Clinical manifestations

Presentation and course

Ciguatera affects multiple organ systems and may have gastrointestinal, neurologic, cardiovascular, dermatological, genitourinary, and emotional components (39; 20). Onset of symptoms is usually within 15 minutes to 72 hours (most within 12 hours) of the ingestion of contaminated fish (07). Acute illness can be prolonged and the resulting neurologic symptoms can last months, with variable asymptomatic and symptomatic periods (28; 32; 33; 39; 30).

Gastrointestinal. Gastrointestinal symptoms are often the most frequent and earliest manifestations, affecting more than 90% of cases (20; 130). Gastrointestinal symptoms include hypersalivation, abdominal cramps and pain, nausea, intense vomiting, and watery diarrhea (130). The symptoms generally resolve within 1 to 2 days (33).

Neurologic. Neurologic manifestations affect more than 70% of cases (20; 130). Neurologic manifestations usually follow the development of gastrointestinal symptoms, suggesting that the neurologic manifestations may be due to a different physiologic process, such as neuronal or Schwann cell swelling through prolonged activation of sodium channels (02). Neurologic symptoms can be protracted, sometimes lasting many months (33).

Neurologic symptoms can include various sensory complaints, including numbness and dysesthesias (eg, prickling and burning sensations) of the extremities; pruritus (either generalized or affecting preferentially the palms and soles); temperature reversal (eg, where cold objects feel hot, or occasionally vice versa: "hot-cold inversion," "temperature reversal," "sensory inversion"); cold allodynia (ie, pain from mildly cold skin temperatures that would not generally be considered painful); toothache; circumoral paresthesia; dysguesia; and burning mouth syndrome (70; 07; 163; 11; 52; 20; 130). The inverted sensory phenomenon is considered by some to be pathognomonic of involvement with marine toxins (09), although it has also been reported rarely in diabetic and uremic polyneuropathies (162). The Lhermitte phenomenon can occur with ciguatera poisoning (78), and hyperintense signal on T2-weighted sequences in the cervical cord has been reported with ciguatera poisoning (155).

Headaches, dizziness or vertigo, malaise or profound fatigue, circumoral tingling, dysgeusia (eg, metallic taste), dry mouth, pain or tingling in the extremities, and a "loose" sensation of the teeth are common complaints. Cranial nerve abnormalities may also include ptosis, miosis, trismus, various oculomotor and lower cranial nerve palsies, spontaneous downbeat and perverted head-shaking nystagmus, impaired smooth pursuit, visual fixation suppression failure during the bithermal caloric test, and aphonia (105). Other central nervous system manifestations may include opisthotonus, meningismus (ie, signs of meningeal irritation without meningitis), ataxia, and rarely intractable seizures (48). Neuromuscular abnormalities may include hyporeflexia/areflexia, stocking-glove hypesthesia or numbness, carpopedal spasm, myalgias, low back pain, muscle stiffness or spasm, fasciculations, and elevated CPK levels (155). Rarely, the patient may proceed to develop peripheral flaccid paralysis, respiratory muscle paralysis with respiratory failure, generalized seizures, stupor, and death.

Cardiovascular. Cardiovascular manifestations are noted in 20% to 40% of cases (20; 130). Cardiovascular manifestations most often involve bradycardia or hypotension but can include hypotension, hypertension, bradycardia, tachycardia, other arrhythmias, heart block, pulmonary edema, and congestive heart failure (07; 34; 32; 03; 20; 130). In a study of 124 cases of ciguatera intoxication from French Polynesia, cardiovascular symptoms were the primary criteria of severity, with bradycardia and hypotension documented in 75% and 43%, respectively (62).

Dermatologic. The patient may develop a rash, which, if present, is usually diffuse, nonraised, confluent, and erythematous. Loss of hair and nails has been reported.

Genitourinary. Genitourinary signs include the following: painful urination; pain in the perineum, penis, or vagina; and pain in the penis during erection, which may be intensified during ejaculation (137). Cases have been reported of dyspareunia in unaffected women following ejaculation by their male partners, suggesting the possibility of sexual transfer of the toxin, although this has not been proven (86; 84; 27). The toxin can cross the placental barrier causing hypoactivity or shivering movements of the fetus that can be detected by sonography, and also similarly causing transient hypoactivity of the newborn. Ciguatoxin can be secreted in the breast milk causing hypersensitivity of the nipples that interferes with breastfeeding, as well as diarrhea in the infant (16).

Emotional. The patient may be emotionally depressed, hyperexcitable, anxious, nervous, giddy, apprehensive, restless, and agitated. Hysteria, delirium, hallucinations, and irrational behavior may occur (58). The varied and often inexplicable symptoms of ciguatera have been postulated in some cases to be related to somatization (156), but this is unlikely to explain many cases, even with unusual complaints, given the consistency of many of the reports of the affected individuals in different times and locales.

Hypothermia. A high frequency (approximately 60%) of hypothermia (ie, body temperature lower than 36.5 °C) was reported in one study (20).

Prognosis and complications

The prognosis of ciguatera poisoning is generally good, with symptoms typically subsiding within 3 to 6 weeks. However, the outcome apparently depends on the dose of toxin or toxins initially ingested, individual susceptibility, and whether sensitization has occurred. Once intoxication has occurred, consuming fish and alcohol may aggravate the condition and should be eliminated from the diet, at least initially.

Ciguatera-related mortality is rare (less than 0.1% of reported cases) (37).

Chronic ciguatera. Chronic ciguatera is marked by disproportionate disability and nonspecific refractory symptoms such as fatigue, cognitive deficits, and pain and has many similarities to chronic Lyme disease. After the acute phase of ciguatera, many bothersome symptoms may linger for months to years, including pruritus after alcohol consumption, dysesthesias, myalgias, arthralgias, sensitivity to cold, marked fatigue, malaise, and depression (09; 99; 68; 139; 116; 51; 93; 35). Ciguatera is a consideration in the differential diagnosis of chronic fatigue syndrome (118). Putative predictors of having symptoms lasting 3 months or longer include age, tobacco consumption, acute bradycardia, laboratory measures of urea, and neutrophils (61).

The disease is vastly underdiagnosed; diagnosis is made almost entirely by history and usually in retrospect. There are few physical findings, none of which are diagnostic.

Any combination of gastrointestinal, neurologic, cardiovascular, dermatological, genitourinary, and emotional symptoms should arouse clinical suspicion to inquire whether fish has been ingested. The initial gastrointestinal phase may be the only manifestation, and similarly isolated neurologic involvement may occur. Occasionally, a patient may present with only the inverted sensory phenomenon or with pruritus after alcohol and have no other symptoms. Reexposure may cause a significant worsening of symptoms (64).

Clinical vignette

An 18-year-old man suddenly developed painful dysesthesias while living in Hong Kong. He recalled no prior illnesses besides some gastrointestinal distress and abdominal pain. The dysesthesias in his hands and feet waxed and waned but were exacerbated by eating certain foods (eg, chicken, fish, and bouillabaisse) and drinking alcohol. He had no weakness. The patient’s neurologic exam was normal, except for some minimal sensory loss to vibration in his feet.

Nerve conduction velocity studies demonstrated a polyneuropathy involving both the hands and feet. The F waves were mildly delayed in his lower extremities, and his distal sensory and motor latencies were mildly delayed with relatively intact amplitudes. EMG showed some chronic denervation, suggesting some prior axonal involvement.

The patient's syndrome was compatible with a CTX-induced neuropathy. The ingestion of fish and alcohol is well known to exacerbate CTX neuropathy.

Biological basis

Etiology and pathogenesis

The disease is contracted by eating any of the many species of fish that have been reported to contain ciguatoxins. These include most of the common shallow-water oceanic game fish and many of the smaller colorful reef dwellers. Common offenders include barracuda, snapper, jacks, grouper, Humphead wrasse, lionfish (including invasive Indo-Pacific lionfish in the western Atlantic Ocean), hogfish, kingfish, parrotfish, surgeonfish, rock hind, triggerfish, bigeye trevally, moray eel, and certain sharks (67; 07; 134; 28; 29; 131; 32; 33; 55; 31; 80; 142; 37).

Toxin-bearing fish appear healthy and are apparently not adversely affected by the toxin. The toxic substance, a lipid-soluble polyether, is acid and heat stable, tasteless, colorless, odorless, and not removed by any known cleaning method; nor is it inactivated by storage conditions, cooking, freezing, salting, drying, smoking, marinating, or gastric juices.

Although it has long been assumed that larger fish within a given species are more likely to contain a significant amount of toxin, empiric studies have not supported this (60); because no relationship between the proportion of toxic fish within a family and the relative total length of individual fish was observed, fish size cannot be used as a reliable predictor of fish toxicity (60). Deep-water fish (especially below 50 fathoms) tend to be safer, but exceptions have occurred (42). Cold water fish outside of the tropical areas are generally free of the problem (eg, flounder, cod, haddock, halibut, perch, scrod, sole, salmon), as are shellfish, including lobster and crab, although a case was reported from eating farm-raised salmon (50). The latter may be related to toxin-laden fishmeal, as even livestock have been contaminated through exposure to fishmeal.

Ciguatera can be the clinical consequence of ingesting multiple toxins found in flagellate protists, in particular benthic dinoflagellates (ie, dinoflagellates occupying the ecological region at the lowest level of a body of water). Ciguatoxins are a class of toxic, high-molecular-weight, polycyclic polyethers. Several have been identified, including CTX-1, CTX-2, CTX-3, CTX4, scaritoxin (a mixture of CTX-4A and CTX-4B), maitotoxin (named from the ciguateric fish Ctenochaetus striatus—called "maito" in Tahiti), palytoxin, and okadaic acid (which can be involved in both diarrheic shellfish poisoning and ciguatera) (81; 146; 160).

A ciguatoxin was first isolated from Gambierdiscus toxicus, a dinoflagellate from the Gambier Islands (a small group of islands, remnants of a caldera, in French Polynesia in the Pacific Ocean) (08). Several additional dinoflagellates have since been demonstrated to harbor the toxins, some more toxic than G toxicus (147). These unicellular flagellated organisms can be found on bottom algae in tropical areas where herbivorous bottom-feeding fish scavenge for food. The same fish are later ingested by carnivorous fish, which may acquire high concentrations of ciguatoxin. Ciguatoxins can also accumulate in sea urchins and gastropods, which can produce ciguatera poisoning when they are eaten by indigenous populations of Pacific islands (44; 43; 63).

Initially considered to be anticholinesterases, ciguatoxins instead generally produce channelopathies affecting particularly voltage-sensitive sodium channels, but also in some cases calcium (eg, maitotoxin) and potassium channels (46; 132; 76; 153). In addition, some ciguatoxins interfere with enzyme systems or have hemolytic effects (106; 158), and others have both cholinergic and adrenergic effects, including inhibitory effects on nicotinic receptors or stimulant effects on muscarinic receptors (56; 98; 104). The order of potency of various ciguatoxins is (from most potent to least) CTX1B, CTX3B, CTX4A, gambierol, gambierone, and MTX3 (129).

CTX-1. Patch-clamping experiments demonstrated that CTX-1 increases neuronal excitability by shifting the voltage of activation of tetrodotoxin-sensitive Na+ channels to more negative potentials (71).

Pacific-CTX-1. Pacific-CTX-1 (P-CTX-1) is the most potent known ciguatoxin (129). It acts on tetrodotoxin-resistant Na+ channels by increasing the rate of recovery from Na+ channel inactivation in dorsal root ganglion neurons, suggesting a mechanism for the sensory symptoms associated with the toxin (143).

In animal experiments, P-CTX-1 can be detected in peripheral nerves within hours of exposure and persists for months; during this period, P-CTX-1 reduces the intrinsic growth capacity of peripheral neurons, which contributes to the delay in functional recovery (06).

Carribean-CTX-1. Carribean-CTX-1 (C-CTX-1) affects nerve excitability and neurotransmitter release at nerve terminals by inducing upregulation of Na+ channels and inhibition of K+ channels, at low nanomolar concentrations (96).

CTX-1 is particularly effective at releasing calcitonin-gene-related peptide (CGRP) from nerve terminals (148). In experimental animal studies, P-CTX-1 reduced delta and theta electroencephalogram activity and disrupted the balance of excitatory and inhibitory neurotransmitters in the motor cortex (82). In a mouse model, persistence of P-CTX-1 in the nervous system induced an irreversible motor deficit that correlated with excitotoxicity and neurodegeneration detected in the motor cortical neurons (05).

Maitotoxins. Maitotoxins act on the calcium channel (66), likely leading to a harmful calcium-dependent generation of intracellular reactive oxygen species (161). Maitotoxins activate extracellular calcium channels, leading to an increase in levels of cytosolic Ca2+ ions (107). Although the exact molecular target of maitotoxins is unknown, maitotoxin may bind to the plasma membrane Ca2+ ATPase, turning it into an ion channel, similar to how palytoxin turns the Na+/K+-ATPase into an ion channel (140). A necroptosis cascade is ultimately activated, resulting in membrane blebbing and eventually cell lysis (Estacion 2001 Schilling 2001). In addition, maitotoxins can indirectly activate calcium-binding proteases calpain-1 and calpain-2, contributing to necrosis (154).

Gambierol. Gambierol blocks voltage-gated potassium channels (40).

Significant slowing of sensory and motor nerve conduction velocities and F-wave latencies with prolongation of the absolute refractory and supernormal periods has been demonstrated in ciguatera poisoning (23; 24). This nerve conduction slowing could be a consequence of nodal swelling, increased internodal length, and increased nodal volume, all of which have been demonstrated with in vitro ciguatoxins (13; 94; 95).

The multiplicity of toxins and their varied actions on nerve, muscle, and the neuromuscular junction, with accompanying presynaptic and postsynaptic effects, account for the diverse clinical manifestations related to the intoxication. The toxins cross the blood-brain and placental barriers and can be secreted in breast milk and semen.

Ciguatoxins produce cold allodynia, without producing heat or mechanical allodynia, by activating sodium channels and producing a large peripheral sensitization to dynamic cold stimuli in thinly myelinated A delta (Aδ) fibers (52). In human experiments using intracutaneous injection of low millimolar concentrations of CTX, brain responses are much less to constant cooling than with dynamic temperature changes cerebellum. Brain areas that respond to dynamic cold stimuli during cold allodynia are located bilaterally and include the medial insula, medial cingulate cortex, secondary somatosensory cortex, frontal areas, and cerebellum. The same brain areas also responded to a dynamic warming stimulus on the control site but remained silent to a dynamic warming stimulus on the injected site.

Ciguatera sensitization occurs when people previously intoxicated with ciguatoxin suffer a recurrence of typical ciguatera symptoms after ingesting fish that do not cause symptoms in ciguatoxin-naive individuals (17). The mechanisms underlying ciguatera sensitization remain undefined but apparently are not mediated by a channelopathy. Axonal excitability studies in patients with ciguatera sensitization found excitability parameters all within normal limits, arguing against dysfunction of axonal membrane ion channels in large-diameter fibers in ciguatera sensitization (152). Chronic ciguatera may involve serotonin metabolism with immune sensitization and delayed-type hypersensitivity (139). Inflammatory factors may also be important in chronic ciguatera. Pathologic activity of the complement/coagulation cascade has been demonstrated in patients with chronic ciguatera poisoning. In addition, gene expression profiling in brain, whole blood, and liver of mice exposed to CTX showed an acute anti-inflammatory response in the brain, blood, and liver that was postulated to represent a systemic antiinflammatory environment to protect against cellular damage caused by the toxin (133).

Most commonly, ciguatera results from a single exposure to ciguatoxin-contaminated fish, but continuous consumption of toxic fish over a period of time may also produce ciguatera poisoning, even when the toxin concentration in the fish consumed is low (41).

Epidemiology

Ciguatera is endemic in a band-like area extending around the globe, generally from 35° North to 35° South latitude (97). The highest incidence rates are consistently reported from two historical endemic areas, ie, the Pacific and Caribbean regions, a situation partly due to the strong reliance of local communities on marine resources (37). Ciguatera poisoning is particularly common in certain areas of the Caribbean (especially the Virgin Islands, Puerto Rico), parts of southern Florida, and certain Pacific regions (eg, Hawaii, Australia, and several of the islands of the South Pacific, including the Marshalls, French Polynesia, American Samoa, Guam, and New Guinea) (91). Cases have been reported from several states in the United States, the Mexican Pacific coast, Baja California, Canada, Japan, and, more recently, the Mediterranean. Some of this spread is due to the consumption of fish shipped in from endemic areas (122) or from travelers arriving home from endemic areas (115; 128; 79; 47; 103), whereas some of it is due to range expansion of ciguatera to subtropical regions because of climate change (36).

Ciguatera toxin is responsible for 40% of all foodborne disease outbreaks in Florida, and only 28% of these outbreaks were detected through complaints (91).

Ciguatera tends to be prevalent where recent algae blooms harbor the toxic dinoflagellates, which depend on a complex interaction of water temperature, disruption of underwater surfaces, and availability of nutrients. The highest rates of ciguatera fish poisoning in the Caribbean Sea and the West Indies between 1996 and 2006 were in the eastern Caribbean, where the water temperatures were highest and least variable (144). There also appears to be a temporal relationship in Hong Kong between the peak incidence of cholera outbreaks and ciguatera, which may be related to a common environmental trigger (83). Algae blooms may result from the availability of new surfaces produced by underwater explosions or recent construction of dams and seawalls. With the advent of dock construction, tourism, sewage outfall, global warming, and consequent coral bleaching, conditions favorable to G toxicus proliferation are increasing (87; 74). The eutrophication of marine environments (ie, excessive richness of nutrients in bodies of water, frequently due to runoff from the land) has also contributed to increasing levels of ciguatera; a study in Cuba found the level of organization of the local sport-fishing community and the degree of degradation of the local near-shore marine ecosystem to be key etiologic factors for the ciguatera outbreaks recorded in the 1990s (100).

Global warming has contributed to the emergence of dinoflagellate species in subtropical and temperate regions that had been limited to tropical areas (97; 36; 145). This may lead to increased ciguatera prevalence and an expanded range of high-risk endemic areas, although there is little evidence this has occurred (127; 145).

Globalization of the fishing industry and tourism have led to a progressive increase in ciguatera cases (97; 47). Ciguatera is the most common nonbacterial form of food poisoning related to seafood ingestion in the United States, Canada, and more recently, Europe (26; 85; 141). Annually, between 50,000 and 500,000 people develop acute ciguatera poisoning from consuming toxic fish, and approximately 5% of these individuals develop chronic ciguatera, a multisystem, chronic illness that can last for decades (138; 97).

The incidence of ciguatera poisoning was 0.67 cases per 10,000 patient-years in Martinique over the 6-year period from October 2012 to September 2018 (130). No patient died, but symptoms persisted in 40% of the 77 patients with follow-up at day 15.

Risk factors for ciguatera toxicity include alcohol consumption at least weekly, a history of previous ciguatera episodes, lower levels of education, and frequent fish consumption (126). Risk factors for severe ciguatera include ingestion of reef fishes and CTX-rich fish parts, ingestion of high-risk fish (eg, barracuda), as well as concomitant alcohol consumption (125; 31; 127). Concomitant alcohol consumption is associated with a much higher risk of developing bradycardia, hypotension, and neuropathic sensory changes (33).

Asian ciguatera outbreaks often present as large disease clusters due to group consumption of a single contaminated fish (37).

Ciguatera toxicity is underrecognized by medical providers, especially when patients present with ciguatera toxicity outside of endemic areas (120; 97; 80; 127).

Prevention

Ciguatera can be prevented by not eating fish from tropical waters, specifically, tropical reef fish. The main species responsible for poisoning include jack, snapper, grouper, barracuda, and goatfish (20). Certain fish (including barracuda, grouper, hogfish, lionfish, and eels, among others) should never be eaten in endemic areas, and sale of these is often prohibited by law because of the recognized risk of toxicity (07; 28; 29; 32; 33; 55; 31; 49). The liver, other viscera, and roe of tropical fish may harbor high concentrations of ciguatoxins (69) and should be avoided in endemic areas. Because of the increased risk of severe symptoms, ingestion of CTX-rich fish parts with alcohol should be avoided (31). To prevent large outbreaks and severe illness, large apex predators from coral reefs should never be served at banquets (28; 33; 31).

Ciguatera cannot be prevented by cooking or freezing contaminated fish (80).

Several novel folkloric methods for detecting affected fish have been described.

In the Grand Caymans, local fishermen reportedly lay a fish down on the sand, and if ants are attracted, the fish is considered safe to eat (77). Experienced fishermen from tropical areas reportedly rub their gums with fish organs, and if their gums tingle afterward, the fish is not safe to eat (25).

Differential diagnosis

Associated or underlying disorders

Many other forms of food poisoning can mimic the initial gastrointestinal presentation of ciguatera, but most do not progress to involve other organ systems. In general, three classes of diseases can result from seafood consumption: allergies, infections, and intoxications (12). An allergic reaction, anisakiasis, results when people become sensitized to Anisakis (a genus of parasitic nematodes of fish and marine mammals) and then have an immunoglobulin E-mediated allergic reaction, potentially including anaphylaxis, after again eating fish infected with the organism (12). Scombroid is an intoxication due to ingestion of histamine that is formed when fish begins to decay; because histamine is also involved in allergic reactions, scombroid food poisoning resembles an allergic reaction and is often misidentified as a food allergy (12). Infections are usually self-limited and respond to supportive care, except for certain Vibrio species (51). The classic marine neurotoxic syndromes include shellfish poisoning, puffer fish ("fugu") poisoning (due to tetrodotoxin-induced inhibition of voltage-gated sodium channels in nerve cell membranes), and ciguatera (04). The symptoms of ciguatera and neurotoxic shellfish poisoning are often similar.

Diagnostic workup

Ciguatera can be confused with many other illnesses (138). The diagnosis of ciguatera is based on appropriate clinical manifestations, a high index of suspicion, and a specific history of reef fish ingestion (11). Note that ciguatera poisoning can present anywhere in the world, from eating fish shipped from affected areas or from travelers returning from trips to affected areas (113).

A case definition of ciguatera fish poisoning has been proposed (59):

Table 1. Case Definition of Ciguatera Fish Poisoning

There are also no specific laboratory abnormalities in humans related to ciguatera, and there is no clinically available test for the detection of ciguatoxins in human body fluids, although the situation is under intense study (19; 18; 108; 65).

Multiple bioassay methods and several sophisticated immunochemical methods for detection of ciguatoxins in fish have been devised for research studies but have not been widely employed in clinical medicine (72; 111; 160; 73; 89; 114; 123; 150; 53; 54; 90; 149; 112).

Reports of brain or spinal cord MRI findings in patients with ciguatera poisoning are limited (155; 92; 159). Wasay and colleagues reported a T2-hyperintense lesion in the cervical spinal cord (155), and Liang and colleagues reported similar MRI changes within the corpus callosum (92). Yalachkov and colleagues reported reversible intramyelinic cytotoxic edema symmetrically affecting distinct fiber tracts in two patients; in the more severely affected patient, there were marked diffusion-weighted imaging hyperintensities and apparent diffusion coefficient reductions throughout the corpus callosum, most pronounced in the splenium, as well as bilaterally in the pyramidal tract, ranging from the posterior portion of the internal capsule to the cerebral crus, and in the middle cerebellar peduncles (159).

Management

Treatment is symptomatic and supportive; no known antidote exists (65). In severe intoxication, basic support measures should be initiated with monitoring of fluid and electrolytes, cardiac function, and blood gases, with awareness that severe bradycardia and respiratory paralysis may occur and that complications stemming from severe dehydration may rarely become life-threatening.

If vomiting has not occurred within 3 to 4 hours after ingestion, emetics or gastric lavage may be utilized to promote elimination of any remaining fish products and their associated toxins, though some discourage use of emetics because they may exacerbate fluid losses. Activated charcoal combined with a nonmagnesium-containing cathartic in a slush can be administered to promote elimination of the toxin.

Intravenous mannitol is considered the drug of choice for severe acute toxicity, especially within the first 24 hours, though this conclusion is not based on well-controlled studies (102). Nevertheless, dramatic effects have been reported when given early, rapidly, and in adequate quantities (1 g/kg of a 20% solution intravenously over 1 to 2 hours). Mannitol has been used effectively in both children and adults with severe initial presenting symptoms, including coma (110; 119; 157). Care must be taken to adequately hydrate the patient, who may have had severe diarrhea and vomiting, and to attend to fluid deficits before and during mannitol use because of its potent osmotic diuretic action. Normal saline or Ringer lactate with additional electrolyte solutions should be used depending on vital signs, urine output, the amount of vomitus and diarrhea, and the results of laboratory studies.

Treatment with mannitol after the first 24 hours has had less dramatic results, and a double-blind study suggests that mannitol is not superior to normal saline in relieving symptoms and signs of ciguatoxin exposure at 24 hours and that mannitol has more side effects than normal saline (135). Nevertheless, one anecdotal report suggests potential benefit of mannitol treatment even a month after ciguatoxin exposure (136). Also, although the neuroprotective effect of mannitol in reducing the neurologic disturbances in ciguatera poisoning in people remains disputed, mannitol can reverse some toxic effects of ciguatoxin in vitro and in animal models (88; 124; 15).

Hypotension can usually be managed with volume replacement; pressor agents are rarely needed, but dopamine infusion (5 mg/kg per minute to 20 mg/kg per minute) can be used for severe and prolonged hypotension (34). Bradyarrhythmias usually respond well to atropine (0.01 to 0.02 mg/kg intravenously every 10 minutes for symptomatic heart rate less than 50 per minute), but transvenous cardiac pacing may be required in the presence of refractory bradycardia or heart block (34). Mechanical ventilatory support and oxygen may be needed in the event of respiratory failure.

In severe poisoning, intravenous calcium gluconate (15 g/kg over 15 minutes, followed by a continuous infusion of 45 to 70 mg/kg until serum calcium is in midnormal range) has been recommended to counteract competitive inhibition of calcium by ciguatoxins.

Certain additional medications may provide relief for individual symptoms. Benzodiazepines (eg, diazepam or lorazepam) and phenytoin have been helpful in treating associated convulsions. Indomethacin, ketorolac, and other nonsteroidal anti-inflammatory agents are useful for dysesthesias, myalgias, arthralgias, and pruritus. Acetaminophen may be more effective than other analgesics for associated headaches. Corticosteroids are reportedly useful for arthralgias not responsive to other anti-inflammatory compounds. Gabapentin and lamotrigine may be helpful in patients with shooting pains, pruritus, dysesthesias, and cold allodynia (121; 163; 52). Amitriptyline may help ameliorate some ciguatera symptoms, including pruritus (21; 45; 22; 93). Fluoxetine may help treat associated chronic fatigue symptoms (14).

There are also anecdotal reports of the use of multiple other medications for symptom relief, including calcium-channel blockers, chlorpromazine, diphenhydramine, H2-receptor blockers, mexiletine, neostigmine, tramadol, vitamin B complex, vitamin B12, tocainide, and procaine, among others.

A “serotonin-sparing” diet eliminating fish or fish products, shellfish or shellfish products, nuts, coconuts, nut products, seeds, seed products (including oils), alcoholic beverages or ethanol-containing products, mayonnaise, chocolate, and mushrooms has also been recommended while a patient remains acutely intoxicated and for 3 to 6 months after symptoms resolve (139).

Anti-ciguatoxin monoclonal antibodies have been developed that exhibit neutralizing activity against ciguatoxins in vitro and in vivo (75). Such work is a first step toward a safe and rational method for in vivo detoxification of ciguatoxins.

Special considerations

Pregnancy

Although most pregnant women diagnosed as having ciguatera have been delivered at term with no apparent sequelae to the fetus, ciguatoxin apparently does cross the placental barrier and may cause premature labor and spontaneous abortion (117; 10). Transmission of ciguatoxin from mother to infant via breast milk has also been reported, producing diarrheal illness in the infant (10; 16).

Anesthesia

An anecdotal report discusses implications in one case of uneventful anesthetic use without complications in a patient intoxicated 6 months previously who had residual muscle pains and weakness before surgery (109).