Page | Multiple Chemical Sensitivity
| Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
Encephalomyelitis/Chronic Fatigue Syndrome as a
L. Pall, Professor Emeritus of Biochemistry and Basic Medical
Research Group Nutritional Support Protocol
NO/ONOO- cycle diseases – Chronic Inflammatory Diseases
fatigue syndrome (CFS),
sometimes called myalgic encephalomyelitis or myalgic encephalopathy
(ME) was the first of these multisystem illnesses to be proposed to
be caused by a vicious cycle (1-11) that has recently been named the
NO/ONOO- (no, oh no!) cycle (8) and is still one where an
increasingly strong case for this etiology can be made. While
I think that there is also an increasingly strong case for calling
this illness ME, I will refer to it here as CFS/ME because both of
these terms are being used in the scientific literature.
appears to have the largest group of initiating short-term stressors
described in the literature of all the multisystem illnesses,
stressors where each may be expected to act to increase nitric oxide
levels. Most of these are documented in a my book and recent review
(8,9) and some of these are also
documented elsewhere (1,2,14). The apparent initiating stressors
implicated in CFS/ME cases are as follows:
1. Viral infections
2. Bacterial infections
3. A protozoan infection, toxoplasmosis
4. Carbon monoxide exposure
5. Physical trauma
6. Organophosphorus poisoning
7. Severe psychological stress
8. Ciguatoxin poisoning
9. Ionizing radiation exposure
the first two of these are implicated most commonly in the
initiation of CFS/ME cases, we need explanations for the apparent
roles of all nine. The fact that all nine can initiate a sequence of
events that leads to increased nitric oxide synthesis (8,9,11)
must be considered to be a striking coincidence that provides a key
clue to CFS/ME etiology. Indeed the genetic evidence implicating
corticosteroid-binding globulin gene (15,16)
and the serotonin transporter gene (17) in determining
susceptibility to CFS/ME, as discussed in Chapter 5, ref.8, also
provides support for a nitric oxide role in CFS/ME initiation.
Both of these genes can act to determine cortisol function and
cortisol is known to lower the induction of the inducible nitric
oxide synthase (iNOS) and therefore partially determine levels of
nitric oxide (8,9).
the nine stressors listed above, the first three act primarily by
inducing iNOS, as does the ionizing radiation (stressor 9) (1,2,8,11).
The others are thought to act, at least in part, by increasing NMDA
activity which acts, in turn, through the other two nitric oxide
synthases, nNOS and possibly eNOS (2,8,12).
Thus the common feature of these initiating stressors is their
common increase in nitric oxide, not the specific form or forms of
nitric oxide synthase involved.
connection between each of the first six initiating stressors and
nitric oxide is very clear. I’d like to discuss the last three.
Number 7, severe psychological stress has been mainly linked to
nitric oxide synthesis through animal models of posttraumatic stress
disorder, where it has been shown to increase NMDA activity and
consequently levels of nitric oxide (7,8).
exposure is known to greatly delay closing of certain sodium
channels and this is known, in turn to be able to stimulate NMDA
activity (Chapter 5, ref. 8). The role of ciguatoxin in increasing
nitric oxide levels is inferred, therefore, from the known role of
NMDA receptors activity in increasing nitric oxide and its oxidant
radiation initiates cases of post-radiation syndrome, a CFS/ME-like
illness (11). Ionizing radiation is known to act to stimulate the
can be seen, from the above, that the pattern of evidence
implicating elevated nitric oxide synthesis activity in the
initiation of CFS/ME cases is quite striking. How can nitric oxide
act to initiate these illnesses? By acting mainly through its
oxidant product peroxynitrite to initiate the vicious cycle
mechanism (1), the NO/ONOO- cycle, that
is responsible for chronic illness. The NO/ONOO- cycle mechanism,
given previously on my main web page, book (8) and elsewhere (9), is
presented again below in Fig. 1.
1 legend. Vicious
(NO/ONOO-) cycle diagram. Each arrow represents one or more
mechanisms by which the variable at the foot of the arrow can
stimulate the level of the variable at the head of the arrow. It can
be seen that these arrows form a series of loops that can
potentially continue to stimulate each other. An example of this
would be that nitric oxide can increase peroxynitrite which can
stimulate oxidative stress which can stimulate NF-kappaB which can
increase the production of iNOS which can, in turn increase nitric
oxide. This loop alone constitutes a potential vicious cycle and
there are a number of other loops, diagrammed in the figure that can
collectively make up a much larger vicious cycle. The challenge,
according to this view, in these illnesses is to lower this whole
pattern of elevations to get back into a normal range. You will note
that the cycle not only includes the compounds nitric oxide,
superoxide and peroxynitrite (abbreviated PRN) but a series of other
elements, including the transcription factor NF-kappaB, oxidative
stress, five inflammatory cytokines (in box, upper right), all three
different forms of nitric oxide synthases (iNOS, nNOS and eNOS), and
neurological receptors including some of the TRP receptors and the
NMDA receptor. Mitochondrial dysfunction leads to ATP
depletion. Tetrahydrobiopterin (BH4) depletion is shown to be
an important aspect of the cycle.
NO/ONOO- Cycle Elements Elevated in the Chronic Phase of CFS/ME?
mechanisms involved in the NO/ONOO- cycle are discussed in many of
my papers (1,2,7-12) and summarized most
completely in my book (8). One very important question is in
determining whether any specific chronic disease/illness is a NO/ONOO-
cycle disease is whether elements of the cycle are elevated in the
chronic phase of illness. The answer, in CFS/ME as is also true of
the other multisystem illnesses, MCS, FM and PTSD: Where they
have been looked at, they are elevated!
of the specific CFS/ME evidence is as follows (8):
Oxidative stress has been reported in 13 earlier studies of CFS/ME,
published by seven research groups on four continents (reviewed in
5,8,13) and two additional studies have been reported recently
(22,23). Such oxidative stress is also supported by reports of
glutathione depletion and cyst(e)ine
depletion in CFS/ME (20,21) and by reported depletion of essential
fatty acids in CFS/ME (24,25). Oxidative stress is expected to lead
to both glutathione/cysteine depletion and essential fatty acid
depletion as I proposed earlier (1). Thus oxidative stress is
probably the best documented change in CFS/ME. Having said that, it
is not a specific response to CFS/ME! Many inflammatory
diseases will lead to elevation of markers of oxidative stress and
in addition, many cases of CFS/ME (presumably among the more
modestly effected) fall into the “normal” range of these
markers. The same pattern occurs with many other changes that are
reported in CFS/ME, where on average there are statistically
significant changes but many individual CFS/ME cases fall well
within the normal range.
Mitochondrial/energy metabolism dysfunction is part of the NO/ONOO-
cycle mechanism because peroxynitrite attacks a number of components
of mitochondria, and nitric oxide and superoxide also inhibit
certain mitochondrial functions (8,9). 18
different studies provide evidence for mitochondrial and/or energy
metabolism dysfunction in CFS/ME (reviewed in 1,8).
This again provides extensive evidence supporting NO/ONOO- cycle
biochemistry in CFS/ME. Among these are studies showing that agents
predicted to improve mitochondrial function such as carnitine/acetyl
carnitine, coenzyme Q10 and lipids designed to help regenerate the
mitochondrial inner membrane are all helpful in the treatment of CFS/ME.
These provide evidence that not only is there mitochondrial
dysfunction but that it contributes to the CFS/ME pathophysiology.
Two studies report increased nitric oxide levels (3,26).
In addition, studies of neopterin levels, a marker of high level
iNOS induction reported statistically significant elevation in three
of five studies of CFS/ME, suggesting that iNOS induction
contributes to the nitric oxide elevation (1). The hydroxocobalamin
form of vitamin B 12, a potent nitric oxide scavenger (4) was
reported to produce statistically significant improvements of CFS/ME-like
patients in a placebo-controlled trial (27). Hydroxocobalamin has
been used clinically to treat CFS/ME-like illnesses for over 60
years, being used in at least 9 countries on three continents,
mainly by IM injection. Patients report rapid improvement of their
entire spectrum of symptoms in response of hydroxocobalamin
injection. The pattern of apparent efficacy suggests that not only
is nitric oxide elevated in CFS/ME, but that it contributes in a
major way to its etiology.
There have not been any published studies on peroxynitrite, but Dr.
Tapan Audhya has shown me his data on this. He finds that many
CFS/ME patients have elevated levels of 3-nitrotyrosine, a marker of
There are 10 studies that report that one or more of the
inflammatory cytokines in the right, upper corner of Fig. 1 are
elevated in CFS/ME (8). These elevations are relatively modest
suggesting that they contribute to but do not dominate the CFS/ME
Two physicians and one research group report clinical observations
supporting an elevation of NMDA activity in CFS/ME, again supporting
the NO/ONOO- cycle etiology (8).
6. Two recent studies have reported elevated NF-kappaB activity in CFS/ME, while mistakenly calling it NF-kappa beta [28,29].
these are all important observations supporting a NO/ONOO- cycle
etiology, additional such observations from clinical trials are
discussed on my therapy web page. However, there are also some
additional clinical observations from therapies that may also
suggest elevation of cycle components. For example, some physicians
have used agents known to lower NF-kappaB activity as part of their CFS/ME
treatment protocols and others have used the drug guaifenesin, a
drug reported to lower capsaicin responses and therefore vanilloid
receptor action (8). The drug thiacetarsamide was reported by
Tarello to produce great improvement animal models of CFS/ME and has
been found by me to scavenge both nitric oxide and peroxynitrite
(reviewed in 8). These studies suggest that elevation of NO/ONOO-
cycle elements and also suggest that because lowering those elements
may produce the improvements reported, the elements may contribute
substantially, to the etiology of CFS/ME.
have already discussed the genetic studies that provide evidence for
a role of nitric oxide in CFS/ME. There are several additional
genetic studies that should be mentioned.
and Natelson (30) reported a role for a polymorphism in the
angiotensin concerting enzyme (ACE) in determining susceptibility to
CFS/ME. This gene regulates the levels of angiotensin II,
which determines, in turn the levels of tetrahydrobiopterin (BH4),
an important cycle element. BH4 depletion produces in turn
increased superoxide, so that this genetic study implicates two
NO/ONOO- cycle elements in CFS/ME, BH4 depletion and
studies (31,32) have implicated
inflammatory cytokines in determining CFS/ME, susceptibility,
arguing in turn for another set of NO/ONOO- cycle elements.
and coworkers (33,34) have reported that
people with mutations in their mitochondrial DNA have CFS/ME-like
symptoms, along with a variety of other symptoms, implicating
mitochondrial dysfunction and consequent ATP depletion, other NO/ONOO-
All of these genetic studies are discussed on somewhat more detail in ref 9. These genetic studies, taken together, implicate the following NO/ONOO- cycle elements in CFS/ME: Nitric oxide, BH4 depletion, superoxide, inflammatory cytokines and mitochondrial dysfunction. Together, they provide substantial support, therefore, for a NO/ONOO- cycle etiology for CFS/ME.
Gene Expression Studies and NO/ONOO- Cycle Elements
There are a number of gene
expression studies that implicate various elements of the NO/ONOO-
cycle in CFS/ME, studies that are reviewed in Ref. 9 and will not be
cited separately here. Specifically, gene expression studies
implicate oxidative stress, mitochondrial dysfunction, chronic
inflammatory responses and excitotoxicity including possible
excessive NMDA activity. Consequently, a number of NO/ONOO-
cycle elements are implicated in CFS/ME, from gene expressions
Animal Models and the NO/ONOO- Cycle
are two animal (mouse) models of CFS/ME, on each of which there are
multiple published studies. In one of these animal models
(reviewed in 8,9), cases are initiated by a stressor that increases
nitric oxide and produces elevated levels of inflammatory
cytokines and also mitochondrial dysfunction. In the other
(also reviewed in 8,9), there is
substantial evidence for oxidative stress. Both of these
animal models seem to be consistent with a NO/ONOO- cycle etiology
and they collectively provide evidence for roles of several cycle
fourth principle underlying the NO/ONOO- cycle is that the basic
mechanism is primarily local. This primarily local nature
shows up in CFS/ME in two distinct ways. One is that there is
stunning variation among different CFS/ME cases which are difficult
to explain without such a local mechanism (discussed in Chapter 4,
ref. 8). This variation is what has made it very difficult to
come up with a simple case definition.
second way in which this primarily local nature shows up is in brain
scan studies where one can directly visualize the tissue variation,
both quantitative and qualitative variation. Perhaps the most
convincing such study for CFS/ME are the two MRI studies published
by the Natelson group (35,36), where the variation is obvious from
the published scans. Other relevant brain scan studies were
discussed in Chapter 4, Ref. 8.
Fatigue Syndrome—Where Should We Search for a Specific Biomarker?
Searching for specific biomarkers for specific multisystem illnesses should focus, according to the NO/ONOO- cycle model, on the effects of the impact of that cycle on whatever tissue impact is most characteristic of a particular illness. In the case of MCS, FM and PTSD, the issue of specificity is readily apparent because the most characteristic symptoms or signs of illness are readily apparent. In the case of CFS/ME, they are not. However the recent deliberations on CFS/ME have focused on the symptom of post-exertional malaise as the most characteristic symptom (37) and Jason and coworkers have also focused on post-exertional malaise as perhaps THE critical symptom of CFS/ME (38,39). It is there that we should focus our search for a specific biomarker, in my view.
malaise is a phenomenon where exercise in CFS/ME patients produces
an exacerbation of their entire spectrum of symptoms,
an exacerbation that the NO/ONOO- cycle model predicts is likely to
be due to up-regulation of NO/ONOO- cycle biochemistry. The view
that excessive exercise in CFS/ME may up-regulate the basic causal
mechanism is supported by some of the pioneering observations of Dr.
Melvin Ramsay. Ramsay observed that CFS/ME sufferers who continued
to work longest before collapse had a much poorer prognosis than
those who were diagnosed early and underwent prolonged bed rest
might one use the phenomenon of post-exertional malaise to develop a
specific biomarker for MCS? When I discussed this issue with Dr.
Paul Cheney, suggesting that this is where we should focus our
efforts to develop a specific biomarker for CFS/ME, he told me that
his CFS/ME patients show a characteristic difference from normal
controls—whereas normal controls show an increase in corticol
levels after exercise, his CFS/ME patients do not. The notion that
changes in cortisol response may cause post-exertional malaise in an
attractive one. Cortisol (like other glucocorticoids) is known to
lower the induction of the inducible nitric oxide synthase (iNOS)
and may have a substantial role, therefore, in controlling nitric
oxide levels. A deficient cortisol response to exercise may lead,
therefore, to increased nitric oxide levels after exercise in CFS/ME
patients vs. controls, leading, in turn, to up-regulation of the NO/ONOO-
there other evidence supporting a specific deficiency in cortisol
control in CFS/ME? After all, the HPA axis control controls cortisol
production and HPA axis dysfunction is known to occur in all of the
multisystem illnesses (8), and so such dysfunction is not specific
to CFS/ME. Two reviews suggest that HPA axis control in CFS/ME is
distinct from that in FM (41,42).
Consistent with such specificity, Ottenweller et al (43) reported
changes in cortisol control in response to exercise in CFS/ME
patients, similar to those found by Cheney. Dinan and coworkers
reported (44) that the adrenal glands of CFS/ME patients were
substantially smaller than those of controls, consistent with an
aberration of HPA axis control. Certain other studies also provide
support (Chapter 5, ref.8).
have expressed views similar to those I write here. Torpy (45)
described CFS/ME patients with “altered dynamic responses to
stress, especially cortisol to stimuli.” Neeck and Crofford (46)
reported “abnormalities of central components of the HPA axis”
prediction, then, is that exercise, acting in part or in whole
through aberrent cortisol control, will act in CFS/ME patients to
up-regulate NO/ONOO- cycle biochemistry in a response that will not
be seen in normal controls . Is there any
evidence for this? Jammes et al (47) reported large increases in
markers of oxidative stress in CFS/ME patients after exercise,
whereas only small increases were seen in controls. LaManca et al
(48) reported much larger cognitive deficits after exercise in CFS/ME
patients compared with controls, consistent with such cognitive
deficits being caused by NO/ONOO- cycle biochemistry.
the major changes in cardiac function found in CFS/ME patients by
Peckerman et al (49,50) and by Cheney (51 and personal
communication) may be caused by lowered cortisol levels because
cardiac dysfunction in humans and animals can be caused by lowered
cortisol levels (reviewed in ref 8, chapter 5).
notion that dysfunctional cortisol control in response to exercise
is behind the phenomenon of post-exertional malaise in CFS/ME should
allow one to use exercise control of almost any easily measurable
NO/ONOO- cycle element to develop a specific biomarker for CFS/ME.
In addition, almost any easily measureable symptom or sign of CFS/ME
might also be used. My own prejudice is that we should use exercise
control of markers of nitric oxide production before and after
exercise or perhaps cortisol levels themselves, but no doubt others
may have other parameters they may prefer to measure.
and the NO/ONOO- Cycle
relevant evidence supporting a NO/ONOO- cycle etiology for CFS/ME is
provided on my main web page in my therapy web page and in my book
(8), as well as above. The evidence for a presumptive nitric oxide
mechanism for initiation is strong for CFS/ME and indeed stronger
than it is for the other multisystem illnesses.
importance of the NO/ONOO- cycle model of CFS/ME is not just that it
is supported by a diversity of experimental observations. That is
important, obviously, but that is just the beginning of what is
needed. The need here is for an explanatory model of great breadth,
one that explains not just one or two of the puzzling features of
this illness, but each of its important features and the features,
both similar and distinctive of this whole group of multisystem
illnesses. It has been the perceived lack of such a model that has
led CFS/ME and this group of illnesses to be repeatedly described as
unexplained. Now we can argue that the whole group of illnesses is
explained. Some of these explanation that have particular
relevance to CFS/ME are as follows:
have the list of nine distinct short-term stressors that can all
apparently initiate cases of CFS/ME, all of which can act to start a
sequence, leading to increased nitric oxide levels. We have, for the
first time an explanation for how this diversity of stressors can
lead to a common response – initiation of cases of CFS/ME.
is chronic because of the action of the NO/ONOO- cycle mechanism. We
can explain the generation of both non-specific and specific
symptoms and signs of CFS/ME, the latter discussed here and the
former in my book (8). We can explain its comorbidity with other
multisystem illnesses and of other well-accepted diseases such as
migraine and asthma as being due to each of these illnesses having
similar causal mechanisms.
can explain the action of certain agents and entire treatment
protocols which appear to be effective in the treatment of CFS/ME,
some discussed above and others discussed on my main web page and in
my book (8). Indeed it is the great promise of this mechanism as a
predictor of therapeutic approaches that is its most important
feature for the many who suffer from CFS/ME and related illnesses.
can explain the stunning variation, both quantitative and
qualitative in the symptoms and signs of illness among CFS/ME
patients and, indeed, among patients of the whole group of
can explain the role of a series of genes reported to influence CFS/ME
susceptibility, roles that to my knowledge have not been previously
has been the many previously unexplained features of CFS/ME and
these multisystem illnesses that has led others to argue we needed a
new paradigm of human of disease in order to explain them. That is
exactly what we have.
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