Ciguatera: Current concepts

DAVID Z. LEVINE, DO

Ciguatera poisoning develops unraveling the diagnosis may prove difficult. after ingestion of certain coral reef-asso­ Although the syndrome has been known for at ciated fish. With travel to and from the least hundreds of years, its mechanisms are tropics and importation of tropical food only beginning to be elucidated. Effective treat­ fish increasing, ciguatera has begun to ments have just begun to emerge. appear in temperate countries with more Ciguatera is a major public health prob­ frequency. The causative agents are cer­ lem in the tropics, with probably more than tain varieties of the protozoan dinofla­ 30,000 poisonings yearly in Puerto Rico and gellate Gambierdiscus toxicus, but bacte­ the US Virgin Islands alone. The endemic area ria associated with these protozoa may is bounded by latitudes 37° north and south. have a role in toxin elaboration. A specif­ Ciguatera in temperate countries is a concern ic "ciguatoxin" seems to cause the symptoms, because people returning from business trips, but toxicosis may also be a result of a fam­ vacations, or living in the tropics may have ily of toxins. Toxicosis develops from 10 been poisoned through food they had eaten. minutes to 30 hours after ingestion of poi­ The development of worldwide marketing of soned fish, and the syndrome can include fish from a variety of ecosystems creates a dan­ gastrointestinal and neurologic symptoms, ger of ciguatera intoxication in climates far as well as chills, sweating, pruritus, brady­ removed from sandy beaches and waving·palms. cardia, tachycardia, and long-lasting weak­ Outbreaks have been reported in Vermont, ness and fatigue. More severe features are Rhode Island, New York State, Montreal, and rare. In this review, the pathophysiologic British Columbia. In Canada alone, ciguatera features and symptoms of ciguatera are costs more than $3 million a year in medical and reviewed and compared with those of other indirect costs.1 seafood-related syndromes. Although no definitive therapy is known, the most Means of toxicosis promising treatment for ciguatera is intra­ Ingestion of anyone of more than 400 species venous administration of mannitol. Physi­ of tropical or subtropical reef fish can cause cians should warn patients who are trav­ ciguatera. Larger reef-associated carnivorous eling to endemic areas about this toxicosis. fish such as barracuda, some groupers, jacks, (Key words: Ciguatera, ciguatoxin, fish, and snappers are most likely to cause toxicosis, mannitol, seafood, shellfish, temperature but many other fish are implicated as well reversal) (Table 1). Ciguatoxin (CTX) itself has been identified Worldwide, ciguatera is the most common tox­ as a lipid polyether with several hydroxyl groups icity borne by fish. Its group of symptoms is and a molecular weight of 1112, one of the most bizarre, and unless the physician is familiar potent nonproteinaceous poisons known. Con­ with the strange manifestations of ciguatera, troversy exists as to whether toxicosis results from one toxin or from many. Through research in the past 5 years, the picture regarding the Dr Levine is board certified in family practice and is in solo practice in Port Orchard, Wash. causative agent has actually become less clear. Correspondence to David Z. Levine, DO, 3280 SE Lund (Yet another example of just how right Heisen­ Ave, Suite 9, Port Orchard, WA 98366. berg really was! The closer we get to a subject,

Review article • Levine JAOA • Vol 95 • No 3 • March 1995 • 193 Table 1 Some Fish Implicated in Cases '-"" ' ....,: :~ .,~, . of Ciguatera Poisoning

Herrings Goatfish ,'.. .. Tarpon Mullet . ~ " ~ : '{,:/ ( :';: Anchovy Triggerfish , .;!;"~';' ...,.:. .P;'~ ~ . True eels Snappers " Flying fish Porgies " Squirrelfish Jacks Sea perch Parrotfish Dolphins Surgeonfish Sailfish Grunts Figure. Author's drawing of GambierdisCllS toxiCllS, a benthic Bass Tunas dinoflagellate involved in ciguatera poisoning. (Source: "Ciguat· era in the North Eastern Caribbean," Datos Marinos, No. 7A, Grouper Swordfish Department of Marine Sciences, UPR·RUM, Mayaguez, PR [undated)) the less we seem able to understand it.) It may rhea, and abdominal pain in common with other be that toxicosis results from a family of tox­ food poisonings. Onset is 10 minutes to 30 hours ins rather than from one specific ciguatoxin.2 after ingestion of a toxic meal, and this gas­ Ciguatoxin(s) are evolved by certain vari­ trointestinal aspect of the intoxication usually eties of the protozoan dinoflagellate Gam­ resolves in 24 to 48 hours. Arthralgia and myal­ bierdiscus toxic us (Figure ). Recently, it has been gia are common. The neurologic symptoms are suggested that they may also be elaborated by the most bizarre and are also most specific to another strain of dinoflagellate, Ostreopsis len­ ciguatera as an entity. The patient may have ticularis, which is found associated with G tox­ dizziness, oral and circumoral paresthesia, icus. To complicate matters even further, recent headache, paresthesia of the extremities, and research indicates that certain bacteria are taste disturbance. Chills and profuse sweat­ found symbiotically associated with dinofla­ ing are relatively common. Whole-body pruri­ gellates and seem to have a role in the elabo­ tus or pruritus limited to the palms and soles ration of toxins by the symbiont dinoflagellates. can be extremely distressing. Bradycardia and Bacteria found associated with dinoflagellates hypotension or tachycardia and mild hyper­ include strains of Pseudomonas (most common), tension may occur. Nocardia, Vibrio, Aeromonas, Flavobacterium, The "signature" of ciguatera is hot/cold and Moraxella. 3,4 reversal. The patient perceives cold sensations Dinoflagellates are responsible for several as hot (for example, interpreting a cool breeze other known toxins, as well as the infamous as burning hot) and vice versa (Table 2). In "red tides." It has been suggested that G toxi­ very rare cases, delirium, coma, cardiac and cus flourishes where reef ecology has been dis­ respiratory failure, and death may occur, but turbed by construction, pollution, military activ­ no deaths from ciguatera have occurred in ity, or natural causes.5 The organism attaches North America. Persistent weakness and fatigue itself to macro algae and is eaten by herbivo­ are the symptoms most responsible for loss of rous reef fish. These herbivores are eaten by working days.6 Discomfort may lead to severe carnivores, and these carnivores are preyed insomnia. upon by larger carnivores, passing on-and con­ centrating-the toxin. When humans are at the Differential diagnosis top of this food chain, they become vulnerable Most other forms of seafood poisoning should to ingestion of ciguatoxin and other benthic be reasonably easy to distinguish from ciguat­ (sea-bottom)-associated) marine toxins. era (Table 3 ). Scombroid poisoning usually results from ingestion of tuna or mackerel that Clinical characteristics has been inadequately refrigerated. The disor­ The symptoms of ciguatera are unique (Table 2), der is histamine mediated and resembles other although ciguatera has nausea, vomiting, diar- histamine reactions. Patients may experience

194· JAOA· Vol 95 • No 3 · March 1995 Review article • Levine Table 2 Signs and Symptoms of Ciguatera

General Gastrointestinal Neurologic

Weakness Nausea Oral and circumoral (especially Vomiting paresthesias lower extremity) Diarrhea Acral paresthesias Malaise Abdominal pain Dizziness Fatigue Temperature reversal Myalgia Pruritus Arthralgia Ataxia Chills flushing, coryza, severe headache, dizziness, the fish is toxic, the coating turns a deep blue­ burning of the mouth and throat, abdominal purple.10 The assay has been used very suc­ cramps, nausea, vomiting, diarrhea, and pruritus. 7 cessfully by commercial fisherman in Hawaii, Paralytic shellfish poisoning and neurotoxic according to Dr Hokama (personal telephone shellfish poisoning result from ingestion of communication, 1992).11 It has been argued, dinoflagellate-contaminated shellfish. Neuro­ however, that the test is inadequately specific toxic shellfish poisoning is typically a mild syn­ and has been tested only in Hawaii, where drome involving the usual gastrointestinal ciguatera is reportedly not a major problem, symptoms, as well as varying paresthesias and and that therefore the appearance of success may cerebellar symptoms. It is limited to a few days' be caused by the Hawthorn effect. (T.R. Toste­ duration.8 (Temperature reversal has also been son, PhD, conversation, December 1992). The noted with this syndrome, which somewhat patent for the stick test was sold by the Uni­ complicates the diagnosis of ciguatera.) Paralytic versity of Hawaii to a California corporation shellfish poisoning, as the name would suggest, (Ciguatect, Hawaii Chemtect International, carries more potential morbidity and mortali­ Pasadena, Calif). Apparently it has been devel­ ty, and is usually encountered in the summer. oped for commercial marketing, but release An initial neurologic symptom, circumoral pares­ has been delayed indefinitely pending litiga­ thesia, may be followed by cerebellar symp­ tion between the company and the University toms, cranial nerve involvement, and motor of Hawaii (Robert Goldsmith, MA, Hawaii paralysis including respiratory failure. Treatment Chemtect International, personal telephone is supportive, and patients usually recover with­ communication, February 1995). It is hoped in a week.9 that the stick test, if proved practical, will soon be available again and that its cost will not Laboratory evaluation prohibit its use in poorer areas where ciguat­ In ciguatera poisoning, physical examination and era is endemic. routine laboratory analyses show no abnor­ malities. A laboratory means of objectively Pathophysiologic features determining whether a patient has ciguatera poi­ The mechanism of ciguatera is beginning to soning is not currently available. come to light. The toxin seems to open (acti­ Several biological assays for determining vate) voltage-dependent sodium channels, affect­ which fish are toxic have been in use for some ing a global array of body functions.12 It has time. An enzyme-linked immunoassay using been reported that Schwann cells surrounding monoclonal antibodies has been developed by peripheral nerve axons become edematous,12 Yoshitsuro Hokama, PhD, and his associates possibly modifying or impeding neural trans­ at the University of Hawaii Medical School. mission. The marked array of symptomatic The test uses coated bamboo sticks that are responses to ciguatera may result in part from stabbed into the flesh of the suspect fish. The metabolic changes in the toxin both within the stick is then treated with several reagents. If host fish and within the human target. A.L.

Review article • Levine JAOA' Vol 95 • No 3 ' March 1995' 195 Hupka, PhD, has stated that ciguatoxin itself ics, epoxies, resins, glues, and solvents is also appears to have different fractions, which may recommened, but these admonitions appear account for variability in symptoms (conversa­ impractical, if not impossible. tion, 1992). Gambierdiscus elaborates another toxin, maitotoxin, which also may be responsi­ Educating the traveler ble for variability in clinical presentation.14 Physicians should inform patients preparing for travel to endemic areas that ingestion of Treatment fish carries the risk of ciguatera. Travelers Numerous treatment regimens for ciguatera should be cautioned to inquire of personnel at have been advocated,15-23 but several that seem eating establishments, local fisherman, or local to have real promise have emerged in the last health officials about potentially toxic varieties 5 years. It seems reasonable that if ciguatera of fish in their area and should avoid those fish affects sodium channels, agents that stabilize that may be dangerous. Admittedly, this may not these membrane channels should be effective. be a simple task. Restaurant workers may not It has been noted for some time that intra­ know, or may be unwilling to risk their jobs by venously administered lidocaine alleviates symp­ being frank. Officials may downplay possible toms15 and, consequently, tocainide, an oral risk to avoid a perceived adverse effect on analog of lidocaine, has been tested in several tourism by admitting that the local delicacies cases of toxicosis, with encouraging results could make people extremely ill. Travelers (dosage and duration of treatment not known).16 should avoid eating larger specimens (weigh­ Another stabilizer of sodium channels, amitripty­ ing more than 5 pounds) of most tropical fish line, 25 mg twice or three times daily, has been and completely avoid barracuda, moray eels, reported to work well in some cases and not at fish roe, fish heads, and viscera. all in others.17,18 It has also been recommend­ ed in one report as the best treatment for the Comments chronic effects of ciguatera.19 Ciguatera is the most common toxic fish poi­ The most promising therapy, intravenous­ soning worldwide and is increasing in incidence, ly administered mannitol therapy, seems to prevalence, and distribution as the world increas­ rapidly reverse ciguatera toxicity, but its mech­ ingly becomes a "global village." The presenta­ anism is unknown. The drug is inexpensive and tion of ciguatera is usually distinctive, which relatively safe. The 20% solution (1 g/5 mL) is facilitates identification. The most promising administered intravenously at a dose of 1 g per treatment seems to be intravenous adminis­ kilogram of body weight, over 30 to 45 minutes. tration of mannitol, but the drug's mechanism Often, the symptoms begin to abate within min­ in reversal of the syndrome remains a mystery. utes. The treatment sometimes needs to be Ciguatera is at least annoying and at worst repeated.2o-23 It has been suggested that the disastrous to the patient. For people living in mechanism of mannitol's efficacy in ciguatera tropical c.ountries who depend on fish for their poisoning may be related to reversal of periax­ subsistence, the potential effects are wider. In a fascinating article, Nancy D. Lewis,24 of the onal Schwann cell edema, but if this is the sit­ University of Hawaii, discusses the impact fur­ uation, similar results might be expected with ther. She points out that ciguatera also limits other diuretics. This has not been the case. the development of export fisheries and may It is important to correct fluid and elec­ adversely affect tourism. She states that an trolyte imbalances resulting from diarrhea or increase in ciguatera makes islanders more vomiting (or both) before initiation of manni­ dependent on imported foods, which decreases tol therapy. Mannitol is a powerful osmotic self-sufficiency and forces native populations diuretic and can cause potentially serious fluid into a cash economy and away from tradition­ shifts. al means of subsistence. This leads to greater Recovering patients should be cautioned to dependence on industrialized countries. avoid eating fish or shellfish for 6 months after Ciguatera may spread when reef ecology is 5 the intoxication. Relapses-sometimes as severe disturbed. It has been hypothesized that it as the original attack-have occurred in patients increases with dredging, shoreline development, who ate fish that were not ciguatoxic. Like­ and pollution. Ifthis is the case, physicians, to wise, patients should avoid alcohol, mayon­ be effective in the broadest possible sense, must naise, seeds, and nuts. Avoidance of cosmet- take a proactive role in issues affecting the

196 • JAOA • Vol 95 • No 3 • March 1995 Review article • Levine Table 3 Common Syndromes Associated With Seafood Consumption

Paralytic Neurotoxic shellfish shellfish Ciguatera Scombroid poisoning poisoning

Most common Reef-associated Tuna, mackerel, Raw or Shellfish sources fish jacks, and cooked (probably others shellfish both raw and cooked - Chemical Ciguatoxin Histamine Saxitoxin Brevetoxin mediator and other associated toxins with associated Ptychodiscus with (dinoflagellate Gonyaulax causing red (dinoflagellate) tide) -- --- .- Onset 30 min to Minutes to Usually within 1hto3h 30 h hours 30 min

'> Signs and Perioral, oral, Flushing Oral, facial, Similar to symptoms and acral (especially and acral those of aresthesias; face, neck, paresthesias; ciguatera emperature upper trunk); "floating but milder reversal; headache; sensation"; headache; dizziness; ataxia; dizziness; pruritus; vertigo; fa tigue/weak- coryza; muscle weakness; ness; arthral- urticaria; paralysis gias; myalgias; bronchospasm; cranial nerve pruritus; vomiting/ dysfunction; vomiting/ diarrhea; nausealvomi ting; diarrhea; ab- abdodminal diarrhea; dominal pain; pain; respiratory coma (rare); tachycardia; collapse (rare) death (rare); hypotension hypotension - Treatment* Mannitol, IV Diphenhydra- Supportive Supportive Amitriptyline, PO mine, 1M gastric symptomatic Cimetidine, IV lavage; activated charcoal; catharsis sodium bi- carbonate, IV ------Recovery Days to years 12 h to 24 h Days to weeks Days

*IM, intramuscularly; IV, intravenously; PO, orally.

Review article • Levine JAOA • Vol 95 • No 3 • March 1995 • 197 environment as well as an active role in treat­ poisoning related to the toxic dinoflagellates. South Med J ing the individual patient. 1987;80:866-872. 9. Eastaugh J , Shepherd S: Infectious and toxic syndromes from fish and shellfish consumption. Arch Intern Med Aclrnowledgments 1989;149:1735-1740. Many thanks to Barbara Shipman, MA, of the Ingham 10. Hokama Y, Smith S: Review: Immunological assessment of marine toxins. Food Agric Immun 1990;2:99-105. Medical Center Library, Lansing, Mich, for her skilled 11. Hokama Y, Asahina AY, Shang ES, et al: Evaluation of the and eternally cheerful assistance, and to Yoshitsuro Hawaiian reef fishes with the solid phase immunobead assay. Hokama, PhD, of the University of Hawaii; Arthur L. J Clin Lab Anal 1993;7( 1):26-30. Hupka, PhD, of the Ponce School of Medicine, Ponce, 12. Schatz IJ: Ciguatera fish poisoning, a jet age peril. Hosp Puerto Rico; and T.R. Tosteson, PhD, of the University Pract 1989;24(9):79-86,89,93-96. of Puerto Rico, for their time and invaluable help. 13. Allsop JL, Martini L, Lebris H, et al: Les manifestations neurologiques de la ciguatera. Rev Neurol (Paris) 1986;142:590- 597. 14. Kodama A, Hokama Y: Variations in symptomatology of References ciguatera poisoning. Toxicon 1989;27:593-595. 1. Todd ECD: How ciguatera affects Canadians, in Tosteson 15. Gillespie N, Lewis RJ, Pearn JH, et al: Ciguatera in Aus­ TR (ed): Proceedings of the 3rd International Conference on tralia. Med J Aust 1986;145:584-590. Ciguatera Fish Poisoning, Puerto Rico, 1990. Montreal, Que­ 16. Lange WR, Krieder SD, Hattwick M, et al: Potential bene­ bec, Canada, Polyscience Publishers, 1992, pp 181-192. fit of tocainide in the treatment of ciguatera: Report of three cases. 2. Lewis RJ, Sellin M: Multiple ciguatoxins in the flesh offish. Am J Med 1988;84: 1087-1088. Toxicon 1992;30:915-991. 17. Davis R, Villar L: Symptomatic improvement with amitripty­ 3. Gonzalez I, Tosteson CG, Hensley V, et al: Role of associat­ line in ciguatera fish poisoning (letter). N Engl J Med 1986;315:65. ed bacteria in growth and toxicity of cultured benthic dinofla­ 18. Bowman PB: Amitriptyline and ciguatera (letter). Med J gellates. Proceedings of the 4th International Ciguatera Con­ Aust 1984;23:2. ference, May 1992. Montreal, Quebec, Canada, Polyscience 19. Lange WR, Snyder FR, Fudala PJ: Travel and ciguatera Publishers, 1992. poisoning. Arch Intern Med 1992;152:2049-2053. 4. Tosteson TR, Ballantine DL, Tosteson CG, et al: Associated 20. Pearn JH, Lewis RJ, RuffT, et al: Ciguatera and mannitol: bacterial flora, growth, and toxicity of cultured benthic dinofla­ Experience with a new treatment regimen. Med J Aust 1989;151:77- gellates Ostreopsis lenticularis and Gambierdiscus toxicus. Appl 80. Env Microbiol 1989;55:137-14l. 21. Palafox NA, Jain JG, Pinano AZ, et al: Successful treat­ 5. RuffTA: Ciguatera in the Pacific: A link with military activ­ ment of ciguatera fish poisoning with intravenous mannitol. ities. Lancet 1989;1:201-205. JAMA 1988;259:2740-2742. 6. Frenette C, MacLean D, Gyorkos T: A large common-source 22. Williamson J: Ciguatera and mannitol: A successful treat­ outbreak of ciguatera fish poisoning. J Infect Dis 1988;158:1128- ment. Med J Aust 1990;153:306-307. 113l. 23. Williams RK, Palafox NA: Treatment of pediatric ciguat­ 7. Sims JK: A theoretical discourse on the pharmacology of era fish poisoning. Am J Dis Child 1990;144:747-748. toxic marine ingestions. Ann Emerg Med 1987;16:1006-1015. 24. Lewis ND: Disease and development: Ciguatera fish poi­ 8. Sakamoto Y, Lockey R, Krzanowski J Jr: Shellfish and fish soning. Soc Sci Med 1986;23:983-993.

198 • JAOA • Vol 95 • No 3 • March 1995 Review article • Levine