eMedicine Specialties > Emergency Medicine > Environmental

Conidae

Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM, Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania; Director of Education and Research, PENN Travel Medicine
William H Shoff, MD, DTM&H, Director, PENN Travel Medicine, Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania

Updated: Apr 30, 2009

Introduction

Background

The dramatic increase in sport diving, ecotourism, and island and coastline travel, perhaps inevitably, has returned people to the sea. Curiosity about our chondrichthyan ancestors, as well as a desire to explore that 70% of our biosphere that remains largely enigmatic, has fostered a siren call to exotic realms. Dangers exist in the sea, as with any environment for which humans are poorly adapted. Contact with hazardous marine organisms is not the least of these dangers.

Many sea creatures have improved their survival through the evolutionary development of offensive and defensive systems that are often elaborate mechanisms for delivering poison or venom to prey or predator. Most of these organisms live in temperate to tropical oceans, especially in the Indo-Pacific regions. Vast arrays of vertebrate and invertebrate creatures can envenomate humans. This article focuses on the more than 500 members of the invertebrate Conidae family of the phylum Mollusca (ie, the cone shells).

In the last 4 decades, toxinologists around the world have elucidated a wealth of information on the various classes of constituent proteins and peptides that provide each cone with its own distinctive, complex and sophisticated bioarmamentarium. It has been estimated that as many as 50,000 venom components may be produced by the Conus genus. These venoms serve the cone as a primary weapon to capture prey, as defense, and possibly for other functions.

Pathophysiology

Cone shells are carnivorous; they are divided into 3 groups, according to their prey items: molluscivorous (hunt other gastropods), vermivorous (hunters of polychaete and other worms), or piscivorous (fish hunting). The largest group of cones are molluscivorous. Their habitats extend from shallow, intertidal areas to extreme deep-water areas. They inhabit primarily tropical marine environments; however, a few species are found in cooler environments. Cone shells are predominantly nocturnal, burrowing in the sand and coral during the daytime.

To capture a much faster prey in a highly dynamic marine environment, this relatively slow-moving snail has evolved into one of the fastest known predators in the animal kingdom, with the average attack lasting only milliseconds. In an attack, the cone shells inject a cocktail of small, rapidly acting paralytic and lethal oligopeptide toxins, each 15-30 residues long, into the prey. 

Almost 200 different conotoxin peptides have been identified to date. These potent peptides target ion channels, either voltage- or ligand-gated receptors and transporters in excitable cells. The venom mixture is specific to each cone shell species, containing 30-200 conotoxin peptides. A group of conopeptides, described as a cabal, act in a coordinated manner to produce a specific physiologic endpoint such as inhibition of both voltage-gated sodium channel activation and potassium channel block, resulting in massive depolarization of axons at the injection site, causing an effect similar to electrocution of the prey and its immediate immobilization. Different toxic cabals in the same venom may act on the same class of target via different mechanisms. Numerous disulfide bonds determine a specific spatial shape for each toxin, while non-conotoxin peptides lack multiple disulfides.

Thirty cases of human envenomation, with occasional fatalities, have been documented worldwide. Human envenomations have involved 18 species of cone shells, including Conus geographus, Conus catus, Conus aulicus, Conus gloria-maris, Conus omaria, Conus magus, Conus striatus, Conus tulipa, and Conus textile.

The cone shell detects its prey via the siphon, which is covered with chemoreceptors, although limited visual signaling may also be involved. Venom, formed in a venom duct, is stored in a less toxic milky slurry in the venom bulb. When required, the precursor undergoes enzymatic cleavage of the signal peptide and the propeptide forms appropriate disulfide linkages.¹ The mature toxic solution is then delivered via a detachable radula. The radula is a dartlike, hollow, chitinous barb, formed in the radular sheath and delivered, after receiving venom in the buccal cavity, by an extensible proboscis. The venom sac contains approximately 20 radula. The muscular proboscis, which may extend the full length to the shell spire in some species, touches a prey item and then thrusts one radula (or more, in some piscivorous cones) into the prey via circular muscles at its anterior tip. Venom rapidly diffuses through the poisoned prey. The radula remains attached to the cone by a cord.

Once the prey is paralyzed, the gastropod retracts the cord and engulfs the prey through the radular opening into its distensible stomach. Other cone species, such as Conus geographus, may distend and "net" prey with their "false mouths" before injecting venom. Digestion occurs over the ensuing several hours.

Cone shell toxins efficiently and highly selectively inhibit an extensive array of ion channels involved in the transmission of neuromuscular signals in animals. The high target specificity of certain conotoxins toward mammalian channels is due to the fact that mammalian receptor isoforms of the specific target (eg, the nicotine receptor) are quite similar in sequence to their physiologic homologue in fish.

In the last few decades, these toxins have become the focus of some exciting molecular biological and pharmacological research. Conus venoms are remarkably diverse among species and the large gene families that encode conotoxins show high evolutionary rates. A recent study suggests that this may result from either lineage-specific dietary modifications or differences in the positive impact of predator-prey interactional selection.² To date, conotoxins have been divided into 7 superfamilies, based on their disulfide bond frameworks, and they have been further divided into families based on their mechanisms of action. Several conotoxins, and their synthetic derivatives, due to their high selectivity and affinity for different ion channels, are the subjects of current clinical trials on chronic pain control, post-traumatic neuroprotection, cardioprotection, and the treatment of Parkinson disease and other neuromuscular disorders.³

While an extensive discussion of all discovered types of conotoxins and their specific activities is beyond the scope of this article and has served as the basis of several extensive reviews (see References), a sample of several distinct types of conotoxins and their effects are found below.

• W-conotoxin - Hinders the voltage-dependent entry of calcium into the nerve terminal and inhibits acetylcholine release
• M-conotoxin - Modifies muscle sodium channels by occluding and thereby blocking ion conduction through the pore of voltage-gated sodium channels (VGSC), at the same site as saxitoxin and tetrodotoxin⁴
• K-conotoxin - Potassium channel (VGPC)-targeting peptides
• A-conotoxin - Blocks the nicotinic acetylcholine receptor, similarly to snake alpha-neurotoxins
• G-conotoxin - Delays or inhibits VGSC inactivation, resulting in prolongation of the action potential; this produces a "hyperexcited state" in involved neurons and can lead to electrical hyperexcitation of the entire organism, eg, seizures in marine snails⁴
• S-conotoxins - Inhibit 5-HT3 channels
• Y-conotoxins - Competitively block muscle acetylcholine receptors
• Conantokins - Target NMDA (N -methyl-D-aspartate) subtype glutamate receptors
• Conopressin - Vasopressin agonist
• Sleeper peptide - Found primarily in C geographus, induces a deep sleep state in test animals

Cone shells are prized by shell collectors for their pleasing shape and beautiful shells, which exhibit varying, intricate, darker geometric patterns on a lighter base. A sting most commonly occurs on the hand and/or fingers of an unsuspecting handler as well as on the feet of swimmers in shallow, tropical waters. Local stinging is followed within minutes by numbness, paresthesias, and ischemia. Serious envenomations may result in nausea, cephalgia, generalized paralysis, coma, and respiratory failure within hours. Death is typically secondary to diaphragmatic paralysis or cardiac failure. C geographus, which produces the most potent conotoxins found to date , may produce rapid cerebral edema, coma, respiratory arrest, and cardiac failure. In significant envenomations, symptoms may take several weeks to resolve. Disseminated intravascular coagulation (DIC) may also be evident.

Frequency

United States

Conus species are not indigenous to United States waters. These are more likely to be encountered while traveling abroad or by specialized aquarium staff.

International

Thirty human envenomations have been documented in Southern Australia and the Indo-Pacific area. Many unreported envenomations may have occurred.

Mortality/Morbidity

A high risk of death is associated with envenomation by certain species of cones, particularly C geographus, C textile, and C marmoreus. Morbidity includes mild symptoms (eg, nausea, weakness, diplopia) lasting several hours. Death has been documented within 5 hours in a C geographus envenomation. Two to 3 weeks of symptoms may be associated with more severe exposures.

Race

No relationship to age, race, or sex exists in Conus envenomation. Envenomation is more an injury of individuals engaged in either recreational or commercial shell collecting, diving, and fishing.

Clinical

History

A typical incident involves walking, swimming, and/or diving in temperate to tropical waters with accidental contact with a cone shell or incorrect handling of a hazardous specimen. Symptoms include the following:

• Sharp burning or stinging sensation at time of envenomation
• Local numbness and paresthesias
• Perioral paresthesias
• Generalized paresthesias
• Nausea
• Blurred vision and diplopia
• Malaise
• Generalized weakness
• Dysphagia
• Areflexia
• Aphonia
• Paralysis
• Apnea
• Pruritus
• Headache

Physical

• A patient with a cone shell envenomation may manifest an array of symptoms. A detailed history is essential (when possible).
  • Time of incident
  • Specimen, if available for identification
• Vital signs - Pulse oximetry
• The envenomed area may become swollen and pale or cyanotic
• Pulmonary examination
  • Hypoxia
  • Respiratory failure and/or respiratory arrest
• Cardiac examination
  • Ectopy
  • Tachycardia
• Detailed neurologic examination
  • Level of consciousness
  • Visual acuity
  • Motor examination
  • Deep tendon reflexes (decreased/absent)
• Repetitive vital signs and cardiopulmonary and/or neurologic examination are imperative.

Causes

• Careless or unknowledgeable handling of a hazardous specimen
• Unsuspecting scuba divers carrying live cone shells in a wet suit, unsecured specimen bag, or buoyancy control device
• Accidental contact while walking, swimming, and/or diving in shallow, tropical waters
• Increased opportunities for exposure (eg, in aquarium keepers and handlers)

Differential Diagnoses

Workup

Laboratory Studies

• No assay for cone toxins are currently commercially available.
• No specific laboratory abnormality is described for cone shell envenomation.
• In acutely ill individuals, obtain blood for complete blood count, electrolytes, and coagulation studies if indicated.
• Measure arterial blood gas levels.

Imaging Studies

• After the airway is secure, imaging studies may aid evaluations for retained stingray barbs, foreign bodies, or other possible causes of local symptoms. Radular teeth are small enough to probably be missed on plain radiography.
• Imaging studies may also be obtained for evaluation of endotracheal tube placement.

Treatment

Prehospital Care

Focus prehospital care on maintenance of vital functions and prevention of toxin transport from the injection site.

• Airway maintenance and ventilation may prove lifesaving.
• Transport the patient appropriately, as the patient may have oropharyngeal muscle paralysis, and the risk of aspirating vomitus is real.
• Keep the stung extremity in a dependent position, and keep the patient still. Careful, knowledgeable use of the lymphatic-occlusion pressure immobilization bandage suggested for Australian snakebites may be effective (for information on the immobilization technique, see Snake Envenomation, Coral). Tourniquet use is not recommended because it may result in significant iatrogenic injury.
• No role exists for attempted suctioning of conotoxin from the wound.

Emergency Department Care

• For initial management of suspected cone shell envenomation, place emphasis on immediate resuscitation and treatment of respiratory failure.
• No antivenin is available for cone shell envenomation.
• Examine the wound for the presence of a radular tooth and cleanse. Determine the patient's tetanus status and update as appropriate.
• Place the affected limb in hot (not scalding) water to tolerance, with pain relief as the goal. Patients who have experienced a significant envenomation may not obtain adequate pain relief with hot-water immersion and may require additional local anesthesia (1-2% lidocaine without epinephrine) and/or oral or intravenous analgesia.
• A lymphatic-occlusive pressure immobilization bandage may have been placed proximal to an extremity wound site in the prehospital setting. Do not jeopardize arterial circulation distal to this bandage. This bandage may be applied for 4-6 hours; do not remove until the provider is prepared to render systemic support. Incision and drainage followed by soaking the affected site in 45°C water (not scalding) has also been recommended.
• Cardiovascular and respiratory supports are the keystones of management; therefore, the provider must be prepared to support the patient systemically.
  • Data from case reports suggest that edrophonium 10 mg IV may be used as empiric therapy for paralysis. A 2-mg test-dose should first be administered, and if effective, followed by an additional 8-mg dose. Atropine 0.6 mg should be immediately available for intravenous administration in case of an adverse reaction to the edrophonium.
  • A 2- to 4-mg dose of intravenous naloxone may help treat severe hypotension because it blocks the beta-endorphin vasodepressor response.
  • Consider central venous access for fluid resuscitation in cases of severe envenomation.
  • Further study of the infrequent coagulopathy associated with these incidents may provide guidelines for the use of blood products, fresh frozen plasma, cryoprecipitate, desmopressin, and fibrinolytic/antifibrinolytic agents.
• Mild envenomations should resolve within 6-8 hours and the patient can be discharged.

Consultations

Upon encountering a cone shell envenomation, consult the appropriate local poison control center or toxicologist.

Medication

No antivenin is available for cone shell envenomation.

Follow-up

Further Inpatient Care

• Intensive care unit monitoring is indicated for patients with conidae envenomation who are experiencing cardiopulmonary arrest and requiring mechanical ventilation.
• Admit patients to a monitored bed for further observation if they exhibit hypoxia, significant muscular weakness, and/or cardiac ectopy.
• Carefully monitor patients with persistent paresthesias and muscular weakness for signs of respiratory compromise.
• Consider inpatient observation for patients with underlying cardiac, pulmonary, or neurologic disease.

Further Outpatient Care

• Monitor the wound for evidence of infection. Patients whose wounds show any evidence of infection should return for evaluation and should inform the examining health care provider that the wound occurred in the marine environment because antibiotic choice will vary accordingly. The wound should be re-examined for foreign body.
• The patient may require oral analgesics for pain control.

Deterrence/Prevention

• Properly identify cone shells and handle them only with protective gloves.
• Never carry a live cone in net bags next to skin, wet suits, or buoyancy control vests.
  • If a live cone must be carried, lift it at the large posterior end of the shell with protective gloves. This is not always adequate protection as the proboscis can extend the entire length of the shell. 
  • If the proboscis protrudes, immediately drop the cone.
• Walk in intertidal areas wearing appropriate footwear. Do not reach blindly under corals or rocks.

Patient Education

• To assist in preventing cone shell envenomation, give patients the following instructions:
  • Properly identify cone shells.
  • Handle cone shells only with proper gloves.
  • Do not carry a live cone in a perforated or thin bag near skin, wet suits, or buoyancy control vests.
  • If a live cone must be carried, lift at the large posterior end of the shell with protective gloves. Remember, this is not always adequate protection as the proboscis can extend the entire length of the shell.
  • If the proboscis protrudes, immediately drop the cone.
  • Walk in intertidal areas wearing appropriate footwear. Do not reach blindly under corals or rocks.
• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Stingray Injury.

Miscellaneous

Medicolegal Pitfalls

• In most countries where cone shells are found, a permit is required for the collection of all species of Conidae.
• Failure to make the diagnosis
• Failure to consult an appropriate poison control center or toxicologist
• Failure to examine the wound for a foreign body
• Failure to inquire regarding the patient’s tetanus immunization status
• Failure to monitor the patient with muscular weakness for evidence of respiratory failure

References

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2. Duda TF Jr. Differentiation of venoms of predatory marine gastropods: divergence of orthologous toxin genes of closely related Conus species with different dietary specializations. J Mol Evol. Sep 2008;67(3):315-21. [Medline].

3. Han TS, Teichert RW, Olivera BM, Bulaj G. Conus venoms- a rich source of peptide-based therapeutics. Current Pharmaceutical Design. 2008;14(24):2462-79. [Medline].

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16. Kobayashi J, Nakamura H, Hirata Y, Ohizumi Y. Effect of venoms from Conidae on skeletal, cardiac and smooth muscles. Toxicon. 1982;20(5):823-30. [Medline].

17. Livett BG, Sandall DW, Keays D, Down J, Gayler KR, Satkunanathan N, et al. Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor. Toxicon. Dec 1 2006;48(7):810-29. [Medline].

18. McIntosh JM, Jones RM. Cone venom--from accidental stings to deliberate injection. Toxicon. Oct 2001;39(10):1447-51. [Medline].

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22. Olivera BM, Rivier J, Clark C, Ramilo CA, Corpuz GP, Abogadie FC, et al. Diversity of Conus neuropeptides. Science. Jul 20 1990;249(4966):257-63. [Medline].

23. Pi C, Liu J, Peng C, Liu Y, Jiang X, Zhao Y, et al. Diversity and evolution of conotoxins based on gene expression profiling of Conus litteratus. Genomics. Dec 2006;88(6):809-19. [Medline].

24. Rauck RL, Wallace MS, Leong MS, Minehart M, Webster LR, Charapata SG, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. May 2006;31(5):393-406. [Medline].

25. Sharpe IA, Gehrmann J, Loughnan ML, Thomas L, Adams DA, Atkins A, et al. Two new classes of conopeptides inhibit the alpha1-adrenoceptor and noradrenaline transporter. Nat Neurosci. Sep 2001;4(9):902-7. [Medline].

26. Teichert RW, Jacobsen R, Terlau H, Yoshikami D, Olivera BM. Discovery and characterization of the short kappaA-conotoxins: a novel subfamily of excitatory conotoxins. Toxicon. Mar 1 2007;49(3):318-28. [Medline].

Keywords

cone shell toxin, cone shell envenomation, cone shell sting, Conidae family, cone shell venom, conotoxin, conus, mollusca envenomation, conotoxin peptides, Conus geographicus, Conus geographus, C geographus, C geographicus, ziconotide, Conus aulicus, C aulicus, Conus gloria-maris, Conus gloriamaris, C gloriamaris, C gloria-maris, Conus marmoreus, C marmoreus, Conus omaria, C omaria, Conus striatus, C striatus, Conus tulipa, C tulipa, Conus textile, C textile, Mollusca, mollusk, mollusc, oligopeptide toxin, radula, radular sheath, cone shell poisoning

Contributor Information and Disclosures

Author

Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM, Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania; Director of Education and Research, PENN Travel Medicine
Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American Society of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for Academic Emergency Medicine, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Coauthor(s)

William H Shoff, MD, DTM&H, Director, PENN Travel Medicine, Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania
William H Shoff, MD, DTM&H is a member of the following medical societies: American College of Physicians, American Society of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for Academic Emergency Medicine, and Wilderness Medical Society
Disclosure: Glaxo Smith Kline Consulting fee Consulting; Glaxo Smith Kline Honoraria Speaking and teaching

Medical Editor

Samuel M Keim, MD, Associate Professor, Department of Emergency Medicine, University of Arizona College of Medicine
Samuel M Keim, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Public Health Association, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

James Steven Walker, DO, MS, Clinical Professor of Surgery, Department of Surgery, University of Oklahoma Health Sciences Center
James Steven Walker, DO, MS is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Osteopathic Emergency Physicians, and American Osteopathic Association
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Barry E Brenner, MD, PhD, FACEP, Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, University Hospitals, Case Medical Center
Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

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