By Alan Cocchetto, NCF Medical Director©2010

From Spring 2010 Forum

The other day I had a conversation with one of my PWC/ME colleagues. I mentioned to them that the true impetus behind the NCF's research efforts was directly aimed at the extrication of patients from the wreckage of this horrible disease. I felt that this simple statement was a fair assessment of our duty to the international CFIDS/ME community. According to the Webster's dictionary, the word extricate means to free or remove from an entanglement. To extricate implies the use of care or ingenuity in freeing from a difficult position or situation. When applied to this disease process, entanglement may be an understatement! In this article, I will explain some of the scientific basics of our ongoing research efforts… efforts that the NCF honestly believes represents the beginning of the end of this arduous journey.

Ciguatera and its critical connections! Hmmm. Like it or not, that is where the NCF's "action" is regarding CFIDS/ME. The NCF firmly believes that a subgroup of CFIDS/ME patients have an ongoing but distinct disease process that is critically tied to ciguatera poisoning. While you read this article, please keep in mind that from a toxicologic perspective, we are talking about toxin levels that are measured in hundreds of parts-per-trillion or stated another way, tenths of parts-per billions! Yes, you are reading this correctly. Such seemingly small toxin amounts have been shown to have a dramatic impact on human health due to their extreme neurotoxic potency.

Since 2002, the NCF has extensively funded various grant projects at the University of Hawaii's John A. Burns School of Medicine. This has allowed scientists there to perform much needed additional research into ciguatera toxin reactivity in blood samples from CFIDS/ME patients worldwide to help unravel the scientific clues associated with the disease. Numerous peer-reviewed medical journal publications on replicated science have directly resulted from these efforts. Many of these can be found on our website and I encourage readers to review this material accordingly. As you may have guessed, this research effort is ongoing.

Ciguatera has some truly remarkable characteristics that cannot be overlooked nor underestimated. According to research completed by Fournier, French scientists reported that ciguatera poisoning has been found to alter a key protein, known as neuropathy target esterase (NTE), in a manner similar to that found with organophosphate (OP) poisonings [1]. In this paper, the authors commented that "NTE may be a useful parameter to demonstrate the toxic origin of chronic neuropathies." Readers may recall that OP's form the fundamental basis of many insecticides, herbicides and nerve agents [2]. While NTE is an integral membrane protein present in all neurons and is mainly distributed in the nervous system, it plays an important role in neural development and axonal maintenance [3,4]. In fact, NTE was discovered originally as the primary target for those OP esters which cause a delayed neuropathy with degeneration of long axons in the peripheral nerves and spinal cord. Alterations to NTE have been associated with neurodegeneration [5].

Another scientific finding of critical importance is that ciguatera has been identified as an anticholinesterase [6-10]. Anticholinesterases, also known as acetylcholinesterase inhibitors, act as chemicals that inhibit the cholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine [11]. Other acetylcholinesterase inhibitors include venoms, poisons, pesticides and nerve agents. In particular, organophosphate pesticides, insecticides or nerve agents act so as to inactivate acetylcholinesterase, which is essential to nerve function in humans. This represents a key mechanism that is tied to their poisoning effects. Furthermore, this can result in organophosphate-induced delayed neuropathy, also called OPIDN, which is a neuropathy caused by the killing of neurons in the central nervous system, especially in the spinal cord, as a result of acute or chronic organophosphate poisoning [12].

How then is ciguatera tied to CFIDS/ME other than by what has been shown by the research funded directly by the NCF? Well, let me review some of the fundamental connections: Let me begin with the easiest connections first. These are the obvious ones that include those that have previously been identified by other global scientists who have published on the direct relationship between CFIDS/ME and ciguatera poisoning. Pearn stated, "The fact that at least one potent mammalian toxin can cause a chronic syndrome indistinguishable from CFS opens the way for further research into this enigmatic condition [13]." One year later, in another publication, Pearn reported that ciguatera toxin produces a syndrome identical to CFS in 2% of those affected [14]. Racciatti published an important paper on "CFS following a toxic exposure [15]." Here, the authors stated that "in at least some subgroups of CFS patients the onset of the illness is well correlated to a previous exposure to a specific environmental and/or food toxins: ciguatera poisoning. [16,17]. " Furthermore, the immune characteristics following toxic exposure included statistically significant reductions in CD56+ NK cells as well as high CD4/CD8 ratios. These authors state that "Our preliminary findings confirm the presence of a dysfunction of the immune system in CFS patients with a history of toxin exposure previous to CFS onset.... So CFS patients with a post-toxic exposure onset might represent a well defined CFS subgroup characterized by specific immune dysfunctions probably precipitated by the toxic exposure itself." This certainly falls into line with the ciguatoxin reactivity discoveries made by Hokama at the University of Hawaii.

Let me now move on to other CFIDS/ME studies that fall into this research camp as well. Kerr reported a significant upregulation in the gene expression for NTE in CFIDS/ME patients [18]. The authors commented that "NTE is a target for organophosphates and chemical warfare agents, both of which may precipitate CFS, on the basis of a neuropathy resulting from inactivation of serine esterase activity." Two years later, Kerr stated that "It is intriguing that within our 88-gene signature, there are several genes with links to various aetiological triggering factors. For example, virus infection and organophosphate exposure (neuropathy target esterase (NTE) [19]." Furthermore, the authors commented, "Three patients had markedly raised levels of NTE, while all normal controls had uniformly low levels; CFS subtypes with significantly raised NTE levels were 1, 2, 5 and 7, of which subtypes 1, 2 and 7 were the most severely affected subtypes. We have previously documented upregulation of NTE in CFS. NTE is the primary site of action of organophosphate (OP) compounds such as sarin, which causes axonal degeneration and paralysis resulting from inactivation of its serine esterase activity, and in the adult chicken nervous system, OP-modified NTE initiates neurodegeneration. Exposure to OP compounds may trigger CFS/ME and Gulf War illness."

Tahmaz reported on their study to investigate a possible association between exposure to organophosphates and the development of "chronic fatigue" among people who consider their health to have been affected by pesticides in sheep farming [20]. The hypothesis investigated was that repeated exposure to organophosphate pesticides in sheep dip may increase the probability of developing chronic fatigue. The authors concluded that "Higher chronic fatigue scores were associated with higher exposure to organophosphate pesticides. Chronic fatigue is very common amongst those who consider their health was affected by pesticides and we have shown there is limited evidence of an association between exposure to organophosphates and chronic fatigue. Further research is needed to investigate the cause of this syndrome amongst farmers exposed to pesticides."

Khan reported that "peripheral cholinergic abnormalities in the vascular endothelium of only patients with CFS, suggesting that this syndrome has a different aetiology, which might involve inhibition of vascular cholinesterase [21]." Khan also has a number of additional research papers that have been published on this subject [22 - 24]. Interestingly, the authors went on to state that "Prolongation of acetylcholine-induced vasodilatation is suggestive of a disturbance to cholinergic pathways, perhaps within the vascular endothelium of patients with CFS, and might be related to some of the unusual vascular symptoms, such as hypotension and orthostatic intolerance, which are characteristic of the condition [23]." In one of their lastest publications, these authors further stated that their research "results point to a problem with AChE under-expression on the vascular endothelium of CFS patients [24]."

In addition, Geller reported that orthostatic hypotension was a characteristic of ciguatera poisoning while Pearn reported that autonomic dysfunction leads to hypotension in severe ciguatera poisoning [25,26]. Streeten and Rowe have previously reported on the role of hypotension in CFIDS/ME patients [27,28].

In conclusion, ciguatera poisoning has been associated with CFIDS/ME. Since ciguatera has been shown to target and alter neuropathy target esterase as well as acting as an anticholinesterase, these two characteristics are of vast medical importance because cholinesterase inhibition is specifically implicated in chronic ill health. This article was aimed at introducing various scientific connections that should serve as a fundamental basis for the evolving NCF disease model for CFIDS/ME.

References:

1. Determination of the neurotoxic esterase in neurologic pathology of toxic origin. Measurement in human lymphocytes in poisoning by organophosphates, ciguatera and ethyl alcohol; Fournier L, Fournier E, Lecorsier A; Ann Med Interne (Paris). 1987;138(3):169-72
2. Organophosphate; http://en.wikipedia.org/wiki/Organophosphate
3. Neuropathy target esterase; Glynn P; Biochem J. 1999 Dec 15;344 Pt 3:625-31
4. Neuropathy target esterase: An essential enzyme for neural development and axonal maintenance; Chang PA, Wu YJ; Int J Biochem Cell Biol. 2009 Dec 16
5. Neural development and neurodegeneration: two faces of neuropathy target esterase; Glynn P; Prog Neurobiol. 2000 May;61(1):61-74
6. Ciguatoxin: more than an anticholinesterase; Rayner MD, Kosaki TI, Fellmeth EL; Science. 1968 Apr 5;160(823):70-1
7. Mass ciguatera poisoning after eating barracuda in Mexico: prognostic and therapeutic implications; De Haro L, Hayek-Lanthois M, Joossen F, Affaton MF, Jouglard J; Med Trop (Mars). 1997;57(1):55-8
8. Ciguatera: neurophysiologic and histoenzymologic studies of several fractions of ciguatoxic extracts; Niaussat PM, Drouet J, Bagnis R, Deloince R, Chanfour B; C R Seances, Soc Biol Fil. 1975;169(4):912-9
9. Ciguatera fish poisoning with cholinesterase inhibition. Report of a case; Okihiro MM, Keenan JP, Ivy AC Jr; Hawaii Med J. 1965 May-Jun;24:354-7
10. Ciguatera fish poison: A cholinesterase inhibitor; Li KM; Science. 1965 Mar 26;147:1580-1
11. Acetylcholinesterase inhibitor; http://en.wikipedia.org/wiki/Anticholinesterase
12. Organophosphate-induced delayed neuropathy; http://en.wikipedia.org/wiki/OPIDN
13. Chronic Ciguatera: One Organic Cause of the Chronic Fatigue Syndrome; Pearn J; JCFS 1996 Aug; 2(2 & 3): 29-34
14. Chronic fatigue syndrome: chronic ciguatera poisoning as a differential diagnosis; Pearn JH; Med J Aust. 1997 Mar 17;166(6):309-10
15. Chronic fatigue syndrome following a toxic exposure; Racciatti D, Vecchiet J, Ceccomancini A, Ricci F, Pizzigallo E; Sci Total Environ. 2001 Apr 10;270(1-3):27-31
16. Ciguatera in Australia. Occurrence, clinical features, pathophysiology and management; Gillespie NC, Lewis RJ, Pearn JH, Bourke AT, Holmes MJ, Bourke JB, Shields WJ; Med J Aust. 1986 Dec 1-15;145(11-12):584-90
17. Ciguatera: a potent cause of the Chronic Fatigue Syndrome; Pearn J; EOS J Immunol Immunopathol 1995 XV 1/2: 63-65
18. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome; Kaushik N, Fear D, Richards SC, McDermott CR, Nuwaysir EF, Kellam P, Harrison TJ, Wilkinson RJ, Tyrrell DA, Holgate ST, Kerr JR; J Clin Pathol. 2005 Aug;58(8):826-32
19. Seven genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis: a detailed analysis of gene networks and clinical phenotypes; Kerr JR, Burke B, Petty R, Gough J, Fear D, Mattey DL, Axford JS, Dalgleish AG, Nutt DJ; J Clin Pathol. 2008 Jun;61(6):730-9
20. Chronic fatigue and organophosphate pesticides in sheep farming: a retrospective study amongst people reporting to a UK pharmacovigilance scheme; Tahmaz N, Soutar A, Cherrie JW; Ann Occup Hyg. 2003 Jun;47(4):261-7
21. Peripheral cholinergic function in humans with chronic fatigue syndrome, Gulf War syndrome and with illness following organophosphate exposure; Khan F, Kennedy G, Spence VA, Newton DJ, Belch JJ; Clin Sci (Lond). 2004 Feb;106(2):183-9
22. Enhanced sensitivity of the peripheral cholinergic vascular response in patients with chronic fatigue syndrome; Spence VA, Khan F, Belch JJ; Am J Med. 2000 Jun 15;108(9):736-9
23. Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome; Khan F, Spence V, Kennedy G, Belch JJ; Clin Physiol Funct Imaging. 2003 Sep;23(5):282-5
24. Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome; Spence VA, Khan F, Kennedy G, Abbot NC, Belch JJ; Prostaglandins Leukot Essent Fatty Acids. 2004 Apr;70(4):403-7
25. Orthostatic hypotension in ciguatera fish poisoning; Geller RJ, Benowitz NL; Arch Intern Med. 1992 Oct;152(10):2131-3
26. Neurology of ciguatera; Pearn J; J Neurol Neurosurg Psychiatry. 2001 Jan;70(1):4-8
27. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome; Streeten DH, Thomas D, Bell DS; Am J Med Sci. 2000 Jul;320(1):1-8
28. Neurally mediated hypotension and chronic fatigue syndrome; Rowe PC, Calkins H; Am J Med. 1998 Sep 28;105(3A):15S-21S

[Ed. Note: Currently chronic ciguatera poisoning is considered incurable.]