The differential diagnosis of patients with foodborne poisoning presenting with neurologic symptoms is vast (Tables 45–2 and 45–3). The sources of many of these cases are ichthyosarcotoxic involving toxins from the muscles, viscera, skin, gonads, and mucous surfaces of the fish; rarely, toxicity follows consumption of the fish blood or skeleton. Shellfish poisoning also must be considered. Most episodes of poisoning are not species specific, although particular forms of toxicity from Tetraodontiformes (puffer fish), Gymnothoraces (moray eel), and newts (Taricha and other species) are recognized.
In cases of ciguatera poisoning, the major symptoms usually are neurotoxic, and the gastrointestinal (GI) symptoms are minor. Scombroid poisoning, which is exceptionally common, is not associated with focal neurologic manifestations, but facial flushing, headache, and dysphagia are its major signs and symptoms.
Knowing where the fish was caught often helps establish a diagnosis, but refrigerated transport of foods and rapid worldwide travel can complicate that assessment. Travelers to Caribbean and Pacific islands, as well as those traveling within the United States, have suffered from ciguatera poisoning.94 In geographically disparate regions of Canada,130 individuals have suffered from domoic acid poisoning due to ingestion of cultivated mussels from Prince Edward Island.
In the differential diagnosis of foodborne poisons presenting with neurologic symptoms, activities other than eating must always be considered. In particular, sport divers often perform their activities in high-risk areas such as Florida, California, and Hawaii, and often during the high-risk periods from May through August. In the process, they may sustain sting from a stingray tail, or laceration (from a deltoid or pectoral fin spine of a lionfish or stonefish) that can cause consequential marine toxicity (Chap. 120).
Ciguatera poisoning is one of the most commonly reported forms of vertebrate fishborne poisonings in the United States accounting for almost half of the reported cases.123 Ciguatera poisoning is endemic to warm-water, bottom-dwelling shore reef fish living around the globe between 35° north and 35° south latitude, which includes tropical areas such as the Indian Ocean, the South Pacific, and the Caribbean. Hawaii and Florida report 90% of all cases occurring in the United States, most commonly from May through August.98
More than 500 fish species have caused human cases of ciguatera poisoning, with the barracuda, sea bass, parrot fish, red snapper, grouper, amber jack, kingfish, and sturgeon the most common sources. The common factor is the comparably large size of the fish involved.
Large fish (4–6 lb or more) become vectors of ciguatera poisoning in accordance with complex feeding patterns inherent in aquatic life. Ciguatoxin can be found in blue-green algae, protozoa, and the free algae dinoflagellates. These plankton members of the phylum Protozoa are single-celled, motile, flagellated, pigmented organisms thriving through photosynthesis. Photosynthetic dinoflagellates such as Gambierdiscus toxicus and bacteria within the dinoflagellates are the origins of ciguatoxin.50,76,102 Dinoflagellates are the main nutritional source for small herbivorous fish which in turn are the major food source for larger carnivorous fish thereby increasing the ciguatoxin concentrations in the flesh, adipose tissue, and viscera of larger and larger fish.11
Ciguatoxin is heat stable, lipid soluble, acid stable, odorless, and tasteless. When purified, the toxin is a large (molecular weight 1100 Da) complex ester that does not harm the fish but is stored in its tissues.98,103 The molecule binds to voltage-sensitive sodium channels in diverse tissues and increases the sodium permeability of the channel.10,158 The ciguatoxins cause hyperpolarization and a shift in the voltage dependence of channel activation, which opens the sodium channels. Ciguatoxins bind selectively to a particular binding site on the neuron's voltage-sensitive sodium channel protein.101
Multiple ciguatoxins are identified in the same fish, perhaps explaining the variability of symptoms and differing severity.102 People can be afflicted after eating fresh or frozen fish that was prepared by all common methods: boiling, baking, frying, stewing, or broiling. The appearance, taste, and smell of the ciguatoxic fish are usually unremarkable. The majority of symptomatic episodes begin 2–6 hours after ingestion, 75% within 12 hours, and 96% within 24 hours.11 Symptoms include acute onset of diaphoresis; headaches, abdominal pain with cramps, nausea, vomiting; profuse watery diarrhea; and a constellation of dramatic neurologic symptoms.175 A sensation of loose, painful teeth may occur. Typically, peripheral dysesthesias and paresthesias predominate. Watery eyes, tingling, and numbness of the tongue, lips, throat, and perioral area occur. A strange metallic taste is frequently reported as is a reversal of temperature discrimination, the pathophysiology of which remains to be elucidated.28 Myalgias, most often in the lower extremities, arthralgias, ataxia, and weakness are commonly experienced.11
Dysuria63 and symptoms of dyspareunia and vaginal and pelvic discomfort may occur in women after sexual intercourse with men who are ciguatoxic.93 Vertigo, seizures, and visual disturbances of blurred vision, scotomata, and transient blindness) are reported.
Bradycardia and orthostatic hypotension are described.59 The GI symptoms usually subside within 24–48 hours; however, cardiovascular and neurologic symptoms may persist for several days to weeks, depending on the amount of toxin ingested. Delayed symptoms may include protracted itching and hiccoughs. Although internationally deaths are reported, none have been documented in the United States.123 When it occurs, mortality is a result of respiratory paralysis and seizures not managed with adequate life support. Ciguatoxin may be transmitted in breast milk20 and can cross the placenta.128
Laboratory analysis using an enzyme-linked immunosorbent assay (ELISA) test for ciguatera toxin can be performed; alternatively, high-pressure liquid chromatography (HPLC) is accurate. A dipstick immunobead assay test being developed for field use will allow testing of fish without laboratory processing of the toxin-containing tissues.10,74,127 A useful approach to diagnosis and management using laboratory testing to exclude other diagnostic possibilities and determine the need for, or extent of, specific therapeutic interventions.
Initial treatment for victims of ciguatoxin poisoning includes standard supportive care for a toxic ingestion.175 In most patients, elimination of the toxin is accelerated if vomiting (40%) and diarrhea (70%) have occurred. Administration of activated charcoal may be of some benefit. In patients with significant GI fluid loss through vomiting and/or diarrhea, intravenous fluid and electrolyte repletion are essential. The orthostatic hypotension may respond to intravenous fluids and α-adrenergic agonists. Bradycardia may be treated with atropine.56
Intravenous mannitol may alleviate neurologic and muscular dysfunctional symptoms associated with ciguatera; however, GI symptoms are not ameliorated.126,129 In one randomized controlled trial, mannitol failed to produce any greater improvement in symptoms than did IV 0.9% sodium chloride solution.147 Mannitol should be used with caution because it may cause hypotension. Vascular reexpansion and cardiovascular stability should be initial treatment priorities.
Admission to the hospital for cautious supportive care is essential when the diagnosis is uncertain or when volume depletion or any consequential manifestations are present (Tables 45–2 and 45–3). The etiology of the symptoms must be rapidly identified to provide specific therapy, if available. Diaphoresis is a common clinical finding and an important factor in the differential diagnosis. Late in the course of ciguatera poisoning, amitriptyline 25 mg orally twice daily may alleviate symptoms,23 which may persist up to 1 year. Victims recovering from ciguatera should avoid alcohol for 3–6 months if exposure exacerbates symptoms.
Moray, conger, and anguillid eels carry a ciguatoxin-like neurotoxin in their viscera, muscles, and gonads that does not affect the eel itself. The toxin is a complex ester that may be structurally very similar to ciguatoxin and is heat stable.122 These same eels also possess an ichthyohemotoxin that is resistant to drying but can be destroyed by heating to >149°F (65°C). Individuals who eat these eels may manifest neurotoxic symptomatology similar to ciguatoxin or may show signs of cholinergic toxicity, such as hypersalivation, nausea, vomiting, and diarrhea. Shortness of breath, mucosal erythema, and cutaneous eruptions may occur. These findings may be present in addition to the neurotoxic symptoms.69 Management is supportive. Mortality is related to the complications of neurotoxicity, such as seizures and respiratory paralysis.
Healthy mollusks living between 30° north and 30° south latitude ingest and filter large quantities of dinoflagellates. These dinoflagellates are the major source of available ocean food during the "non-R" months (May through August) in the northern hemisphere. During this time, these dinoflagellates are responsible for the "red tides" that may be seen from California to Alaska, from New England to the St. Lawrence, and across the west coast of Europe.109 The number of toxic dinoflagellates may be so overwhelming that birds and fish die, and humans who walk along the beach may suffer respiratory symptoms caused by aerosolized toxin.111
Ingestion of shellfish, including oysters, clams, mussels, and scallops, contaminated by dinoflagellates or algae may cause neurotoxic, paralytic, and amnestic syndromes. The dinoflagellates most frequently implicated are Karenia brevis (originally named Gymnodinium breve in 1948, renamed Ptychodiscus brevis in 1979, and reclassified again to the current nomenclature in 2000). The diatoms causing neurotoxic shellfish poisoning include Protogonyaulax catanella and Protogonyaulax tamarensis, which cause paralytic shellfish poisoning; and Nitzschia pungens, the diatom implicated in amnestic shellfish poisoning. Proliferation of these diatoms may cause a red tide, but shellfish poisoning may occur even in the absence of this extreme proliferation.
Paralytic shellfish poisoning is caused by saxitoxin. Saxitoxin blocks the voltage-sensitive sodium channel in a manner identical to tetrodotoxin (see later). The shellfish implicated usually are clams, oysters, mussels, and scallops, but poisoning has occurred through consumption of crustaceans, gastropods, and fish.
The higher the number of shellfish consumed the more severe the symptoms. Symptoms usually occur within 30 minutes of ingestion. Neurologic symptoms predominate and include paresthesias and numbness of the mouth and extremities, a sensation of floating, headache, ataxia, vertigo, muscle weakness, paralysis, and cranial nerve dysfunction manifested by dysphagia, dysarthria, dysphonia, and transient blindness. GI symptoms are less common and include nausea, vomiting, abdominal pain, and diarrhea. Fatalities may occur as a result of respiratory failure, usually within the first 12 hours after symptom onset. Muscle weakness may persist for weeks.
Treatment is supportive. Early intervention for respiratory failure is indicated. Orogastric lavage and cathartics were used to remove unabsorbed toxin from the GI tract but probably are not necessary or efficacious.26,99,115,152 Activated charcoal may be given. Antibodies against saxitoxin have reversed cardiorespiratory failure in animals,14 but this therapy is not yet available for humans. Assays for saxitoxin include a mouse bioassay, ELISA, and HPLC. High-pressure liquid chromatography has good interlaboratory accuracy,170 but the differences in saxitoxin derivatives make standardization of an analytic test difficult.9,95
Neurotoxic shellfish poisoning (NSP) is caused by brevetoxin. Brevetoxin, which is produced by Karenia brevis (previously Gymnodium brevis, and subsequently Ptychodiscus brevis), is a lipid-soluble, heat-stable polyether toxin similar to ciguatoxin. It acts by stimulating sodium flux through the sodium channels of both nerve and muscle.6,29 NSP is characterized by gastroenteritis with associated neurologic symptoms. GI symptoms include abdominal pain, nausea, vomiting, diarrhea, and rectal burning. Neurologic features include paresthesias, reversal of hot and cold temperature sensation, myalgias, vertigo, and ataxia. Other symptoms may include headache, malaise, tremor, dysphagia, bradycardia, decreased reflexes, and dilated pupils. Paralysis does not occur. The combination of bradycardia and mydriasis is unusual. The incubation period is 3 hours (range 15 minutes to 18 hours). GI and neurologic symptoms appear simultaneously. Other manifestations of brevetoxin poisoning include mucosal irritation, cough, and bronchospasm, which occur when P. brevis is aerosolized by wave action during red tides. Duration of symptoms averages 17 hours (range 1–72 hours).115
Brevetoxins can be assayed using mouse bioassay, ELISA, and, more recently, antibody radioimmunoassay (RIA) and reconstituted sodium channels.132,167 Treatment is supportive, and severe respiratory depression is very uncommon. Therapy includes removal of the patient from the environment and the administration of bronchodilators. Neurotoxic shellfish poisoning is not fatal.
Amnestic shellfish poisoning is caused by domoic acid, a structural analogue of glutamic and kainic acids produced by the diatom N. pungens. The most extensively documented human outbreak occurred in Canada in 1987, when 107 individuals who had consumed mussels harvested from cultivated river estuaries on Prince Edward Island were affected.130 Other human outbreaks may have occurred due to a similar diatom—Pseudonitzschia australis—which has been isolated in shellfish from other areas.57 Pelican deaths caused by domoic acid—laden anchovies were reported in 1991 and Canada instituted monitoring for domoic acid after this outbreak.163 The death of 400 sea lions in California in 1998 was linked to domoic acid from the diatom N. pungens f multiseries.148
Amnestic shellfish poisoning is characterized by GI symptoms of nausea, vomiting, abdominal cramps, diarrhea, and by neurologic symptoms of memory loss and, less frequently, coma, seizures, hemiparesis, ophthalmoplegia, purposeless chewing, and grimacing. Other signs and symptoms include hemodynamic instability and cardiac dysrhythmias. Symptoms typically begin 5 hours (range 15 minutes to 38 hours) after ingestion of mussels. The mortality rate is 2%, with death most frequently occurring in older patients, who suffer more severe neurologic symptoms. Ten percent of victims may suffer long-term antegrade memory deficits, as well as motor and sensory neuropathy. Postmortem examinations have revealed neuronal damage in the hippocampus and amygdala.162
This type of fish poisoning involves only the order Tetraodontiformes. Although this order of fish is not restricted geographically, it is eaten most frequently in Japan, California, Africa, South America, and Australia.69 Cases have also occurred in Florida and New Jersey. Approximately 100 freshwater and saltwater species exist in this order, including a number of puffer-like fish such as the globe fish, balloon fish, blowfish, and toad fish.117 Tetrodotoxin (TTX) found in these fish is also isolated from the blue-ringed octopus54 and the gastropod mollusk,177 and has also been responsible for fatalities from ingestion of horseshoe crab eggs.79 Certain tetrodotoxin-containing newts (Taricha, notophthalmus, triturus, and cynops), particularly Taricha granulosa, found in Oregon, California, and southern Alaska, can be fatal when ingested. Most newts and salamanders with bright colors and rough skins contain toxins.24 In Japan, fugu (a local variety of puffer fish) is considered a delicacy, but special licensing is required to prepare this exceedingly toxic fish. In 1989, the FDA legalized the importation of puffer fish. However, prior to exportation from Japan, the fish must be laboratory tested and certified by two Japanese organizations to be tetrodotoxin free.
Tetrodotoxin is a heat-stable (except in alkaline milieu), water-soluble nonprotein, found mainly in the fish skin, liver, ovary, intestine, and possibly muscle.69,143 The ovary has a high concentration of the toxin and is most poisonous if eaten during the spawning season. Tetrodotoxin is detected by mouse bioassay. It is unstable when heated to 212°F (100°C) in acid, distinguishing it from saxitoxin. Tetrodotoxin from fish can be detected using fluorescent spectrometry9 or from the urine of poisoned patients using a combination of immunoaffinity chromatography and fluorometric HPLC.82
Tetrodotoxin and saxitoxin are produced by marine bacteria and likely accumulate in animals higher on the food chain that consume these bacteria.121 Accumulation of toxins, primarily in the skin, of two species of asian puffer fish has been documented. Whether this accumulation of toxin is simply an evolutionary adaptation, to remove a toxic substance, or one that has evolutionary advantages of protection is unclear.120
Neurotoxicity is produced by inhibition of sodium channels and blockade of neuromuscular transmission.118 The sodium channel is blocked from the external surface of the neuron, by the TTX molecule which contains a guanidinium group that fits into the external orifice of sodium channel. This causes external "plugging" of the sodium channel, though the gating mechanism is functional.119
Symptoms of tetrodon poisoning typically occur within minutes of ingestion. Headache, diaphoresis, dysesthesias, and paresthesias of the lips, tongue, mouth, face, fingers, and toes evolve rapidly. Buccal bullae and salivation may develop. Dysphagia, dysarthria, nausea, vomiting, and abdominal pain may ensue. Generalized malaise, loss of coordination, weakness, fasciculations, and an ascending paralysis (with risk of respiratory paralysis) occur in 4–24 hours. Other cranial nerves may be involved. In more severe toxicity, hypotension is present. In some studies, mortality has approached 50%.155
Therapy is supportive. Removal of the toxin and prevention of absorption are the essential measures. Supportive respiratory care emphasizing airway protection, including intubation, if necessary, is extremely important.
Less Common Poisonings: Echinoderms
The sea urchin usually causes toxicity by contact with its spinous processes, but this Caribbean delicacy also is toxic upon ingestion. When the sea urchin is prepared as food, the venom-containing gonads should be removed because they contain an acetylcholine-like substance that causes the cholinergic syndrome of profuse salivation, abdominal pain, nausea, vomiting, and diarrhea. The sea star is considered edible by some individuals, although an asteriotoxin with saponin-like activity that produces nausea and vomiting is reported.