A 2-year-old male neutered crossbreed dog was referred with a 6-month history of seizures. The episodes were described by the owner as typical for generalised tonic-clonic seizures: the dog would become vacant, turn and then fall onto one side, paddle the limbs as well as chomp the jaw, salivate, urinate and sometimes vocalise. The episodes would last between 60 and 90 seconds, following which he would appear disorientated, blind and anxious for around 15 minutes before returning to normal. At the point of referral, the dog was experiencing around one seizure every 2 weeks, but there was a tendency for the seizures to cluster. There was one described episode consistent with status epilepticus (four seizures with incomplete recovery occurring in between, lasting more than 1 hour). Between episodes, the dog was reported to be normal. However, he was hyperaesthetic, restless and anxious in general, with fear-related aggression to people and other dogs.
The dog had been rescued by the owners around 15 months previously. There was no known travel history, and the dog was up to date with all routine vaccinations, flea and worm treatment (with products not commonly associated with seizures). Two months before the onset of the seizures, the dog had been transitioned onto a commercially available frozen raw-meat diet (with no additional supplements or nutrients) for management of recurrent diarrhoea. Since the transition, no further diarrhoea was reported. There was no other significant medical history and no sign of other systemic disease.
Following the onset of the seizures, the referring veterinary surgeon had started treatment with phenobarbitone (2 mg/kg twice daily) – however, the frequency of seizures increased from one seizure every 6 weeks to seizures every 1–2 weeks. There had also been two episodes of cluster seizures (two seizures within a 24-hour period). Serum phenobarbitone concentration was low (14 mg/litre, reference range 15–40 mg/litre) so the dose was increased to 3 mg/kg twice daily. At the point of referral 2 months later, there had still been no further improvement in the seizure frequency.
On presentation, the dog was bright, alert and responsive. A full physical and neurological examination was not possible because of the temperament of the dog, but those tests that could be performed were normal. Consent was obtained to proceed with investigations – given the age of the dog and lack of reported interictal neurological abnormalities, idiopathic epilepsy was considered the primary differential diagnosis. Therefore, investigations were planned according to the International Veterinary Epilepsy Task Force (IVETF) guidelines in order to achieve a Tier II level of confidence (Table 1) (De Risio et al, 2015).
Table 1. Diagnostic criteria for the diagnosis of idiopathic epilepsy in dogs, according to the International Veterinary Epilepsy Task Force (IVETF) (De Risio et al, 2015) *Optional tests based on clinical suspicion.
| Tier I | Tier II | Tier III |
|---|---|---|
|
|
|
The results of the diagnostic investigations were as follows:
- Haematology: unremarkable
- Serum biochemistry: unremarkable
- Electrolytes: unremarkable
- Bile acid stimulation test: unremarkable
- Urinalysis: isosthenuria (1.014), otherwise unremarkable
- Blood serologies for Toxoplasma gondii and Neospora caninum: negative
- Total thyroxine (T4): high 80 nmol/litre (reference range 15.0–50.0 mg/litre)
- Serum phenobarbitone concentration: 22 mg/litre (reference range 15–40 mg/litre)
- Brain magnetic resonance imaging: unremarkable
- Cerebrospinal fluid analysis: unremarkable
Given the abnormal total thyroxine result, serial monitoring was performed:
- Day 1: 80 nmol/litre
- Day 2: 55.1 nmol/litre
- Day 4: 67.1 nmol/litre, thyroid-stimulating hormone 0.05 ng/ml (reference range 0.0–0.60 ng/ml).
Given the young age of the dog and the history of raw-meat feeding, there was a suspicion of dietary hyperthyroidism. The dog was therefore discharged with instructions to transition it onto a complete cooked feed and the phenobarbitone dose was increased to 4 mg/kg twice daily. Unfortunately, 2 weeks following discharge, the dog suffered an episode of status epilepticus from which he died.
Samples of the raw food diet were provided by the owner for the purposes of analysis. The samples were submitted to a commercial laboratory, where 0.5 g of each sample were suspended in saline, mixed and centrifuged. The supernatant was assayed on a total T4 radioimmunoassay with a lower limit of detection of <4.0 nmol/litre. The results of these assays are shown in Table 2.
Table 2. Results of T4 radioimmunoassay of samples of raw meat diet
| Flavour | Total T4 concentration |
|---|---|
| Beef and offal | 6.1 nmol/litre |
| Beef, tripe and offal | 39.0 nmol/litre |
| Lamb and offal | <4.0 nmol/litre |
| Beef, chicken and offal | 5.5 nmol/litre |
| Chicken and offal | <4.0 nmol/litre |
Hyperthyroidism in dogs
Hyperthyroidism is rare in dogs compared to cats. The most common cause of hyperthyroidism in dogs is a functional thyroid tumour, either benign or malignant, whereas cats and humans are more often affected by benign thyroid hyperplasia (Scharf et al, 2020). Clinical signs reported in dogs with hyperthyroidism include polyuria-polydipsia (Scharf et al, 2020), weight loss (Scharf et al, 2020), behavioural changes (Camps et al, 2019) and hypertension (Looney and Wakshlag, 2017). In dogs with a thyroid mass, other clinical signs are usually also present, including presence of a palpable mass, coughing, dysphagia and dyspnoea (Scharf et al, 2020). The other most common reported cause of hyperthyroidism is dogs is iatrogenic thyrotoxicosis, through oversupplementation of dogs with l-thyroxine.
Dietary hyperthyroidism
Dietary hyperthyroidism, also known as dietary thyrotoxicosis, is caused by ingestion of food containing thyroid tissue. This is typically associated with raw-meat diets and treats made from dried gullets or necks (Köhler et al, 2012; Zeugswetter et al, 2013), however air-dried foods have also been implicated (Broome et al, 2015). There is one report that also attributes dietary thyrotoxicosis to canned dog food, although this is considered much rarer. High levels of triiodothyronine (T3), rather than T4, were found in some samples of canned food. T3 is formed through deiodination of T4, and T3 is considered to be the more metabolically active form. Rotstein et al (2021) theorise that T4 may be left intact in raw and dried diets, however the pressures and temperatures used in the canning process may cause deiodination of T4 to T3.
Clinical signs of dietary hyperthyroidism are similar to those reported for hyperthyroidism related to a functional thyroid tumour, with weight loss, aggression, tachycardia, panting and restlessness all reported, although some cases may have no clinical signs (Köhler et al, 2012).
Thyroid tissue is considered inedible and must be removed from all carcasses following slaughter. The reason for this was well demonstrated in humans in the 1980s, when an outbreak of ‘hamburger thyrotoxicosis’ was attributed to inadvertent inclusion of bovine thyroid tissue in ground beef from one meat processing plant (Hedberg et al, 1987). One report suggests dietary thyrotoxicosis to be more likely to occur in canine diets containing bovine meat (Rotstein et al, 2021), which would appear to be in agreement with the current case, as all of the food samples containing beef had detectable concentrations of T4. However, there is no known ‘normal’ range of T4 content in meat-containing diets, and no validated methods for quantification. The reason for this association is unclear, and may reflect differences in slaughterhouse procedures, but also may reflect an inherent variation in the power of detection of bovine T4 using commercially available assays.
Hyperthyroidism and seizures
Seizures have been attributed to hyperthyroidism in both humans (Koch, 2010) and cats (Pakozdy et al, 2014). The pathophysiology is not fully understood, but hyperthyroidism can affect the antioxidant/oxidant balance leading to the formation of reactive oxygen species, as well as causing oxidative stress in mitochondria (Tamijani et al, 2015). In cats, hyperthyroidism is considered a metabolic cause of epilepsy, distinct from the hypertensive encephalopathy that may or may not be concurrent in those patients (Pakozdy et al, 2014).
Hyperthyroidism is not a reported cause of seizures in dogs, but there is no reason to believe the pathophysiology should be any different to that of cats and humans. The lack of reports of hyperthyroid-related seizures in dogs may instead reflect the rarity of the disease in this species, as opposed to in humans and cats. The IVETF does not list total T4 measurement as an essential test to be performed to achieve a tier I, II or III level of confidence in the diagnosis of idiopathic epilepsy in dogs. Rather, the clinician must assess whether a case is likely to have thyroid dysfunction, and test as they deem appropriate. Most clinicians will be aware of the association between hypothyroidism and seizures in dogs but may not suspect hyperthyroidism as a potential cause, especially given that the clinical signs of hyperthyroidism in dogs are nonspecific or may even be non-existent.
Conclusions
The case described here demonstrates the presence of suspected dietary hyperthyroidism in a dog presenting with seizures that were refractory to phenobarbitone treatment. There are no reference ranges for T4 concentration in dog food and the dog did not survive long enough to repeat serum T4 concentrations following a change of diet. Additionally, no neck imaging or scintigraphy was performed to assess the thyroid glands in the current case, so it is not possible to conclude definitively that the diet was the cause of the elevated serum T4 levels.
Despite this, the detection of T4 even in this rudimentary assay in the beef-containing flavours of food is highly suspicious. Furthermore, there are multiple reports of dietary thyrotoxicosis in dogs fed raw meat diets or dried gullet treats, and the present case also had behavioural changes that can be associated with hyperthyroidism. A link between the thyrotoxicosis and the seizures is suspected here, although this has not previously been reported. It is also possible the hyperthyroidism was incidental in an otherwise idiopathic epileptic dog.
In the author's opinion, a thorough dietary history should be collected in all dogs presented with seizures, and serum total T4 levels as a minimum should be assessed in all dogs fed uncooked or dried meat diets.
KEY POINTS
- Dietary hyperthyroidism is a potential cause of epileptic seizures.
- In this case, the raw food diet contained detectable levels of thyroxine, leading to the suspicion of dietary hyperthyroidism.
- The inclusion of thyroid tissue in raw food diets can lead to thyrotoxicosis.
- An animal's diet should be adjusted in a case of suspected thyrotoxicosis to determine if there is improvement in the clinical signs.
- A full neurological workup should be performed if possible, to rule out any other cause of seizures.