Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

According to the World Health Organization, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neurological disease characterized by widespread inflammation and multi-systemic neuropathology. Aetiology and pathogenesis are unknown, and several agents have been proposed as causative agents or as factors perpetuating the syndrome. Exposure to heavy metals, with particular reference to mercury and gold in dental amalgams, has been considered among the triggers of ME/CFS. Here we hypothesize that cadmium, a widespread occupational and environmental heavy metal pollutant, might be associated with some of the neurological findings described in ME/CFS. In fact, ME/CFS patients show a decrease of the volume of the gray matter in turn associated with objective reduction of physical activity. Cadmium induces neuronal death in cortical neurons through a combined mechanism of apoptosis and necrosis and it could then be hypothesized that cadmium-induced neuronal cell death is responsible for some of the effects of cadmium on the central nervous system, i.e. a decrease in attention level and memory in exposed humans as well as to a diminished ability for training and learning in rats, that are symptoms typical of ME/CFS. This hypothesis can be tested by measuring cadmium exposure in a cohort of ME/CFS patients compared with matched healthy controls, and by measuring gray matter volume in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. In addition, we hypothesize that cadmium exposure could be associated with reduced cerebral blood flow in ME/CFS patients because of the disruptive effects of cadmium on angiogenesis. In fact, cadmium inhibits angiogenesis and low global cerebral flow is associated with abnormal brain neuroimaging results and brain dysfunction in the form of reduced cognitive testing scores in ME/CFS patients. This hypothesis can be tested by measuring cerebral cortex blood flow in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. If our hypothesis is demonstrated correct, the consequences could affect prevention, early diagnosis, and treatment of ME/CFS. Implications in early diagnosis could entail the evaluation of symptoms typical of ME/CFS in cadmium-exposed subjects as well as the search for signs of exposure to cadmium in subjects diagnosed with ME/CFS. Nutritional supplementation of magnesium and zinc could then be considered, since these elements have been proposed in the prophylaxis and therapy of cadmium exposure, and magnesium was demonstrated effective on ME/CFS patients’ symptom profiles.

Introduction

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is the term used to define a complex array of symptoms that includes, but is not limited to, profound, debilitating fatigue, lasting for at least six months and resulting in a substantial reduction of daily activities [1]. It is classified as a neurological disease in the World Health Organization’s International Classification of Diseases (ICD G93.3), and it is characterized by widespread inflammation and multi-systemic neuropathology [2]. Although according to the recent International Consensus Criteria it is probably more appropriate to use only the term “Myalgic Encephalomyelitis” [2], in this article we refer to the syndrome using the traditional double acronym ME/CFS. Under this definition, it is estimated that the syndrome affects millions people worldwide, and its prevalence is calculated in between 400 and 2500 adults per 100,000 population [3].

Both aetiology and pathogenesis are unknown, and a number of agents have been proposed either as causative agents or as factors contributing to the perpetuation of the symptoms. As in many syndrome, it is likely that there are multiple causes leading to a common clinical picture. Although a trigger cannot be necessarily considered an etiological agent, according to a recent review, several events may act as triggers, from external environmental or infectious events, such as chemical exposure or infections, to psychological and social factors that may be critical in maintaining the chronic condition of the syndrome [4]. The hypothesis of a retrovirus being associated with ME/CFS was postulated in 2009 [5], but further studies rejected this hypothesis [6], and, as of today, the causes of ME/CFS remain obscure. Drawing an analogy from the evolution of the human brain, ME/CFS may even be regarded as a “phylogenic disease” [7], [8], [9], [10], [11], according to principle of “integrated phylogeny” of the primate brain [12].

Exposure to heavy metals, with particular reference to dental amalgams, has been considered among the triggers of ME/CFS, and the attention has been focused mostly on mercury and gold [13], [14]. According to Stejskal et al. [13], heavy metals might be responsible for inflammatory processes that may modulate the hypothalamic-pituitary-adrenal axis and trigger the multiple, non-specific, symptoms characterizing ME/CFS. These Authors noticed in 1999 that in certain ME/CFS patients cadmium was a sensitizer for blood lymphocytes, and this observation was confirmed in 2006 by Valentine-Thon et al. [15] who described cadmium-sensitization in metal-exposed individuals showing a number of symptoms superimposable to those of ME/CFS. Nevertheless, the precise role of cadmium in the aetiology or pathogenesis of ME/CFS is not well understood, and the target organ of cadmium toxicity responsible for ME/CFS symptoms is not known. Probably, also because of this lack of knowledge, ME/CFS is not considered among the risk hazards associated with cadmium exposure. Here we hypothesize that cadmium, one of the most important occupational and environmental heavy metal pollutants, might be associated with, or responsible for, some of the neurological findings recently described in ME/CFS.