These four illnesses,
chronic fatigue syndrome (CFS/ME),
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 (1,2). They also share a common pattern of case initiation: 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 most 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. What many have called the
Gulf War Syndrome is a combination of all four (3; Chapter 10, ref.1).
It is my goal for this web page, to provide a detailed explanation for their overall mechanism and provide a proposed mechanism for the many symptoms and signs that they share. In web pages linked to this one, I will discuss some specific features of these illnesses and how each of these specific features may be generated by this same basic mechanism. I also provide more detailed support for the NO/ONOO- cycle mechanism outlined on this main web page, in these other web pages. My overall goal, here, is to outline the understanding of these illnesses that is documented in much greater detail in my book, ¡°Explaining ¡®Unexplained Illnesses¡¯¡± (1), as well as in many other publications (2-12).
The stressors implicated in the initiation of these illnesses are summarized in Table 1.
Table 1. Illness: Stressors Implicated in Initiation of Illness
Chronic fatigue syndrome
Viral infection, bacterial infection, organophosphorus pesticide exposure, carbon monoxide exposure, ciguatoxin poisoning, physical trauma, severe psychological stress, toxoplasmosis (protozoan) infection, ionizing radiation exposure
Multiple chemical sensitivity
Volatile organic solvent exposure, organophosphorus/carbamate pesticide exposure, organochlorine pesticide exposure, pyrethroid exposure, mercury exposure, carbon monoxide exposure, hydrogen sulfide exposure
Fibromyalgia
Physical trauma (particularly head and neck trauma), viral infection, bacterial infection, severe psychological stress, pre-existing autoimmune disease
Post-traumatic stress disorder
Severe psychological stress, physical (head) trauma
The stressors indicated in bold are the ones most commonly implicated for that specific illness. It should be noted that the majority of such stressors are implicated in the initiation of more than one illness.
The stressors indicated in bold are the ones most commonly implicated for that specific illness. It should be noted that the majority of such stressors are implicated in the initiation of more than one illness.
We have, here, 17 diverse stressors implicated in initiating these illnesses, leading one to ask, how they may do so? What I have argued, in my book (1) and elsewhere (2-10), is that each of these can act to increase nitric oxide levels. Each is reported to increase the levels of nitric oxide, or in three cases where that has not been studied, to stimulate a process which is itself known to increase nitric oxide. This is a striking common response and leads to the question about how nitric oxide increases might lead to chronic illness? My answer to that question is that nitric oxide, acting primarily through its oxidant product peroxynitrite, initiates a biochemical vicious cycle that is responsible, in turn, for the chronic illness. We have, then, an initial cause of illness (short-term stressor or stressors) acting to start this vicious cycle, with the cycle responsible for causing the chronic phase of illness. We are now calling the cycle the NO/ONOO- cycle after the structures of nitric oxide (NO) and peroxynitrite (ONOO-) but pronounced no, oh no! The cycle mechanism is outlined in Figure 1:....
There are five principles underlying the NO/ONOO- cycle as an explanatory model:
- Short-term stressors that initiate cases of multisystem illnesses act by raising nitric oxide synthesis and consequent levels of nitric oxide and/or other cycle elements
- 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. This principle predicts that the various elements of the NO/ONOO- cycle will be elevated in the chronic phase of illness.
- 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.
- 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. The consequences of this primarily local mechanism show up in the multisystem illnesses through the stunning variations one sees in symptoms and signs from one patient to another. Different tissue impact of the NO/ONOO- cycle mechanism is predicted to lead to exactly such variations in symptoms and signs. One also sees evidence for this fourth principle in published brain scan studies where one can directly visualize the variable tissue distribution in the brains of patients suffering from one of these illnesses.
- Therapy should focus on down-regulating the NO/ONOO- cycle biochemistry. In other words, we should be treating the cause, not just the symptoms.
Of these principles, we have discussed 1 and 2 above. Principle 3 predicts that the symptoms and signs of illness can be generated by elevation of one or more elements of the cycle. Some examples of how symptoms and signs of illness may be explained by the cycle are discussed below.
Principle 4 is so important that it takes up an entire chapter in my book (1). Because nitric oxide, superoxide and peroxynitrite, the three chemical compounds most central to the NO/ONOO- cycle have relatively short half lives in biological tissues, they don¡¯t diffuse very far from their site of origin in the body. Nitric oxide has the longest such half-life and it only diffuses about one millimeter from its origin or less. Furthermore, most of the mechanisms implicated by the arrows act at the cellular levels. The consequence of all of this is that the NO/ONOO- cycle may be elevated in one tissue of the body but an adjacent tissue may show little elevation and therefore have little impact by the cycle. This local nature of the cycle biochemistry means that we can have all kinds of variations in tissue impact from one patient to another, leading in turn to all kinds of variation in symptoms and signs from one individual to another. This striking variation in symptoms from one individual to another has been repeatedly been noted in these illnesses and has been one of the great puzzles about this group of illnesses. The variation can be easily explained by the local nature of the NO/ONOO- cycle mechanism.
The primarily local nature, outlined in Principle 4 does not imply that there are no systemic effects. The antioxidant depletion produced by local oxidative stress will be, to a substantial extent, systemic and some of the effects of the inflammatory cytokines are also systemic. These may, in turn, produce changes in neuroendocrine function and immune function that are also systemic. However the primary local nature helps us to understand the profound variations in symptoms and signs seen from one patient to another, how these different diseases may differ from one another and also differ from possible additional diseases that may share this NO/ONOO- cycle etiology, such as tinnitus (12).
