Envenomation and Consumption of Poisonous Seafood

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Natural toxins destruction of the nerve terminal and ...... the terminal parts of the motor axon. Many of the presynaptically active neurotoxic phospholipases are also potent Envenomation and consumption of myotoxins, and therefore the victims of envenoming bites by some snakes (for poisonous seafood example, sea snakes, Australian elapids, Berg adders, South American rattle- A Goonetilleke, J B Harris snakes) may be weak as a result of both neurotoxic and myotoxic damage...... The varied aetiology of neurotoxic involvement in snake envenomation in- Effects of naturally occurring toxins on the human nervous fluences the treatment and management system and available treatments are discussed of individual snakebites. Elapid snakes will always inoculate postsynaptically xposure to natural toxins is becom- cobras) can emit a fine spray of venom active neurotoxins. Severely envenomed ing more commonplace because of from the tips of their fangs and thereby victims will need ventilatory support. Egreater worldwide travel, increasing “spit” the venom for a distance of several The dissociation of neurotoxins from metres into the eyes of their prey. The AChR is probably accelerated by anti- captivity of exotic animals in private and 7 institutional collections, and an expan- vipers and pit vipers (families Viperidae venom and possibly by anticholineste- sion in the trade in tropical seafood. and Crotalidae) are relatively bulky rases. If ventilatory support is main- Although the effects of natural toxins are snakes with large heads and fangs that tained and appropriate treatment with often trivial, some may result in neuro- fold into the roof of the mouth at rest— antivenom and possibly anticholinesterases is available, recovery will be rapid logical emergencies. A good understand- envenomation always causes defibrina- and uneventful. If appropriate antiven- ing of the origin and management of tion, extensive soft tissue haemorrhages, oms are unavailable respiratory support neurotoxic poisoning is therefore impor- and bleeding from gums, old wounds for 24 hours will usually allow full recov- tant for the neurologist interested in and orifices. In contrast the snakes of the ery. Venoms of most elapid snakes (for tropical medicine. The true incidence of family Elapidae (for example, kraits, example, cobras and coral snakes) typi- neurotoxic poisonings is impossible to mambas, cobras) and of the related family Hydrophiidae (sea snakes) have short cally contain only postsynaptically active ascertain because of underreporting. It neurotoxins. If the victim exhibits neuro- has been suggested that each year there fixed fangs and inoculate a venom that is characteristically neurotoxic; an enveno- toxic signs but shows little or no may be up to 1000 deaths in the Mahar- response to the relevant antivenoms or ashtra state of India 1 and 600 deaths in mation by these snakes, though often associated with defibrination, is rarely anticholinesterases it is likely that the Sri Lanka resulting from snake bites, and venom contains presynaptically active 1000 to 2000 deaths in Mexico after associated with significant haemorrhage or local tissue damage. This distinction neurotoxins; the victim will therefore scorpion stings. Tick paralysis has been need ventilatory support and conserva- estimated to cause the death of 10 000 may be misleading, as envenoming bites 2 by some viperids and crotalids (for tive management for several days until calves each year. There are thought to be damage to the neuromuscular systems around 50 000 human victims of ciguat- example, the Berg adder, Bitis atropos of 3 Southern Africa, and the South Ameri- are repaired. Myotoxicity may be recog- era poisoning each year. can rattlesnake, Crotalus durissus terrifi- nised by the presence of muscle pains, This editorial briefly outlines some of cus) inflict an envenoming bite that pro- especially on movement, and myoglo- the effects of naturally occurring toxins 8 http://jnnp.bmj.com/ duces significant neurotoxic signs; an binuria. Such patients need careful on the human nervous system. We envenoming bite by the Asian monocel- management to prevent acute renal fail- suggest that a general awareness of the lated cobra, Naja kaouthia, is responsible ure caused by the release of myoglobin circumstances in which exposure to for very severe and disfiguring local from the damaged muscle. Envenoming natural toxins may occur and of the superficial necrosis. bites by the South American rattlesnake, expression of poisoning in the form of The neurotoxic signs (for example, Australian tiger snake, Australian king clinical features will improve the preven- ptosis, ophthalmoplegia, dysphoria, in- brown (mulga) snake, the taipans of tion, detection, and management of ability to protrude the tongue or smile, Australia and Papua New Guinea and these potentially fatal conditions. Three generalised weakness) can be caused by sea snakes are particularly liable to cause on September 26, 2021 by guest. Protected copyright. recent texts discussing some of these the actions of three major groups of muscle damage. issues are available to the interested toxin. Postsynaptically active neurotox- Two groups of elapid snakes, the kraits 4–6 reader. ins bind to the α-subunit of the acetyl- and mambas, are worthy of special men- choline receptor (AChR) at the neuro- tion. Kraits are nocturnal, snake-eating ENVENOMATION muscular junction, causing what is animals. Envenoming bites may be so Snakes somewhat loosely called a curare-like innocuous as to fail to arouse a sleeping Venoms enable snakes to immobilise and neuromuscular paralysis. These toxins victim, and it is uncommon for the initiate the digestion of their prey. The are found in the venoms of all elapid and offending snake to be seen. A victim who venom is usually introduced into the vic- hydrophid snakes. Presynaptically active sleeps in the open or in a simple rural tim through a pair of fangs. Inspection of neurotoxins are found in the venoms of shelter anywhere in South East Asia and the bite site may show one or two fang many elapid snakes, especially the elapid who awakes with morning weakness, puncture marks, single or multiple snakes of Australia and Papua New loin pain, and a metallic taste in the scratch marks where fangs were dragged Guinea, the kraits of South East Asia, mouth has possibly been bitten by a across the skin, or a mixture of puncture and in the venoms of some vipers and krait. The difficulty of identifying a marks and scratches. The presence of crotalids (for example, Berg adder, South biting snake, and the fact that the onset multiple puncture marks at different American rattlesnake, Russell’s viper of of serious weakness may be slow can sites and in different orientations is sug- southern India and Sri Lanka). The tox- mean that victims often delay seeking gestive of multiple bites and a potentially ins are active phospholipases. They bind medical attention. This can be a signifi- serious envenomation. Some snakes (for to motor nerve terminals, causing the cant problem. Envenoming bites by example, African and Asian spitting depletion of synaptic vesicles and the kraits are difficult to manage because the

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Table 1 Envenomation

Envenoming species Location Features

Snakes Elapidae Cobras, kraits, mambas, coral Africa, Asia, Australasia Local effects unusual.* Early neurotoxic effects, especially snakes, Australasian venomous blurred vision and ptosis. Some Australasian elapids† cause snakes haemostatic effects, rhabdomyolysis and renal failure Viperidae/Crotalidae Vipers, adders, rattlesnakes, Africa, Asia, Europe, N and S Severe local and haemostatic effects (especially gingival moccasins America bleeding) common. Hypertension and shock (especially N American rattlesnakes). Renal failure commonest cause of death. Neurotoxic effects unusual‡ Colubridae Comprise & all known species of Africa, Asia, Australasia, Europe, Envenomation may develop slowly over many days, varying snake S America from local swelling to repeated vomiting, abdominal pain, headache, haemostatic effects and renal failure Atractaspididae Burrowing asps or stiletto snakes Africa, Middle East Local effects. Violent gastrointestinal (nausea, vomiting, diarrhoea) and respiratory (dyspnoea, respiratory failure) effects Hydrophiidae Sea snakes Pacific and Indian oceans Initial headaches, thick feeling of tongue. Flaccid paralysis and rhabdomyolysis later

Spiders Latrodectus Black widow or redback spiders Asia, Australasia, Europe, N Painful needle-like bite, may lead to painful local America lymphadenopathy within 30 minutes. Painful muscle spasms§ and rigidity throughout body. Autonomic effects Phoneutria Wandering or banana spiders S America Painful bite leading to burning sensation, spreading proximally in limb. Autonomic effects, temporary blindness, respiratory distress Atrax Funnel web spiders Australasia Painful bite. Neurotoxic symptoms (perioral numbness, spasms of tongue) may occur within 10 minutes. Autonomic effects, muscle spasms, dyspnoea, and coma

Scorpions Buthus N Africa, S Europe, Middle East Painful sting. Cardiac dysrythmias, thirst, urinary retention, mydriasis, aphonia Leiurus N Africa, Middle East Painful sting. Cardiac and respiratory failure. Muscle spasms and twitching. Autonomic effects, irritability. Centruroides N America, Mexico Coagulation defects in some species of Centruroides¶ Androctonus N Africa,** Middle East Painful sting. Hypertension, cold peripheries, ↑ lacrimation and salivation, dyspnoea Tityus Caribbean, S America Painful sting, spreads to affect entire limb. Numbness, tightness in throat, muscle twitching, respiratory paralysis. Trinidad black scorpions lead to severe gastrointestinal effects†† and cardiac irregularities Heterometrus Asia Painful sting, effects vary from mild (nose itching, salivation, dyspnoea) to severe (local swelling, haemorrhage and weakness in affected limb). Cardiovascular effects common Mesobuthus Asia (India) Severe cardiovascular effects common. Fatalities reported in adults as well as children

Ticks

Acari Australasia, N America Progressive weakness and paraesthesiae. Respiratory failure http://jnnp.bmj.com/ commonest cause of death. Children aged 1–5 years mostly affected. Tick usually found in scalp, especially behind ears

Local effects=skin blistering and necrosis, pain, tenderness and swelling of local lymph nodes, swelling of limb. Neurotoxic effects=early ptosis, aphonia, external ophthalmoplegia, weakness, respiratory failure, autonomic effects (blurred vision, hypersalivation, piloerection). Haemostatic effects=defibrination, haemolysis, haemorrhages. *Local pain, swelling, blistering, necrosis, and painful regional lymphadenopathy can occur with Asian and African spitting cobras. Corneal erosions may occur if venom spat into eyes. †Examples include tiger snake, taipan and common brown snake. ‡Neurotoxicity a significant feature of envenomation in a few species (for example, C d terrificus, Far Eastern Agkistrodon sp, Bitis atropos, Sri Lankan D russelii pulchella). §Effects include a painful grimace (“facies latrodectisimina”). ¶Venom of C sculpturatus may cause platelet aggregation in children. **Androctonus accounts for 80% of all scorpion stings in N Africa. ††Nausea, vomiting, severe abdominal pain, haematemesis, hyperglycaemia, acute on September 26, 2021 by guest. Protected copyright. pancreatitis. venoms are rich in pre-synaptically The defibrination of the blood may Other interventions (for example, cut- active β-bungarotoxins, and so recovery give rise to bleeding into the CNS. This is ting, sucking, freezing, cauterising, ap- may be prolonged.9 Bites by mambas (an a rare but difficult neurological problem plication of arterial tourniquets, foreign exclusively African genus) are always associated with some snakebites.11 12 It is materials, or chemicals at bite site, etc) serious. Their venoms contain postsyn- often slow in onset and may not be clini- are potentially dangerous and should be aptically active neurotoxins that are cally apparent for several weeks.13 avoided. The pain after snakebites may typical of elapids, and a number of be severe, but can usually be controlled unique toxins some of which target Treatment of snakebites by standard analgesics—narcotic analge- muscarinic ACh receptors. It is not 1 Appropriate first aid at the scene of the sics should be avoided because of the known to what extent these toxins com- envenomation can be critical and in- risks of respiratory depression. plicate an overwhelming syndrome of cludes patient reassurance, immobilisa- post-synaptic neurotoxicity, but a single tion of the bitten limb, and application of 2 A description of the offending snake paper described decreased parasympa- a pressure bandage (as if for a sprain) should be obtained if possible—if it has thetic activity in an envenoming incident over the bite site. These manoeuvres may been killed it should be kept for formal by the Malaysian krait (mydriasis, tachy- delay toxin absorption. Care should be identification. cardia, constipation, and defective mic- exercised when releasing pressure band- 3 If there are signs of systemic poisoning turition) lasting for up to two years ages in case there is a sudden release of (ptosis and dysphonia are early indica- (table 1).10 venom into the systemic circulation. tors of neurotoxicity) the patient should

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K+, and Ca2+ channels in mammals. Although the toxins of spider and scorpion venoms have been widely stud- ied because of their importance as tools in neuroscience research, it is still difﬁ- cult to relate knowledge of molecular and cellular biology of individual toxins to the clinical expression of envenoming spider bites and scorpion stings in human victims (table 1).

Spider bites Bites by Latrodectus species (the black widow, red-back or button spiders), Atrax species (the funnel web spiders), Missu- lena species (the mouse spiders), and Phoneutria (the banana spiders) are clini- cally important. Latrodectus is the only widespread genus and is found all over the warmer parts of the world, avoiding only the cooler temperate and cold regions. Atrax and Missulena are Australa- sian spiders and Phoneutria is Brazilian. Bites by exotic spiders are not unknown as the result of the transport of spiders in shipments of goods.14 Latrodectus is small and may not be immediately identified as the biting ani- mal. Bites are painful and the symptoms and signs of envenomation (for example, hyperexcitability, local sweating, colic or abdominal stiffness, fasciculation, muscular weakness, tachycardia, and palpi- tations) develop slowly. The venom is complex but the toxins responsible for the neurotoxic signs are the latrotoxins. The toxins cause the release of transmitters (by mechanisms that are as yet unclear) from nerve terminals in both the autonomic and somatic nervous system and that is reflected in the symptoms and signs of such bites. Acute renal failure and a late Horner’s syndrome http://jnnp.bmj.com/ have both been reported as complica- 15 16 Figure 1 (A) Australian paralysis tick (Ixodes holocyclus). (B) South American rattlesnake tions arising from latrodectism, but (Crotalus durrissus terrificus). (C) Head of Latrodectus (black widow spider) to show fangs. (D) such complications seem rare. Fang of venomous snake. Funnel web spiders are large and can cause a lethal bite. The bite is painful, be transferred to the local hospital or Envenomation involving presynaptically partly because the fangs are large and clinic. Swabs of the bitten area and blood active neurotoxins or myotoxic toxins partly because the venom is acidic. The samples should be taken for detection of are more difficult to manage and pa- venoms are complex, but the group of on September 26, 2021 by guest. Protected copyright. venom antigens and coagulation profile. tients may require supportive treatment toxins responsible for most problems in The blood pressure, respiratory and renal (for example, artificial ventilation), humans are the atracotoxins. These tox- + function should be closely monitored, sometimes for weeks, until the nerve ins delay the inactivation of Na chan- and patients should be observed for terminals and/or muscle fibres have nels in the nervous system, causing signs of neurotoxicity, myoglobinuria, regenerated. spontaneous repetitive firing in periph- cardiac abnormalities, and coagulation Spiders and scorpions eral nerves. The signs of envenomation disturbances. The venoms of spiders and scorpions are (for example, hyperexcitability, fasciculation, fluctuating blood pressure, mus- primarily used for the capture of inverte- 4 Specific antivenoms (ideally active cular weakness)17 all reflect the excessive brates. The composition of the venoms against the venoms of local snakes) should discharge of transmitter from nerve reflects this function, with hydrolytic be administered, with facilities available to terminals in the autonomic and somatic deal with any early or delayed immuno- enzymes such as hyaluronidase and nervous system. Missulena venoms con- logical reactions against the antivenoms. phospholipases being typical compo- tain toxins structurally and functionally The same dose is given to children as for nents as well as small chemical media- similar to the atracotoxins, and the adults. Multiple doses of antivenom may tors such as serotonin and a range of symptomology after a bite is also similar + + 2+ be required to control circulating levels of toxins targeting Na ,K , and Ca chan- to that of funnel-web spiders. toxins, and should be given until the nels specific to invertebrate nervous sys- The venom of Phoneutria has not been patient shows no signs of relapsing. tems. The spiders and scorpions that are fully characterised but toxins that block 5 Anticholinesterases may have poten- dangerous to humans all inoculate tox- Ca2+ channels, activate Na+ channels and tial value in treating neurotoxic signs. ins with a high level of affinity for Na+, inhibit Na+ channel inactivation have all

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.73.2.103 on 1 August 2002. Downloaded from 106 EDITORIAL been identified. Envenomation by is an important consideration for treat- in eastern Australia are caused by Ixodes Phoneutria gives rise to all of the signs of ment as even successful antivenom holocyclus and maximal weakness may autonomic hyperactivity and is entirely therapy (in terms of venom clearance) not be achieved for up to 48 hours after consistent with a venom induced en- may not reverse secondary damage and removal of the tick, with full recovery hanced release of neurotransmitters its consequences. taking several weeks. from nerve terminals in all parts of the 2 Supportive therapy (for example, as- autonomic nervous system. Treatment of scorpion stings sisted ventilation) may be required. 1 Pain at the sting site may be relieved by Treatment of spider bites 3 Specific antitoxin is not very effective, local infiltration of local anaesthetics or a 1 Immediate first aid should include and can be associated with a high ring block. Narcotic analgesics should be incidence of allergic responses and reassurance, maintenance of the airway avoided in patients showing features of and respiration. If there is ready access to serum sickness. Its use is therefore only neurotoxicity as they may contribute to recommended for patients at high risk of a clinic holding stocks of antivenom respiratory failure. immobilisation and splinting of the a poor outcome, such as severely affected bitten limb before moving the patient is 2 Available specific antivenoms should or very young patients. recommended in the treatment of bites be given immediately to young children by Atrax, but not for bites by Latrodectus. stung by dangerous species or to patients CONSUMPTION OF POISONOUS This is because signs of systemic enven- showing signs of systemic involvement. SEAFOOD oming with Latrodectus develop slowly The efficacy of antivenom is unproven if In this brief review we concentrate on and antivenom can be used as soon as administration is delayed for more than neurologically important poisonings re- systemic signs began to appear. two hours. Only a few of the antivenoms sulting from the consumption of sea- available have been subject to formal food. All the well documented syn- 2 Calcium gluconate is useful in relieving clinical trials, and the efficacy of many dromes that are characteristic of seafood the pain and muscle spasms caused by antivenoms is questionable. poisoning result either from the accumu- Latrodectus. Atropine and diazepam are lation of algal or bacterial toxins through effective for bites by Atrox. Although 3 Cardiac arrhythmias, convulsions and pulmonary damage may require addi- the food chain, or from toxins produced corticosteroids may relieve some symp- 22 tional management because the prob- by symbiotic micro-organisms. The di- toms they have no effect on overall mor- agnosis of seafood poisoning is primarily tality. lems are probably secondary and are not reversed during antivenom therapy. by exclusion as most incidents share 3 Specific antivenoms for Latrodectus, Ticks common features of nausea, vomiting, Phoneutria and Atrax are available for the Human tick paralysis occurs most com- diarrhoea and gastrointestinal pain and seriously envenomed patient. They monly in eastern Australia and North an onset time of 3–12 hours. Many docu- should be given in facilities available to America. The tick may be picked up mented cases of severe poisoning involve deal with any immune reactions against directly from the countryside or from holiday makers enjoying an exotic meal the antivenoms. domestic animals, particularly dogs. before presenting to a physician on their return home. The principal syndromes of Scorpions Neurotoxins (present in the tick’s saliva) importance are ciguatera, shellfish poi- Scorpions also use venoms to subdue are introduced while the tick engorges soning (paralytic, neurotoxic, amnesic, prey items, most of which are inverte- itself with the host’s blood, and cause a and diarrhetic forms), tetrodotoxic and brates. Their venoms contain toxins spe- presynaptic neuromuscular block possi- palytoxic fish poisoning. cific for invertebrate ion channels as well bly by impairing the excitation-secretion as small mediators such as serotonin and coupling at the neuromuscular junction Ciguatera fish poisoning enzymes such as phospholipases and 19

by reducing calcium availability. Chil- http://jnnp.bmj.com/ hyaluronidase. The effects of a sting on The syndrome of ciguatera poisoning has dren aged 1–5 years are most commonly human victims are largely attributable to been discussed in detail in a recent affected, with a non-speciﬁc prodome 3 the presence of serotonin and other review. Occasional references to ciguat- (for example, anorexia, lethargy, and mediators and of toxins that act on era poisoning are to be found in the irritability) followed by the onset of an vertebrate ion channels to either block world literature dating back to the 16th unsteady gait and then an ascending, K+ channels or delay the inactivation of century, with clearer references originat- symmetrical, ﬂaccid paralysis resem- Na+ channels. These toxins enhance the ing from the West Indies in the 18th bling the Guillan-Barre syndrome.20 A release of transmitters from nerve termi- century. The term ciguatera is derived

fatal paralysis may be caused by a single on September 26, 2021 by guest. Protected copyright. nals in all parts of the autonomic and from the American-Spanish word cigua, tick. Ticks embedded behind the ear or in somatic nervous systems. the name of a poisonous sea snail (Livona the external auditory meatus can cause Scorpion stings are a significant prob- pica) that produces a similar illness in the an ipsilateral facial weakness. The diag- lem throughout the tropical and sub- Spanish Antilles. Ciguatera poisoning is nosis depends on finding the tick, the tropical world, and the specific symp- caused by the consumption of coral scalp and the back of the ear being com- toms of an envenoming sting can vary grazing fishes or of the larger pelagic greatly according to the geographical mon sites where they are to be found. predatory fishes (for example, snappers, region, the species involved, and the age groupers, and sea trout). Most cases of of the victim. All stings are painful and Treatment of human tick paralysis poisoning are to be found in the Carib- all produce symptoms that have the 1 Treatment consists of carefully detach- bean, Pacific Islands (including the characteristics expected of toxins that ing the tick from the host while keeping north eastern seaboard of Australia), cause the enhanced release of neuro- it intact. Killing the tick with pyrethrin and the United States (especially Hawaii transmitters (for example, vomiting, based insecticides before removal may and south eastern Florida); however, the colic, diarrhoea, sweating, pilo-erection, help. Older techniques (for example, increasing worldwide trade in exotic fish hypertension, cardiac arrythmia, pria- heat, lighted matches, alcohol, etc) has led to outbreaks throughout the pism, etc). Secondary damage, especially should generally be avoided. Human tick world, including Europe. The global inci- to the cardiac and pulmonary systems, paralysis encountered in North America dence of such poisoning has been esti- results from both the “autonomic storm” are attributable to Dermacentor andersoni mated at between 50 000 and 500 000 and the peripheral mediators either and D variabilis, and there is usually a cases per year (table 2). inoculated with the venom or released as rapid clinical recovery after tick The toxins responsible for the clinical a result of mast cell degranulation.18 This removal.21 In contrast, cases encountered features include ciguatoxins (which can

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Table 2 Seafood poisoning

Cause of seafood poisoning Location Features

Ciguatera fish poisoning Consumption of large fish, such as moray eel, All tropical/subtropical regions, Nausea and vomiting within 3–24 groupers, snappers and reef grazers especially Caribbean, Indo-Pacific hours of consumption of shellfish (including Xanthic crabs) Principal toxins are Abdominal pain, numbness and ciguatoxins tingling of mouth and digits. Unstable heart rate and blood pressure Paralytic shellfish Alexandrium, Gymnodinum, Gonyaulax All areas, temperate and tropical Tingling and numbness of mouth and poisoning (PSP) Principal toxin are saxitoxins digits, headache. Neuromuscular weakness after 3–24 hours of consumption of shellfish Neurotoxic shellfish Gymnodinium Principal toxin are brevetoxins Gulf of Mexico, Florida Similar to PSP but milder. Often poisoning (NSP) associated with respiratory difficulties Amnestic shellfish Pseudonitzschia Principal toxin is domoic acid Temperate: N America, N Europe, S Nausea, vomiting, diarrhoea after 3–6 poisoning (ASP) Antipodes hours. Dizziness in more severe cases Most severe cases associated with confusion, short-term memory loss and seizures Diarrhetic shellfish Dinophysis and Prorocentrum Principal toxin is All areas, temperate and tropical Diarrhoea, vomiting and stomach poisoning (DSP) okadaic acid pains develop after 30 minutes to 24 hours of consumption of shellfish Tetrodotoxin fish Consumption of puffer fish liver, ovaries Indo-Pacific, especially S E Asia Nausea, vomiting, numbness, tingling poisoning Principal toxins are tetrodotoxins and neuromuscular weakness Palytoxic fish poisoning Palythoa Principal toxins are palytoxins Indo-Pacific and Caribbean Indistinguishable from ciguatera fish poisoning

exist in many forms), maitotoxin, and treatment consists of the administration is saxitoxin. The gonyautoxins blocks scaritoxin. The toxins are initially of hyperosmotic mannitol infusions,27 28 voltage gated channels, thus blocking formed by the dinoflagellate Gambierdis- with a report of positive responses being action potential generation in skeletal cus toxicus,23 24 which are then accumu- noted within 10 minutes in all of 24 muscle and sensory and motor axons. lated by grazing fish and subsequently patients treated and a mean time to The early signs of gastrointestinal distur- concentrated along the food chain. The complete resolution of symptoms of 10 bance (three to six hours) may progress toxins are to be found in their highest hours and complete recovery in 17 to include numbness of mouth and concentration within the liver, viscera, patients within 48 hours.27 Because of digits, visual disturbance, dysphagia, and gonads of the larger fish. The toxins the osmotic effects of mannitol treat- neuromuscular weakness and, in severe are lipid soluble, relatively heat stable, ment any dehydration present attribut- cases, a potentially fatal respiratory and resistant to gastric acid. Once the able to vomiting should first be cor- paralysis. Treatment is symptomatic, but ciguatoxins are absorbed they bind to the rected. The recommended regimen is the observation is essential because the voltage sensitive sodium channels of cel- administration of 10 ml/kg of 20% man- development of severe paralysis may be lular membranes. nitol, infused slowly over a minimum relatively slow (up to 24 hours). Recov- Features of acute ciguetera poisoning period of 30–45 minutes28; the dose may ery takes three to seven days and is usu- usually occur within one to six hours be repeated after three to four hours, and ally uneventful.30 (range of few minutes up to 30 hours) of again the following day. The mechanism Neurotoxic shellfish poisoning (NSP) http://jnnp.bmj.com/ ingestion.25 The onset of the disorder of action of mannitol in ciguatera poi- is much rarer than PSP.It is largely con- may be with either gastrointestinal (for soning may be by competitive inhibition fined to the Florida coast, the Gulf of example, abdominal cramps, nausea, of the toxin’s effect on Na+ channels, or Mexico, and possibly the east coast of vomiting, watery diarrhoea) or neuro- by neutralisation of the toxin. The overall South America. The responsible dino- logical (for example, paraesthesiae, dys- mortality of acute poisoning was esti- flagellate is usually Gymnodinium brevis. aesthesiae, blurred vision, transient mated to be 0.1% in a series of 3009 poi- This is accumulated by filter feeding blindness, vertigo, ataxia, tremor, insom- sonings during 1964–1977 (that is, an shellfish, which in turn become a carrier nia) symptoms. Paraesthesiae are ini- era prior to the routine use of mannitol) for a group of toxins collectively known on September 26, 2021 by guest. Protected copyright. tially circumoral in nature and then in the French Polynesia and New Caledo- as the brevetoxins. These toxins are lipid spread centrifugally to the limbs, and nia Pacific Islands group.29 soluble and they bind to a poorly defined usually persist for many days and on region of the voltage gated Na+ channel occasions for many weeks. The dysaes- Shellfish poisoning to cause repetitive firing of action poten- thesiae are characterised by a painful Cases of shellfish poisoning typically tials. The toxins may also enhance the reversal of hot-cold sensation. The aver- arise after the consumption of filter release of transmitters from autonomic age duration of illness is 8.5 days, with a feeding shellfish (for example, mussels, nerve terminals. It has also been sug- median hospital stay of six days.26 The scallops, clams), the causative agents gested that they initiate the degranula- chronic effects of ciguatera poisoning being dinoflagellates that are ingested by tion of mast cells and thus contribute to has been estimated to affect 3%–20% the shellfish during feeding. The toxins respiratory problems (see below). The cases of acute poisoning, and is charac- responsible are non-proteins that are symptoms of NSP depend on the route of terised by excessive fatigue. Other stable and resist most of the forms of ingestion. If infected shellfish are eaten chronic effects described include hyper- rapid cooking typically applied to sea- the symptoms are similar to, but less somnolence, peripheral neuropathy, and food. severe than, those associated with PSP. polymyositis. Paralytic shellfish poisoning (PSP) is The brevetoxins are powerful irritants General treatment consists of at- caused by the ingestion of toxin produc- and inhalation of aerosols containing the tempts at reducing further toxin absorp- ing dinoflagellates of several genera by toxins (for example, sea spray, or sprays tion by inducing emesis or performing a filter feeding shellfish. The toxins in- created during storms) causes broncho- gastric lavage followed by the adminis- volved are all members of a family of constriction and lacrimation rather than tration of activated charcoal. Specific gonyautoxins, the best known of which “neurological” signs. The possible role of

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.73.2.103 on 1 August 2002. Downloaded from 108 EDITORIAL histamine and other peripheral media- larger predatory fish that feed on the 3 Were the food items invertebrate (for tors from mast cells has been noted. No primary grazers. The toxins responsible example, filter feeding shellfish) or ver- human fatalities have been reported and are known as palytoxins. They are large, tebrate? Ciguatera is unlikely to be the recovery is rapid and uneventful. lipid soluble polyethers, and produce diagnosis for invertebrate food poison- Amnesic shellfish poisoning is also symptoms indistinguishable from those ing. Of the types of shellfish poisonings caused by consumption of filter feeding of ciguatera. The biological basis of the paralytic shellfish poisoning, with its shellfish that have accumulated domoic toxicity is still controversial but there is neurological features of neuromuscular acid from the causative dinoflagellates of no doubt that it is neurotoxic. It is prob- weakness, is the most important. able that many cases of “ciguatera” are the genera Pseudonitzchia or Nitzchia. 4 Was the fish consumed a large pelagic misdiagnosed cases of palytoxic poison- Domoic acid is an excitatory neurotoxin fish? If yes, the problem is almost active at kainate receptors in the CNS. A ing. Properly documented cases are very rare but usually fatal.33 certainly ciguatera. The likelihood of major outbreak occurred in Nova Scotia ciguatera is also stronger if the place in 1987 and 1998 and minor outbreaks General measures to prevent where the fish was caught was from a have occurred in the Pacific coast of USA, seafood poisoning reef area anywhere in the Caribbean or Scandinavia, and New Zealand. The syn- It can be difficult to predict cases of sea- Pacific, or off the coast of Florida or drome begins with gastrointestinal dis- food poisoning. The toxic animals ex- Queensland. Palytoxic poisoning will be ease, but in severe poisoning patients hibit no obvious signs of being poison- indistinguishable from ciguatera even if become dizzy, ataxic, and experience ous, and of two animals caught in the small reef grazers (file fish, parrot fish, cognitive difficulties. Treatment is symp- same area at the same time only one surgeon fish) have been consumed as all tomatic, but the loss of short-term might be poisonous. Therefore care of these fishes may accumulate either (or memory, confusion, and seizures may be should be taken when eating shellfish, both) ciguatoxins and palytoxin. permanent.31 and special caution exercised with very Diarrhetic shellfish poisoning is wide- 5 Was the fish a puffer fish? If so a tetro- large predatory tropical fish—ideally spread and causes gastrointestinal prob- dotoxic poisoning is probable. smaller fish should be consumed. The lems without neurological symptoms. broth in which the seafood has been As a note of caution, it is becoming The responsible toxin is okadaic acid. cooked should be discarded, and the vis- increasingly clear that in the tropics ani- Recovery is uneventful after two to three cera of any fish should not be consumed. mals that either graze on coral reefs or days. A simple precaution for potentially prob- feed in the benthos may accumulate a It is important to note that although lematical fish includes rubbing a little range of potential toxins, all of which shellfish poisoning (and ciguatera) are raw flesh on the lips before cooking and enter the food chain. The hapless human caused by the ingestion of blooming spe- eating the entire fish—if the lips go victim may therefore in turn have cies of marine algae, a bloom is not a for- numb the fish should be discarded. accumulated a cocktail of toxins. mal requirement. This is because the Extensive washing of seafood is not a J Neurol Neurosurg Psychiatry dinoflagellates involved can rest in the suitable precaution; for example, boiling 2002;73:103–109 benthos on the sea bottom in an mussels for three hours only reduces encysted form. Activation or disturbance okadaic acid levels by 50%. It can take ...... of the benthos may disturb these forms days to reduce the toxicity of affected Authors’ affiliations and allow their ingestion in the absence food items by simply soaking in clean A Goonetilleke, Department of Neurology, of a bloom. water. No seafood should be collected or Newcastle General Hospital, Regional consumed during or for several days Neurosciences Centre, Newcastle upon Tyne Tetrodotoxin fish poisoning NE4 6BE, UK after a bloom (red or green tide). No sea- Tetrodotoxic poisoning usually results J B Harris, School of Neurosciences and

food should ever be eaten uncooked and http://jnnp.bmj.com/ from the consumption of puffer fish, but Psychiatry, The Medical School, University of only freshly caught fish should be Newcastle, Newcastle upon Tyne, UK bites by the blue ringed octopus (an purchased. Australasian species) can also result in Correspondence to: Dr A Goonetilleke; [email protected] the introduction of tetrodotoxin from Differential diagnosis of seafood 32 the saliva. The toxin is probably pro- poisoning duced by a marine Vibrio that enjoys a The differential diagnosis of seafood poi- symbiotic relationship with the host. The soning is by exclusion. The following toxin is concentrated in the skin and vis- factors may be helpful: REFERENCES cera of fish. Most cases of poisoning 1 World Health Organisation. Progress in the on September 26, 2021 by guest. Protected copyright. 1 Was the food properly cooked? The occur in Japan or in Japanese communi- characterization of venoms and consumption of uncooked seafood can standardization of antivenoms. WHO Offset ties elsewhere where puffer fish are be the cause of botulism and meningitis Publ No 58. Geneva: WHO, 1981. eaten as a delicacy. The principal toxin 2 Stone BF. Tick paralysis, particularly involving (a result of infestation with Angiostrongy- (tetrodotoxin) blocks the voltage gated Ixodes holocyclus and other Ixodes species. lus cantonensis). This form of meningitis In: Harris KF, ed. Advances in disease vector Na+ channel at the same site as saxitoxin has an incubation period of four to six research. Vol 5. New York: Springer-Verlag, and causes numbness, tingling, visual 1988:61–85. weeks. disturbances, and a potentially fatal 3 Pearn J. Neurology of ciguatera. J Neurol 2 Was the food fresh when purchased Neurosurg Psychiatry 2001;70:4–8. neuromuscular weakness within 10–15 4 Miller DM. Ciguatera seafood toxins. minutes of ingestion. Treatment is symp- and prepared? Some fish (especially Boca-Raton, FL: CRC Press, 1991. tomatic and recovery is usually unevent- mackerel, tuna, and bonito) convert his- 5 Blain PG, Harris JB. Medical neurotoxicology: tidine to histamine if kept at ambient occupational and environmental causes of ful provided the patient in neuromusc- neurological dysfunction. London: Arnold, ular paralysis is artificially ventilated and temperature for several hours and this 1999. the circulation is maintained. causes scromboid poisoning. The symp- 6 Spencer PS, Schaumberg HH. Experimental toms are caused by the histamine (head- and clinical neurotoxicology. 2nd edn. Palytoxic fish poisoning ache, nausea, urticaria, flushing and Baltimore: Williams and Wilkins, 2000. 7 Boulain J-C, Ménez A. Neurotoxin-specific Palytoxic poisoning is encountered in the fever, gastric pain) and can be treated immunoglobulins accelerate dissociation of the Indo-Pacific and Caribbean, and results with antihistamines. Other fish kept for neurotoxin-receptor complex. Science from the consumption of fish, soft crabs long periods may be dusted with organo- 1982;217:732–3. 8 Reid HA, Lim KJ. Sea-snake bite. A survey of or other animals that graze on the tropi- phosphates or other insecticides to allow fishing villages in north west Malaya. BMJ cal soft anthozoan Palythoa,orofthe flies to be brushed off easily. 1957;ii:1266–72.

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Call for peer reviewers

Clinical Evidence is a regularly updated evidence based journal available world wide both as a paper version and on the internet. Clinical Evidence urgently needs to recruit a number of new contributors. Contributors are health care professionals or epidemiologists with experience in evidence based medicine and the ability to write in a concise and structured way. Clinical Evidence needs to recruit a number of new peer reviewers. Peer reviewers are health care professionals or epidemiologists with experience in evidence based medicine. http://jnnp.bmj.com/ As a peer reviewer you would be asked for your views on the clinical relevance, validity and accessibility of specific topics within the journal, and their usefulness to the intended audience (international generalists and health care professionals, possibly with limited statistical knowledge). Topics are usually 2000–3000 words in length and we would ask you to review between 2–5 topics per year. The peer review process takes place throughout the year, and our turnaround time for each review is ideally 10–14 days. If you are interested in becoming a peer reviewer for Clinical Evidence, please complete the peer review questionnaire at www.clinicalevidence.com or contact Polly Brown on September 26, 2021 by guest. Protected copyright. ([email protected]).