Kirsten Waratuke, DVM, DABT, received her degree in biology and doctorate of veterinary medicine from the University of Illinois. After working at a small animal practice and emergency clinic, she joined the ASPCA Animal Poison Control Center (APCC) as a consulting veterinarian in clinical toxicology. In addition to answering calls on the APCC hotline, Dr. Waratuke also co-authors the Tox Insider, a monthly e-newsletter for veterinarians and veterinary staff, and has published several papers and book chapters. She received her Diplomate of the American Board of Toxicology credential in 2016.Read Articles Written by Kirsten Waratuke
Tremorgenic mycotoxins are metabolites produced by fungi that cause neurotoxicosis in dogs. While several fungal metabolites may cause this intoxication, current research supports penitrem A as the primary mycotoxin involved. The fungi most commonly associated with penitrem A, Penicillium species, grow on meat, cereals, nuts, cheese, eggs, fruits, processed/refrigerated food, refuse, and compost.1,2
Welcome to Practical Toxicology, brought to you in partnership between Today’s Veterinary Practice and the ASPCA Animal Poison Control Center (APCC). This column provides practical clinical information about diagnosing and treating pets that have been exposed to potentially harmful substances.
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If treating a patient that requires emergency care for poisoning, call the APCC at 888-426-4435.
Small animal veterinarians most commonly treat dogs for penitrem A intoxication; however, rats, mice, rabbits, guinea pigs, hamsters, and calves have also been affected.3 There are no published reports of penitrem A toxicosis in cats. Based on the current understanding of the toxin’s mechanism of action, there is no reason to believe cats could not be affected by penitrem A; most likely, the absence of feline cases is explained by the more discerning eating habits of cats.
Muscle tremors are the hallmark clinical sign of tremorgenic mycotoxin intoxication (Box 1). Aspiration has been reported and is a worrisome complication; when heavy sedation is necessary to control tremors, the risk of aspiration increases.4,5
Baseline laboratory tests should include a complete blood cell count (CBC), blood chemistry, electrolytes, and urinalysis.
Elevations in liver and kidney values as well as creatine kinase have been noted.2 Penitrem A has been isolated from the liver and kidney in an intoxicated dog, but the role it plays in the liver and kidneys is not known.2 Other potential causes of elevations in liver and kidney values include significant muscle activity and adverse effects of drugs used to control clinical signs.2
Patients may develop dehydration and electrolyte changes secondary to vomiting and diarrhea. Additionally, disseminated intravascular coagulopathy may occur secondary to severe hyperthermia.
In many cases, a presumptive diagnosis of tremorgenic mycotoxin toxicity is made based on clinical signs and a history including access to compost piles, moldy food, or roaming behavior. A more definitive diagnosis may be made through testing suspected foodstuffs, stomach ingesta, or vomitus for the presence of penitrem A or another metabolite, roquefortine C, which is often found in tandem with penitrem A.6 On necropsy, penitrem A has been isolated from the liver, kidney, and brain.2
Since patients may present with an unknown exposure history, considering other diagnostic differentials is important. These differentials may include pyrethroids, metaldehyde, bromethalin, strychnine, organophosphates/carbamates, paintballs, methylxanthines (caffeine, theophylline, theobromine), ivermectin, macadamia nuts, cocaine, amphetamines, ethylene glycol, and some heavy metals.7
Nontoxic diagnostic differentials may include steroid-responsive tremor syndrome (idiopathic tremor syndrome), cerebellar disease, idiopathic episodic tremors, metabolic disorders (eg, hypoglycemia), hypocalcemia, and hepatic encephalopathy. Infectious diseases such as distemper and rabies should also be included under nontoxic differentials.7
Mechanism of Action
As with many toxins, the exact mechanism of action of penitrem A is not known. However, it is known that its primary site of action is the central nervous system. Most likely, penitrem A has dual roles affecting both inhibitory and excitatory neurotransmission.8
Penitrem A appears to be rapidly absorbed, with onset of clinical signs starting as soon as 15 minutes after exposure up to several hours later. The dose of penitrem A may affect how quickly clinical signs occur. In one study, mice administered larger doses of penitrem A had faster onset of clinical signs.8
In most patients, signs resolve within 24 to 48 hours; however, there are rare reports of signs lasting longer. In one patient, mild signs persisted for 7 months, and another patient had signs still present 3 years later.2
There are two important goals when treating toxicosis:
- Prevent absorption of the toxin (decontamination).
- Treat the clinical effects of the intoxication.
Induction of emesis, gastric lavage, and administration of activated charcoal have all been used to address tremorgenic mycotoxin toxicity. Because of the rapid absorption of penitrem A and rapid onset of clinical neurologic signs, the window of opportunity to safely induce emesis and administer activated charcoal is generally limited.4,9
As the ability to safely induce emesis and/or give activated charcoal may be limited, gastric lavage may provide some benefit. Patients presenting with severe signs (eg, notable hyperthermia, severe muscle tremors, seizures) may require heavy sedation or even anesthesia to control clinical signs.
Once clinical signs are appropriately controlled, patient size and time of toxin exposure become important factors in deciding whether gastric lavage should be performed. Radiographs may be useful to assess how much material is in the stomach. The size of the patient dictates the bore of orogastric tube that can be used; recovering food material through a small-bore tube may prove futile.5 Instilling activated charcoal after gastric lavage via stomach tube may be considered but should be weighed against risk for aspiration.9
Control of tremors is paramount (Box 2); however, this may be a challenge. While diazepam and barbiturates are advised, they may not always be effective (eg, diazepam). Heavy sedation also places the pet at risk for aspiration. Methocarbamol has been used with success. Other drugs used to control tremors include propofol and gas anesthesia.
IV fluids should be administered to all patients that do not have physical contraindications to fluid therapy. Benefits of IV fluids include correction of electrolyte abnormalities and fluid loss secondary to vomiting or diarrhea, cooling (in patients with hyperthermia), and minimizing the risk of kidney injury from myoglobinuria secondary to rhabdomyolysis.
Antiemetics should be used in vomiting patients to limit risk of aspiration, dehydration, and electrolyte abnormalities.
The patient’s temperature should be monitored closely for hyperthermia. Management of muscle tremors will help address the cause of hyperthermia, but other cooling measures may be warranted, such as wetting the patient, fans, and IV fluids; in severe cases, cold packs or running the IV fluid line through cool water may be warranted. Cooling measures should be discontinued when the temperature reaches 102.5°F to prevent rebound hypothermia.12
Intravenous Lipid Emulsion Therapy
Intravenous lipid emulsion (ILE) therapy is a newer therapy that is gaining popularity in veterinary medicine. Although initially designed to treat local anesthetic overdoses in humans, its use has been expanded to include a variety of lipophilic drug overdoses in both humans and veterinary species.
The mechanism of action of ILE therapy is not known; however, it likely includes a “lipid sink” or “lipid shuttle,” where lipid-soluble drugs are transiently sequestered in intravenous liposomes, as well as direct cardiovascular effects.13
Penitrem A is believed to be a lipid-soluble compound, making it a potential candidate for ILE therapy. However, information regarding the use of ILE with tremorgenic mycotoxin intoxication is limited.14,15 ILE therapy may be indicated in patients with a lipophilic toxicosis that does not respond to standard therapy and when signs are serious or life-threatening.
Evaluation of liver, pancreas, and kidney functions, as well as correction of any electrolyte abnormities, is best done before administration of ILE.15-17 Adverse effects of and contraindications to ILE therapy include:
- Allergic or anaphylactoid reactions to components in the lipid emulsion
- Inability or decreased ability to clear lipids from the bloodstream
- Volume overload
- Interference with common laboratory testing
- Interference with other treatment modalities (the “lipid sink” is not selective and may affect lipophilic drugs as well as toxins)
- Recurrence of clinical signs if lipid emulsion is eliminated prior to the toxin
Because many dogs have indiscriminate eating habits, tremorgenic mycotoxicosis is an intoxication small animal veterinarians may see in practice. Ingestion of moldy foods may not be witnessed; therefore, it is important for veterinarians to be familiar with clinical signs and differential diagnoses commonly associated with tremorgenic mycotoxin intoxication. In addition, because of the potential for rapid onset and potentially life-threatening signs, prompt care may affect the outcome in these cases.
- Evans TJ, Gupta RC. Tremorgenic mycotoxins. In: Gupta RC, ed. Veterinary Toxicology Basic and Clinical Principles. 2nd ed. San Diego: Elsevier; 2012:1231-1237.
- Eriksen GS, Jaderlund KH, Moldes-Anaya A, et al. Poisoning of dogs with tremorgenic Penicillium toxins. Med Mycol 2010;48(1):188-196.
- Arp LH, Richard JL. Intoxication of dogs with the mycotoxin penitrem A. JAVMA 1979;175(6):565-566.
- Boysen SR, Rozanski EA, Chan DL, et al. Tremorgenic mycotoxicosis in four dogs from a single household. JAVMA 2002;221(10):1441-1444.
- Lowes NR, Smith RA, Beck BE. Roquefortine in the stomach contents of dogs suspected of strychnine poisoning in Alberta. Can Vet J 1992;33(8):535-538.
- Tiwary AK, Puschner B, Poppenga RH. Using roquefortine C as a biomarker for penitrem A intoxication. J Vet Diagn Invest 2009;21(2):237-239.
- Barker AK, Stahl C, Ensley SM, Jeffery ND. Tremorgenic mycotoxicosis in dogs. Compend Contin Educ Vet 2013;35(2):E2.
- Moldes-Anaya A, Rundberget T, Faeste CK, et al. Neurotoxicity of Penicillium crustosum secondary metabolites: tremorgenic activity of orally administered penitrem A and thomitrem A and E in mice. Toxicon 2012;60(8):1428-1435.
- Crandell D. Toxicological emergencies. In: Mathews KA, ed. Veterinary Emergency and Critical Care Manual. 2nd ed. Guelph: Lifelearn Publishers; 2006:630-640.
- Plumb DC. Plumb’s Veterinary Drug Handbook. 8th ed [online]. plumbsveterinarydrugs.com. Accessed February 2017.
- Plumb DC. Plumb’s Veterinary Drug Handbook. 7th ed. Ames: Wiley-Blackwell; 2011.
- Mathews KA. Hyperthermia, heatstroke, and malignant hyperthermia. In: Mathews KA, ed. Veterinary Emergency and Critical Care Manual. 2nd ed. Guelph: Lifelearn Publishers; 2006:297-303.
- Fettiplace MR, Weinberg G. Past, present and future of lipid resuscitation therapy. J Parenter Enteral Nutr 2015;39(1 Suppl):72S-83S.
- Eriksen GS, Moldes-Anaya A, Faeste CK. Penitrem A and analogues: toxicokinetics, toxicodynamics including mechanism of action and clinical significance. World Mycotoxin J 2013;6(3):263-272.
- Robben JH, Dijkman MA. Lipid therapy for intoxications. Vet Clin North Am Small Anim Pract 2016;47(2):435-450.
- Gwaltney-Brant S, Meadows I. Use of intravenous lipid emulsions for treating certain poisoning cases in small animals. Vet Clin North Am Small Anim Pract 2012;42(2):251-262.
- Marwick PC, Levin AI, Coetzee AR. Recurrence of cardiotoxicity after lipid rescue from bupivacaine-induced cardiac arrest. Anesth Analg 2009;108(4):1344-1346.