Neurological toxicities are common emergencies in veterinary practice. Toxins that cause neurological signs can be endogenous or exogenous. Endogenous neurotoxins are the result of metabolic dysfunction, such as liver or kidney failure. This article will discuss some of the frequently encountered exogenous neurotoxins such as chocolate, metronidazole, tremorgenic mycotoxins, metaldehyde and cannabis.
Common exogenous neurotoxins
Chocolate: methylxanthines
The primary toxic substances in chocolate are methylxanthines (theobromine and caffeine). Humans can easily digest and excrete methylxanthines; the half-life of theobromine in humans is between two and three hours. In dogs, absorption is slow with metabolism in the liver and enterohepatic recirculation before excretion in the urine. The half-life of theobromine in dogs is about 18 hours.
The amount of methylxanthines present depends on the type of chocolate. Chocolate with a high cocoa content, such as baking chocolate and dark chocolate, contains a significantly higher concentration of methylxanthines compared to milk chocolate. The amount of methylxanthines in white chocolate is considered too low to induce intoxication.
Clinical signs of chocolate intoxication
Methylxanthines are phosphodiesterase inhibitors that cause an elevation in intracellular cyclic adenosine monophosphate (cAMP). Increased cAMP results in increased intracellular calcium causing neuromuscular excitability, as well as a positive inotropic effect. Competitive inhibition of adenosine receptors (adenosine is an inhibitory neurotransmitter) also results in CNS stimulation.
Chocolate products are also high in fat and sugar which can lead to gastrointestinal signs. The high amount of fat can lead to pancreatitis. For caffeine and theobromine, the LD50 in dogs is between 100 and 200mg/kg. In cats, the lethal dose is lower, although cats rarely suffer from chocolate intoxication because of their more selective eating behaviour.
Clinical signs of intoxication occur one to two hours post-ingestion. Animals ingesting 20mg/kg may have mild clinical signs such as vomiting, diarrhoea and polydipsia. Cardiotoxic effects may be seen at 40 to 50mg/kg and seizures may occur at 60mg/kg. Clinical signs generally last between 12 and 24 hours but can persist for up to 72 hours.
Diagnosis and treatment of chocolate intoxication
The diagnosis of chocolate intoxication is based on history and clinical signs. Blood tests often reveal hypokalaemia and an increase in aspartate transferase (AST) and alanine aminotransferase (ALT) (Weingart et al., 2021). Stomach contents, serum, plasma or urine can be analysed for methylxanthine levels.
Treatment consists of decontamination and symptomatic treatment. Emesis should be induced in patients presenting within two to four hours of ingestion. Care should be taken when using apomorphine in dogs with seizures, heart disease and recent abdominal surgery. Activated charcoal (1 to 5g/kg PO) every six hours over a period of 72 hours may help to further reduce absorption and increase excretion.
Symptomatic treatment consists of fluid therapy with correction of the electrolyte deviations, sedatives and antiepileptics if necessary. Cardiac arrhythmias are treated medically. In general, the prognosis is good if treated early and aggressively, or if the signs are mild. In cases of severe seizures or arrhythmias, the prognosis is more guarded (Weingart et al., 2021).
Metronidazole
Metronidazole is an antibacterial, antiprotozoal and anthelmintic medication. It is commonly used to treat systemic and enteric obligate anaerobic bacterial infections and some protozoal infections. The recommended metronidazole dose in canine patients for anaerobic infections and gastrointestinal conditions is 10 to 15mg/kg every 12 hours and the dose for protozoal infections is 25mg/kg every 12 hours.
In a recent study, evidence of neurotoxicity in dogs was seen at a median dose of 21mg/kg every 12 hours, regardless of the duration of treatment
In a recent study, evidence of neurotoxicity in dogs was seen at a median dose of 21mg/kg every 12 hours, regardless of the duration of treatment (Tauro et al., 2018). The most-reported clinical signs of neurotoxicity are ataxia, nystagmus, paresis and hypermetria. Treatment consists of stopping the metronidazole, supportive treatment and diazepam treatment. Treatment with diazepam (0.5mg/kg three times daily for three days) can speed up the recovery from one to two weeks to one to two days (Evans et al., 2003).
Fungi: tremorgenic mycotoxins
Tremorgenic mycotoxins are toxins produced by fungi resulting in neurological signs. The most commonly recognised neurotoxins are penitrem A and roquefortine C. Tremorgenic mycotoxins are frequently found in mould-ripened cheese, meat, rice, cereals, eggs, nuts, fruits, processed foods, dog food or compost.
Clinical signs of fungal intoxication
The exact mechanism of action is unknown: tremorgenic mycotoxins are suspected to cause an imbalance between inhibition and excitation in the CNS resulting in excitation. The toxins are absorbed quickly. Clinical signs and symptoms can appear within 15 minutes of digestion. Larger amount of toxins can result in a faster onset of clinical signs.
The most common signs are vomiting, diarrhoea, tremors, epileptic seizures and hyperthermia. In many cases, a presumptive diagnosis of tremorgenic mycotoxin toxicity is made based on clinical signs and a patient history including access to compost or mouldy food, or scavenging behaviour. A more definitive diagnosis can be reached by identification (culture) of penitrem A or roquefortine C in food or stomach contents. The rapid absorption and onset of neurological signs result in a limited window of opportunity to safely induce emesis or administer activated charcoal. Gastric lavage can be considered but depends on size of patient and time of exposure.
The main challenge in these cases is the treatment of tremors and seizures and the prevention of hyperthermia
The main challenge in these cases is the treatment of tremors and seizures and the prevention of hyperthermia. Possible treatments that can be considered are methocarbamol, benzodiazepine, barbiturates and dexmedetomidine. Monitoring of the body temperature is crucial in cases with difficult to control tremors/seizures as these patients are prone to hyperthermia. The signs often resolve after one or two days but can last for longer (Novotna et al., 2023).
Slug pellets: metaldehyde
Metaldehyde is a common ingredient used in pellets for slug and snail baits. The pellets have a blue colour. The reported LD50 covers a wide range with 60mg/kg the lowest published value. Metaldehyde reduces the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) which is most likely the cause of epileptic seizures seen in intoxication. Metaldehyde also increases monoaminoxidase activity resulting in decreasing levels of noradrenaline and serotonin.
The most common clinical signs are ataxia, seizures, hypersalivation and tremors. Treatment consists of emetic therapy, activated charcoal, control of seizures and appropriate supportive treatment (Dutil and Berny, 2023). Metaldehyde has been banned in the UK to protect wildlife and the environment; however, it is still used in EU countries.
Cannabis-induced toxicosis
Cannabis-induced toxicosis is increasingly reported in small animals
Cannabis-induced toxicosis is increasingly reported in small animals. The marijuana plant contains more than 100 cannabinoids, but the main toxic element is psychoactive tetrahydrocannabinol (THC). THC binds to CB1 (psychoactive) and CB2 (pain and inflammation) receptors. Dogs and cats become intoxicated by eating edibles such as brownies, gummy bears or cookies, or by ingesting the plant or human faeces. The concentration of THC in the edibles or plants is very variable.
The signs can be seen within 30 minutes of oral ingestion, but can be delayed several hours, and may last up to 72 hours. The most common signs in dogs are urinary incontinence, disorientation, ataxia, lethargy, hyperaesthesia and bradycardia (Amissah et al., 2022). The most common signs in cats are ataxia and lethargy.
Diagnosis is mainly based on history and clinical signs. Urine tests have not been validated for animals and can give false-negative results. Treatment is symptomatic and supportive. No antidote is available. THC has anti-emetic properties so induction of emesis can be difficult. The prognosis is usually good.
