A case of primary hypothyroidism causing central nervous system atherosclerosis in a dog

Abstract

A 2-year-old, castrated male, Australian shepherd was presented with a history of chronic mild ataxia, obesity, and lethargy. The dog was treated with levothyroxine, but the ataxia worsened. Cranial nerve abnormalities developed and the dog was euthanized. Postmortem examination revealed marked thyroid gland atrophy and widespread, severe central nervous system atherosclerosis.

A 2-year-old, 30-kg, castrated male, Australian shepherd was presented to the referring veterinarian with a history of mild ataxia, obesity, and lethargy first identified when he was a puppy. The dog had 2 episodes of ataxia and circling to the left in the 3 mo prior to presentation, and was treated for otitis externa with miconazole/polymyxin/prednisolone (Surolan; Merial Canada, Baie d’Urfé, Québec) for each episode. The dog was diagnosed with hypothyroidism 1 wk prior to referral, based on low total thyroxine [T₄ (< 5.15 nmol/L; reference interval, 15.0 to 58.0 nmol/L)] levels. The canine thyroid-stimulating (TSH) level was normal (0.24 ng/mL; reference interval, 0 to 0.35 ng/mL), while thyroglobulin autoantibodies were positive. At the time of diagnosis, the dog was treated with levothyroxine (Synthroid; Abbott Laboratories, Sainte-Laurent, Québec), 0.6 mg, PO, q12h. One week after initiating treatment, the dog exhibited acute worsening of ataxia, which progressed to tetraparesis and recumbency.

Case description

On clinical examination, the dog was obese and anxious. The dog was in sternal recumbency with the head and neck turned to the left. Cranial nerve (CN) examination revealed absence of menace response; no direct or consensual pupillary light reflex in the right eye; anisocoria with miosis of the right pupil; bilateral exophthalmos; medial strabismus of the right eye; pathological vertical nystagmus; and bilateral head tilt, mostly left-sided. Abnormalities of the gait and posture included vestibular ataxia with a tendency to fall to the left and decreased proprioception of all limbs, worse on the left side.

A complete blood (cell) count (CBC) revealed mild normocytic, normochromic, nonregenerative anemia, with a hematocrit of 0.30 L/L (reference interval, 0.39 to 0.56 L/L); red blood cell (RBC) count 5.9 × 10¹²/L, reference interval, 5.9 to 8.5; mean cell volume (MCV) 71 fL, reference interval, 62 to 72; mean cell hemoglobin concentration (MCHC) 347 g/L, reference interval, 330 to 360; absolute reticulocyte count 36 × 10⁹/L, reference interval, > 80 × 10⁹/L); and a mild mature neutrophilia (13.56 × 10⁹/L; reference interval, 2.9 to 10.6 × 10⁹/L). The serum biochemical profile showed marked hypercholesterolemia (25.38 mmol/L; reference interval, 3.6 to 10.2 mmol/L). Free T4 level by equilibrium dialysis was measured at 56.7 pmol/L (reference interval, 6.0 to 42.0 pmol/L). Brainstem auditory evoked response (BAER) testing showed normal responses on the left side, but lack of response on the right side at all levels of the brainstem. Analysis of cerebrospinal fluid collected under general anesthesia from a cysternal tap collection revealed xanthochromic fluid with mixed inflammation (cell count of 0.008 × 10⁹/L; reference interval, < 0.003 × 10⁹/L) and elevated protein (0.48 g/L; reference interval, < 0.25 g/L). Due to the presence of multiple neurological abnormalities, including multiple CN deficits, magnetic resonance imaging of the brain was recommended but declined by the owner for financial reasons, and the dog was euthanized.

Postmortem examination revealed marked atrophy of the right and left lobes of the thyroid gland. There was widespread atherosclerosis, particularly affecting the middle and rostral cerebral arteries and basilar artery of the brainstem, and the ventral spinal artery of the cervical spinal cord (Figure 1). These arteries appeared thickened, rigid, and tortuous, and the lumens were obstructed by cohesive, but friable, yellow-tan to brown material.

Figure 1.

Photograph of the ventral surface of the brain and cervical spinal cord of a 2-year-old Australian shepherd. Basilar and ventral spinal arteries (arrows) are thickened, nodular, and rigid (atherosclerosis).

Histologic examination of the thyroid gland revealed marked atrophy and loss of thyroid follicles, with focally extensive fibrosis, fatty replacement, and patchy infiltrates of lymphocytes and plasma cells within the intervening connective tissue (Figure 2).

Figure 2.

Photomicrograph of a section of thyroid gland. Note the lymphoplasmacytic inflammatory infiltrate, fibrosis, and paucity of normal thyroid follicular structures. Hematoxylin and eosin. Bar = 100 μm.

The basilar artery of the brainstem was completely occluded by a circumferential, subintimal mass of eosinophilic, vacuolated lipid and cholesterol-laden debris, which reduced the lumen to a slit-like opening. This atheromatous plaque material extended up into the branching arteries, with localized rupture of the vessel wall and focal aggregates of lipid-laden macrophages, lymphocytes, and plasma cells within the adjacent leptomeninges (Figure 3). Examination of multiple sections of the brain revealed patchy, locally extensive areas of encephalomalacia, with vacuolation and gitter cells extending from the medulla oblongata (Figure 4) to the rostral colliculi and thalamus.

Figure 3.

Photomicrograph of the ruptured basilar artery at the level of the rostral colliculus. Note the near total occlusion of the arterial lumen by atheromatous plaque, leaving only a slit-like lumen (arrow). The lipid-rich amorphous material occludes an arterial branch, which is partially ruptured, releasing cholesterol-laden debris (arrowhead) into the adjacent leptomeninges eliciting a localized inflammatory response. Hematoxylin and eosin. Bar = 500 μm.

Figure 4.

Photomicrograph of a section of the obex identifying the extensive encephalomalacia associated with ischemic necrosis. Hematoxylin and eosin. Bar = 500 μm.

The lumen of the ventral spinal artery was completely occluded by a mass of fibrin with enmeshed erythrocytes and amorphous vacuolated eosinophilic debris with numerous cholesterol clefts. Areas of malacia, vacuolation, and Wallerian degeneration were present within the dorsal, lateral, and ventral funiculi of the cervical spinal cord (Figure 5).

Figure 5.

Photomicrograph of a section of the lateral funiculus at the level of the second cervical spinal cord vertebrae identifying vacuolation and Wallerian degeneration. Hematoxylin and eosin. Bar = 200 μm.

Discussion

Primary hypothyroidism is a common canine endocrine disorder that typically produces clinical signs of alopecia, mental dullness, lethargy, and unexplained weight gain (1). Reported prevalence of hypothyroidism in dogs is 0.2% to 0.8%, with a mean age at diagnosis of 7 y (2,3). Older, large-breed dogs are typically affected (4). In a retrospective study of the neurological manifestations of canine hypothyroidism, a mean age of 11 y for dogs affected with lower motor neuron signs and of 8.5 y for those dogs affected with vestibular signs was found (4). Primary hypothyroidism accounts for over 95% of canine hypothyroid cases (1).

Histologic findings in this case were consistent with primary hypothyroidism, but the dog was much younger (2 y) than the typical age of onset for canine hypothyroidism. Additionally, the signs of lethargy, obesity, and mild ataxia observed prior to 1 y of age may have been related to hypothyroidism and development of central nervous system (CNS) atherosclerosis.

A diagnosis of canine hypothyroidism is supported by a low serum total T4 or free T4 with clinical signs compatible with hypothyroidism when nonthyroidal illness has been ruled out (1). An elevated TSH level provides further evidence of primary hypothyroidism, but similar to the reported case, up to 40% of dogs with primary hypothyroidism have a TSH level within the normal reference interval (1).

Up to 7.5% of hypothyroid dogs have been reported to display neurological dysfunction (5). The most common neurological sign associated with hypothyroidism is generalized lower motor neuron paresis (4). The paresis often affects the pelvic limbs first, but it can become generalized. Progression from a mild gait deficit to paraparesis or tetraparesis is common and suggestive of polyneuropathy when associated with decreased to absent spinal reflexes. Weakness, hyporeflexia, and postural reaction deficits are commonly observed in this condition. Electromyography in affected dogs is consistent with denervation potentials, while motor nerve cell conduction velocity is usually decreased. Histologically, muscle and nerve biopsies support the presence of neurogenic atrophy (6).

Vestibular disease associated with hypothyroidism is usually a peripheral dysfunction, with signs of head tilt, ventral strabismus, horizontal nystagmus, and circling. While the vestibular disease can be the only neurological deficit, it is more commonly associated with ipsilateral CN deficits (4). Cranial nerve deficits associated with hypothyroidism can involve single or multiple nerves, but those most commonly affected are the vestibular, trigeminal, and facial nerves. Clinical manifestations can be unilateral or bilateral; they include head tilt, nystagmus, strabismus, decreased facial sensation, and facial paralysis (7). Megaesophagus and laryngeal paralysis have each been reported as being associated with hypothyroidism, but the causal relationship in each case has not been proven (4). Other neurological abnormalities associated with canine hypothyroidism include unilateral forelimb lameness, encephalopathy, and myasthenia gravis (1,4–9).

Treatment of hypothyroid dogs consists of oral levothyroxine supplementation. Supportive care may be required, depending on the severity of associated conditions (1). The majority of hypothyroid dogs with neurological deficits will show partial or complete resolution of their neurologic signs over 2–4 mo, with improvement often noted within the 1st week of treatment (4,6,7,9). The dog in this report received levothyroxine supplementation 1 wk prior to referral; however, unlike many previously reported cases, clinical signs worsened despite therapy. The clinical worsening was likely related to the degree of severity of the atherosclerosis, with almost complete occlusion of the basilar artery and extensive cerebral ischemia. These lesions were most likely irreversible.

Neurological signs resulting from hypothyroidism could be attributed to impaired metabolism by the neuron, resulting in axonal degeneration. Thyroxine is responsible for facilitating production of adenosine triphosphate via mitochondrial respiration. Thyroxine increases adenosine triphosphatase (ATPase) activity, thus increasing sodium-potassium pump ATPase activity. Lack of T₄ alters axonal transport and may lead to axonal degeneration and secondary neuropathies (10).

While dogs are naturally resistant to development of atherosclerosis, the condition has been associated with canine hypothyroidism (11). Lipid synthesis, mobilization, and degradation are stimulated by thyroid hormone. Hypothyroidism depresses lipid metabolism, resulting in accumulation of plasma lipids (11). A report of neurologic dysfunction in 4 Labrador retrievers suggested that this breed may be predisposed to severe hyperlipidemia associated with primary hypothyroidism. The neurologic signs displayed by these 4 dogs included paresis, central vestibular disease, and cranial nerve dysfunction, and were attributed, at least in part, to thromboembolic events and atherosclerosis (12). Marked hypercholesterolemia, especially if combined with endothelial damage, is a risk factor for development of atherosclerosis (13). Hypercholesterolemia leading to atherosclerosis was demonstrated by postmortem findings in this case. No other factors responsible for the development of hypercholesterolemia, such as excessive dietary lipid consumption, were identified in this dog.

Atherosclerosis is characterized by focal thickening of the tunica media and tunica interna of arterial walls associated with lipid deposition (14,15). Atheromatous plaques are accompanied by macrophage and smooth muscle cell proliferation, and a fibrous cap can form as the lesion progresses. Necrotic debris, cholesterol clefts, lipids, and calcium deposits can be found in the core of the plaque. Blood vessel rupture, hemorrhage, and thrombosis occur with advanced lesions (15).

The neurological deficits observed in this case appear to correlate with the presence of severe atherosclerosis in the CNS. The dog presented in this report had abnormal mentation and multiple CN abnormalities. Specifically, the severe dullness and bilaterally absent menace response (with intact vision ability) may be suggestive of a bilateral lesion in the cerebral cortex. Atherosclerotic plaques (acting as emboli) leading to multifocal areas of hypoxia and necrosis were observed in the cerebral cortex.

Patchy areas of encephalomalacia, related to basilar artery occlusion, were identified histologically in areas extending from the brainstem to the thalamus. These histopathological abnormalities could explain clinical findings of multiple CN deficits including CN III (lack of bilateral pupillary light responses with intact vision ability); CN VI (medial strabismus of the right eye); CN III, IV, VI, VIII or medial longitudinal fasciculus (pathological vertical nystagmus); CN VIII in the rostral medulla (presence of vertical nystagmus, bilateral head tilt, and suspected vestibular ataxia). The lack of response to BAER testing on the right side could be explained with a peripheral vestibular lesion at the level of the inner ear located on the right side.

Occlusion of the ventral spinal artery was associated histologically with malacia and degeneration of the spinal cord in the cervical region. These histopathologic features could explain the lack of proprioception identified clinically in all limbs and the presence of tetraparesis suggestive of a cervical spinal cord lesion.