Primary hyperlipidemia with associated ischemic strokes in a West Highland white terrier dog

Abstract

A 3-year-old spayed female, West Highland white terrier dog was evaluated because of a 4-month history of recurrent brain clinical signs. Magnetic resonance imaging (MRI) revealed multifocal brain lesions consistent with ischemic injuries. Blood analysis was unremarkable aside from severe hypertriglyceridemia and hypercholesterolemia with no underlying cause, suggesting primary hyperlipidemia. The patient was treated for hyperlipidemia and started on a low-fat diet and omega-3 supplementation. Clinical signs resolved over the following 12 months along with improvement in lipidemia. This represents the first reported case of MRI findings suggestive of multiple cerebrovascular injuries associated with primary hyperlipidemia in a dog, and the first primary hyperlipidemia reported in a West Highland white terrier dog.

Case description

A 3-year-old spayed female, West Highland white terrier dog, which had been in her owner’s possession since she was a puppy, was presented for evaluation because of a 4-month history of right-sided head tilt and circling to the left. Previous medical history included 1 episode of walking diagonally in an unusual manner. The dog was also noted to have been particularly clumsy from a young age, but had otherwise been healthy. These clinical signs mostly resolved over the following few days; however, she had a milder, persistent head tilt. A repeat episode occurred 1 mo later, with the same clinical signs: right-sided head tilt, spontaneous nystagmus, and circling to the left. These signs again improved without intervention. A subsequent, more severe episode occurred 1 wk before presentation, which prompted the owners to investigate further. On presentation, the dog showed similar clinical signs to those mentioned before; however, these were noted to be more severe by the owners. The owners also observed that the dog had developed ptyalism, which was a novel clinical sign at this point.

A physical examination revealed a body condition score of 7 out of 9, but was otherwise unremarkable, and no hypertension was noted. On neurological examination the dog was quiet, but responded appropriately to stimuli. No obvious ataxia or paresis was present, but there was a right-sided head tilt and left pleurothotonus. The dog would also stop intermittently when walking and turn to the left in a tight circle. There were no cranial nerve deficits other than absent menace response on the right side. Postural reactions were mildly delayed in both right limbs, but normal in both left limbs. Spinal reflexes and nociception were normal, and there was no pain response elicited on spinal palpation or cervical manipulation. Based on the neurological examination, it was determined that there were lesions localized to the left forebrain and the cerebellovestibular system, with differential diagnoses including cerebrovascular accidents, meningitis of unknown etiology (MUE) or, less likely, neoplasia.

A complete blood (cell) count (CBC) and serum biochemistry were performed. The CBC revealed markedly elevated total solids (TS)/protein of 102 g/L [reference range (RR): 55 to 75 g/L] but no other abnormalities. Biochemistry revealed a marked hypercholesterolemia of 49.95 mmol/L (RR: 3.60 to 10.20 mmol/L). The rest of the biochemistry profile was unremarkable. A thyroid panel, fasting cholesterol/triglyceride panel and an adrenocorticotropic hormone (ACTH) stimulation test were performed to determine whether the hypercholesterolemia was primary, or secondary to an underlying cause. Fasting cholesterol/triglyceride panel confirmed hypercholesterolemia (41.07 mmol/L) and also revealed hypertriglyceridemia (3.4 mmol/L, RR: 0.2 to 1.3 mmol/L) indicating a general hyperlipidemia. An ACTH stimulation test and thyroid panel were both normal, ruling out hypothyroidism and hyperadrenocorticism. Based on this information, primary hyperlipidemia was suspected. Abdominal ultrasound was considered, but ultimately not performed due to lack of indication based on blood analysis and physical examination.

The dog underwent general anesthesia and a magnetic resonance imaging (MRI) study of the brain revealed multifocal intra-axial lesions (Figure 1). One of these was a well-circumscribed oval lesion at the level of the left caudate nucleus, which was 0.65 cm × 0.7 cm, mildly T2 hyperintense, with a prominent T2 hyperintense rim. There was a slightly T1 hyperintense lesion adjacent to this, extending caudally into the thalamus. The left piriform lobe showed moderate T2 hyperintense and T1 hypointense heterogenicity, with a poorly defined, slightly hypointense, wedge-shaped lesion. The last lesion was a wedge-shaped T2 hyperintense, and mildly T1 hyperintense, heterogenous lesion affecting the dorsolateral parietal cerebral cortex (Figures 1E, F). This lesion was much more prominent on the T2W sequence and could be visualized running medially from the dorsolateral border of the parietal cerebral cortex. Only the most medial aspect of this lesion could be clearly visualized on the T1W sequence. All lesions were mildly contrast enhancing. It was also noted that the lesion at the level of the caudate nucleus showed restricted diffusion (bright or hyperintense signal) on diffusion weighted imaging (DWI) and was hypointense on apparent diffusion coefficient (ADC) map MRI sequences, suggestive of ischemic stroke (Figures 1C, D). The appearance of the lesions suggested that they could have been the result of multiple ischemic accidents, which could be associated with metabolic causes (e.g., hypothyroidism, hypoadrenocorticism, hypercoagulable state, or protein-losing nephropathy), infectious/inflammatory causes (e.g., vasculitis or septic thromboembolism), parasitic emboli, migrating parasites or neoplastic conditions (e.g., intravascular lymphoma or metastatic thromboembolism). Given the T1 hyperintensity and known hyperlipidemia, it was thought lipid deposition within the infarcts could also be a possibility. Cerebrospinal fluid (CSF) was collected and analysis revealed a mononuclear pleocytosis with a cell count of 0.006 × 10⁹/L [reference range (RR): < 0.005 × 10⁹/L] and a borderline elevated CSF protein level of 0.31 g/L (RR: < 0.3 g/L). Thromboelastography was also performed and revealed the patient to be mildly hypercoagulable, with a coagulation index of 3.2 (RR: –3 to 3).

Figure 1.

A—T1W transverse MRI showing a mildly T1 hyperintense lesion at the level of the caudate nucleus and a mildly hypointense lesion at the level of the left piriform lobe (indicated by arrows). B—T2W transverse MRI showing T2 hyperintense, heterogeneous lesions at the level of the left pirifom lobe and a slightly T2 hyperintense lesion surrounded by a strongly T2 hyperintense rim at the level of the caudate nucleus. C—DWI MRI showing a hyperintense lesion surrounded by a less hyperintense rim at the level of the caudate nucleus. D—ADC MRI showing a hypointense lesion surrounded by a hyperintense rim at the level of the caudate nucleus. E—T2W FLAIR MRI showing a heterogeneous, wedge shaped, T2 hyperintense lesion at the dorsolateral aspect of the left parietal lobe. F—T1W MRI showing a mildly T1 hyperintense lesion at the dorsolateral aspect of the left parietal lobe.

The dog was discharged on a low-fat diet to attempt to reduce her hyperlipidemia. At recheck 2 wk after initial presentation, the dog’s owners reported that her neurological clinical signs were much improved. Blood analysis was repeated at that time and revealed that the patient was still markedly hyperlipidemic, with a blood cholesterol of 42.09 mmol/L (RR: 3.60 to 10.20 mmol/L) and triglycerides of 4.3 mmol/L (RR: 0.2 to 1.3 mmol/L). The dog was continued on the low-fat diet. Since it was noted that transitioning to this diet had not had a significant impact on the dog’s hyperlipidemia, the dog was started on omega-3 fatty acids supplementation.

By her following recheck, 8 mo after initial presentation, the dog’s clinical signs had almost completely resolved, with only a mild head tilt noted on occasion. Omega-3 fatty acids supplementation was continued.

Cholesterol and triglyceride levels were rechecked approximately 1 y after initial development of clinical signs. Both were still elevated; however, there had been a marked decrease in the dog’s hypercholesterolemia, with a blood cholesterol of 18.34 mmol/L (RR: 3.60 to 10.20 mmol/L). Triglycerides, however, had increased, with a reading of 5.5 mmol/L (RR: 0.2 to 1.3 mmol/L). The dog was to be continued on her low-fat diet and was prescribed bezafibrate [50 mg; approximately 6 mg/kg body weight (BW) q24h] to help control her hyperlipidemia. She was discharged, with regular monitoring of her cholesterol and triglyceride concentrations to continue at the hospital. Neurological examination at time of discharge confirmed that her clinical signs had completely resolved.

Discussion

The case of a dog which developed recurrent neurological signs with concurrent severe hypercholesterolemia and hypertriglyceridemia is described in this report. However, no underlying cause for this hyperlipidemia could be identified. The thyroid panel ruled out hypothyroidism and an ACTH stimulation test ruled out hypoadrenocorticism. Serum biochemistry did not reveal any evidence of hepatic damage, insufficiency, or cholestasis and there was no evidence of pancreatitis or other pancreatic issues. Abdominal ultrasound was not performed as there was no indication for further diagnostics at the time. Retrospectively, this may have been valuable to confirm the absence of gross changes to the patient’s liver and pancreas. There was also no history of urinary abnormalities and no evidence of renal disease on blood analysis. The dog was not on any medications at the time of presentation. Diabetes mellitus and recent ingestion of a high-fat meal were considered as other potential causes of hyperlipidemia. Diabetes mellitus was ruled out because the dog never showed any evidence of hyperglycemia or other clinical signs suggestive of this. Additionally, the patient was fasted for at least 12 h before blood sampling on each occasion, ruling out recent ingestion of a high-fat meal. On this basis, all known causes of secondary hyperlipidemia were ruled out, suggesting a primary hyperlipidemia as the underlying etiology for the patient’s clinical signs. West Highland white terriers have no known familial predisposition to hyperlipidemia, making this the first report of such a case.

The dog in this case had neurological signs and MRI findings consistent with multiple ischemic strokes and blood analysis revealing a severe hypercholesterolemia, with levels 4 to 5 times the upper end of the reference range. This correlates with the literature in human medicine, in which it has long been demonstrated that there is a strong positive correlation between stroke incidence and hypercholesterolemia. In particular, it has been shown that a reduction in low-density lipoprotein (LDL) cholesterol of 1 mmol/L can reduce the incidence of major coronary events, coronary revascularization, and stroke by approximately 20% over a 5-year period (1). An association has also been noted between total cholesterol (TC)/high-density lipoprotein (HDL-C) ratio and recurrence of embolic stroke (2–4).

The patient in this case was presented with severe hyperlipidemia, with no underlying cause found on diagnostic tests, suggesting primary hyperlipidemia. In humans, familial hypercholesterolemia is attributed to approximately 2% of cases of hypercholesterolemia in the population, with 15% being attributed to primary hypercholesterolemia in general (5). Three main mechanisms are suspected to be responsible for the remaining cases: hepatic overproduction of lipoproteins, reduced affinity of LDL for their receptors, and reduced LDL receptor activity (5,6).

Although primary hyperlipidemia is relatively common in humans, it is very rare in dogs. There is a familial component, with miniature schnauzers first being implicated as a predisposed breed by Rogers et al (7) who noted hypertriglyceridemia in 6 dogs, 5 of which were miniature schnauzers. Since then, numerous studies have found hypertriglyceridemia with or without concurrent hypercholesterolemia to be overrepresented in this breed (8–10). Although there have been associations noted with other breeds (beagles, Labradors, Shetland sheepdogs, Briards, rough collies, and poodles) (11–13), a familial predisposition in West Highland white terriers has not been noted in the literature.

As in humans, there appears to be an increased incidence of cerebrovascular events in dogs with hyperlipidemia; however, in previous case reports and studies this has either been secondary, or due to familial hyperlipidemia. Patterson et al (14) reported on a 6-year-old, obese, spayed doberman pinscher which was presented because of a 1-day history of seizures. The dog also had a long history of intermittent bouts of ataxia, circling, and head tilt. This dog had multifocal lesion localization, and died 2 d after presentation despite adequate control of seizures using phenobarbital. On necropsy, generalized atherosclerosis was noted, along with cortical laminar necrosis, acute vasculitis within the cerebrum, and congestive heart failure. This was consistent with severe hypoxic, ischemic injuries to the cerebrum (strokes), most likely secondary to vascular occlusion as a result of cerebrovascular atherosclerosis. Severe follicular atrophy of the thyroid gland supported hypothyroidism as the primary disease process. This case had many similarities to one reported by Blois et al (15), who described an obese, 2-year-old male, castrated Australian shepherd dog which was presented with multifocal neurological deficits. Blood analysis revealed a marked hypercholesterolemia of 25.38 mmol/L (RR: 3.6 to 10.2 mmol/L), as well as a mild non-regenerative anemia. The dog was ultimately euthanized due to multiple neurological deficits, with necropsy revealing marked atrophy of both lobes of the thyroid gland and generalized atherosclerosis of vasculature supplying the cerebrum, brainstem, and cervical spinal cord.

Vitale and Olby (16) also noted neurological signs secondary to severe hyperlipidemia associated with primary hyperlipidemia. Vitale and Olby (16) studied the medical records of 4 dogs, 3 of which were Labrador retrievers, and another a Labrador cross. Each had severe hypertriglyceridemia with concurrent severe hypercholesterolemia and neurological signs. Two of these dogs exhibited chronic neurological signs, whereas the other 2 had more acute onset signs, which resolved. Each showed different clinical signs and lesion localizations, with the 1 common clinical sign being lethargy. Interestingly, in these 4 cases, hypercholesterolemia was more severe than in previous studies, with mean serum cholesterol concentration of 1568 mg/dL (40.55 mmol/L) (14) compared to 417 mg/dL (10.78 mmol/L) (17), and 11.4 mmol/L (18) in other studies. Chikamune et al (17) and Dixon et al (18) studied the association between obesity and hyperlipidemia in dogs, and hypothyroidism and hyperlipidemia in dogs, respectively. Both studies compared serum triglyceride concentrations and clinical signs among populations. Neurological signs were not noted in either of these studies; however, the mean serum cholesterol levels in reports were much lower than in the study performed by Vitale and Olby (16). Interestingly, the dog herein had a serum cholesterol concentration of 41.07 mmol/L, which was similar in severity to the cases in Vitale and Olby’s study (16). This suggests that, as in humans, the severity of hyperlipidemia positively correlates with incidence of vascular injury as these neurological signs only appear to be described in dogs with severe hyperlipidemia, but not in milder cases.

Finally, a study carried out by Liu et al (19) looked at necropsies of 21 dogs from 1970 to 1983, all of which had atherosclerosis, and most of which had had hypercholesterolemia, hypertriglyceridemia, and hypothyroidism noted on ante-mortem blood analysis. Among the most common clinical signs seen across these dogs was collapse, due to neurological or cardiopulmonary pathology. On necropsy, atherosclerosis was seen to have affected arteries in multiple locations, including cerebral arteries. This study also suggests that neurological signs, or at least neurological pathology, are associated with hyperlipidemia and atherosclerosis. Although atherosclerosis could not be confirmed in the patient in this report, MRI images revealed multifocal lesions consistent with ischemic stroke within the telencephalon and diencephalon. This was associated with marked hypercholesterolemia and hypertriglyceridemia confirmed on blood analysis, similar to the dogs mentioned in the study by Liu et al (19).

The neurological examination localized multifocal intra-axial forebrain lesions, which were confirmed on MRI. It was noted that there were no brain stem or cerebellar lesions, which could have accounted for the head tilt and nystagmus that were noted. Vestibulocerebellar signs such as these, however, have been previously reported in association with thalamic or midbrain lesions such as those described in this case (20). It has been inferred by Wijesinghe et al (21) that the thalamus plays a key role in processing of vestibular information, and integration of other sensory inputs. A study performed by Kirsch et al (22) describing multiple projections, which course from the vestibular nuclei to the thalamus, support this theory. Given the close association between the thalamus and vestibulocerebellar system, it makes sense that thalamic lesions could present with vestibulocerebellar signs, as has previously been described in human patients. Saiki et al (23) described 2 patients, both of whom presented with loss of balance and astasia, amongst other neurological signs. Magnetic resonance imaging in these cases revealed lesions in the ventrolateral thalamus, which had terminated fibers from the vestibulocerebellum. Despite these being human cases, it could be inferred that a similar mechanism was responsible for the clinical signs shown by the dog reported in this case.

The appearance of these lesions on MRI was suggestive of ischemic vascular injuries (i.e., stroke). This dog was presented with recurrent neurological signs localizing to multifocal regions in the brain, similar to the dogs mentioned in case reports by Patterson et al (14), Vitale and Olby (16), and Blois et al (15) as well as the study conducted by Liu et al (19). Unlike the dogs in these previous studies, the patient discussed in this study had no known breed predisposition to hypothyroidism. The MRI and clinical signs were in accordance with ischemic vascular injury to the brain and clinical signs reported in case reports and studies of neurological issues in dogs with secondary hyperlipidemia.

In conclusion, this appears to be the first reported case of MRI findings suggestive of multiple cerebrovascular injuries associated with primary hyperlipidemia in a dog and the first primary hyperlipidemia reported in a West Highland white terrier dog. Cholesterol and triglyceride blood levels should be evaluated in cases of suspected cerebrovascular ischemic injury since, despite being much less common, primary hyperlipidemia can be associated with cerebrovascular incidents in dogs as well as humans. CVJ