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Tremorgenic Neuromycotoxicosis in Dogs

By

Michelle S. Mostrom

, DVM, MS, PhD, DABVT, DABT, NDSU Veterinary Diagnostic Laboratory Toxicology

Last full review/revision Nov 2021 | Content last modified Mar 2022

Growth of mold, particularly Penicillium species (eg, Penicillium crustosum) in food (walnuts, peanuts, dairy products), feed (silage), or food waste (compost) can result in the production of secondary fungal metabolites or mycotoxins. Several tremorgenic substances can be produced, but the most extensively studied toxins are penitrems A and E, roquefortine C, verruculogen (a Penicillium or Aspergillis metabolite), and thomitrems. The predominant clinical signs in dogs are vomiting, tremors, intention tremors, hyperesthesia, ataxia, nystagmus, tachycardia, and seizures. Other species at risk include cattle, sheep, rabbits, poultry, and rodents.

Etiology of Tremorgenic Neuromycotoxicosis in Dogs

The production of mycotoxins in human food or animal feed or food waste will depend on the genus and species of mold, with Penicillium a dominant tremorgen producer. Several mechanisms of action have been proposed and involve neurotoxins affecting CNS synapses, such as penitrem A inhibition of the calcium regulated potassium channels and affecting secretion of the neurotransmitter’s glutamate, aspartate, and gamma-aminobutyric acid (GABA) in cerebrocortical synaptosomes. Penitrem A inhibits the inhibitory neurotransmitter glycine in mice. Verruculogen, a metabolite produced by Penicillium or Aspergillus, reduces concentrations of GABA, an inhibitory neurotransmitter in the brain.

After ingestion, the onset of clinical signs can occur in a few hours. Toxins ingested in lower concentrations appear to cause fine muscle tremors lasting for hours to days, whereas large tremorgenic toxin ingestions can cause seizures and death. Vomiting can be the first clinical sign and may help limit the severity of the intoxication. To date, there are no cause-effect relations or dose-effect relations for single toxins in tremorgenic toxicosis.

Although roquefortine C is classified as a tremorgenic mycotoxin, roquefortine C has been shown to be not very toxic after intraperitoneal injection in a mouse, with no tremorgenic signs observed. Also, in suspect tremorgen cases where roquefortine C was reported, penitrems and thomitrems were not analyzed, suggesting that roquefortine C may not be an important tremorgen.

Clinical Findings of Tremorgenic Neuromycotoxicosis in Dogs

The patient history of a dog with tremorgenic neuromycotoxicosis can involve the dog running unsupervised and accessing compost or food waste or a known ingestion of moldy foods (eg, dairy products, nuts, pasta). Common clinical signs include vomiting, salivation, vocalization, blepharospasm, hyperthermia, ataxia, tachycardia, hyperesthesia, fasciculations, tremors, and seizures. Onset of clinical signs can be within 1–2 hours or up to several hours. Aspiration pneumonia can complicate the clinical prognosis due to initial vomiting or during gastric lavage to decontaminate the GI tract. Clinical signs can resolve in a few days with treatment or may require several weeks. Although not common, there are several reported cases of dogs with ongoing ataxia for months to years after tremorgen exposure.

Lesions

Many tremorgen exposures in dogs are nonlethal, although some dogs with severe seizures may be euthanized. Ischemic neuronal necrosis in the cerebellum probably develops from excitotoxic neurotransmitters such as glutamate and aspartic acid. In one case of euthanasia due to seizures, the dog had multifocal hemorrhages in the cerebellum, tunica muscularis of the stomach, periportal hemorrhages in the liver and hemorrhages in lung alveoli, and moderate tubulonecrosis in the kidneys. In the stomach, liver, and kidney, penitrems A, B, D, and E and roquefortine C were detected. Only penitrem A was found in the brain; penitrem A appears capable of crossing the blood-brain barrier. The liver and kidney damage could be related to the tremorgenic toxins, drug therapy, occurrence of other mycotoxins not analyzed in the animal or feed, and shock. Aspiration pneumonia can be another complication with vomiting or gastric lavage occurring during CNS stimulation.

Diagnosis of Tremorgenic Neuromycotoxicosis in Dogs

Diagnosis of tremorgenic mycotoxin exposure is based on the clinical signs of CNS stimulation and can include vomiting and tremors. Tremors can be intensified by handling or sound, intentional tremors, hyperesthesia, tachycardia, and seizures in dogs. A differential diagnosis could include ingestion of strychnine, plant toxins, acetylcholinesterase inhibitors or pesticides, metaldehyde, ethylene glycol, methylxanthines, and illicit drugs. The patient history may include recent access to moldy foods (walnuts, peanuts, dairy products), free-ranging behavior, access to compost, and, in ruminants, possible ingestion of moldy silage. A veterinary diagnostic laboratory can conduct mass spectrometry chemical testing of source material, vomit or GI tract contents, and possibly serum or urine. Several tremorgens (penitrem A and E and roquefortine C) have be detected in liver and kidney tissue, and penitrem A has been detected in the brain. Analysis for tremorgenic mycotoxins in tissues may not be routinely available.

Control of Tremorgenic Neuromycotoxicosis in Dogs

Control of tremorgenic mycotoxin exposure hinges on preventing animals' access to moldy foods, feeds, and food waste, including compost. To control severe seizures, the use of a barbiturate such a pentobarbital sodium (3–15 mg/kg, slowly administered IV, to effect) or diazepam (0.5–1 mg/kg, IV) may be required, followed by methocarbamol to control tremors (55–220 mg/kg, IV, to effect and at a rate not greater than 2 mL/minute). If the animal has not vomited, decontamination of the GI tract is important, via gastric lavage and the use of activated charcoal (1–2 g/kg body weight, PO) and a cathartic such as magnesium sulfate (250 mg/kg, PO) or 70% sorbitol (3 ml/kg, PO). With CNS clinical signs, it is important to prevent aspiration pneumonia when performing gastric lavage. Additional supportive treatment can include intravenous fluids, steroids to manage shock, thermoregulation if animals are hyperthermic during CNS signs or become hypothermic during therapy, and monitoring or treatment for metabolic acidosis and rhabdomyolysis. Oral treatment with methocarbamol may be needed for several days after the patient is discharged from the hospital. Results of CBC and serum biochemical analysis may be within reference ranges or muscle enzyme activity may be elevated. Recovery can be complete within several days or occur gradually over several weeks. Several reports of tremorgenic toxicosis in dogs have reported ataxia in dogs for months to years after exposure.

Key Points

  • Mold growth, particularly Penicillium mold, and production of mycotoxins in food (walnuts, dairy products, pasta), animal feed, or food waste (compost) can result in tremorgenic toxin production.

  • Penitrems A and E, roquefortine C, verruculogen, and thomitrems are the more studied tremorgens.

  • Clinical signs can include vomiting, tremors, intention tremors, hyperesthesia, ataxia, nystagmus, tachycardia, and seizures.·

  • Control of seizures with a barbiturate or diazepam, administered IV, may be required with methocarbamol to control tremors, and decontamination of the GI tract with gastric lavage and the use of activated charcoal and a cathartic is recommended.

  • Additional supportive treatment can include intravenous fluids, steroids, thermoregulation, and monitoring and treatment of metabolic acidosis and rhabdomyolysis.

  • Recovery takes days to weeks in most cases, but some dogs have remained ataxic for months to years.

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