Novel Disease Paradigm Produces Explanations for a Whole Group of Illnesses

A Common Causal (Etiologic) Mechanism for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia and Posttraumatic Stress Disorder

Martin L. Pall, Professor of Biochemistry and Basic Medical Sciences
Washington State University
martin_pall@wsu.edu
509-335-1246

Specific web pages:
Multiple Chemical Sensitivity
Chronic Fatigue Syndrome
Fibromyalgia

These four illnesses, chronic fatigue syndrome (CFS), multiple chemical sensitivity (MCS), fibromyalgia (FM) and post-traumatic stress disorder (PTSD) often occur together in the same individuals (they are comorbid) and share many symptoms in common (1-15). Gulf War syndrome is a combination of all four (16-20). These four illnesses also share a common pattern of case initiation (15,21): Each is often initiated (that is started) by a short-term stressor only to be followed by chronic illness that typically lasts for years and often for life. These various similarities and overlaps among these four have led many scientists to suggest that they may share a common etiology (cause), however they have been uncertain what the cause may be. I will call these four illnesses multisystem illnesses, following the lead of some others, and will challenge here the claims they are unexplained and that even their symptoms are unexplained. Indeed my goal for this web page is to provide a detailed explanation for their overall mechanism and provide a proposed mechanism for many of the symptoms and signs that they share. Therapy should be based on down-regulating the overall mechanism. In web pages linked to this one, I will discuss some specific features of each of these illnesses and how each of these specific features may be generated by this same basic mechanism.

This web site outlines the understanding of these illnesses that is documented in great detail in my forthcoming book (21).

Short-Term Stressors and the Cycle They Initiate

The stressors implicated in the initiation of these illnesses (21) are summarized in Table 1.

Table 1 Illnesses Initiated by Short Term Stressors

IllnessStressors

The stressors most commonly involved in the initiation of each type of illness are indicated in bold face.

These 12 diverse stressors can all act to increase the levels of the compound nitric oxide in the body (15,21-27). Eight of these have been shown to increase nitric oxide in animal models and/or in humans. The other four, ciguatoxin, severe psychological stress, organochlorine pesticides and pyrethroid pesticides, have all been shown to initiate a response that leads to increased NMDA receptor activity and it is known that increased NMDA receptor activity produces increased levels of nitric oxide and its oxidant product, peroxynitrite. Thus, all 12 can produce a common biochemical response and the consequent increase in nitric oxide may explain the common roles of these stressors in initiating cases of these chronic illnesses. How can a short-term increase in nitric oxide produce chronic illness that typically lasts for years and often for life? It may be argued that it may act through its oxidant product, peroxynitrite, to initiate a vicious cycle mechanism which is responsible for the chronic illness. In other words, we have an initial cause (one or more short-term stressors) and then an ongoing cause of chronic illness (vicious cycle). The cycle that is proposed to be responsible is diagrammed in Figure 1 (15,21-28).

Fig. 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- kB 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 but a series of other elements, including the transcription factor NF- kB, oxidative stress, five inflammatory cytokines (in box, upper right), all three different forms of nitric oxide synthases (iNOS, nNOS and eNOS), and two neurological receptors the vanilloid receptor and the NMDA receptor.

We are now calling this cycle the NO/ONOO- cycle, based on the structures of nitric oxide (NO) and peroxynitrite (ONOO-), but pronounced no, oh no!

One of the features of the NO/ONOO- cycle that may not be obvious from Fig. 1, is that mitochondrial (energy metabolism) dysfunction is an integral part of the cycle. It is known that peroxynitrite attacks a number of the components of mitochondria, inhibiting their ability to generate energy in the form of ATP (21,23,25). Several of these components are certain proteins known as iron-sulfur proteins and have key roles in the generation of energy in mitochondria and are inactivated by peroxynitrite. Nitric oxide and superoxide can also inhibit energy metabolism in mitochondria, as well (21,25). The lowered energy metabolism has important roles in the NO/ONOO- cycle, leading to increased NMDA activity and increased levels of intracellular calcium (Ca 2+). Lowered energy metabolism may also lead to lowered ability of the impacted cells to recover from the impact of other elements of the cycle.

There are 22 different mechanisms represented by the arrows in the NO/ONOO- cycle, of which 19 are well-accepted biochemistry (21). The other 3 are less well documented, but have been reported in apparently reliable studies. Overall, there is extensive evidence supporting the individual mechanisms of the NO/ONOO- cycle and what needs to be questioned is its physiological relevance to these multisystem illnesses.

Five Principles

There are five principles underlying the NO/ONOO- cycle as an explanatory model of these illnesses (21), the first two of which we have already discussed:

1. Short term stressors that initiate cases of multisystem illnesses act by raising nitric oxide synthesis and consequent levels of nitric oxide and its oxidant product peroxynitrite.
2.  Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of nitric oxide and peroxynitrite and other cycle elements is produced and maintained.
3.  Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity.
4.  Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because the mechanisms involved in the cycle act at the level of individual cells, the fundamental mechanisms are local.
5.  Therapy should focus on down-regulating NO/ONOO- cycle biochemistry.

I’ll discuss examples of principle 3 later on this web page as well on the specific pages dedicated to three of these illnesses, multiple chemical sensitivity, chronic fatigue syndrome and fibromyalgia.

The fourth principle is a very important one. Because the compounds involved, nitric oxide, peroxynitrite and superoxide have relatively short half lives in biological tissues and because the mechanisms of the cycle act at the cellular level, the basic mechanism of the cycle is local. Consequently, the cycle may severely impact one tissue of the body but an adjacent tissue may be largely unimpacted. Thus because the tissues impacted by the cycle may vary from one patient to another, this easily explains why the symptoms and signs of illness vary so much from one patient to another. This variability in symptoms and signs has been one of the great puzzles of these multisystem illnesses and it is easily resolved by the NO/ONOO- cycle mechanism. I am not saying that there are no systemic changes in these illnesses, but rather that the main changes are local.

The fifth principle is the most important one for the sufferers of these illnesses and for the dedicated physicians and other health care providers who are trying to effectively treat them. We need to lower the NO/ONOO- cycle biochemistry for effective treatment; treating symptoms will never be very effective because symptomatic treatment does not get at the basic cause of illness. I will argue below that we do have five effective treatment protocols, each using multiple agents that down-regulate NO/ONOO- cycle biochemistry.

Elevation of NO/ONOO- Cycle Elements in the Chronic Phase of Illness

The chronic phase of these multisystem illnesses, the only phase that can usually be studied in humans, is typically studied years or decades after the initiation of illness. Nevertheless, where NO/ONOO- cycle elements have been studied, they have been reported to be elevated. Clearly one needs to explain how these may be elevated years after the initiation of illness, and the NO/ONOO- cycle mechanism provides such an explanation. Among the cycle elements that have been studied are oxidative stress, nitric oxide synthesis, inflammatory cytokine levels, lower mitochondrial/energy metabolism, NMDA activity and vanilloid activity. Peroxynitrite itself has not been studied but its elevation can be inferred from the elevation of nitric oxide synthesis and of oxidative stress. Some of these elements have only been studied in some multisystem illnesses. For example, vanilloid activity has only been studied, to my knowledge, in FM and in MCS, being apparently elevated in both. Inflammatory cytokines have only been studied in CFS, FM and in PTSD, but not in MCS; however it is reported that chemical exposure can increase such cytokine levels.

In general, where data are available, elements of the NO/ONOO- cycle appear to be elevated in the chronic phase of multisystem illnesses (15,21-28).

Three Generic Types of Evidence for the Existence of the NO/ONOO- Cycle

There are three generic types of evidence – that is evidence not linked to any specific disease--supporting the existence of the NO/ONOO- cycle (reviewed in my book, ref 21). One is a series of studies showing that treatment with two drugs known to act to increase nitric oxide levels can produce increases in nitric oxide synthesis. These two drugs, nitroglycerine and nitroprusside, are both known to chemically break down and one of the break down products is nitric oxide. They are reported to lead to increased nitric oxide synthesis in the body due to the action of all three nitric oxide synthases. This provides evidence for a vicious cycle leading to increased nitric oxide synthesis via all three synthases, but does not provide evidence for any of the other elements of the NO/ONOO- cycle.

A second type of generic evidence is from studies of hyperalgesia, the process that produces excessive perception of pain. It has been shown that all of the elements of the NO/ONOO- cycle are involved in the generation of excessive pain hyperalgesia. It is difficult to see how all of these elements can be involved here unless they are linked together by such a cycle as the NO/ONOO- cycle. What is surprising is that cycle elements are elevated both in the painful tissues and also in that region of the spinal cord that is involved in pain processing – the dorsal horn region(s) of the spinal cord. Thus two types of regions of the body appear to have NO/ONOO- cycle elevation in hyperalgesia. One of the consequences of these mechanisms is that it provides a simple explanation for the excessive pain in these multisystem illnesses – NO/ONOO- cycle elevation produces chronic pain through the same mechanisms previously documented in hyperalgesia.

The third type of generic evidence for the cycle reviewed in my book is the finding that NMDA stimulation leads to increased activity for essentially all of the elements of the NO/ONOO- cycle. NMDA stimulation is known to allow the flow of calcium ions (Ca 2+) into the cytoplasm of the cell, leading, in turn to stimulation of the two nitric oxide synthases that are calcium-dependent, nNOS and eNOS. Thus two cycle elements are elevated initially, intracellular calcium and nitric oxide but this leads to elevation of the other cycle elements, as well. All the major elements of the NO/ONOO- cycle are reported to be elevated following NMDA stimulation (21). This provides evidence that the NO/ONOO- cycle or something very similar to it can act in living cells in response to NMDA stimulation.

Shared Symptoms and Signs Found in Multisystem Illnesses

In Chapter 3 in my book (21), I look at a 17 distinct symptoms and signs that are found in several of these multisystem illnesses and several of these were discussed in an earlier paper (23). Most of these are often found in all four of these illnesses, although there are some which have only been studied in two or three of them. Most of these only occur in some patients, reflecting the high variability of symptoms and signs that was discussed above. Many people have repeatedly claimed that these symptoms and signs are unexplained, but that is no longer true. In my book and, in some cases, in an earlier paper (23), I present a number of plausible mechanisms by which these symptoms and signs can be generated by NO/ONOO- cycle elements. These are presented as plausible mechanisms, not as established mechanisms in these illnesses. Several of these are listed in Table 2:

Table 2 Plausible Mechanisms for Symptoms and Signs of Multisystem Illnesses

Symptom or sign Plausible mechanism

Evidence for each of these is presented in my book (21).

It can be seen from Table 2, that a diverse group of shared symptoms and signs can be generated via known mechanisms from elements of the NO/ONOO- cycle, providing plausible mechanisms for such symptom generation. Thus these symptoms and signs should no longer be considered to be unexplained. I will consider how what are viewed as unique symptoms of signs of MCS, CFS or FM may be generated on the web pages dedicated to each of these individual illnesses.

Therapy

The fifth principle of the NO/ONOO- cycle is that therapy should focus on down-regulating NO/ONOO- cycle biochemistry. In other words, lower the cause of illness. Let me state at the outset that I am a Ph.D., not an M.D. and nothing here should be viewed as medical advice.

There are several challenges to therapies aimed at lowering NO/ONOO- cycle biochemistry.

• The first of these is that we need to stop doing things that up-regulate this biochemistry and there are various stressors that up-regulate this biochemistry therefore are of obvious concern.
• The second is that the complexity of the NO/ONOO- cycle makes it difficult to down-regulate and makes it likely that we will need to use multiple agents in order to be effective in such down-regulation. We don’t have a magic bullet to treat these illnesses and may have to rely, therefore, on complex combinations of agents each of which may produce an incremental improvement by lowering aspects of the cycle mechanism.
• The third is that peroxynitrite, the most central element in the NO/ONOO- cycle is difficult to effectively scavenge in vivo and therefore approaches based solely on scavenging peroxynitrite may not be expected to be effective.

Let’s consider the first of these challenges. Such stressors as chemical exposure in MCS, excessive exercise in CFS and psychological stress, especially in PTSD, should be avoided to have any expectation of effective therapy. Each of these stressors are expected to up-regulated NO/ONOO- cycle activity in these individual illnesses. Foods to which individuals have developed food allergies should be avoided, as antibody-antigen reactions cause tissues to increase nitric oxide synthesis. Excitotoxins can stimulate NMDA activity and up-regulate NO/ONOO- cycle biochemistry and should therefore be avoided. Excitoxins include monosodium glutamate, aspartame and possibly certain other flavorings such as hydrolyzed vegetable proteins.

In Chapter 15 of my book, I consider 30 different agents or classes of agents that are available today and are predicted to down-regulate NO/ONOO- cycle biochemistry and are predicted, therefore, to be potentially useful therapeutic agents. I will add a 31 st such agent that was suggested to me by Dr. Jacob Teitelbaum. Each of these are listed in the long table that follows.

Table 3 Agents Predicted to Down-Regulate NO/ONOO Cycle Biochemistry

Agent (or class) Mechanism(s) Evidence

Evidence is listed as being clinical trial evidence (CT) or clinical observations/anecdotal evidence (CO/A) or none, based solely on studies of CFS, MCS, FM or closely related illnesses.

It can be seen from Table 3 that there are many different agents that are promising candidates for therapy. Most of them are nutritional supplements. There is some evidence for efficacy of individual agents based on clinical trials (CT) or from clinical observations and/or anecdotal evidence (CO/A) but in most cases, the individual agents where they seem to be effective, have relatively modest effectiveness. The suggestion is that combinations of these agents may be much more effective than individual agents. This combination therapy has been the approach taken by five different physicians in developing their treatment protocols and such combination therapy approaches appear to be the most promising of all therapeutic approaches for treatment of these illnesses.

Five physicians have developed complex treatment protocols for these multisystem illnesses. Three of these have focused on the treatment of chronic fatigue syndrome or closely related fatiguing illness, one on both chronic fatigue syndrome and fibromyalgia and one on chemically sensitive patients. Each of these protocols uses from 14 to 18 different agents or classes of agents that are predicted to down-regulate NO/ONOO- cycle biochemistry! While two of these protocols (Teitelbaum’s and Cheney’s) contain substantial numbers of agents not obviously related to the NO/ONOO- cycle, each contains many agents predicted to down-regulate the cycle. The treatment protocols are outlined in the lists that follow:

Dr. Paul Cheney has developed his treatment protocol based on clinical observations and has honed it over the past two decades of treatment of chronic fatigue syndrome patients. He advises trying to avoid things that exacerbate the NO/ONOO- cycle mechanism, some of the same things that I discussed above. Specifically he suggests attenuating GI tract problems by such strategies as going on a low food allergen diet, minimizing environmental chemical exposure and also minimizing inflammatory diseases, such as around the teeth. The agents that I list are followed, in some cases, by comments on how they may act—those comments are mine, not Cheney’s.

• High dose hydroxocobalamin (B12) injections— potent nitric oxide scavenger
• Whey protein—glutathione precursor
• Guaifenesin—vanilloid antagonist?
• NMDA blockers
• Magnesium—lowers NMDA activity
• Taurine—antioxidant and acts to lower excitotoxicity including NMDA activity
• GABA agonists—GABA acts as an inhibitory neurotransmitter to lower NMDA activity—these include the drug neurontin (gabapentin)
• Histamine blockers—mast cells which release histamine are activated by both nitric oxide and vanilloid stimulation (Chapter 7) and may therefore be part of the cycle mechanism
• Betaine hydrochloride (HCl)—Betaine lowers reductive stress, the hydrochloride form should only be used in those with low stomach acid. Betaine (trimethylglycine) is also listed separately in the protocol description

Antioxidants listed as follows:

• Flavonoids, including “bioflavonoids,” olive leaf extract, organic botanicals, hawthorn extract
• Vitamin E (forms not listed)
• Coenzyme Q10—acts both as antioxidant and to stimulate mitochondrial function
• a-lipoic acid
• Selenium
• Omega-3 and –6 fatty acids
• Melatonin—as an antioxidant that may act in the brain
• Pyridoxal phosphate—improves glutamate/GABA ratio
• Folic acid—lowers uncoupling of nitric oxide synthases

Cheney prescribes for his patients a total of 18 distinct agents or classes of agents, each of which can be viewed as down-regulating aspects of the NO/ONOO- cycle. I would argue that this in not just coincidental, that it argues in support of the NO/ONOO- cycle mechanism.

Dr. Jacob Teitelbaum has published placebo-controlled trial data supporting the efficacy of one version of his protocol (29,30), something none of these other physicians has done. It seems to be effective on both chronic fatigue syndrome and fibromyalgia patients. I am going to describe a recent version of his complex protocol, focusing on what may be the central parts of the protocol, the parts described as “nutritional treatments” and “mitochondrial energy treatments.” The last agent in the list, D-ribose, was added to the protocol recently (personal communication).

• Daily energy B-complex—B vitamins including high dose B 6, riboflavin, thiamine, niacin and also folic acid. These fall into four categories that I have listed earlier in the chapter
• Betaine hydrochloride (HCl)—lowers reductive stress, hydrochloride form should only be taken by those deficient in stomach acid
• Magnesium as magnesium glycinate and magnesium malate—lowers NMDA activity—often uses magnesium injections
• a-Lipoic acid—important antioxidant helps regenerate reduced glutathione
• Vitamin B 12 IM injections, 3 mg injections (does not state whether this is hydroxocobalamin)—may act as potent nitric oxide scavenger
• Eskimo fish oil—excellent source of long chain omega-3 fatty acids. Lowers iNOS induction, anti-inflammatory
• Vitamin C
• Grape seed extract (flavonoid)
• Vitamin E, natural—does not state whether this includes g-tocopherol or tocotrienols
• Physician’s protein formula, used as glutathione precursor
• Zinc—antioxidant properties and copper/zinc superoxide dysmutase precursor
• Acetyl-L-carnitine—important for restoring mitochondrial function
• Coenzyme Q10—both important antioxidant properties and stimulates mitochondrial function
• D-ribose—acts to increase rate of ATP and reduced glutathione regeneration

If you consider that the oral B vitamins fall into four categories listed earlier in the chapter, Teitelbaum uses a total of 18 agents or classes of agents that are predicted to down-regulate the NO/ONOO- cycle, in the core part of his treatment protocol.

Dr. Garth Nicolson started his scientific career developing the famous Singer/Nicolson, fluid mosaic model of biological membranes, a model that is described in essentially all of the standard biochemistry textbooks. He and his colleagues have published on open label trials of a complex proprietary mixture known as NT factor TM, apparently designed to improve mitochondrial and thus energy metabolism function. The trials have been on a group of older patients with unexplained chronic fatigue, and consequently there is some question whether these patients have CFS. Nevertheless, Nicolson and coworkers (31-33) report statistically significant improvements in fatigue and in several other changes often found in multisystem disease patients, affective/meaning, sensory and cognitive/mood. Many of the NT factor components are predicted to lower much of the NO/ONOO- cycle biochemistry. Unfortunately, there is no detailed description of the concentrations of the components of the NT factor proprietary mixture. The mixture contains the following components that are predicted to lower NO/ONOO- cycle biochemistry:

• Polyunsaturated phosphatidyl choline—predicted to lower reductive stress
• Other phosphatidyl polyunsaturated lipids—this and the phosphatidyl choline are predicted to help restore the oxidatively damaged mitochondrial inner membrane
• Magnesium—lowers NMDA activity, may aid in energy metabolism
• Taurine—antioxidant activity and lowers excitoxicity including NMDA activity
• Artichoke extract—as flavonoid source?
• Spirulina—blue-green alga is a highly concentrated antioxidant source
• Natural vitamin E—does not tell us whether this includes g -tocopherol or tocotrienols
• Calcium ascorbate—vitamin C
• a -Lipoic acid—important antioxidant, key role in regeneration of reduced glutathione, but also has role in energy metabolism
• Vitamin B 6—balance glutamate and GABA levels, lowers excitotoxicity
• Niacin—role in energy metabolism
• Riboflavin—important in reduction of oxidized glutathione back to reduced glutathione; also has important role in mitochondrial function
• Thiamin—role in energy metabolism
• Vitamin B 12—as nitric oxide scavenger?
• Folic acid—lowers nitric oxide synthase uncoupling

The way I have categorized these earlier on this site and in Chapter 15 of my book, these agents fall into 15 distinct classes of agents expected to lower NO/ONOO- cycle biochemistry.

Dr. Neboysa (Nash) Petrovic is a South African physician who, I believe, also has a clinic in England. His CFS treatment protocol (34) has been described as follows (I am unsure how current this is):

• Valine and isoleucine—branched chain amino acids known to be involved in energy metabolism in mitochondria, and may be expected,therefore, to stimulate energy metabolism; modest levels may also lower excitotoxicity
• Pyridoxine (B 6)—improves balance between glutamate and GABA, lowers excitotoxicity
• Vitamin B 12 in the form of cyanocobalamin—cyanocobalamin is converted to hydroxocobalamin in the human body but the latter form will be more active as a nitric oxide scavenger, since it does not require such conversion
• Riboflavin—helps reduce oxidized glutathione back to reduced glutathione
• Carotenoids (alpha-carotene, bixin, zeaxanthin and lutein)-lipid (fat) soluble peroxynitrite scavengers
• Flavonoids (flavones, rutin, hesperetin and others)
• Ascorbic acid (vitamin C)
• Tocotrienols—forms of vitamin E reported to have special roles in lowering effects of excitotoxicity
• Thiamine (aneurin)—B vitamin involved in energy metabolism
• Magnesium
• Zinc
• Betaine hydrochloride (HCl)—lowers reductive stress, hydrochloride form should only be used by those deficient in stomach acid
• Essential fatty acids including long chain omega-3 fatty acids
• Phosphatidyl serine—reported to lower iNOS induction (35,36)

According to the way I have listed these agents, his protocol contains 14 agents or classes of agents predicted to down-regulate NO/ONOO- cycle biochemistry.

My Own Effort to Develop a Treatment Protocol

My effort to apply the NO/ONOO- cycle mechanism to the treatment of these multisystem illnesses was in cooperation with Dr. Grace Ziem in Maryland. The history of this collaboration and our respective roles are described in my book. The protocol was developed to try to effectively treat Dr. Ziem’s chemically sensitive, chemically injured patients, patients that she does not consider to be MCS patients. Her views on this are described in my book (21) and on her web site (37).

The protocol described below is only effective, according to Dr. Ziem when her patients minimize chemical exposure, consistent with the view that we need to avoid up-regulating the NO/ONOO- cycle for these agents to be effective. The protocol as described in my book contains the following agents:

• Nebulized, inhaled reduced glutathione
• Nebulized, inhaled hydroxocobalamin (some use sublingual)
• Mixed, natural tocopherols including g -tocopherol
• Buffered vitamin C
• Magnesium as malate
• Four different flavonoid sources: Ginkgo biloba extract, cranberry extract, silymarin, and bilberry extract
• Selenium as selenium-grown yeast
• Coenzyme Q10
• Folic acid
• Carotenoids including lycopene, lutein and b -carotene
• a -Lipoic acid
• Zinc (modest dose), manganese (low dose) and copper (low dose)
• Vitamin B 6 in the form of pyridoxal phosphate
• Riboflavin 5’-phosphate (FMN)
• Betaine (trimethylglycine)

Patients are advised to use environmental controls to reduce exposure to volatile organic solvents, pesticides and other irritant chemicals wherever possible. Dr. Ziem finds that her most severely chemically injured patients need to be started on much lower doses of the glutathione and a -lipoic acid, increasing exposure as they see initial improvement. The therapeutic agents were compounded by Key Pharmacy in Kent, Washington which has been calling it their “neural sensitization protocol.” Key Pharmacy has a web site that lists their email address and phone number and consequently further information can be easily obtained.

Dr. Ziem reports four distinct observations about her patients (21):

• The majority of her patients suffering from reactive airways were placed on this protocol during the first half of 2004 and almost all of them were on it or most of it by spring 2005. Patients coming back to see her report consistent improvement of their symptoms, including respiratory symptoms, fatigue, cognitive function and usually migraine. Improvements were well above those seen with her previous treatment approach.
• Historically, Dr. Ziem has gotten many emergency calls each summer from patients who have become very ill from nearby pesticide spraying. In the summer of 2004 she did not receive any such calls from her patients on the protocol. In the summer of 2005 she received only one such call, from a patient on the protocol who was directly exposed to pesticide spray.
• Two of her patients reported being completely asymptomatic, something she had not seen before. These were, however, still controlling their environment to minimize exposure and still on the protocol.
• Patients seem to be improving at such a rapid rate that many are no longer coming in regularly to see her. She is now able to take new patients at 10 to 15 times the previous rate. In order to assess the progress of the patients who are no longer coming in, Mr. Jim Seymour has contacted 30 such patients and all 30 report substantial improvement in their symptoms. However, the majority of them are not on the complete protocol, reporting that they are unable to afford it. Seymour’s subjective assessment is that those on the complete protocol have seen much greater improvement than have those on only part.

As of the beginning of 2006, two additional agents are being added to the oral part of the protocol, acetyl-L-carnitine and taurine. We are considering adding one or two flavonoid-containing extracts that scavenge superoxide. The current protocol, then contains 17 different agents or classes of agents that are predicted to down-regulate NO/ONOO- cycle biochemistry.

Dr. Ziem states, in a personal communication (21) that “I consider the protocol to be the most significant medical advance ever for chemical injury, but it is not a substitute for environmental controls. It does gradually allow patients to be in social environments with fewer symptoms and less severe exacerbation.”

I have talked with other physicians who have used this protocol with apparent favorable response in their CFS and FM patients. It may be effective, therefore, in a variety of NO/ONOO- cycle diseases.

The Tenth Paradigm of Human Disease

What we have been describing here is an etiologic mechanism centered on certain morbid processes which explain the four multisystem illnesses and possibly other diseases/illnesses both prominent and obscure. It argues that the multisystem illnesses are true diseases caused by this mechanism, albeit diseases that are highly variable from one individual to another because of the variation of tissue distribution of the underlying biochemistry. They constitute, in other words, a disease spectrum.

The NO/ONOO- cycle mechanism fits into the history of diseases (21, Chapter 14) as shown in Table 4:

Table 4 Ten Paradigms of Human Disease

The reported prevalences of multisystem illnesses have been fairly well-studied in the U.S. at least, and they are comparable with the prevalences of the other major disease paradigms, shown in bold face. It can be argued that the tenth paradigm, NO/ONOO- cycle diseases, may well be one of the top four disease paradigms in terms of its overall impact on human health.

Could It Be Wrong?

Could the NO/ONOO- cycle explanation of multisystem illnesses be wrong? Could this tenth paradigm of human disease be fictional?

There are certainly many areas where there are little or no data to support predictions of the cycle model and many others where the data that is available is inadequate to support current standards of evidence. In addition, the cycle as outlined in Figure 1 may be oversimplified both because certain aspects of it may be missing in certain tissues and because additional cycle elements are likely to be involved in certain tissues, as well. Nevertheless the therapy discussion strongly suggests that the cycle makes very useful predictions in terms of therapy and therefore is sufficiently comprehensive to be a useful, predictive model.

Let me focus on two important features. Firstly it is the only explanatory model that explains not just one but all of these multisystem illnesses. Consequently it is the only available model to fit the prediction that many scientists have made that these must share a common etiologic mechanism. Secondly, the cycle mechanism itself as diagrammed in Figure 1 is based almost entirely on well-established biochemical mechanisms. The only thing that is new about it is the assumption that the elements of the cycle fit together as predicted by these mechanisms and constitute, therefore, a vicious cycle. It is that simple prediction that underlies all of the explanatory power of the model.

In the last chapter of my book, I list 12 puzzling features of these illnesses that are explained by the NO/ONOO- cycle mechanism, including its five underlying principles. None of these had been previously explained and this lack of explanation has been what has led, in part, to the repeated claims that these are unexplained illnesses. The 12 features explained by the NO/ONOO- cycle are as follows:

It provides explanations for the etiology of not just one but all four of these multisystem diseases.

1. It explains their chronic nature.
2. It explains how cases can be initiated by 12 diverse and distinct stressors.
3. It explains the diverse biochemical and physiological properties of the chronic phase of these diseases.
4. It explains how 18 different agents or groups of agents may individually produce reported improvements and how the complex treatment protocols of five different physicians may lead to major improvements in sufferers.
5. It explains 16 of the shared symptoms and signs of these diseases, symptoms and signs that have repeatedly been described as being previously unexplained.
6. It explains the symptoms that are specific for each type of disease, symptoms that can be explained by the influence of the NO/ONOO- cycle on specific tissues.
7. It explains their high comorbidity with each other.
8. It explains their high comorbidity with such well-accepted diseases as tinnitus, asthma, migraine, lupus and rheumatoid arthritis.
9. It explains 11 distinct puzzling feature of MCS, only one of which was adequately explained previously.
10. It explains the properties of animal models of CFS, MCS and PTSD, each of which provides evidence, in turn, supporting a NO/ONOO- cycle etiology.
11. It explains the stunning qualitative and quantitative variation in symptoms from one patient to another.

If you take away the central mechanism of the NO/ONOO- cycle as it is described in Figure 1, all of these explanations disappear and we are left with an unstructured list of unexplained observations. It is this stunning fit between observation and prediction that tells us that the basic features of the NO/ONOO- cycle explanatory model cannot be wrong! The NO/ONOO- cycle explanatory model is like an arch, where the basic cycle mechanism is the keystone. If you remove the keystone, the whole arch collapses into a rubble of scattered stones and it is the complete collapse that tells us how the arch is organized to make a compelling structure. The cycle mechanism, which is based on a simple and evident assumption, is the keystone that is essential for understanding these multisystem illnesses.

Richard Feynman, the great 20 th century scientist was called by Omni magazine “the smartest man in the world” and has also been considered to be a great skeptic. Feynman wrote that “It is possible to know when you are right, way ahead of checking all the consequences. You can recognize truth by its beauty and simplicity.” It is that beauty and simplicity and comprehensiveness that tells us that the NO/ONOO- cycle model is fundamentally right.

Specific web pages:
Multiple Chemical Sensitivity
Chronic Fatigue Syndrome
Fibromyalgia

How to Support this Research

References:

1. Miller CS. (1999) Are we on the threshold of a new theory of disease? Toxicant-induced loss of tolerance and its relationship in addiction and abdiction. Toxicol Ind Health 15:284-294.

2. Buchwald D, Garrity D. (1994) Comparison of patients with chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities. Arch Int Med 154:2049-2053.

3. Ziem G, Donnay A. (1995) Chronic fatigue, fibromyalgia, and chemical sensitivity: overlapping disorders. Arch Intern Med 155:1913.

4. Donnay A, Ziem G. (1999) Prevalence and overlap of chronic fatigue syndrome and fibromyalgia syndrome among 100 new patients. J Chronic Fatigue Syndr 5(3/4),71-80.

5. Clauw DJ, Crousos GP. (1997) Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features. Neuroimmunomodulation 4,134-153.

6. Yunus MB. 2001 Central sensitivity syndromes: a unified concept for fibromyalgia and other similar maladies. J Indian Rheumatism Assoc 8(1),27-33.

7. White KP, Speechley M, Harth M, Ostbye T. 2000 Co-existence of chronic fatigue syndrome with fibromyalgia in the general population - A controlled study. Scand J Rheum 29:44-51.

8. Rowat SC. 1998 Integrated defense system overlaps as a disease model: with examples for multiple chemical sensitivity. Env Health Perspect 106(Suppl 1):85-109.

9. Clauw D. 2002 Fibromyalgia associated syndromes. J Musculoskeletal Pain 10(1/2):201-214.

10. Wessely S, Nimnuan C, Sharpe M. 1999 Functional somatic syndromes: one or many? Lancet 354:936-939.

11. Aaron LA, Buchwald D. 2001 A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med 134:868-881.

12. Lipschitz EL 2001 Chronic fatigue syndrome and posttraumatic stress disorder. JAMA 286:916-917.

13. Cohen H, Neumann L, Haiman Y, Matar MA, Press J, Buskila D. 2002 Prevalence of post-traumatic stress disorder in fibromyalgia patients: overlapping syndromes of post-traumatic fibromyalgia syndrome? Semin Arthritis Rheum 32:38-50.

14. Friedman MJ. 1994 Neurobiological sensitization models of post-traumatic stress disorder: their possible relevance to multiple chemical sensitivity syndrome. Toxicol Ind Health 10:449-462.

15. Pall ML. 2001 Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Med Hypoth 57:139-145.

16. The Iowa Persian Gulf Study Group. 1997 Self-reported illness and health status among Gulf War veterans – a population-based study. JAMA 227:238-245.

17. Kipen MH, Hallman W, Kang H, Fiedler N, Natelson BH. 1999 Prevalence of chronic fatigue and chemical sensitivities in Gulf War Registry Veterans. Arch Environ Health 54:313-318.

18. Nicolson GL, Nicolson NL. 1998 Gulf War illnesses: complex medical, scientific paradox. Med Confl Surviv 14:156-165.

19. Hodgson MJ, Kipen HM. 1999 Gulf War illnesses: causation and treatment. J Occup Environ Med 41:443-452.

20. Baker DG, Mendenhall C L, Simbartl LA, Magan LK, Steinberg JL. 1997 Relationship between posttraumatic stress disorder and self-reported symptoms of Persian Gulf War veterans. Arch Intern Med 157:2076-2078.

21. Pall ML. 2007 Explaining “Unexplained Illnesses”: Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others, Haworth Medical Press, in press.

22. Pall ML. 2000 Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypoth 54:115-125.

23. Pall ML. 2000 Elevated peroxynitrite as the cause of chronic fatigue syndrome: Other inducers and mechanisms of symptom generation. J Chronic Fatigue Syndr 2000;7(4):45-58.

24. Pall ML and Satterlee JD. 2001 Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome and posttraumatic stress disorder. Ann NY Acad Sci 933:323-329.

25. Pall ML. 2002 NMDA sensitization and stimulation by peroxynitrite, nitric oxide and organic FASEB J 16:1407-1417.

26. Pall ML. 2003 Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity: central role of N-methyl-D-aspartate receptors in the sensitivity mechanism. Environ Health Perspect 111:1461-1464.

27. Pall ML, Anderson JH. 2004 The Vanilloid Receptor as a Putative Target of

Diverse Chemicals in Multiple Chemical Sensitivity. Arch Environ Health 59:363-375.

28. Pall ML. 2006 Multiple chemical sensitivity: towards the end of controversy. Townsend Lett Doctors Patients August/September:52-56.

29. Teitelbaum J. 2003. Effective treatment for CFS/FM - Part I & II. Syllabus AAEM, 38 th Annual Meeting, The Walking Wounded: Identifying the Causes and Exploring the Newest Treatment Options for Chronic Fatigue Syndrome, Fibromylagia and Environmental Sensitivities, pp 73-118.

30. Teitelbaum JE, Bird B, Greenfield RM, Weiss A, Muenz L, Gould L. 2002 Effective treatment of chronic fatigue syndrome and fibromyalgia: a randomized, double-blind, placebo-controlled, intent to treat study. J Chronic Fatigue Syndr 8(2):3-28.

31. Ellithorpe RR, Settinery RA, Nicolson GL. 2003 Pilot study: reduction of fatigue by use of a supplement containing dietary glycophospholipids. J Am Neutraceutical Assoc 6:23-28.

32. Agadjanyan M, Vasilevko V, Ghochikyan A, et al. 2003 Nutritional supplement (NT Factor TM) restores mitochondrial function and reduces moderately severe fatigue in aged subjects. J Chronic Fatigue Syndr 11(4):1-12.

33. http://www.cfidshealth.com/

34. http://home.earthlink.net/~stompinangel/recovering.html#petrovic

35. Calderon C, Huang ZH, Gage DA, Sotomayor EM, Lopez DM. 1994 Isolation of a nitric oxide inhibitor from mammary tumor cells and its characterization as phosphatidyl serine. J Exp Med 180:945-958.

36. DiNapoli MR, Calderon CL, Lopez DM. 1997 Phosphatidyl serine is involved in the reduced rate of transcription of the inducible nitric oxide synthase gene in macrophages from tumor-bearing mice. J Immunol 158:1810-1817.

37. http://www.chemicalinjury.net/