Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis, 2020, L'Herondelle et al

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Hutan

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Killian L’Herondelle,1 Matthieu Talagas,1,2 Olivier Mignen,3Laurent Misery,1,2 and Raphaele Le Garrec1,*
(French researchers)

Abstract
Ciguatera fish poisoning (CFP), the most prevalent seafood poisoning worldwide, is caused by the consumption of tropical and subtropical fish contaminated with potent neurotoxins called ciguatoxins (CTXs). Ciguatera is a complex clinical syndrome in which peripheral neurological signs predominate in the acute phase of the intoxication but also persist or reoccur long afterward.

Their recognition is of particular importance in establishing the diagnosis, which is clinically-based and can be a challenge for physicians unfamiliar with CFP. To date, no specific treatment exists. Physiopathologically, the primary targets of CTXs are well identified, as are the secondary events that may contribute to CFP symptomatology.

This review describes the clinical features, focusing on the sensory disturbances, and then reports on the neuronal targets and effects of CTXs, as well as the neurophysiological and histological studies that have contributed to existing knowledge of CFP neuropathophysiology at the molecular, neurocellular and nerve levels.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602189/
free access
 
Clinically, CFP is a polymorphous syndrome. Furthermore, in some cases, the time course of its symptomatology is unusual. Indeed, in addition to disturbances that immediately follow the ingestion of the toxic fish, it is not rare that some symptoms reoccur months or even years after exposure.
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The persistence or relapse of these for weeks, months, and sometimes beyond, is undoubtedly one of the most distressing and disabling characteristics of CFP. These symptoms include pruritus, distal paresthesia, cold dysesthesia and arthralgia associated with fatigue [32,87,88]. The frequency of cases of so-called chronic ciguatera (i.e., chronic symptoms after acute exposure to CTX) has been estimated to be 5%–20% [88,89] but reached 34% in one study [90]. These symptoms persist intermittently without any particular triggering factor and/or reappear after the consumption of certain drinks or foods, especially alcohol but also peanuts, nonciguateric seafood, pork or poultry [64,66,91].
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In addition, unusual cases of chronic inflammatory conditions such as polymyositis and arthritis occurring months or years following CFP have been reported [92,93,94]. Whether these are related to CTX immune effects or immune parameter dysfunctions found in CFP patients remains to be clarified [95,96,97]. In addition, a few case reports or studies have documented repercussions on the mind and cognitive functions, including a tendency to develop depression, in CFP cases with chronic symptoms [98,99,100]. Such alterations have been observed in mice following repeated exposure to P-CTX-1 [101].
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The paper mentions voltage-gated sodium channels (Nav) as the primary target of the toxins. Downstream effects include an increase in intracellular calcium concentration by various mean, including calcium influx through transient receptor potential (TRP) channels.

A blood transcriptomic study suggested activation of inflammatory pathways and genetic variants of the adaptive immune system are involved in the persistence of CFP disturbances.

I thought this was interesting - the idea that the toxins bind to the sodium channels and are difficult to dislodge. And more toxin might be released over time from other binding sites (tissue or plasma proteins or lipoproteins):

Other toxicokinetic factors, including the quasi-irreversible binding of CTXs to Nav and a potential release from binding sites (tissue or plasma proteins or lipoproteins), likely contribute to the persistence and reoccurrence of CFP sensory disorders. P-CTX-1 was indeed still detected in peripheral nerves 2 months after exposure [209]. However, CFP sensory disturbances can persist and/or reoccur many months or even years (see Section 2.3). The mechanisms involved remain to be clarified.
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However, another study showed a recurrent motor strength deficit associated with neuronal apoptosis, reduced spontaneous firing rate and astrogliosis in the motor cortex 4 to 6 months after intraperitoneal administration
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It's known that ciguatera poisoning can develop gradually over time - with small exposures building up the toxin levels.


Further to triggers of symptoms
Management of the ambulatory patient with ciguatera rests on avoidance of potential exacerbating triggers. Although large rigorous studies are lacking, reports of consumption of caffeine, peanuts, 8 seafood8,9 and alcohol8,9 have all been associated with worsening of symptoms, as has exercise.
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Even if none of the findings about ciguatera poisoning are helpful for us, it's good to be aware of it as a differential diagnosis. It sounds as though it is often mis-diagnosed as chronic fatigue syndrome.
 
One of the studies referenced by this paper is
https://pmj.bmj.com/content/75/889/678

Ciguatera fish poisoning, 1999

Pralidoxime chloride has been used as a cholinesterase reactivator based on laboratory data that suggests that ciguatera toxin acts as a cholinesterase inhibitor, although a controlled trial has not been carried out.7 Amitriptyline has been shown to provide variable relief from the neurological symptoms associated with ciguatera poisoning, perhaps by membrane stabilisation via sodium channel blockade, or through its anticholinergic activity.
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That ciguatera toxin acts as a cholinesterase inhibitor has been disputed - saying that while it acts so in vitro, it does not act so in vivo.

However, a document on suggested treatments
https://www.ciguatera.pf/index.php/en/la-ciguatera/les-traitements
says
pralidoxime (Contrathion®…; 200 to 1000 mg, slow infusion) for its cholinesterase reactivator property.

cholestyramine (Questran®…), an anticholesteremic, which seems to be a ciguatoxins-antagonist, demonstrated some efficiency on neurological symptoms improvement in numerous patients.
 
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A researcher into ciguatera poisoning at the University of Hawaii became interested in ME. Most of the work was done before I had internet access so I can't remember much about it and he died so his research was never followed up.

He found something he called ciguatera (?) factor in people with ME which he thought caused a channelopathy. I read that part there was confusion because the NIH was doing similar work but they called the factor something like else.

I've always felt that channelopathy would be worth examining in ME.
 
Is this similar to the covid finding of snake venom mimick
Low complement c3 will mimic this I think
 
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