Canine Cerebrovascular Disease: Do Dogs Have Strokes?

Introduction

Cerebrovascular accidents (CVA) are one of the major causes of disability among adult humans. Previously considered uncommon, CVA are increasingly recognized in dogs or cats with the advances of neuroimaging. A “stroke” is a focal neurological deficit of sudden onset, resulting from a cerebrovascular accident.¹ The causes of strokes can be divided into two basic groups: obstruction of the blood vessels, leading to infarction [Table 1]; and rupture of blood vessel walls, leading to hemorrhage [Table 2].² Most types of CVA that are seen in humans have been documented in dogs;³ however, recovery from cerebrovascular disorders in animals is probably more spectacular than in humans, because animals have a less prominent pyramidal system.⁴

The central nervous system (CNS) requires a continuous supply of glucose and oxygen to sustain its high expenditure of energy. The transportation of these fuel molecules requires sufficient blood flow through a cerebral vasculature with adequate capacity. In the dog, blood supply to the brain arises from the basilar and internal carotid arteries, which join at the base to form the arterial circle of Willis.⁵ The cerebrum is supplied by three pairs of cerebral arteries arising from this arterial circle, with each one responsible for the perfusion of large but overlapping areas of the cerebrum.⁵ Any diseases that affect the cerebral blood vessels will cause disturbances of the cerebral blood flow (CBF), which in turn can lead to tissue damage. The metabolism of the brain is solely aerobic and without any significant energy reserves. The exceptionally high demand for circulating blood and oxygen is reflected in the disproportionately high rate of CBF compared with flow to other parts of the body, comprising 20% of the cardiac output and 15% of oxygen consumption when the body is at rest, even though the brain makes up only 2% of the body weight.²

Cerebral ischemia is the reduction, although not necessarily the cessation, of blood flow to a level incompatible with normal function; the impairment may be global or regional.²⁶ Ischemia, viewed simplistically as hypoxia plus hypoglycemia, will affect the most sensitive elements in the tissue and if severe, persistent, or both, perturb all components. In its mildest form, impaired regional CBF causes a transient ischemic attack (TIA); TIA has an abrupt onset but is a rapidly diminishing neurological deficit of vascular origin, with clinical signs dependent on the affected blood vessel and representative area of perfusion, which lasts <24 hours.²⁵ This is well documented in humans but has not been studied in dogs, although the authors do believe that this occurs in dogs, occasionally as a historical (e.g., rapidly resolving focal deficits in a middle-aged to older dog) precursor to an infarction. Severe ischemia, producing necrosis of the neurons and glial elements, results in an area of dead tissue termed an infarct.⁶

Severe arterial hypotension produces bilateral infarction in the boundary or watershed zones between major arterial territories.² The critical threshold values of CBF needed for the maintenance of functional and structural integrity of the brain have been determined to be approximately 40% (i.e., approximately 22 mL/100 g per minute) of the normal value.² With reductions in CBF from about 40% to 30%, increasing numbers of neurons are unable to produce sufficient energy to maintain the functions needed for the transmission of nerve impulses, and at about 30% of normal CBF transmission ceases completely, although the cells can stay alive, as in a TIA. If regional CBF further diminishes below about 15% of normal (i.e., 10 to 12 mL/100 g per minute), there is absolute membrane failure culminating in an irreversible nerve cell injury, resulting in an infarct.² These threshold values of CBF can be higher in an already compromised brain. In humans, there are regions of vulnerability within the brain where neurons are prone to be injured by global hypoxia-ischemia. These areas are the cerebral cortex, the hippocampus, the amygdala, several basal and thalamic nuclei, and the cerebellar cortical Purkinje cells.⁶

Infarction can result from arterial or venous disease; arterial infarction can be due to either obstruction from thrombosis or embolism, or due to occlusion from blood vessel abnormalities such as vasculitis [Table 1].⁵ A number of classification systems for ischemic stroke have been proposed in humans. The most commonly used clinical systems divide ischemic stroke into three major subtypes: large artery or atherosclerotic infarctions, cardioembolic infarctions, and small vessel or lacunar infarctions.⁷ Atherosclerotic infarctions are the most common subtype documented in humans.⁷ Although the frequency of the three different subtypes is as yet unknown in dogs, atherosclerosis has been reported in dogs, especially in older dogs, dogs with hypothyroidism, and miniature schnauzers with idiopathic hyperlipoproteinemia.⁵ Other diseases associated with infarction in dogs include sepsis, coagulopathy, neoplasia, and heartworm disease.⁵ The use of magnetic resonance (MR) imaging with techniques such as diffusion-weighted imaging and angiography may well help to define the subtype of infarction in the future. Because of abundant venous anastomoses, venous infarction is uncommon in dogs; as arterial blood flow is preserved, hemorrhage and edema tend to be more severe in venous infarction than in arterial infarction.⁸

Cerebrovascular accidents can, on occasion, result from hemorrhage.⁵ Hemorrhage involving the CNS is classified as epidural, subdural, subarachnoid, intraparenchymal (primary or secondary), or intraventricular.⁵ When the bleeding is substantial enough to form an excessive additional volume (i.e., mass effect) within the CNS, the results can be fatal. The presence of a hematoma initiates edema and neuronal damage in surrounding parenchyma.⁹ Fluid begins to collect immediately in the region around the hematoma, and edema usually persists for up to 5 days⁹ and in some cases as long as 2 weeks.¹⁰ Early edema around the hematoma results from the release and accumulation of osmotically active serum proteins from the clot.⁹ Vasogenic edema and cytotoxic edema subsequently follow, owing to the disruption of the blood-brain barrier, the failure of the sodium pump, and the death of neurons.¹¹ The delay in the breakdown of the blood-brain barrier and the development of cerebral edema after intracerebral hemorrhage suggest that there may be secondary mediators of both neural injury and edema. It had been thought that cerebral ischemia occurred as a result of mechanical compression in the region surrounding the hematoma, but recent studies in animals and humans have not confirmed this.¹² It is currently thought that blood and plasma products mediate most secondary processes that are initiated after an intracerebral hemorrhage.¹² Neuronal death in the region around the hematoma is predominantly necrotic, with recent evidence also suggesting apoptosis (programmed cell death) as a contributing factor.¹²

The source of primary intraparenchymal hemorrhage is incompletely understood, but human patients often have systemic hypertension with concurrent fibrinoid degeneration of arteries in the brain.¹³ Hypertension in dogs may be primary or secondary to disorders such as renal disease and hyperadrenocorticism; these animals may be predisposed to intracranial hemorrhage.¹⁴ A variety of secondary causes of hemorrhage exists in dogs [Table 2]. Dogs with brain infarction can have associated hemorrhage, as can dogs with intracranial tumors, vasculitis, or coagulopathies.⁵

Clinical Signs

Cerebrovascular accidents are characterized clinically by a peracute or acute onset of focal, asymmetrical, and nonprogressive brain dysfunction.⁵ Worsening of edema (associated with secondary injury phenomenon) can result in progression of neurological signs for a short period of 24 to 72 hours. Hemorrhage may be an exception to this description and be presented with a more progressive course. Clinical signs usually regress after 24 to 72 hours; this is attributable to diminution of the mass effect secondary to hemorrhage and reorganization or edema resorption.¹⁵ With brain stem involvement, neurological examination of the cranial nerves will define the exact location and extension of the lesion. With forebrain lesion, the clinical sign may vary from simple disorientation to death. A unilateral lesion will induce ipsilateral circling, hemi-inattention syndrome (lack of recognition of sensory stimuli by one side of the brain and often manifested by eating out of only one side of the bowl or turning to the wrong side to respond to a name call), contralateral central blindness, as well as contralateral ataxia and proprioception deficits. Seizures are reported to be very common in association with CVA in dogs.¹⁶ Clinical signs are dependent on lesion location and in the dog include torticollis (i.e., cervical dystonia), head turn, head tilt, hypermetria, and proprioception and motor deficits that are distinctly asymmetrical. For hematomas, seizures and dementia are common signs.

Diagnosis

Imaging studies of the brain (i.e., computed tomography [CT] or MR imaging) are necessary to confirm the clinical neurolocalization, reinforce the suspicion of CVA, identify any associated mass effect, and rule out other causes of focal brain disorders (e.g., trauma, tumor, inflammation). Computed tomography also allows rapid image acquisition, in addition to the fact that changes associated with ischemia/infarction can be detected as early as 3 to 6 hours after their onset [Table 3].⁷ Enhancement usually appears after 24 to 48 hours and is most evident after 1 or 2 weeks, especially in the periphery where neovascularization exists.¹⁷

Magnetic resonance imaging is more sensitive than CT in early infarction, with changes seen within an hour of onset.¹⁸ Magnetic resonance imaging is also more sensitive in the detection of edema, provides multiplanar views, and lacks beam-hardening artifact (i.e., an area of signal loss due to absorption of photons by surrounding bony structures) when compared with CT.⁷ The conventional MR imaging findings in evolving cerebral infarction are well characterized and follow a temporal evolution similar in many ways to that seen on CT.¹⁸ These changes seen in ischemic parenchyma rely on an increase in tissue water content.⁷ Gradually, and beginning in the acute stage [Table 4], the T2-weighted image becomes more hyperintense in the ischemic region, particularly over the first 24 hours [Figure 1].⁷ These initial MR image changes are best appreciated in gray matter and are well visualized in deep gray matter structures, such as the thalamus or basal ganglia [Figure 2], in addition to cortical gray matter. Contrast administration (i.e., gadolinium) enhances infarcts because of vascular rupture but does not enhance ischemia or edema [Table 4].

In the authors’ experience, common lesion location of infarcts are the caudate nucleus, deep midline thalamic nuclei, and cerebellar gray matter, although there is a potential for them to occur in any area.

Computed tomography is very sensitive for acute hemorrhage, with a linear relationship demonstrated between CT attenuation and hematoma hematocrit.¹⁹ In a patient with a normal hematocrit, acute hemorrhage is seen as an area of increased attenuation, which tends to progress for the first 72 hours and then slowly decrease to isodensity at about 1 month posthemorrhage.¹⁹ The periphery of the lesion may enhance on CT imaging from approximately 6 days to 6 weeks after onset.

The initial MR image appearance of hemorrhage is dependent on the age of the hematoma [Figure 3] among other determinants [Table 5], which result in the hematoma’s unique signal intensity patterns [Table 6].²⁰ Localization of hemorrhage to the parenchyma or “extra-axial” space is central to assessing the etiology and the initiation of treatment.²⁰ In dogs, it is more common to see intraparenchymal than “extra-axial” hemorrhage, the latter of which is typically subdural in location [Figure 4].

In the authors’ experience, there are no areas of high prevalence for hemorrhage in the dog except to remark that, in general, they seem to occur more commonly supratentorially and in the brain parenchyma.

Other imaging modalities which may be utilized to investigate CVA include cerebral angiography to demonstrate vascular malformations; cerebral scintigraphy as a nonspecific way to identify a brain lesion; Doppler ultrasonography to analyze cerebral blood flow; and single photon emission computed tomography (SPECT) to analyze regional blood flow. These modalities are not frequently used now, as the advances possible with MR imaging technology mean that blood vessel abnormalities and regional blood flow can be assessed in conjunction with the structural abnormalities suggestive of a CVA.

A complete blood count, serum biochemical analysis, and urinalysis are indicated to identify potential underlying causes, as described earlier. Thyroid function testing (total thyroxin [T₄], free T₄, and endogenous canine thyroid-stimulating hormone concentrations), a coagulation profile (including a buccal mucosal bleeding time, a prothrombin time, a partial thromboplastin time, and fibrinogen degradation products), and, if possible, multiple systolic blood pressure measurements and an electrocardiogram, should be evaluated in any animal suspected of having CVA. A fecal analysis should be performed to rule out parasitic infestation. Blood and urine cultures are indicated in case of sepsis. Cerebrospinal fluid analysis is unlikely to confirm a diagnosis of CVA but may help to rule out inflammatory CNS disease or may on occasion reveal recent hemorrhage (i.e., xanthochromia), normal to increased protein, and a mild neutrophilic or mononuclear pleocytosis.⁵

Treatment and Prognosis

There is no specific treatment for infarctions and the majority of intraparenchymal hemorrhages. The treatment of any type of CVA focuses on maintaining cerebral perfusion, through maintenance of systemic blood pressure and subsequent tissue oxygenation, as well as the management of secondary neurological sequelae (e.g., seizures) and the treatment of any underlying diseases. The outcome of dogs with CVA depends on the size of the lesion, the location of the lesion, and the severity of the clinical signs. Many cases of cerebral infarctions can improve dramatically over a few days to weeks; however, these cases are at risk of multiple (future) events. Intraparenchymal hemorrhage may also cause reversible signs, but the severity of both the clinical signs and the underlying diseases may often be more severe.