Transient loss of consciousness in boxer dogs with hypothyroidism: 3 cases (2015–2018)

TL;DR

Three Boxer dogs with hypothyroidism showed transient loss of consciousness, which improved after treatment with levothyroxine.

Contribution

This study highlights hypothyroidism as a potential cause of transient loss of consciousness in Boxer dogs.

Findings

Transient loss of consciousness in Boxers was associated with hypothyroidism.

Levothyroxine treatment resolved or improved the symptoms in all three dogs.

Second-degree atrioventricular block and sinus bradycardia were observed during an episode.

Abstract

Three Boxers, two neutered females and one neutered male, aged from seven to eleven years, were presented for investigation of transient loss of consciousness.

In each case, physical examination revealed no significant abnormalities and echocardiography, and electrocardiography did not identify a cause of transient loss of consciousness. Twenty-four-hour electrocardiogram (Holter) monitoring was performed in all three dogs. One dog had an episode of transient loss of consciousness whilst wearing the Holter, during which second-degree atrioventricular block and sinus bradycardia were observed. Based on clinicopathological testing, all three dogs were diagnosed with hypothyroidism. Once hypothyroidism was diagnosed all dogs were started on levothyroxine. In all cases the transient loss of consciousness resolved or improved once the treatment was started.

Hypothyroidism should be considered as a differential diagnosis in Boxers presenting with transient loss of consciousness. Treating hypothyroid Boxers may decrease or resolve the clinical signs.

Full text

Background

Syncope, a common condition in Boxers, is described as a brief loss of consciousness due to decreased cerebral blood flow [1]. Transient loss of consciousness (TLOC) is a more general term used to describe all disorders resulting in loss of consciousness, regardless of the underlying cause [2, 3]. Diagnosis of TLOC and syncope can be challenging due to the many aetiologies and intermittent nature. Accordingly, a diagnosis is only reached in 40 to 50 per cent of dogs presenting with syncope [4]. Transient loss of consciousness is especially common in Boxers, in part due to the high prevalence of increased vagal tone leading to vasovagal syncope, subaortic stenosis (SAS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) in the breed [5, 6]. Boxers presenting for syncope, collapse and exercise intolerance without a diagnosis are significantly more likely to suffer from premature death compared with other breeds, making an accurate diagnosis imperative [7].

There are many known causes of TLOC, including neurological conditions like epilepsy, cardiorespiratory disease, for example dilated cardiomyopathy, and metabolic diseases like hypoglycemia. Whilst hypothyroidism is known to cause cardiogenic changes [8, 9] it is not a commonly recognised cause of TLOC in dogs. Hypothyroidism is the result of impaired production of the thyroid hormones, triiodothyronine (T_3_) and thyroxine (T_4_). Due to the diffuse and diverse role of the thyroid hormones in homeostasis, hypothyroidism is characterised by a variety of clinical signs however, it most frequently presents with a combination of metabolic and dermatological changes [10, 11]. A spectrum of other conditions have also been attributed to hypothyroidism including anaemia, megaesophagus, peripheral neuropathy and keratoconjunctivitis sicca [10, 12, 13, 14].

Tests routinely used to achieve a diagnosis of hypothyroidism include measurement of total thyroxine (tT_4_), free thyroxine (fT_4_) and thyroid stimulating hormone (TSH) [15, 16, 17]. However, interpretation of test results can be challenging due to several factors that affect the concentration of thyroid hormones, including nonthyroidal illness, administration of certain drugs, and age [18] and can lead to misdiagnosis [19]. The challenges involved in diagnosis make understanding the presentation and associated conditions important.

The objective of this case series was to describe Boxer dogs that presented for syncope which resolved or improved following the diagnosis and treatment of hypothyroidism.

Case one

Case presentation

A 27 kg (BCS 4/9) 10-year-old female neutered Boxer was examined following one episode of TLOC after rest. There were no significant findings on physical examination.

Clinicopathologic analysis

Complete blood count and serum biochemistry were performed at admission (Table 1) using a commercial veterinary laboratory (IDEXX Laboratories, Kornwestheim, Germany). Analyses were conducted with an automated haematology analyser (Siemens ADVIA 2120i, Siemens Healthcare Diagnostics, Erlangen, Germany). The dog had mild hypercholesterolemia, a moderate increase in lipase, mild hyperphosphataemia and a borderline decrease in total calcium. Cardiac troponin I concentration was measured using a commercial veterinary laboratory (IDEXX Laboratories, Kornwestheim, Germany) and an automated immunoassay analyser (Immulite 2000 XPi, Siemens Healthcare Diagnostics, Erlangen, Germany). The value was elevated but not considered consistent with myocarditis or acute myocardial injury [20].

Table 1A summary of the abnormalities found during routine serum biochemistry, complete blood count (CBC) and cardiac troponin I resultsHctRBCHGBReticulocyte countSerum potassiumSerum cholesterolSerum ALPSerum ureaSerum LipaseSerum phosphorusSerum CreatinineTotal calciumCardiac Troponin I Case one 0.50 L/L (RI:0.35–0.55)6.81 × 10^12^/L (RI:5.4-8.0)15.3 g/dL (RI:12–18)0.02 × 10^12^/L (RI: 11–110)4.87mmol.L (RI:3.6–5.6)6.3mmol/L (RI:3.2–6.2)50.0U/L (RI:<=130)5.0mmol/L (RI:3.1–10.1)463.0U/L (RI:0.1–200)1.74mmol/L (RI:0.8–1.6)79µmol/L (RI: 44–133)2.3mmol/L (RI:2.31–2.84)0.18ng/mL (RI:<0.15) Case two 0.29 L/L (RI:0.35–0.55),3.91 × 10^12^/L (RI:5.4-8.0)9.7 g/dL (RI:12.18)0.01 × 10^9^/L (RI: 11–110)3.7mmol/L (RI:3.8–5.3).4.0mmol/L (RI:3.2–6.5)102U/L (RI:0-100)2.9mmol/L (RI:3.5-6)96U/L (RI:0-100)0.92mmol/L (RI:0.8-2.0)67µmol/L (RI:44–159)2.58mmol/L (RI:2.2–2.7)0.688ng/L (RI:0.01–0.15) Case three 0.44 L/L (RI:0.35–0.55)6.89 × 10^12^/L (RI:5.4-8.0)15.1 g/dL (RI:12–18)100.6 × 10^9^/L (RI: 11–110)3.8mmol/L (RI:3.5–5.8)10.66mmol/L (RI:2.8–8.2)647 U/L (RI:23–212)4.9mmol/L (RI:2.5–9.6)1411U/L (RI:200–1800)1.3mmol/L (RI:0.8–2.2)122 µmol/L (44–159)3.07 mm/L (RI:1.98-3.00)Not performedALP = Alkaline phosphatase. HGB = heamoglobin. RBC = Red blood cell. Hct = Heamatocrit

Diagnosis of hypothyroidism

Canine TSH concentration was borderline increased and total T4 (tT4) was low-normal, as measured using an automated immunoassay analyser (Immulite 2000 XPi, Siemens Healthcare Diagnostics, Erlangen, Germany). Free T4 (fT4) was subsequently assessed by equilibrium dialysis, and repeat measurements of tT4, fT4, and TSH were performed one month later by a commercial veterinary laboratory (Axiom Veterinary Laboratories, Newton Abbot, UK). On the second occasion, tT_4_ was decreased and TSH was within normal limits. Free T_4_ was decreased on both occasions (Table 2).

Table 2A summary of the serum tT_4,_ TSH and fT_4_ resultstT_4_TSHRepeated tT_4_Repeated TSHfT_4_ Case one 7.2nmol/L(RI:5.0–44.0)0.51ng/mL (RI:0.03–0.5)8.4nmol/L (RI:10.0–55.0)0.26ng/mL (RI:0.01–0.6)5.2pmol/L (RI:6.6–40) Case two 5.25nmol/L (RI:6.5–44.0)2.11ng/mL (RI:0.03–0.50)Not performedNot performedNot performed Case three 6.72nmol/L (RI:5–44.0)1.86ng/mL (RI:0.03–0.5)Not performedNot performedNot performedfT4 = Free T_4_. TSH = Thyroid stimulating hormone. tT_4_ = Total T_4_. The reference ranges are specific to the laboratory used to perform the test

Diagnostic imaging findings

Doppler echocardiography (GE Vivid E95, GE Healthcare, Chicago, Il, USA) (Table 3), thoracic radiography and abdominal ultrasound were performed and revealed no significant abnormalities.

Table 3. Selected measurements from the echocardiography performed on the three casesLA/AoLVSd (mm)LVIDs (mm)LVIDd (mm)%FS (%)LVD_indIVSd_indLVESV_ind (ml/m^2^)TAPSE (cm) Reference range 1.05–1.75^(Rishniw et al. 2019)^12.1 (8.3–16.1)^(Cunningham et al. 2008)^24.5 (16.7–33.0)^(Cunningham et al. 2008)^39.6+/-3.4 ^(Smets et al. 2014)^ 31.3+/- 4.6 ^(Smets et al. 2014)^1.27–1.85^(Cunningham et al. 2008)^0.29–0.59^(Cunningham et al. 2008)^36+/-7^(Smets***et al.***2014)^RR for 27 kg: 1.5 (1.2–2.6).RR for 46 kg: 1.8 (1.2–2.7)^(Feldhutter et al. 2022)^ Case one 1.219.131.043.3281.640.4134.51.74 Case two 1.1914.823.438.0391.270.6027.0N/A Case three 1.5210.4427.139.9321.290.4114.92.00LA/Ao = Left atrium/aorta. LVSd = Left ventricular septum diastole. LVIDs = Left ventricular internal diameter end systole. LVIDd = Left ventricular internal diameter end diastole. FS = Fractional shortening. LVD_ind = Left ventricular diameter indexed to body weight. IVSd_ind = Interventricular septum end diastole indexed to body weight. LVESV_ind = left ventricular end systolic volume indexed to body weight. TAPSE = Tricsupid anular plane systolic excursion. RR = Reference range

ECG

Sinus rhythm with a mean heart rate of 79 bpm and occasional ventricular premature complexes (VPCs).

Holter ECG (24-hour ECG) findings

A 24-hour ECG was performed prior to diagnosis and treatment of hypothyroidism. The predominant rhythms were sinus rhythm and sinus arrhythmia with ventricular ectopy (112/24 hours; RI ≤ 91/24 hours) that occurred singly (similar to ECG findings) [21]. No episodes of syncope occurred whilst wearing the Holter (Table 4).

Table 4. Selected 24-hour ECG results from the first 24-hour ECG performed in each casePredominant rhythmMinimum heart rate (bpm)Maximum heart rate (bpm)Mean heart rate (bpm)VPCsNumber of sinus pauses > 3s Case one Sinus arrhythmia4715879Aberrant total: 145VPCs: 1120 Case two Sinus arrythmia5417987Aberrant total: 20Single VPCs: 11Two couplets1 ventricular run3 Case three Sinus and sinus arrythmia6119391Aberrant total: 62VPCs: 230VPCs = Ventricular premature complexes

Treatment and outcome

Following the diagnosis of hypothyroidism, treatment with 0.5 mg (0.02 mg/kg) levothyroxine (Leventa, MSD Animal Health, Milton Keynes, UK) PO every 24 h was started. After starting treatment no further episodes of TLOC occurred and blood tests performed two months after diagnosis confirmed appropriate supplementation with suppression of thyroid stimulating hormone (TSH) (< 0.03ng/ml, RI: <0.50) and normal free thyroxine (fT4) (36.8pmol/L, RI: 7.7–47.6). At this point, a further 24-hour ECG was performed, with similar results to the first.

Follow up

Several months after diagnosis, case one acutely deteriorated after being found dyspneic and unable to walk. Unfortunately, a diagnosis was not reached, and the dog was euthanased.

Case two

Case presentation

A 41 kg (BCS 7/9) 7-year-old female neutered Boxer presented with a two-week history of episodes of TLOC; the episodes occurred when standing after being asleep and lasted for around two minutes. The owner had reported that she was quieter in herself. There was a II/VI left basilar systolic murmur on cardiopulmonary auscultation.

Clinicopathologic analysis

Complete blood count and serum biochemistry were performed at admission (Table 1) using an automated haematology analyser (Advia 2120i, Siemens Healthcare Diagnostics, Erlangen, Germany) and analysed by a commercial laboratory (IDEXX Laboratories, Kornwestheim, Germany). Findings included a mild, non-regenerative anaemia and a moderate increase in alkaline phosphatase activity (ALP). Cardiac troponin I concentration (Table 1) was increased, but not consistent with myocarditis or acute myocardial injury, as measured using an automated immunoassay analyser (Immulite 2000 XPi, Siemens Healthcare Diagnostics, Erlangen, Germany) [20].

Diagnosis of hypothyroidism

Total T_4_ was less than the reference interval and thyroid stimulating hormone was increased (Canine total T4, Immulite 2000 XPi, Siemens Healthcare Diagnostics, Erlangen, Germany) (Table 2).

Diagnostic imaging findings

Mild aortic stenosis was identified on Doppler echocardiography (Table 3) (GE Vivid E95, GE Healthcare, Chicago, Il, USA). Abdominal ultrasound and thoracic radiography were performed and revealed no significant abnormalities.

ECG

Sinus rhythm with a mean heart rate of 93 bpm and no VPCs.

Holter ECG (24-hour ECG) findings

The predominant rhythm was sinus rhythm. The dog had two syncopal events whilst wearing the Holter. During these events the ECG showed periods of sinus slowing and high grade second degree atrioventricular block (AVB) with idiojunctional and idioventricular escape mechanisms. During the first episode the escape rate was 25 bpm but returned to sinus rhythm after six beats. Upon returning to sinus rhythm, the rate was initially bradycardic (46 bpm) but then increased to 85 bpm. The total episode occurred over a period of 30 s. During the second syncopal episode the escape rate was 40 bpm. It then returned to sinus arrythmia (66 bpm), and this recovery happened in 15 s. The longest R to R interval was 4.2 s (Table 4).

Treatment and outcome

Subsequent to the 24-hour ECG the dog was started on 5 mg of terbutaline (Bricanyl; AstraZeneca, Cambridge, UK) PO every 12 hours due to the suspicion of a neurocardiogenic component. For the week following commencement of treatment, there was an initial period without TLOC however, following this an episode of weakness was noted and the dose of terbutaline was increased to 5 mg PO every 8 h. A follow up 24-hour ECG was performed which recorded 13 ventricular premature complexes, 1 couplet, and 1 supraventricular premature complex over the full recording. No episodes of TLOC occurred during the ECG recording. The owner reported progressive lethargy, and a worsening anemia was documented (HCT 0.204 L/L (0.35–0.55), RBC 2.52 × 10^12^/L (5.4-8.0), Hgb 6.3 g/dL [12, 13, 14, 15, 16, 17, 18], MCV 81.1fL (65–75), MCHC 33.4 g/dL (32–37), reticulocyte count 68 × 10^9^/L (11–110)) in addition to hyperkeratosis of the nasal planum. At this time the dog was diagnosed with hypothyroidism and therapy with 0.8 mg (0.02 mg/kg) of levothyroxine PO every 12 hours (Thyforon, Dechra, Shrewsbury, UK) was initiated. A significant improvement in the dog’s demeanor and energy levels were noted two weeks after starting treatment with levothyroxine and no further syncopal episodes were recorded. An improvement in the anaemia was documented (HCT 0.236 L/L (0.35–0.55, was 0.204), RBC 2.82 × 10^12^/L (5.4-8.0, was 2.52), Hgb 7.3 g/dL (12–18, was 6.3), MCV 83.8fL (65–75), MCHC 30.7 g/dL (32–37), reticulocyte count 84.6 × 10^9^/L (11–110)). Three months after this appointment the haematology showed a normal haematocrit (0.407 L/L, Ref. 0.38–0.57) and the owner reported that she had continued to be more playful. The terbutaline dose was tapered over six weeks and then stopped. No further episodes of TLOC or weakness were reported.

Follow up

Case two was presented as an emergency six months after starting treatment with levothyroxine (two months after the last presentation) and was diagnosed with high-grade abdominal lymphoma and received palliative treatment. She was euthanised 9 days later.

Case three

Case presentation

A 46 kg (BCS 9/9) 11-year-old male Boxer was evaluated after experiencing four episodes of TLOC over a 7-month period. All episodes started with coughing and lasted for around 30 s before rapid, complete recovery. There was a II/VI left basilar systolic murmur on cardiopulmonary auscultation.

Clinicopathologic analysis

Complete blood count and serum biochemistry were performed at admission (Table 1) using an automated haematology analyser (Advia 2120i, Siemens Healthcare Diagnostics, Erlangen, Germany), with analysis conducted by a commercial laboratory (IDEXX Laboratories, Kornwestheim, Germany). Findings included mild hypercholesterolaemia, mild hypokalaemia, and a mild decrease in urea.

Diagnosis of hypothyroidism

Total T_4_ was low normal and thyroid stimulating hormone was increased (Canine total T4, Canine total T4, Immulite 2000 XPi, Siemens Healthcare Diagnostics, Erlangen, Germany) (Table 2).

Diagnostic imaging findings

Degenerative mitral valve disease (ACVIM stage B1) was identified on Doppler echocardiography (GE Vivid E95, GE Healthcare, Chicago, Il, USA) (Table 3) [22]. Computed tomography (CT) of the thorax and abdomen was performed and revealed a small left thyroid/parathyroid nodule but no further abnormalities.

ECG

Sinus rhythm with a mean heart rate of 180 bpm and the presence of frequent VPCs of right ventricular origin.

Holter ECG (24-hour ECG) findings

The 24-hour ECG was performed two weeks after treatment for hypothyroidism had commenced but euthyroidism had not been achieved. The trace from the 24-hour Holter ECG showed that the predominant rhythms were sinus and sinus arrhythmia. There were 62 ventricular complexes of which 23 were VPCs (RI ≤ 91/24 hours) [21], one was a triplet (instantaneous heart rate of 219 bpm), and the remaining complexes were due to ventricular bigeminy (Table 4).

Treatment and outcome

The diagnosis of hypothyroidism was made following presentation for investigation of TLOC. Treatment with 0.8 mg (0.02 mg/kg) of levothyroxine (Thyforon, Dechra, Shrewsbury, UK) PO every 24 h was started. Ten days later the dog was presented following two further episodes of TLOC. These differed from the previous episodes in that they were not preceded by coughing and there was a period of disorientation post-TLOC. Total T_4_ was repeated and was increased (83.3nmol/L, RI: 5–44), with TSH in the upper end of the reference range (0.388ng/mL, RI: 0.03–0.50). The dose of levothyroxine was adjusted to 0.4 mg PO every 12 h (no decrease in total dose). A 24-hour ECG was performed at this time (105 VPCs, mostly singular monomorphic, two couplets). Two weeks later tT_4_ was high-normal and the hypothyroidism was considered well controlled (tT_4_ 48.8nmol/L, RI: 13–51; TSH 0.33ng/mL, RI: <0.50).

Follow up

A 24-hour ECG was repeated six months later following one episode of TLOC, and the results indicated likely ARVC (999 aberrant complexes, 229 VPCs with near R on T, 218 complexes were less premature, 5 couplets with an instantaneous rate of 264 bpm, 1 triplet with an instantaneous rate of 348 bpm at the time of stress and excitement). Seven instances of bradycardia (Heart rate < 45 bpm for > or equal to 4 beats) were also noted. Treatment was not started as it was not considered indicated at this time.

Discussion

This case series describes three Boxer dogs that were presented for investigation of TLOC. All three dogs were diagnosed with hypothyroidism and TLOC appeared to improve or they had no further TLOC following treatment with levothyroxine. However, a direct causal relationship cannot be definitively established.

Whilst TLOC is common in Boxer dogs, an association with hypothyroidism has not previously been reported. Thyroid hormones have direct and indirect effects on the cardiovascular system [8, 9], and hypothyroidism can lead to cardiogenic abnormalities, including bradycardia and atrioventricular block (AVB) in both dogs and humans [23, 24, 25, 26]. Aetiologically, it is hypothesised that reduced beta-adrenergic stimulation in hypothyroid states allows parasympathetic tone to dominate, prolonging the refractory period and predisposing to AVB [27]. In human medicine, this heightened parasympathetic activity is well documented [28, 29], and a similar pattern has been observed in dogs. One case report described a hypothyroid Dalmatian exhibiting bradycardia, pause events, AVB, and ventricular ectopy, all of which resolved following levothyroxine treatment as sympathetic tone increased, and parasympathetic tone diminished [26].

Comparable findings were seen in case two of our series, in which 24-hour ECG during syncopal episodes revealed high-grade second-degree AVB and sinus slowing. The longest R–R interval was 4.2 s, insufficient alone to cause TLOC, suggesting the combination of AVB and sinus slowing as the likely cause, consistent with type 1B syncope, characterised by advanced AVB and progressive sinus rate reduction [3].

In the other two cases no episodes of TLOC were reported whilst the Holter was in place, so it is not possible to ascertain the cause of TLOC in these Boxers. In case one and two there was resolution of TLOC after treatment with levothyroxine. However, as case one only had one episode prior to diagnosis with hypothyroidism, it cannot be certain that the treatment resulted in resolution of TLOC.

In this case series, the only breed investigated were Boxers. As a brachycephalic breed, they are identified as having increased vagal tone [5]. It is possible that the combination of the two disorders results in further increase in parasympathetic activity, the consequence of which is a decreased threshold for episodes of TLOC. Furthermore, brachycephalic breeds have several anatomical abnormalities such as nasal stenosis and elongated soft palates, which can result in hypoxia [30]. This could be a contributing factor the TLOC [31].

Anemia occurs in 32 to 44 per cent of dogs with hypothyroidism [12] and was seen at initial presentation in case two. Severe anemia can cause TLOC [32] in dogs but is unlikely to be a significant contributing factor in this case.

Arrhythmogenic right ventricular cardiomyopathy is an inherited myocardial abnormality common in Boxers, characterised by ventricular arrhythmias which can result in TLOC [33]. Neurocardiogenic bradycardia is another common cause of TLOC in Boxers which occurs when there is reflex vasodilation without a relative increase in heart rate [34]. In case three the TLOC improved following treatment with the correct dose of levothyroxine. The first two Holter readings did not indicate the presence of ARVC and although there was variation between the two Holters, up to 80 per cent variation between recordings has been reported in Boxers with this disease [35]. However, six months later one further syncopal episode was reported after initiation of the correct dose of levothyroxine and the final Holter recording revealed likely ARVC and periods of bradycardia, either of which could result in TLOC. It is feasible that this dog had hypothyroidism, and then later developed ARVC and neurocardiogenic bradycardia concurrently, which would have contributed to the final TLOC episode reported.

It is not yet clear what would cause TLOC in hypothyroid Boxers, but it is likely that cardiovascular changes such as an increase in parasympathetic tone play a role. The presence of an already increased vagal tone in the breed combined with the occurrence of other abnormalities common to Boxers, such as ARVC and neurocardiogenic bradycardia, could further increase the likelihood of TLOC compared with other dogs with hypothyroidism. Further research is required to investigate if Boxers with hypothyroidism have higher vagal tone compared with other breeds with the same condition.

There are several limitations to this case series. The diagnosis of hypothyroidism in case one is more equivocal than in the other two cases. However, it should be noted that that reference ranges for the tT4 are lower than most other laboratories which confounds results that would be considered consistent with hypothyroidism elsewhere. This applies to case one and three, where a tT4 of 7.2nmol/L and 6.7nmol/L, respectively, would generally be considered low but are within the reference range for the laboratory used. Furthermore, it is not possible to say with certainty that hypothyroidism is the cause of the episodes of TLOC. For example, case one only had one episode of TLOC before the diagnosis of hypothyroidism. Additionally, two of the dogs did not have episodes of TLOC whilst wearing the Holter, meaning the reference standard for diagnosis of TLOC was non-diagnostic [30]. Finally, due to the retrospective nature there were some aspects of the history that were not reported, which would have been useful in understanding the cases.

When evaluating a Boxer with syncopal episodes, it is important to assess thyroid function. While correcting hypothyroidism in such cases may lead to a reduction in the frequency or severity of syncopal episodes, further research is needed to establish a definitive link. It is also important to continue to try to identify any concurrent diseases that may contribute to the syncopal episodes.