There’s Something Fishy Going On Here

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Ruben Santiago
Ruben Santiago
Emergency Medicine Pharmacist and medication hustler at a level I trauma center in Miami, FL. Interests include trauma, toxicology, and infectious diseases.

The Pre-brief

  • Ciguatera fish poisoning (CFP) is the most common worldwide fish poisoning 
  • Annually, estimates of the number of people who live in or visit tropical or subtropical areas who suffer from CFP range from 10,000 – 500,000 cases; however, the true incidence is difficult to determine due to underreporting 
  • CFP is the most common fish-related foodborne illness reported in the United States
  • CFP arises from ingesting fish containing ciguatoxin (CTX), is not due to mishandling, and is not prevented by any storage, handling, or cooking method 

Ciguatera Toxicity – A Short Story of Dangerous Delicious Delicacies:

Microscopic algae known as dinoflagellates produce CTX, a class of tasteless, heat-stable, polycyclic toxins. In addition to being tasteless and heat stable, CTXs are also colorless, odorless, acid stable, and stable for at least six months at commercial freezing temperatures. The best known and most likely the most common dinoflagellate that produces ciguatoxin is Gambierdiscus toxicus, but other dinoflagellates may also produce CTX or similar toxins. These dinoflagellates are typically attached to seaweed, living and dead coral, and other substrates in shallow tropical and subtropical waters. These dinoflagellates are ingested by herbivorous reef fish, which in turn are consumed by larger carnivorous fish, with the latter serving as the primary source of human illness.

CTXs are lipid-soluble and bioaccumulate through the food chain, having larger concentrations in larger carnivorous fish in tropical, pelagic (open) waters. These fish are more likely to cause toxicity in humans; however, ingestion of any fish in the coral reef food chain may cause harm. There are case reports of passage of CFP as a result of human-to-human transmission through sexual intercourse, from nursing mother to infant, and pregnant mother to fetus.

More than 500 species of fish are associated with CFP. This poisoning is endemic in tropical and subtropical areas, particularly in the Caribbean and Indo-Pacific regions; however, due to international seafood trade, travel, and climate change, CFP is increasingly encountered in non-endemic regions. 

CTXs interfere with neuronal voltage-gated sodium channels, rendering sodium channels open at resting membrane potential. This causes an influx of sodium, resulting in uncontrolled membrane depolarization and repetitive action potentials. Neuronal potassium channels may also be inhibited. The sodium influx draws water into the neurons and as animal evidence illustrates, results in axonal edema at the nodes of Ranvier. This swelling impairs saltatory conduction along the axon, slowing sensorimotor conduction velocities. Edema may also occur in Schwann cells and myelin fibers, affecting nerve conduction. Intracellular calcium also increases, disrupting intestinal cell-ion exchange mechanisms, producing fluid secretion and diarrhea

Clinical diagnosis of CFP consists of presenting symptoms, time course, history of eating reef fish, and the exclusion of other diagnoses (particularly other marine ingestion toxicities such as paralytic and neurotoxic shellfish poisonings, scombroid, and tetrodotoxin). Scombroid, another common fish poisoning, is associated with oceanic fish, with symptoms largely attributed to histamine reaction (swelling, flushing, hives, etc.). Other items on the differential include botulism, enterovirus, bacteremia, and organophosphate poisoning. CFP also shares clinical features with polyneuropathies such as multiple sclerosis. Currently, the gold standard for the confirmation of CFP is the detection of CTX in the flesh of the consumed fish. CTX may be detected in fish flesh through a number of assays; however, these tests are rarely available to the treating physician and are not completed in a timely fashion that would impact acute clinical management.

Symptoms:

Gastrointestinal (GI), neurological, and cardiovascular symptoms may occur and could begin as early as six hours post-ingestion. GI symptoms usually begin within six to 12 hours and may resolve spontaneously within one to four days. The most commonly reported GI symptom is diarrhea. Other symptoms include abdominal pain, nausea, and vomiting. Neurological symptoms present within the first two days of illness, often becoming more prominent after GI symptoms. These symptoms begin appearing within 24 hours post-ingestion, but may be delayed up to 72 hours. Symptoms include circumoral and extremity paresthesias, metallic taste, pruritus, myalgias, and arthralgias. The sensation of loose teeth, headache, and dizziness may also occur. One of the coolest symptoms (no pun intended) is cold allodynia, which is pathognomonic for ciguatera toxicity. This distinctive neurologic symptom causes a reversal of temperature sensation: cold feels hot and hot feels cold. In essence, when a patient touches something cold it causes a burning sensation or dysesthesia, an unpleasant, abnormal sensation. Coma and hallucinations have also been reported. Neurological symptoms may persist for months and up to years. Cardiovascular symptoms generally manifest in the early stage of the illness in conjunction with GI and/or neurologic signs and symptoms and include bradycardia and hypotension. 

Treatment – Serendipitous Sugary Discovery:

Management of CFP is largely supportive and includes treating hypovolemia with intravenous fluids, correcting electrolyte abnormalities, and using atropine in instances of bradycardia. The use of mannitol began in the 1980s, when two patients were treated with mannitol for presumed cerebral edema due to ciguatera poisoning. The ciguatera symptoms quickly and unexpectedly improved. This serendipitous discovery led to the use of mannitol in 22 additional patients with presumed CTX exposure. Mannitol was administered as 1 g/kg in this case series. The mean time to complete resolution of neurological and neurosensory symptoms of all cases was 10 hours. The authors concluded that mannitol should be considered in patients with signs and symptoms consistent with CFP. 

When reviewing the evidence beyond the case series by Palafox et. al., much of the literature is anecdotal and reported in case reports and case series. There are two randomized trials comparing mannitol to other therapies. One trial by Bagnis et. al. compared mannitol to a combined infusion of glucose, calcium gluconate, pyridoxine, and ascorbic acid. In this study, patients who received mannitol had greater improvement in paresthesias and GI symptoms with no significant difference for asthenia, aches, and cardiovascular signs compared to the combination therapy. 

Another trial by Schnorf et. al. compared mannitol to normal saline for patients presenting with suspected CFP. This study found similar rates of the resolution of symptoms between mannitol and normal saline groups; however, there were limitations to this trial. Patients were treated all the way up to 672 hours post-exposure (for maximal benefit, it is recommended to treat within the initial 48 to 72 hours), only observed for 24 hours (benefits may be seen 48 to 72 hours after the administration of mannitol), and was not known if this was the initial episode of CFP, as subsequent episodes could be more severe.

As a result, through case studies, case series, and anecdotal reports, mannitol may be considered for patients presenting with CFP that present within 48 to 72 hours of exposure. The use of mannitol is two-fold: (1) to reduce symptoms in the acute phase of illness (primarily neurologic symptoms); and (2) to shorten the duration of symptoms beyond the acute phase. The beneficial effects of mannitol are thought to be attributed to the osmotic reduction of neuronal edema. Mannitol may also act as a scavenger of free radicals produced by CTX, may reduce the action of CTX at sodium and/or potassium channels, and may increase dissociation of CTX from its binding site. Mannitol is an osmotic diuretic, therefore, patients must be adequately fluid resuscitated prior to initiating therapy. Mannitol is dosed at 0.5 – 1 g/kg (commonly 1 g/kg), is administered over 30 – 45 minutes, and should be given within 48 – 72 hours of toxic fish ingestion, although benefits have been observed for weeks after ingestion. Always consult your poison center for poisonings and overdoses at 1-800-222-1222.

The Debrief

  • CFP is the most common fish poisoning both worldwide and in the United States
  • CTXs are tasteless, colorless, odorless, heat and acid-stable, and stable for at least six months at commercial freezing temperatures
  • CFP is not due to mishandling and is not prevented by any storage, handling, or cooking method
  • Clinical diagnosis of CFP consists of presenting symptoms, time course, history of eating reef fish, and the exclusion of other diagnoses
  • Management is largely supportive, with consideration given to mannitol for acute presentations 
  • Mannitol is normally dosed at 0.5 – 1 g/kg for this indication (more commonly 1 g/kg) and infused over 30 – 45 minutes 
  • Consult your poison center at 1-800-222-1222 when these patients present

References

  1. Traylor J, Singhal M. Ciguatera Toxicity. StatPearls. Treasure Island (FL): StatPearls Publishing. 2021. https://www.ncbi.nlm.nih.gov/books/NBK482511/#article-30321.s2. 
  2. Friedman M, Fleming L, Fernandez M, et. al. Ciguatera fish poisoning: treatment, prevention and management. Mar Drugs. 2008; 6: 456 – 479.
  3. Friedman M, Fernandez M, Backer L, et. al. An updated review of ciguatera fish poisoning: clinical, epidemiological, environmental, and public health management. Mar Drugs. 2017; 15(72): 1 – 43. 
  4. Copeland N, Palmer W, Bienfang P. Ciguatera fish poisoning in Hawai’i and the Pacific. Hawai’i Journal of Medicine and Public Health. 2014; 73(11): 24 – 27. 
  5. Greene S. Ch. 103 Ciguatera. Critical Care Toxicology. Springer International Publishing AG 2017. Pp 2033 – 2043. 
  6. Mullins M, Hoffman R. Is mannitol the treatment of choice for patients with ciguatera fish poisoning? Clinical Toxicology. 2017; 55(9): 947 – 955. 
  7. Ting J, Brown A. Ciguatera poisoning: a global issue with common management problems. European Journal of Emergency Medicine. 2001; 8: 295 – 300.  
  8. Palafox N, Jain L, Pinano A, et. al. Successful treatment of ciguatera fish poisoning with intravenous mannitol. JAMA. 1988; 259: 2740 – 2724. 
  9. Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy. Neurology: 2002; 58: 873 – 880. 
  10. Schwarz E, Mullins M, Brooks C. Ciguatera poisoning successfully treated with delayed mannitol. Annals of Emergency Medicine. 2008; 52(4): 476 – 477.
  11. Suguitan M, Rao R. Ch. 105 Scombroid. Critical Care Toxicology. Springer International Publishing AG 2017. Pp 2075 – 2083. 

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