ID Case Conference January 9, 2008 Carlos M. Perez, MD, FACP Associate Professor of Medicine Pontificia Universidad Catolica de Chile

Case 1 & 2 HPI: Two women (sisters in law), 30 yo and 37 yo respectively, while they were on vacations with their husbands and children (three each), in Punta Cana, Dominican Republic, developed similar symptoms. They saw several Physicians before coming to see us.

Case 1 & 2 HPI Patient # 1: Episode of watery diarrhea. Several hours later, dysesthesia developed, along with intense pruritus of the legs, hands, and breasts, which increased with exposure to cold. HPI Patient # 2: Episode of watery diarrhea. Several hours later developed dysesthesia, generalized pruritus and sharp, shooting pain in her legs. In both patients, the symptoms were disabling and persisted for weeks. They are sportswomen and denied eating “junk food” as their families did. No mosquito bites. No consumption of uncooked shellfish/fish. No contact with animals. Husbands and children were healthy and asymptomatic.

Case 1 & 2 PMH & PSH: Unremarkable Medications: Acetaminophen, Ibuprofen. NKDA SH: Married, three children. No sexual contact other than husband. No Etoh or tobacco use. ROS: Fever(-), weight loss (-), skin rash (-), HA (-), insomnia (+) (due to pruritus and pain), GI symptoms (-) except for initial diarrhea. Join pain or swelling (-)

Case 1 & 2 PE: Both afebrile, normal pulse and BP. No skin rash. No lymphadenopathy. HEENT wnl. Lungs and Heart wnl. Breasts wnl. Abdomen wnl. Neurological examination: Mental status wnl. Normal sensation and strength. Normal reflexes. Meningeal signs (-)

Case 1 & 2 Laboratory test: CBC, chemistry, UA, Sed rate, CRP wnl.

Case 1 & 2 Discussion

Case 1 & 2 Diagnosis: Ciguatera Poisoning

Case 1 & 2 Diagnosis: Ciguatera Poisoning How they got it?

Case 1 & 2 Because they ate Dusky grouper (“Mero”) (Epinephelus marginatus)

Marine Toxins As world travel and trade grow, physicians are increasingly likely to encounter patients suffering from marine toxins. The world's oceans harbor hundreds of different types of marine toxins, and the epidemiology and clinical manifestations of these toxins vary widely. The most frequent are: ciguatera, scombroid, paralytic shellfish poisoning, neurotoxic shellfish poisoning, diarrheic shellfish poisoning, and pufferfish poisoning See Table #1 from Marine Toxins in UpToDate (on campus access only)UpToDate

Ciguatera Named by the Portuguese biologist Parra in 1771, ciguatera toxicity has existed in the tropics for centuries. Some authors have speculated that Alexander the Great refused to let his troops eat fish because of ciguatera. Ciguatera poisoning accounts for more than half of the fish-related foodborne disease outbreaks in the United States, and is the most common fish food poisoning in tropical coastal regions. An estimated 20,000 to 50,000 people develop ciguatera each year throughout the world.

Ciguatera Most cases originate in the tropics and subtropics, between 35 degrees north latitude and 35 degrees south latitude. Two cases of ciguatera poisoning reported in 2004 represent the first known cases caused by fish (barracuda) caught off the coast of South Carolina.

Ciguatera More than 400 different fish species have been associated with ciguatera. Reef- dwelling tropical fish such as barracuda, moray eel, amberjack, and certain types of grouper, mackerel, parrotfish, and red snapper are the most common sources of ciguatera toxicity.

Ciguatera Pathogenesis: Ciguatera is caused by several distinct toxins, of which ciguatoxin is the best known. These toxins are formed by dinoflagellates of the genus Gambierdiscus, single-celled algae-like organisms that grow on and around coral reefs. Gambierdiscus toxicus, which produces ciguatoxin, tends to proliferate on denuded coral surfaces.

Ciguatera Pathogenesis: The toxin is transferred through hervivorous reef fish to carnivorous reef fish which are consumed by humans. Ciguatera toxin-containing fish does not taste, smell, or appear unusual. Cooking, marinating, freezing, and stewing fish does not destroy the toxins.

Ciguatera Pahogenesis: Ciguatoxin is a lipid soluble, heat stable, acid resistant neurotoxin. It opens voltage dependent sodium channels in cell membranes, triggering membrane depolarization. Maitotoxin, another ciguatera associated toxin, increases calcium ion influx through excitable membranes. Scaritoxin increases the permeability of sodium channels and causes norepinephrine and acetylcholine release.

Ciguatera Clinical manifestations: gastrointestinal symptoms, including vomiting, diarrhea, and abdominal cramping, beginning three to six hours after eating contaminated fish, but the incubation period may be up to 30 hours. Neurologic symptoms usually begin 3 to 72 hours after the meal. The neurologic symptoms can include paresthesias, painful teeth, painful urination, blurred vision, nerve palsies, and hot/cold temperature reversal. Cardiovascular symptoms include bradycardia, heart block, and hypotension.

Ciguatera Diagnosis: Clinical Fish can be tested using a mouse bioassay and an IgG immunoassay, but these tests are costly and time consuming and are not widely used. In many tropical cultures, local inhabitants believe that contaminated fish will not fight back as hard as other fish, and that cats will refuse contaminated fish.

Ciguatera Treatment

Ciguatera One month after the onset of symptoms the patients were treated with Gabapentin (400 mg TID), with rapid improvement. Twenty days later, we stopped the drugs; the symptoms returned in a few hours in both patients. Gabapentin therapy was resumed, and the patient had immediate relief of symptoms. See Perez CM, Vasquez PA, Perret CF. (2001)Treatment of ciguatera poisoning with gabapentin.N Engl J Med,344(9):692-3.)

Ciguatera Other Drugs used to treat Ciguatera Poisoning Initial treatment of ciguatera is supportive. Multiple uncontrolled trials have found that intravenous mannitol, given at a dose of 1 g/kg, reduces neurologic symptoms when given within the first 48 hours. See Abstract for Palafox, NA, Jain, LG, Pinano, AZ, et al. Successful treatment of ciguatera fish poisoning with intravenous mannitol. JAMA 1988; 259;2740Abstract Amitriptyline and fluoxetine have been reported to benefit ciguatera patients suffering from chronic fatigue, insomnia, and depression. Gabapentin was reported to improve polyneuropathic symptoms in two patients, but it is an expensive therapy. See Blythe, DG, Hack E, Washington, G. The medical management of seafood poisoning. Foodborne Disease Handbook: Seafood and Environmental Toxins (vol. 4)Foodborne Disease Handbook: Seafood and Environmental Toxins

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