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NCF Identifies Other Notable Discoveries Tied to Ciguatera Toxins
By Alan Cocchetto 2002

    
Since the discovery of ciguatera toxin (ciguatoxin), the National CFIDS Foundation (NCF) has focused its efforts
on several other significant scientific aspects that will likely impact patient health. First, there appears to be a
definitive link between ciguatera poisoning and the development of polymyositis [1,2]. From several published case
reports physicians, from Dartmouth's Medical School and Stanford University's School of Medicine, made an
important discovery relative to ciguatoxin exposure. These researchers had shown that biopsy-proven
polymyositis subsequently developed in several patients who were severely poisoned by ciguatera toxin years earlier.

    Polymyositis is an inflammatory muscle disease of unknown etiology and is considered an idiopathic
inflammatory myopathy. In polymyositis, immune-mediated muscle inflammation and vascular damage occur due to
the fact that the immune system becomes primed to act against previously unrecognized muscle antigens. This often
results in muscular pain, weakness and wasting, arthralgias, joint pain, as well as muscular tenderness, inflammation, and atrophy.

    The researcher's concluded that "the patients' clinical courses and the unlikelihood of
coincidence of contracting both diseases suggest to us a causal relationship." In fact, biopsies
"showed scattered necrotic muscle fibers and infiltration with mononuclear inflammatory cells
consistent with polymyositis." Furthermore "the association of polymyositis with several
autoimmune diseases suggests an underlying autoimmune mechanism."

    As to a potential mechanism as to how these muscle changes occur, they stated that
"how muscle breakdown occurs following ciguatera toxin exposure remains unclear. Membrane
disruption of myelin has been demonstrated following toxin exposure [3]. Large inward fluxes
of sodium across cell membranes could cause osmotic disruption of cell membranes, exposing intracellular structures
and proteins as new antigens to the immune system. Sensitized lymphocytes could then attack muscle at a later time,
resulting in an inflammatory myopathy." Treatment for these polymyositis patients included tapered or low doses of
prednisone or methylprednisolone.

    Next, the NCF found that the apparent connection between ciguatera and polymyositis was consistent with
previous discoveries in Chronic Fatigue Syndrome patients. Dr. Carolyn Warner, from the Dent Neurologic Institute
at SUNY Buffalo School of Medicine, previously reported her findings of neuromuscular abnormalities in CFS
patients. She found biopsy-proven muscle inflammatory infiltrates that included polymyositis [4]. The NCF feels this
prior work, connecting patient muscle abnormalities to polymyositis, greatly strengthens this hypothesis since we
now know that a ciguatera toxin epitope is involved in the etiology of CFS. Likewise, the NCF can report an
apparent increased risk of cancer in patients with polymyositis [5,6] and this is in agreement with previous
publications linking CFS to increased cancer risks as well.

The NCF has also discovered that in the liver biopsies of some CFS patients, there was
the formation of mallory bodies. Mallory body formation, in the liver, is associated with a condition known as
NonAlcoholic SteatoHepatitis (NASH) or NonAlcoholic Fatty Liver Disease [7]. A related polyether toxin, okadaic
acid, is associated with the formation of mallory bodies [8], so this may also be the case for ciguatera toxins.

    Nonalcoholic fatty liver disease is histologically indistinguishable from the liver damage
resulting from alcohol abuse. Liver biopsy features include steatosis, inflammatory cell infiltration, Mallory's hyaline
and fibrosis. The presence of these features, alone or in combination, accounts for the wide spectrum of nonalcoholic
fatty liver disease. In patients with NASH, some degree of liver fibrosis may be present.

    A retention of lipids within hepatocytes, mostly in the form of triglycerides, is a
prerequisite for the development of nonalcoholic fatty liver disease. The abnormalities leading
to lipid accumulation are not well understood but could include alterations in the metabolic
pathways of uptake, synthesis, degradation, or secretion in hepatic lipids resulting from
insulin resistance. Likewise, patients identified with steatohepatitis have structural lesions
in the liver and have impaired ATP recovery. Drug therapy for these conditions have included Gemfibrozil, vitamin
E (alpha-tocopherol), metformin, Ursodiol, and betaine.

    Last of all, the NCF wishes to comment about certain specifics regarding ciguatera
toxins. Due to the large number of phone calls and emails, we would like to address the
following:

    Acute ciguatera toxin poisoning has utilized IV-mannitol for treatment. This, however,
doesn't appear to work in the case of chronic ciguatera poisoning, which is the current model
that we believe applies to this disease.

    What about Pfiesteria and the use of cholestyramine? First of all, Pfiesteria and ciguatera
are not the same. Ciguatera toxin is associated with a sodium ion channelopathy. This is not the
case with Pfiesteria. In fact, the ciguatera toxin molecular structure is very complicated and there
are many variations of ciguatera depending upon where you are on the globe! Will a bile acid resin
(cholestyramine) acting as a toxin binder work? We don't know at this point! However we did hear from a well
known CFS specialist who informed us that they tried this on their patients years ago but were unable to get a
response. Is it worth trying? The NCF encourages you to discuss this with your own physician as they may agree to a
trial period for the drug.

    One thing we do know for certain, is that the ciguatoxin is being generated by
an infectious agent and therefore its production is guaranteed until you either bind it via an
anti-toxin, or some yet unrecognized entity, or inhibit the infectious agent that causes its production. The NCF is
working very hard to identify appropriate therapies that can universally be applied here given the current knowledge
about ciguatera. Once again, we certainly hope that all CFS patients will be screened for ciguatera toxin poisoning.

    In closing, the NCF encourages the CFS patient community to alert and discuss these findings with their personal
physicians since, with each new discovery, drug intervention and treatment may lead to improvements in quality of
life.

References:
1. Stommel EW, Parsonnet J, Jenkyn LR
Polymyositis after ciguatera toxin exposure.
Arch Neurol. 1991 Aug;48(8):874-7
2. Stommel EW, Jenkyn LR, Parsonnet J
Another case of polymyositis after ciguatera toxin exposure.
Arch Neurol. 1993 Jun;50(6):571
3. Palafox NA, Jain LG, Pinano AZ, Gulick TM, Williams RK, Schatz IJ
Successful treatment of ciguatera fish poisoning with intravenous mannitol.
JAMA. 1988 May 13;259(18):2740-2.
4. Warner CL, Heffner RR, Cookfair D
Neuromuscular Abnormalities in Patients with Chronic Fatigue Syndrome
Chapter 38, 348-351; The Clinical and Scientific Basis of Myalgic Encephalomyelitis,
Chronic Fatigue Syndrome 1992
5. Sigurgeirsson B, Lindelof B, Edhag O, Allander E
Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study.
N Engl J Med. 1992 Feb 6;326(6):363-7
6. Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E, Mellemkjaer L, Airio A, Evans SR,
Felson DT
Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based
study.
Lancet. 2001 Jan 13;357(9250):96-100
7. Angulo P
Nonalcoholic fatty liver disease.
N Engl J Med. 2002 Apr 18;346(16):1221-31 Review
8. Yuan QX, Nagao Y, Gaal K, Hu B, French SW
Mechanisms of mallory body formation induced by okadaic acid in drug-primed mice.
Exp Mol Pathol. 1998 Oct;65(2):87-103
9. Shoemaker RC
Residential and recreational acquisition of possible estuary-associated syndrome: a new
approach to successful diagnosis and treatment.
Environ Health Perspect. 2001 Oct;109 Suppl 5:791-6

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