysfunction and, to
some degree, cognitive dysfunction, suggests the use of these
agents as first choices inadults and, increasingly, in children.
While I do not regard these medications as a cure, they may be
a useful tool in helping to restore function to areas of the brain
that are dysfunctional. However, these medications, as in all
cases, should not be used if any negative effects are noted. As
this is a long-term condition, the clinician must avoid any agent
that creates negative or potentially negative effects. An individual
should not stay on a medication that does not agree with them,
choosing to avoid such agents, particularly in children. Long-term
safety and side effects must always be of concern.
consistent with the above approach and clinical experience, there
were a few reports at the recent AACFS conference showing that
a patient being on a tricyclic type of antidepressant showed no
change on the
parameters being evaluated. As part of this overall approach,
this author cannot over stress the idea of trying to help "normalize"
function, not just put a "band-aid" on the symptoms.
has shown that afflicted patients can avoid some of the typical
"down time" if secondary infections are treated as early
as possible. Swollen glands, redness, and pain in the throat should
not be accepted as just part of the CFIDS profile. I consider
any antibacterial or antiviral therapies to fall under the heading
of supportive therapies at present. If the body is trying to fight
an infection with a compromised/dysregulated immune system, clearly
it needs the help of supportive resources. Antibiotics are indicated
to help fight recurrent sinusitis, pharyngitis, bronchitis, etc.
Antibiotics should always be used judiciously, choosing the most
specific medication that will work. Frequently, based on findings
or blood count, a course of Erythromycin (a unique, bacteriostatic
medication, it "paralyzes" the function of many organisms,
but the body must finish off the "killing", thus being
less disruptive to the bodies normal flora/organisms), or perhaps
a heavier antibiotic, can help reversehese "low" periods.
It has been my experience, that many "flare-ups" of
this syndrome seem traceable to the stress of an infection, and
there has been a notable improved recovery for patients who are
treated for this "stress". Often when I see a red throat,
cervical adenoapthy (frequent flare-ups in patients), I turn to
the use of Erythromycin with good success. With a lack of controlled
studies, one must individualize treatment to each patient. However,
in all cases the physician
should respond rapidly to secondary flare-ups and discourage the
patient from accepting them as unavoidable or untreatable.
antivirals have their place as "supportive" therapy.
Depending upon blood count, viral titers, clinical symptoms, etc.,
there may be applications for Zovirax, Amantadine, Flumadine,
and others. As always, clinical judgment, safety, and individualization
are essential. There are multiple antedotal stories of agents
helping, and there are times when these agents seem to be very
helpful. Again, subject to conflicting reports about various treatments,
we will one day be able to define this "heterogeneous"
epiphenomena we call CFS/CFIDS, and thus evaluate under which
circumstance or within which group of patients an agent may be
helpful. Without this "subdivision" of patients, most
therapies are likely to remain confusing and of
questionable significance, even if very helpful within a sub-group
of this disorder.
category of symptomatic therapies are nonsteroidal anti-inflammatories
and other analgesics. Physicians have prescribed these agents
for the last 20-30 years to treat muscle pains, body aches, joint
and bone discomfort. They are still used to routinely treat patients
with rheumatoid diseases, symptomatically, not "long-term"
curatively. To this day there remains no "cure" for
most of these diseases. On a short-term basis this approach relieves
some pain and, certainly in regards to an arthritic process, may
help slow down or minimize long term damage. The treatment of
the syndrome we call CFIDS demands a common-sense approach to
the symptoms and an effort to provide what relief possible. Aches,
pains, sore throats, and headaches can be alleviated with anti-inflammatory
drugs, milder analgesics, antihistamines, decongestants, antibiotics
or anti-virals where indicated. Habit-forming
medications or medications without long term safety should be
avoided. On a long-term basis, it is preferable "shut-off"
the "negative" process by creating a remission or cure,
rather than simply treating the "external"/reactive
of exercise is an area of concern for most patients and physicians.
When a patient is very ill, exercise does not help; and in fact
may be harmful or another "negative". At the point where
one crosses over into an anaerobic metabolism, the effect is probably
harmful to the CFS patient, further stressing their systems. We
know that patients with CFIDS whose metabolism is "off-balance"
suffer ill effects from exerted exercise. My advice generally
is if the patient feels worse the day following exercise, such
activity should be curtailed or stopped if necessary. Once the
patient's condition shows improvement, moderate, non-aerobic exercise
can be reinstitued. Slowly, the patient can rebuild their strength
and exercise tolerance, but I believe only as part of an "up-cycle"
has never been a major emphasis of medical research in this country.
Europe, Asia and most other industrialized countries have always
been ahead of us in the area of alternative medications. Asia
has an ancient history in herbal medicine. Without a specific
agent to direct therapy toward, attempting to "re-normalize"
the body's function makes great sense. The frustration is that
we need to be open to untraditional treatments, but somehow avoid
"scams." Most sufferers are fatigued to some degree
and metabolically dysfunctional. Nutritional support or herbal
therapies may be appropriate, but there must be a mechanism of
testing for efficacy, or at least absorbability and potential
function. Many "nutritional" therapies as marketed are
not absorbable, and while appearing in theory to be a good idea,
are often useless. Work I did in the mid 1980's supports the potential
usefulness of some of these remedies. Without appropriate clinical
trials (a primary reason I pulled away from further
researcin these fields at the time), patients and doctors have
no way to judge potential
efficacy, safety, cost effectiveness, etc., of these agents.
the patient should take care to supply their body with the basic
vitamins, minerals and energy sources that it needs. While there
are several theories on appropriate diets for CFS patients, I
generally stress a diet that is high in protein as a source of
amino acids. I recommend that patients consume large portions
of chicken, fish, turkey, some red meats and protein-composed
vegetables. Protein supplements may be helpful, but remain difficult
to evaluate for efficacy and legitimacy at present. My findings
from work in the mid 1980's revealed that many of my CFS/CFIDS
patients appeared to have 30% to 50% of their amino acids below
normal on a reliable serum electrophoresis type of report. Whether
low from lack of absorption or over-utilization (both concepts
logical), the body cannot function normally when the amino acids
are low, for they are the building blocks of most chemicals and
hormones in the body. While some researchers have expressed concern
over "stressing" the liver, I have fod that mild liver
enzyme elevations often improve as a patient's body became healthier.
Providing an adequate quantity of protein and their amino acids
particularly within an overall treatment plan.
may yield some benefit, but I do not believe megavitamin therapy
provides long-term help, and in some cases, may be harmful. I
have never subscribed to high-dose mega-vitamin or IV supplements
for that reason. Their potential harm never seemed outweighed
by their potential benefits. Subsequently, while there are antedotal
reports of short-term success, vitamin therapy does not appear
to have produced any long-term results in a significant number
of patients, or in any controlled trials. I do believe a good,
high potency multiple vitamin, iron, mineral combination can be
helpful. Depending upon lab test results, at times I recommend
extra calcium, extra magnesium or extra iron to be indicated along
with prescribing extra doses of vitamin C, usually 1000 to 2000
mg. per day. I view using mega-dose vitamin modalities as an effort
to "squeeze" some energy out of a depleted body; while,
in fact, having done nothing to build up that body or to turn
off the dysregulatory
has been very little in the way of properly controlled trials
therapies published, Behan et alexamined 63 adults in a double-blind
placebo study using essential fatty acids. They noted a 74% improvement
compared to 23% on placebo. Serum fatty acid levels tend to fall
in acute and severe chronic viral infections. These fatty acids
may be important in neuronal metabolism, but their effect has
not been established in children. Interestingly, at the NIH-sponsored
conference in Albany, N.Y., in Oct. 1992, EFA's (Essentially Fatty
Acids) were mentioned a number of times antedotally. As always,
care must be taken in obtaining products that are pure and of
high quality. At the recent AACFS Ft. Lauderdale conference Oct.
1994, some researchers looking at EFA's actually reported an improvement
in "normals" compared to patients. This should re-emphasize
the need for all of us to further refine and define patient populations,
to appropriately judge therapeutic trials. Unfortunately, as noted,
there are many products offered to the public with no efficacy
and no proof of absorbability or usability. Until we learn more
about supplements from future studies,
I would caution all patients to follow common sense nutritionally,
avoiding any unnecessary and expensive products unless they are
proven to be safe and come with a "money-back guarantee"
for a reasonable trial period.
supportive therapies, one deals with the issue of Candida. While
we cannot measure the presence of Candida accurately, we can treat
its theoretical effect through a therapeutic trial. If appropriate
anti-fungal/Candida therapy is effected and no "kill-off"
or die-off (a period of feeling "worse" shortly after
starting therapy) is experienced, then yeast is probably not a
significant problem for that patient. If, however, a clinical
trial shows "kill-off" followed by improvement, continued
therapy is warranted. Until better markers or lab tests evolve,
there will remain a very high level of controversy regarding Candida
or "yeast". Acknowledging the controversy, my first
choice of treatment is Nizoral with an increasing preference for
Diflucan, were it not for its expense. Generally, if working successfully,
I will prescribe Nizoral for at least 5 - 6 months. Patients should
be monitored regularly while on this drug for elevations of liver
enzymes. Later, I switch to an oral "maintenae" medicine
such as Nilstat (often not strong enough) or oral Amphoterecin
B. While significantly stronger than
Nilstat, Amphoterecin B is very safe when taken orally, but highly
toxic as licensed in this country for IV usage. It is available
over the counter in many parts of Europe, and can be obtained
by prescription via special "compounding" at College
Pharmacy in Denver, Colorado. While one should try to avoid sugars
and yeast-containing foods such as breads,rolls, beer, wine, etc.,
a sensible diet, avoiding the worst offenders, is most practical
for a long-term therapy. Severely restrictive diets are too difficult
to follow and only represent supportive help in general, not a
cure for this disorder. Positive results have been easier to obtain
with the combined help of medication, rather than by diet alone.
In this author's
opinion, "Immune Modulators" remain the hope for the
These are agents that re-regulate and adjust the immune system.
It will probably be years before we will have specific treatments
to cure CFIDS in those patients in whom specific etiologies may
be present. Therefore, for all patients, we need to try to understand
and combat the dysregulated immune system in the interim. A dysfunctional/dysregulated
immune system responds inappropriately by fighting off an illness
or stress that may no longer be there. Such a state produces a
variety of symptoms caused by the immune system's faulty regulation.
As noted, research is confirming cytokine abnormalities and the
concept of a dysregulated, often inappropriately activated immune
system in CFS/CFIDS patients.
As a result
of immune system research relating to AIDS/HIV over the last 10
- 12 years,
certain agents have been uncovered that may have the potential
to help patients with CFIDS, or other immune-modulated disorders.
DNA/gene therapy may one day be developed for treatment of CFIDS
and other dysregulatory states. But that sort of treatment is
the medicine of the future, not the present. For today, immune
modulators may provide solutions while we continue to search for
specific etiologies and other areas of treatable dysfunction.
This author suspects that this approach has the potential to help
people with many of the collagen vascular/autoimmune related disorders
including lupus, and rheumatoid arthritis among other illnesses.
Through an understanding of cytokine profiles or other specific
can be evaluated in appropriately structured trials that will
likely provide much needed help NOW.
an agent that has been a part of traditional medical treatment
for years, may temporarily help some patients. Gamma globulin's
effectiveness is as an immune modulator. Since it does not in
general seem curative or even universally successful, I do not
generally agree with prescribing IV gamma globulin for CFIDS,
as do some other physicians. There are limited and inconsistent
reports of patient response and it is extremely costly. There
are dangers of severe "reactions" to this product and
a possible transmission of Hepatitis C (low probability). None-the-less,
it may improve the level at which some patients function at times,
but at a very questionable "cost vs. gain" comparison.
IM gamma globulin, which is given by
an injection, is relatively inexpensive, safer than the type administered
by IV, and may have
similar benefits in some patients. It has been this author's experience
that as many as 50-60% of patients may benefit by its use when
they are in a "down" condition. When the iness has exacerbated
and the sufferer is feeling especially weak and tired, a shot
of gamma globulin can yield some relief. If helpful, it may be
repeated at intervals from 1 to 4 weeks for a short period of
time. For those who do respond, repeated injections of gamma globulin
are safe, but should be used judiciously. Unfortunately, between
40 to 50% of patients seem to experience no improvement from gamma
globulin, and in those cases, continued use would seem futile.
is a mixture of agents prepared from pig liver. Dr's Steinbeck
defined this mixture in the early 1980's as about 20-25% "immune
active". Kutapressin has been used for the last 40 years
as therapy for a wide variety of dermatologic conditions. Favorable
response to administration of Kutapressin in patients with acne
vulgaris, Herpes Zoster, Poison Ivy Dermatitis, Pityriasis Rosea,
Seborrheic Dermatitis, Urticaria, Eczema, Severe Sunburn, and
Rosacea has been reported in the past. Kutapressin has seemed
very helpful (antedotally) in my practice and that of others when
used as an immune modulator in treating CFIDS.
In a number
of pharmacologic systems, researchers have been able to demonstrate
that the active peptides in Kutapressin potentiate the action
of bradykinin. Bradykinin is a vaso-active peptide generated by
the blood plasma-kinin system. Plasma-kinin and its role in the
inflammatory process has been a subject of great interest to researchers
seeking novel anti-inflammatory drugs. A proceeding of a research
symposium, published in the Federation Proceedings provides some
insight into our present understanding of the effect of plasma
kinins in the inflammatory process. Several investigators have
independently shown the presence of bradykinin in inflamed tissues.,
In animal models, Kutapressin produces significant change in the
capillary permeability to improve leukocyte migration. Kutapressin
peptides stimulate rapid multiplication of thymocytes in tissue
cultures. It drastically reduces edmma induced by carageen in
animals. It maintains the integrity of the cell structure as demonstrated
by higher survival time of cells in the tissue culture.
wide anecdotal use by clinicians across the country, the manufacturer
Kutapressin does not intend to invest in further studies to investigate
its potential use as an immune modulator at this time. As with
all agents, Kutapressin does not benefit every patient, but when
it works, the results can be dramatic. In fact, the objectionable
need to administer it by injection is tolerated surprising well
by children and adults when they experience pronounced improvement
in their condition.
only significantly negative effect of Kutapressin is the possible
danger of allergy. The patient must be screened against possible
allergy to Kutapressin, which seems present in approximately one
per cent of patients. The course of therapy I generally follow
is based on original protocols by Dr's Steinbeck and Hermann;
one 2cc (for adults) intramuscular injection daily for one month,
then 2cc every other day for a month, followed by one injection
3x's a week for 6 - 7 months, then 2 x's a week, tapering according
to patient response. The many possible variations in the use and
dosage of this drug, coupled with patient heterogeneity explain,
in part, the contradictory reports of this agent's efficacy; along
with the fact that as noted, this author does not feel that any
one agent is the full answer to therapy at this time.
Duration of usage of Kutapressin varies widely among individuals.
Unlike the first protocols by Dr. Steinback and Dr. Herman, I
do not assume therapy can end at five or six months. Discontinuation
of its use before the patient feels "normal/well" often
results in backsliding over time. Happily, many patients in my
practice have seemed to reach a state of complete recovery after
usage for a year or longer (usually in combination with other
therapies). Maintenance for longer periods is acceptable if indicated
and helpful. Whether "cured" (a word I would use cautiously)
or in a "remission" as a result of Kutapressin, the
patient will generally be at a significantly improved level of
functioning within a 3 - 6 month period, with some positive response
expected within the first 4 - 12 weeks. Short of the drawbacks
regarding allergies, Kutapressin appears to be a very safe agent,
especially compared to some alternative treatments. I must strongly
reemphasize, when treating any chronic condition, an agent's ng
term safety and efficacy is of extreme importance, in adults as
well as children. This is true whether the treatment is a prescription
drug, OTC, Herbal, or any other agent.
has seemed of particular help to patients with neurocognitive
problems and/or patients with multiple viral elevated titers and
an abnormal NeuroSPECT scan. Generally. Generally, this author
accepts elevated viral titers as a reflection of an activated,
dysregulated immune system, not necessarily or usually an acute
viral infection. Kutapressin's effectiveness in children with
cognitive problems is still diminished by the need to administer
it by injection. Otherwise, it seems an extremely safe and frequently
a very efficacious agent. In the past, I chose Kutapressin for
those patients with predominantly cognitive dysfunction, not for
those patients who suffered more with "fibromyalgia"
symptomlogy, such as body aches and muscle pains. (Antedotally,
low-dose, oral interferon has seemed better for these patients.)
I would readily speculate that Kutapressin, as well as other Immune
Modulators, are likely to have the ability to return the body
to normal. I would stress that this has generally been in the
context of "combined" therapy approaches, aimed at "normalization"
of the body and relief of symptoms. It has been my frustration
to know for years of a number of potential new "immune-modulating"
agents that are unavailable to be used because they lack appropriate
evaluation and testing. Without a means of accurately sub-defining
a group of CFIDS patients, and lacking an "incidence"
reflecting its true frequency, pharmaceutical companies have been
reluctant to invest funds for testing these new agents for this
capacity. While there has been a number of "pure" agents
developed, it is urgent to create a means to bring these agents
controlled tests now, not five or ten years from now.
are produced by normally-functioning lymphocyte cells during the
activation of an immune response and are part of a "cascade"
of lymphokine chemical messengers. The role of interferon (IFN)
alphas in the immune system and their relationship to the other
lymphokines is not completely understood. Still, there is compelling
evidence of the significance of IFN-alphas in the regulation of
the immune response.
has been shown to have antiproliferative, antiviral and immunomodulatory
activities in vitro, and in animals and humans. Recent animal
studies have indicated that very low doses of oral interferon
have beneficial effects in diseases induced by viruses. In calves
with viral respiratory tract infections, low doses of oral human
interferon alpha significantly stimulated the immune response
and appetite, resulting in weight gain. In cats infected with
feline leukemia virus, oral interferon treatment delayed the onset
of leukemia, stimulated appetite, and significantly increased
survival. Although high-dose parenteral interferon has been extensively
evaluated in human patients, there are virtually no studies in
humans with low-dose interferon. At high dosage, trials may be
limited by side effects, many of which
reflect symptoms we associate with Immune activation/CFIDS. High
dosage of most of the Cytokines/Interleukins create many of the
symptoms we associate with CFS/CFIDS.
I have used
oral alpha-interferon antedotally in my practice. Clinically I
find it more helpful for relief of muscle, bone, joint, aches
and pain, but it may also aid in reaching an overall"normalization"
of the body/immune system. It's mode of operation needs further
understanding, as controlled trials are lacking. Still, alpha-Interferon
is generally a safe and benign agent. It is given by oral drops
or tablet, either of which must be kept in the mouth about 20
minutes, and is generally well tolerated. Currently, I am using
a dosage equivalent to 150-200 units.
While no one
knows for certain, low-dose oral interferon may be functioning
by interrupting what is known as a "negative feedback loop."
Assuming that the immune system is firing off inappropriately,
then alpha interferon given at a very low dosage may have the
ability to shut off that loop at some point. While not likely
curative, low-dose oral alpha-interferon appears to be another
resource to help the body feel healthier and aid a return toward
"normal". It certainly seems worthy of controlled trials
in the future.
one of the first agents used in a controlled trial of CFIDS patients.
Opinions differ as to whether it is an antiviral or an immune
modulator or both. Clinical improvements were obtained with Ampligen
when administered intravenously twice weekly to 15 individuals
who met the CDC criteria for CFS and showed evidence of encephalopathy
(CFSE). Wechsler scores improved >50% in these patients. Full
scale IQ increased by 12% from 106 to 119. Performance IQ increased
19% while verbal IQ increased 10%. "Viral reactivation"
was reduced in 13 of 14 patients. These clinical and laboratory
changes, while not judged as conclusive (perhaps a factor of the
heterogenicity of patients noted above), suggest that Ampligen
is a biologically active agent potentially useful in combating
CFS/CFIDS. Ampligen may have the dual ability to restore immunological
function and to control virus replication. Unfortunately this
is a very expensive course of treatment requiring intravenous
infusions. Long-term gain has yet to be proven and, as many CFS/CFIDS
patients are aware, further trials with this agent remain uncertain.
After initial encouraging work with this agent the
manufacturer, for a variety of reasons has hesitated continue
the costly types of trials currently required by the FDA.
the report of raising objectively patient IQ's and cognitive ability,
many bedridden patients were able to walk and function fairly
normally as a result of its use. Ampligen became the wonder drug,
with a huge following eager to use it. In fact, Ampligen is both
very expensive and potentially toxic, although certain newer versions
are reported to be safer. Ampligen's successes and failures illustrate
the problems inherent in any new medication and therapy for CFIDS.
Without the "umbrella" of a scientifically validated,
controlled database or other means of objectively separating patient
groups, it remains this author's fear that most, if not all drug
therapy trials are doomed to confusion and probable failure. As
the NIH, CDC, and rest of our medical establishment come to recognize
this for the "heterogeneous" mixture of patients currently
represented, it remains this author's strong opinion that without
to sort out groups of patients (as per the initial work of Dr.
Klimas's prested at the Oct. 1994, Ft. Lauderdale AACFS meeting),
defining success for any given agent will remain confusing and
difficult. As the patients are appropriately defined (back to
the concept and necessity of a database, or other means of classification),
determining which group of patients respond to which drug or type
of therapeutic approach, will begin to make sense and be able
to be applied clinically to appropriate patients in general.
with CFS/CFIDS present with a complex series of problems. This
approach is to reduce the condition to a series of individual
pieces of a puzzle, and to then treat each one individually. This
does not mitigate the need to focus on the underlying dysfunction
and the source of the problem but is, rather an effective and
immediate action against this devastating condition. Therefore,
a patient presenting with a lot of allergies requires allergy
control measures, elimination diets, and supportive medications.
If yeast appears by markers or by clinical suspicion, it too should
be combated in ways that are readily at our disposal. When the
sleep cycle is dysfunctional, as noted earlier, often the use
of low-dose Prozac, low-dose Zoloft or similar agents can provide
help. My experience has shown the effectiveness of using agents
that help "normalize" the body's or CNS function, rather
than treating lack of sleep with sleeping medications, pain with
pain medications. etc. Symptomatic thapies may help at times or
"mask" the symptoms, but do not seem to produce long
symptoms or effects can be reduced or eliminated, the introduction
Kutapressin, Interferon and "immune" or anti-viral agents
deserves consideration. In general, it has been this author's
experience that younger patients have the advantage of a healthier,
more restorative body with more inherent body reserve, than do
older sufferers or those ill for a protracted period (greater
than 3-5 years). Each treatment that can help make the body healthier
by stopping some of the dysfunction, increases the chances for
the patient to become well, and their body to return to a healthier,
physiologic state. The meaning of the term "well" may
mean cured and fully functioning, or merely improved and functioning
on some type of maintenance medication. There is clinical logic
in trying to help "normalize" function as much as possible,
as well as minimize or stop potential long term stress and dysfunction.
There are measures and medications that can help "antedotally"
now, while we await the application of new medications and "controlled"
trials, hopefully in the near future.
and support groups can be of great help to patients and their
families. These groups should not disintegrate into "gripe
sessions". They should be a forum in which patients can discuss
their condition and all of its effects. These groups should be
used to exchange emerging information, function as a power base,
helping to raise funds and lobby for increased research, and accelerate
paths leading to therapeutic answers.
In spite of
increased recognition of an immune dysregulatory state as a physical
disease, underestimates (as low as 1 in 14,000, 6 or 7 per 100,000)
of those affected by the CDC and NIH, indirectly slowed potential
progress. Neither drug manufacturers nor Congress has been willing
to fund therapeutic trials or accelerate research at appropriate
levels based on these figures. Fortunately, with the reports of
multiple investigators at the recent Oct. 1994, Fort Lauderdale,
Fl. conference showing numbers far higher than expected, there
is an emerging recognition of the potential scope of this problem.
Respected researchers and epidemiologists have begun citing incidences
of anywhere from 1 - 1 ½% of the population. Consistent
with many other clinicians, this writer would predict an occurrence
rate that will most likely be as high as 3-5%, perhaps even higher.
Certainly, if understand in the concept of an immune dysregulatory
state, rather than the perhaps too narrow concept of CFIDS, the
be aggering. We urgently need to define, address and answer epidemiological
questions: How extensive is this immune dysfunction phenomenon?
How do we identify it? What is its origin? Is the cause a virus,
retro—virus, ozone layer depletion, toxins or something(s)
as yet unidentified? What are the co-factors? Most importantly,
within this context, what can be done therapeutically, both now
and in the near future?
In the final
analysis, research is the key factor for the eventual control
of CFIDS. We cannot hope to know the safety and efficacy of agents
in the immediate future unless they are monitored in controlled
trials, ultimately under the umbrella of a large national clinical
data base. This is similar to clinical protocols developed and
used as a standard for other chronic illnesses. Any untried agent
is potentially dangerous. It would seem inarguable that recognizing
an epiphenomena exists and responding rapidly will ultimately
be the most cost effective approach for the government, physicians,
and patients. Underestimating, or frankly, ignoring this need
will result in increased, long-term costs on our medical, social
and business systems. Delays in research for adults were rationalized
on the "belief" that this condition does not result
in deaths. Sadly this ignores the huge amount of morbidity occurring
in patients over time. This
is NOT a "benign" disease. The loss to the minds and
bodies of chilen who are too
dysfunctional to attend school regularly is inestimable. This
writer is currently working with other researchers to expedite
much-needed trials. The mounting written and antedotal incidents
of success using agents such as Gamma Globulin, Ampligen, Kutapressin,
and Interferon give cause for sincere optimism in treating CFIDS
patients. But research must be funded to find more agents and
determine how they work in carefully controlled studies.
With the presentation
of information at the Ft. Lauderdale conference, it is this author's
firm feeling that there are no questions regarding the reality
of the problem. The difficulty ahead is to find the scientific
answers and explanations for this "new" phenome