At least four distinct toxins can produce the clinical manifestations of ciguatera poisoning [1, 6, 7]. These toxins originate in dinoflagellates, and the toxins become more concentrated as they move up the food chain [1]. The classic ciguatoxins (for example, ciguatoxin-1 from the liver of the moray eel) increase the permeability of sodium channels in excitatory membranes [6].

Symptoms typically begin within a few hours after fish containing ciguatoxins are ingested [1]. Although gastrointestinal complaints are common early in the illness, the most pronounced and persistent symptoms are neurosensory. A sensation of loose teeth and problems with temperature differentiation are almost pathognomonic of ciguatera intoxication, but some patients have neither of these symptoms [1, 2]. With severe poisonings, neurologic complaints persist for as long as 6 months [1, 2].

We describe a patient with the ciguatera poisoning syndrome acquired from a farm-raised salmon. Neurosensory symptoms persisted for more than 2 years. Partial characterization of the toxins extracted from the salmon implicates a novel ciguatoxin that blocks, rather than opens, sodium channels.

Methods

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Case Report

A 30-year-old white woman in good health suddenly developed numbness in her distal extremities within 2 hours of eating dinner. At that time, she had eaten two pieces of a farm-raised salmon (which she had poached and then sauteed in garlic) and fettuccine Alfredo and had drunk beer. The other family members had also eaten the fettuccine, but no one else ate salmon. During the previous few days, the family had eaten all the same meals together. The salmon had been purchased the previous day from a local supermarket, which apparently obtained its fish from several farms located in the United States, Canada, and Chile.

The patient developed shooting pains down her arms and legs shortly after noting numbness in her hands and feet. She then had multiple bouts of watery diarrhea associated with nausea. She also reported a "lump in her throat" and could not swallow. Her symptoms persisted for days and were exacerbated by attempts to eat. She required hospitalization for volume depletion. The dysphagia, nausea, and diarrhea slowly resolved. She continued to have severe head, neck, and back pain radiating down her arms; her legs were much less involved. Approximately 1 week into her illness, she noticed an unpleasant taste in her mouth, had the sensation that her teeth were loose and "going to fall out," and experienced jaw numbness. She subsequently recognized that she could not identify "hot" by either taste or touch.

During the next few months, these symptoms occurred intermittently, although the pain and numbness became less intense. Episodic interscapular pain associated with tingling in her hands has persisted for more than 2 years. Chocolate, coffee, and tea exacerbate her symptoms. A piece of the salmon that had been frozen since purchase was analyzed as described below.

Analysis of Salmon

A latex solid-phase immunobead assay with a monoclonal antibody directed against ciguatoxin-1 was used to detect antigenically related substances in multiple samples of the salmon suspected of causing the symptoms [8]. The flesh of the salmon was soaked in acetone, extracted with chloroform, and fractionated into equal volumes of 80% aqueous methanol and hexane. After vaporization of the 80% methanol fraction, the residue was injected intraperitoneally into four mice that were then observed for signs of illness [9]. Six mice injected with the diluent (1% Tween 60 in saline) served as controls.

The inotropic effect of the 80% methanol fraction was assayed using guinea pig atrium [9, 10]; modulation of this effect by ciguatoxin-1 (which opens sodium channels), by tetrodotoxin (which blocks sodium channels), and by verapamil (which blocks calcium channels) was also assessed.

Results

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Our patient developed classic symptoms of ciguatera poisoning from farm-raised salmon that may have originated in Chile during the South American summer. Her sensation of "loose teeth" and her inability to differentiate hot from cold are characteristic (but not invariably so) symptoms of ciguatera poisoning, although patients commonly describe frank hot-cold reversal [1, 2]. Monoclonal antibody to ciguatoxin-1 unequivocally reacted with multiple samples extracted from the salmon. Within approximately 7 hours after injecting mice with the methanol fraction of a chloroform extract of the salmon flesh, all four mice died. None of the six control animals became ill.

The methanol fraction was weakly inotropic in the guinea pig atrium assay; this effect was similar but much smaller than that observed with ciguatoxin-1 [5, 9]. The inotropic effect of the salmon toxins was slightly inhibited by tetrodotoxin and was moderately inhibited by verapamil. Further, the salmon extract diminished the inotropic effect of ciguatoxin-1. These findings suggest that the salmon contained multiple toxins, including a classic ciguatoxin, another toxin that opens calcium channels, and a novel toxin that blocks sodium channels in cardiac muscle (in contradistinction to the effect of ciguatoxin-1 in opening these channels).

Discussion

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Ciguatera poisoning has not been previously associated with salmon or any farm-raised fish. Symptoms, even the neurosensory complaints, usually abate after 6 months [1, 2]. Our patient acquired prototypical ciguatera poisoning from a farm-raised salmon that probably originated in Chile. The salmon presumably acquired the toxin from eating contaminated food. The patient's symptoms were disabling, and dysesthesias have persisted for more than 2 years.

Substances cross-reactive with monoclonal antibodies raised against ciguatoxin-1 were identified in multiple portions of the salmon [8]. In our experience during the last decade with the solid-phase immunobead and similar assays, "false-positives" have only been recognized in fish containing related polyethers [8, 9]. The methanol fraction of chloroform extracts from the salmon flesh were quickly lethal to four mice after intraperitoneal injection [9]. Before their deaths, the mice developed the characteristic signs of ciguatera intoxication, including tachypnea, cyanosis, ataxia, and eventually paralysis [9].

Similar to ciguatoxin-1, a positive inotropic effect of the methanol fraction of the chloroform extract of the salmon was shown using the guinea pig atrium assay [9, 10]. However, this fraction antagonized the inotropic effects of ciguatoxin-1, and its inotropic effect could be diminished by sodium and calcium channel blockers. These results are consistent with a chloroform-soluble fraction containing multiple toxins (or activities) that activate and block sodium channels and that open calcium channels in cardiac muscle. An analogous polyether toxin that inhibits sodium channels has recently been partially characterized from "top minnows" (Poecilia vittata) harvested in waters off of the Hawaiian Islands.