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  3. Clinical entry: Tetrodotoxin poisoning

Clinic: Tetrodotoxin poisoning

Examine for venom effects

Local (gastrointestinal) Effects

  • Nausea, vomiting, and abdominal pain.

Neurological effects (Peripheral and central nervous system)

  • Peripheral nervous system

    • Sweating, vomiting,

    • Paraesthesias of the lips, the tongue and the oropharynx, 

    • Paraesthesias of the (distal) extremities,

    • Cranial nerve deficits,

    • Paralysis of the skeletal musculature including the respiratory musculature, with dyspnoea and respiratory failure, 

  • Central nervous system

    • Seizures, ataxia.

Cardiac effects

  • Bradycardia, tachycardia, arrhythmia, hypotension, hypertension. 

Laboratory method to confirm ciguatera poisoning

Detection of toxins

  • Detection of TTX in remains of fish tissue using thin-layer and high-performance liquid chromatography.
  • Detection of TTX in blood and urine using gas chromatography (Suenaga and Kotoku 1980).
  • See also reviews Bian et al (2024).

Electrophysiological investigations

  • Electrophysiological findings indicate that TTX blocks the Na channels on myelinised nerves and thus impairs nerve conduction. TTX and saxitoxin have the same mechanism of action, with the difference that saxitoxin has a weaker action (Kao 1972, Long et al. 1990; Oda et al. 1989; Trevett et al. 1997).

Species-specific envenoming pattern

  

Local
(gastrointestinal)
effects1
 

Neurological effects2

Peripheral and central nervous system

 Cardial effects3

Tetrodotoxin poisoning

      

Differential diagnosis 
see also
Emergency flowchart: Poisonous animals

Bacterial and viral food poisonings, allergic reactions, neurotoxic, paralytic shellfish poisoning, scombroid fish poisoning, botulism, acute arsenic and organophosphate poisoning and a multitude of others.
See Friedman et al. (2017)
See also Anagnostou and Abrams (2023), Patel et al. (2023)
   

1Local (gastrointestinal) effects

Nausea, vomiting, and abdominal pain may manifest shortly after ingestion, may, however, be completely absent.

Time between ingestion and onset of symptoms

 See ‘Grade of poisoning’ below.

2Neurological effects 

Sweating, vomiting,
Paraesthesias of the lips, the tongue and the oropharynx, the (distal) extremities,
Cranial nerve deficits, paralysis of the skeletal musculature including the respiratory musculature, with dyspnoea and respiratory failure
Ataxia, seizures (primary/secondary hypoxic?). 

Time between ingestion and onset of symptoms

 See ‘Grade of poisoning’ below.

 3Cardial effects

  • Bradycardia, tachycardia, arrhythmias, Arterial hypotension.

Time between ingestion and onset of symptoms

 See ‘Grade of poisoning’ below. 

Grade of poisoning

Isbister et al. (2005) citing Fukuda and Tani (1941)

Grade 1

Perioral numbness and paraesthesia, with or without gastrointestinal symptoms (mainly nausea).
Onset as early as 5 min. after ingestion.

Grade 2

Lingual numbness, numbness of face, and other areas (distal). Early motor paralysis and incoordination. Slurred speech. Normal reflexes.
Onset as early as 10 min. after ingestion.

Grade 3

Generalised flaccid paralysis, respiratory failure, aphonia, and fixed or dilated pupils. Patient is conscious.
Onset as early as 15 min. after ingestion.

Grade 4

Severe respiratory failure and hypoxia. Hypotension, bradycardia, and cardiac dysrhythmias. Unconsciousness may occur.
Onset as early as 15 min. after ingestion

Morbidity

If a patient survives the first 24 hours, the prognosis is good. The symptoms of poisoning generally disappear within a period of days.

Case fatality rate

Mortality rate from TTX poisoning depends on the availability of intensive care facilities. In severely poisoned patients it reaches > 50% if no facilities are available. Causes of death are respiratory paralysis and cardiovascular failure. Death can occur very rapidly; within 30 minutes.

Species-specific publications 
see ‘References’ at the end of the file.

Clinical management

See also Clinical Management: poisonous animals

for advice on diagnosis (clinical, laboratory) and treatment (supportive)

First Aid

If ingestion occurs within 60 minutes and no contraindications, such as vomiting and decreased mental status are present, activated charcoal and/or gastric lavage may be administered.
Gastric lavage with a 2% sodium bicarbonate solution. Instillation of activated charcoal (Sims and Ostman 1986).

Systemic supportive treatment

A general understanding of emergency medicine is required, or can be found in emergency medicine guidelines, e.g. ABCDE approach, WHO-ICRC Basic Emergency Care.

Obey Tetrodotoxin poisoning - specific features

see 'Species-specific envenoming pattern' above.

Key issues

Live-saving interventions
The mainstay of treatment is respiratory support and supportive care until the tetrodotoxin is eliminated.

  1. Oxygen, endotracheal intubation, artificial respiration (How et al. 2003, Sims and Ostman 1986, Tibballs 1988).
  2. Plasma expansion (physiological salt solution etc.) for arterial hypotension (How et al. 2003, Sims and Ostman 1986, Tibballs 1988).
  3. Atropine for bradycardia; possibly temporary pacemaker (Sims and Ostman 1986, Tibballs 1988).
  4. If 2. and 3. are unsuccessful, i.e. persistent hypotension and reduced cardiac output, vasopressors (How et al. 2003, Sims and Ostman 1986, Tibballs 1988).
  5. Positive effects of acetylcholinesterase inhibitors have been reported in some cases (e.g., Chew et al. 1984), but not in others (Lyn 1985, Tibballs 1988). No evidence base for or against the use of neostigmine in adults with tetrodotoxin-associated respiratory failure (Liu et al. 2015):
  6. Severely poisoned and paralysed patients are fully conscious and cannot respond. Sedation is very important.

Specific treatment (antidote)

No specific antidote is available. 

References

Reviews 

  • Bian Y, Zhang Y, Feng XS, Gao HY. Marine toxins in seafood: Recent updates on sample pretreatment and determination techniques. Food Chem. 2024 Apr 16;438:137995. Epub 2023 Nov 20. PMID: 38029684. https://doi.org/10.1016/j.foodchem.2023.137995
  • Isbister GK, Kiernan MC. Neurotoxic marine poisoning. Lancet Neurol. 2005 Apr;4(4):219-28. PMID: 15778101. https://doi.org/10.1016/s1474-4422(05)70041-7
  • Katikou P, Gokbulut C, Kosker AR, Campàs M, Ozogul F. An Updated Review of Tetrodotoxin and Its Peculiarities. Mar Drugs. 2022 Jan 3;20(1):47. PMID: 35049902; PMCID: PMC8780202. https://doi.org/10.3390/md20010047

Original publications

  • Chew SK, Chew LS, Wang KW, Mah PK, Tan BY. Anticholinesterase drugs in the treatment of tetrodotoxin poisoning. Lancet. 1984 Jul 14;2(8394):108. PMID: 6145998. https://doi.org/10.1016/s0140-6736(84)90282-4
  • Fukuda A, Tani A. Records of puffer poisonings. Report 3. Nippon Igaku Oyobi Kenko Hoken 1941; (3528): 7-13.
  • How CK, Chern CH, Huang YC, Wang LM, Lee CH. Tetrodotoxin poisoning. Am J Emerg Med. 2003 Jan;21(1):51-4. PMID: 12563582. https://doi.org/10.1053/ajem.2003.50008
  • Kao, C. Y. (1972) Pharmacology of tetrodotoxin and saxitoxin. Federation Proceedings 31: 1117-1123
  • Liu SH, Tseng CY, Lin CC. Is neostigmine effective in severe pufferfish-associated tetrodotoxin poisoning? Clin Toxicol (Phila). 2015 Jan;53(1):13-21. Epub 2014 Nov 20. PMID: 25410493. https://doi.org/10.3109/15563650.2014.980581
  • Long RR, Sargent JC, Hammer K. Paralytic shellfish poisoning: a case report and serial electrophysiologic observations. Neurology. 1990 Aug;40(8):1310-2. PMID: 2381544. https://doi.org/10.1212/wnl.40.8.1310
  • Lyn PC. Puffer fish poisoning: four case reports. Med J Malaysia. 1985 Mar;40(1):31-4.PMID: 3831731.
  • Oda K, Araki K, Totoki T, Shibasaki H. Nerve conduction study of human tetrodotoxication. Neurology. 1989 May;39(5):743-5. PMID: 2710368. https://doi.org/10.1212/wnl.39.5.743
  • O'Leary MA, Schneider JJ, Isbister GK. Use of high performance liquid chromatography to measure tetrodotoxin in serum and urine of poisoned patients. Toxicon. 2004 Oct;44(5):549-53. PMID: 15450930. https://doi.org/10.1016/j.toxicon.2004.07.008
  • Sims JK, Ostman DC. Pufferfish poisoning: emergency diagnosis and management of mild human tetrodotoxication. Ann Emerg Med. 1986 Sep;15(9):1094-8. PMID: 3740600. https://doi.org/10.1016/s0196-0644(86)80135-4
  • Suenaga K, Kotoku S. Detection of tetrodotoxin in autopsy material by gas chromatography. Arch Toxicol. 1980 Apr;44(4):291-7. PMID: 7396715. https://doi.org/10.1007/bf00278036
  • Tibballs J. Severe tetrodotoxic fish poisoning. Anaesth Intensive Care. 1988 May;16(2):215-7. PMID: 3394918. https://doi.org/10.1177/0310057x8801600216
  • Trevett AJ, Mavo B, Warrell DA.Tetrodotoxic poisoning from ingestion of a porcupine fish (Diodon hystrix) in Papua New Guinea: nerve conduction studies. Am J Trop Med Hyg. 1997 Jan;56(1):30-2. PMID: 9063357.

Systemic supportive treatment

  • WHO ABCDE Approach. https://cdn.who.int/media/docs/default-source/integrated-health-services-(ihs)/csy/bec-quick-cards/becp-edu29-pdf-en-finl.pdf?sfvrsn=2532d61b_2
  • WHO-ICRC Basic Emergency Care: approach to the acutely ill and injured. https://www.who.int/publications-detail-redirect/basic-emergency-care-approach-to-the-acutely-ill-and-injured. https://cdn.who.int/media/docs/default-source/integrated-health-services-(ihs)/csy/bec-quick-cards/becp-edu29-pdf-en-finl.pdf?sfvrsn=2532d61b_2

Internet links providing specific information
CDC

Species-specific evidence

Taiwan

Studies

  • Deng JF, Tominack RL, Chung HM, Tsai WJ. Hypertension as an unusual feature in an outbreak of tetrodotoxin poisoning. J Toxicol Clin Toxicol. 1991;29(1):71-9. PMID: 2005668. https://doi.org/10.3109/15563659109038599 
    Outbreak investigation. 30 cases. Identification: TTX in the remains of the meal; 1 fatality.

Australia

Case reports

  • Tibballs J. Severe tetrodotoxic fish poisoning. Anaesth Intensive Care. 1988 May;16(2):215-7. PMID: 3394918. https://doi.org/10.1177/0310057x8801600216
    1 patient. Identification:
  •  Isbister GK, Son J, Wang F, Maclean CJ, Lin CS, Ujma J, Balit CR, Smith B, Milder DG, Kiernan MC. Puffer fish poisoning: a potentially life-threatening condition. Med J Aust. 2002 Dec 2-16;177(11-12):650-3. PMID: 12463990. https://doi.org/10.5694/j.1326-5377.2002.tb04999.x
    Retrospective study; 11 patients; 4 patients had extensive neurophysiological investigations.

Hawaii

  • Sims JK, Ostman DC. Pufferfish poisoning: emergency diagnosis and management of mild human tetrodotoxication. Ann Emerg Med. 1986 Sep;15(9):1094-8. PMID: 3740600. https://doi.org/10.1016/s0196-0644(86)80135-4
    1 case

Israel

  • Eisenman A, Rusetski V, Sharivker D, Yona Z, Golani D. An odd pilgrim in the Holy Land. Am J Emerg Med. 2008 Mar;26(3):383.e3-6. PMID: 18358973. https://doi.org/10.1016/j.ajem.2007.05.035

Malaysia

  • Lyn PC. Puffer fish poisoning: four case reports. Med J Malaysia. 1985 Mar;40(1):31-4.PMID: 3831731.
    4 cases. Identification: description by the patient; 1 fatality.

Papua New Guinea

  • Trevett AJ, Mavo B, Warrell DA. Tetrodotoxic poisoning from ingestion of a porcupine fish (Diodon hystrix) in Papua New Guinea: nerve conduction studies. Am J Trop Med Hyg. 1997 Jan;56(1):30-2. PMID: 9063357. https://doi.org/10.4269/ajtmh.1997.56.30
    3 of 4 patients severely poisoned; 2 fatalities.

South Pacific

  • Doherty MJ. Captain Cook on poison fish. Neurology. 2005 Dec 13;65(11):1788-91. PMID: 16344524. https://doi.org/10.1212/01.wnl.0000187128.80551.1b

Spain

  • Fernández-Ortega JF, Morales-de los Santos JM, Herrera-Gutiérrez ME, Fernández-Sánchez V, Rodríguez Loureo P, Rancaño AA, Téllez-Andrade A. Seafood intoxication by tetrodotoxin: first case in Europe. J Emerg Med. 2010 Nov;39(5):612-7. Epub 2009 Feb 6. PMID: 19201132. https://doi.org/10.1016/j.jemermed.2008.09.024 
    1 case

Taiwan

  • Hwang, D. F., W. C. Wang, H. M. Chung, S. S. Jeng (1989) First identification of acute tetrodotoxin-associated food poisoning in Taiwan. J. Formosan Med. Ass. 88: 289-291
    2 patients. Identification: TTX in the remains of the meal; 1 fatality.

Taiwan Strait

  • How CK, Chern CH, Huang YC, Wang LM, Lee CH. Tetrodotoxin poisoning. Am J Emerg Med. 2003 Jan;21(1):51-4. PMID: 12563582. https://doi.org/10.1053/ajem.2003.50008
    Outbreak investigation. 6 Patients. 1 fatality.

Thailand

  • Laobhripatr S, Limpakarnjanarat K, Sangwonloy O, Sudhasaneya S, Anuchatvorakul B, Leelasitorn S, Saitanu K. Food poisoning due to consumption of the freshwater puffer Tetraodon fangi in Thailand. Toxicon. 1990;28(11):1372-5. PMID: 2087700. https://doi.org/10.1016/0041-0101(90)90105-g
    6 patients. Identification: freshwater Puffer

Japan

  • Oda K, Araki K, Totoki T, Shibasaki H. Nerve conduction study of human tetrodotoxication. Neurology. 1989 May;39(5):743-5. PMID: 2710368. https://doi.org/10.1212/wnl.39.5.743
    1 patient
  • Tsunenari S, Uchimura Y, Kanda M. Puffer poisoning in Japan--a case report. J Forensic Sci. 1980 Jan;25(1):240-5. PMID: 7190185.
    3 patients. Identification: description by the patient, mouse assay; 1 fatality.

Comprehensive collection of outbreaks globally

  • Katikou P, Gokbulut C, Kosker AR, Campàs M, Ozogul F. An Updated Review of Tetrodotoxin and Its Peculiarities. Mar Drugs. 2022 Jan 3;20(1):47. PMID: 35049902; PMCID: PMC8780202. https://doi.org/10.3390/md20010047