Small Vessel Disease

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Chapter 7 Small Vessel Disease

Alejandro A. Rabinstein, Steven J. Resnick

Small vessel disease is the less understood of the major mechanisms of cerebral ischemia. This is the case despite its high prevalence in the elderly population, in whom it can present in the form of lacunar strokes, intracerebral hemorrhage, and cognitive decline.¹

The seminal work of Dr. C. M. Fisher based on his clinicopathological observations led to the definition of lacunar strokes as small subcortical infarcts measuring between 3 mm and 2 cm and caused by the occlusion of penetrating branches of cerebral arteries.² He described lipohyalinosis, a hypertensive microvasculopathy, as the main anatomical substrate for the development of lacunar infarctions and also deep cerebral hemorrhages.³ However, he recognized that plaques of atheroma in the parent vessel occluding the origin of the penetrating branch⁴ and probably microembolism (in patients with structurally normal penetrating branch corresponding to the area of small infarction and a systemic cause of embolism)⁴ could also produce lacunar strokes. He characterized the classic lacunar syndromes but noted that a number of atypical clinical presentations could also occur. He was then well aware of the fact that small vessel disease does not constitute a uniform disorder but rather may result from a complex spectrum of conditions with various clinical manifestations.

Unfortunately, the conceptualization of lacunar strokes became quite simplified and dogmatic (and therefore untrue) over time. Lacunar infarctions had to manifest with one of the traditional “lacunar syndromes,” they had to be less than 15 mm in size, they only happened in hypertensive patients, and they were always caused by “small vessel disease” (typically understood as lipohyalinosis according to what became known as the “lacunar hypothesis”). However, the advent of brain imaging techniques came to prove that these general assumptions cannot be always applied. First, computed tomography (CT) scan and most recently and especially magnetic resonance imaging (MRI) have reactivated research on this topic by uncovering the real dimension of the intricate disorder we now call small vessel disease to include small subcortical infarctions, microhemorrhages, and white matter changes (also known as leukoaraiosis for the rarefaction of the white matter seen on pathological specimens) (Figure 7-1).

Figure 7-1 The spectrum of small vessel disease.

Longitudinal studies using serial MRI scans are shedding light on the incidence, progression, and severity of cognitive decline in patients with white matter disease. As a consequence, vascular dementia is emerging as a major public health concern.⁵ Neuroimaging is replacing pathology in the study of the pathophysiology of small vessel strokes, a remarkable indication of progress because small subcortical strokes are not fatal and therefore pathological examinations only allow the examination of chronic lesions. In fact, new theories defying the preeminence of lipohyalinosis have been postulated to explain the genesis of small subcortical strokes.^6,⁷ Additionally, hemosiderin-sensitive sequences (such as gradient recall echo) allow visualization of areas of microhemorrhage, which were previously impossible to diagnose in vivo.^8,⁹

In this chapter, we attempt to illustrate the contribution of neuroimaging to the understanding of small vessel disease, acknowledging that most is still to be learned in this fascinating field.

SMALL SUBCORTICAL INFARCTIONS

Case Vignette

A 78-year-old man with history of hypertension and type 2 diabetes awoke with inability to move his right side. On examination, his blood pressure was 180/98, his pulse was regular, and he had no carotid bruits. He had a dense right hemiparesis with no other associated neurological deficits. Initial CT of scan of the head did not reveal any acute intracranial abnormalities. Brain MRI (Figure 7-2) showed an acute small subcortical stroke in the posterior limb of the left internal capsule. Carotid ultrasound and cardiac workup were unremarkable. The patient was discharged on antiplatelet therapy, antihypertensives, an adjusted regimen for his diabetes, and a statin. He evolved favorably over the subsequent few months.

Figure 7-2 Magnetic resonance imaging scan of the brain showing a small subcortical acute ischemic infarction in the posterior limb of the left internal capsule (arrows). Diffusion-weighted imaging and apparent diffusion coefficient map are shown in the upper row. Fluid-attenuated inversion recovery sequence is shown in the lower left. Computed tomography scan 3 days after symptom onset is presented in the lower right.

♦ Small subcortical infarction is a term that, in our opinion, should be preferred over lacunar infarction when describing findings on brain scans to avoid the pathophysiological implication commonly ascribed to lacunes (i.e., caused by lipohyalinosis). This distinction is pertinent because arterial or cardiac sources of embolism are present in 10% to 15% of patients presenting with small subcortical infarctions.¹⁰^–¹³

♦ The most common locations of small subcortical infarctions are illustrated in Figure 7-3: putamen, caudate, thalamus, internal capsule, corona radiata, pons, and medulla.

♦ MRI is the modality of choice for the diagnosis of small subcortical infarctions, especially early after symptom onset.^14,¹⁵

♦ However, CT scans can also provide useful information to help determine the underlying mechanisms of stroke and the extent of the necessary workup.¹⁶ For example, in our experience, when a small subcortical infarction is seen on CT scan in a patient presenting with classical lacunar syndrome and no evidence of atrial fibrillation, the yield of transesophageal echocardiogram is low.¹⁷

♦ Diffusion-weighted imaging (DWI) sequence is particularly useful for various reasons:

♦ It allows confirmation of small subcortical infarctions in patients presenting with lacunar syndrome.^14,^15,¹⁸

♦ It precisely depicts the exact subcortical location of the infarction.¹⁹

♦ It differentiates between small subcortical infarctions and larger striatocapsular infarcts.²⁰

♦ It may identify otherwise unsuspected embolic stroke patterns in up to one third of patients with lacunar presentations.^21,²² Sometimes DWI discloses an embolic mechanism by showing coexistent small cortical lesions in conjunction with a small subcortical infarction.¹⁰

♦ It identifies acute from chronic subcortical infarctions.²³ Small subcortical infarcts seen acutely on DWI can later be visualized on T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR) as well as on CT scan (Figure 7-4). However, timing of the infarctions in patients with multiple subcortical lesions is often possible only by using DWI during the acute phase.

Figure 7-3 Illustration of the most common locations of small subcortical infarctions. Top row: medullary pyramid (left) and basis pontis (right). Middle row: cerebral peduncle (left) and thalamus (right). Lower row: internal capsule (left) and corona radiata (right). All infarctions are shown on diffusion-weighted imaging sequence of magnetic resonance imaging scan.

Figure 7-4 Another example of a small subcortical infarction (arrow) presenting with pure motor syndrome, but the images shown were obtained 10 days after symptom onset, thus representing a later phase of evolution of the ischemic lesion. Notice bright signal on diffusion-weighted imaging (top left) with corresponding high diffusion coefficient (increased signal intensity) on the apparent diffusion coefficient map (top right). Fluid-attenuated inversion recovery (lower left) clearly delineates the hyperintense lesion, which is also visible on the T1-weighted sequence as an area of hypointensity (lower right).

LACUNAR SYNDROMES

Case Vignette

A 72-year-old obese woman with history of hypertension and metabolic syndrome presented with acute onset of right-sided numbness and weakness. Symptoms had started the day before, but she had not come to the emergency department because they had fluctuated in severity to the point that a few times she felt almost back to normal. However, over the previous 6 to 8 hours before her arrival to the emergency department, her deficits had become constant. Examination demonstrated right hemiparesis and hypoesthesia without associated cortical signs. Brain imaging confirmed the clinical suspicion that the patient had a small subcortical stroke (Figure 7-5) that had presented with an initially stuttering course. Her deficits improved over the following days, and she had nondisabling residual motor and sensory sequelae 3 months later.

Figure 7-5 Small subcortical infarction in the posterior limb of the left internal capsule (arrow) showing restricted diffusion on diffusion-weighted imaging (top left) and apparent diffusion coefficient map (top right). T2-weighted sequence is shown on the lower left and computed tomography scan on the lower right.

♦ The classical lacunar syndromes are the following:

♦ Pure motor hemiparesis

♦ Pure sensory stroke

♦ Sensorimotor stroke

♦ Ataxia hemiparesis

♦ Dysarthria—“clumsy hand syndrome”

♦ Traditional lacunar syndromes are reliable predictors of small subcortical infarctions on brain imaging.^18,¹⁹

♦ The correlation between traditional lacunar syndromes and specific anatomical locations is limited.¹⁹ For instance, pure motor hemiparesis can be due to lesions in the posterior limb of the internal capsule, basis pontis, corona radiata, or medial medulla.

♦ It is important to recognize that small subcortical infarctions can have atypical presentations, including facial sparing, dysarthria with facial palsy, isolated dysarthria, isolated hemiataxia, horizontal gaze palsy (affecting the contralateral III or VI nerves; causing transient internuclear ophthalmoplegia or one-and-a-half syndrome), abulia and paresis of vertical gaze, transient subcortical aphasia, and hemichorea-hemiballismus, among many other clinical manifestation.^2,²⁴ Neuroimaging is crucial to recognize the site and mechanism of infarction in these cases.²⁴

♦ Certain indistinguishable clinical syndromes can correspond to various mechanisms that can be discriminated with brain imaging. One of the best examples of this situation is illustrated by Figure 7-6. A small subcortical infarction in the basis pontis and a paramedian pontine infarction can have the same clinical manifestations (typically ataxia hemiparesis). However, their radiological appearance reliably differentiates the two and predicts the presence of basilar atherosclerosis in patients with paramedian pontine lesions.

♦ Most small subcortical infarctions are actually asymptomatic. However, these silent infarctions are far from benign because their accumulation over time leads to gait dysfunction, cognitive decline, and eventually dementia.⁵

Figure 7-6 Top row: small infarction in the left basis pontis ascribed to penetrating artery disease (diffusion-weighted imaging on the left and T2-weighted sequence on the right, infarction signaled by open arrows). Lower row: left paramedian pontine infarction (shown on T2-weighted magnetic resonance imaging scan on the left, lesion pointed by arrowhead) related to the occlusion of the paramedian penetrating artery due to an atherosclerotic plaque in the basilar artery, as indicated by magnetic resonance angiography (right, solid arrow). Both patients had presented with a combination of right ataxia and hemiparesis.

STRIATOCAPSULAR INFARCTIONS

♦ Striatocapsular infarctions are larger lesions than lacunes and involve the internal capsule and corpus striatum, sometimes extending into the corona radiate (Figure 7-7).

♦ They correspond to the territory of more than one and often several penetrating branches. The mechanism may be occlusion of a single common stem from which these branches arise or microatheromatosis of the parent vessel (horizontal segment of the middle cerebral artery). Embolic sources may be encountered slightly more often than in patients with small subcortical infarctions.

♦ These infarctions are symptomatic, and atypical subcortical manifestations are common.

♦ When differentiating small subcortical infarcts from striatocapsular lesions, one should be mindful that DWI may overestimate the final size of subcortical strokes.²⁵

Figure 7-7 Fluid-attenuated inversion recovery magnetic resonance imaging showing an example of a striatocapsular infarction (arrows). Notice the extension of the lesion into the corona radiata.

CAPSULAR WARNING SYNDROME

♦ Small subcortical and striatocapsular infarctions share the distinctive feature that they can present in a “stuttering” fashion, with deficits fluctuating or progressing over hours and less often even days before becoming fully established (as illustrated by the case shown in Figure 7-5).^26,²⁷ This clinical presentation is not restricted to capsular infarctions and can be also seen in patients with small strokes in other locations, such as the pons.²⁸ Thus brain imaging is necessary to define reliably the topography of the lesion.

♦ MRI obtained during the acute phase may demonstrate growth of a lesion on serial DWI and discrepancies between the size of lesions on DWI and FLAIR while clinical deficits are still fluctuating or progressing.²⁹

♦ The pathophysiology of this phenomenon is debated. Intermittent or worsening hypoperfusion in the territory of the penetrating artery, intermittent peri-infarct depolarizations, and endothelial failure with progressive extravasation of blood components have been postulated as possible mechanisms.^6,²⁹ The latter hypothesis appeared to be supported by an autopsy study that reported evidence of perivascular edema in lesions resembling “incomplete” lacunar infarctions.³⁰

MULTIPLE LACUNAR INFARCTIONS

♦ Multiple bilateral lacunes (Figure 7-8) can produce a fairly characteristic clinical syndrome manifested by executive dysfunction with slowing of mental and motor processes, gait disturbance with small steps, hesitancy and apraxia, and urinary incontinence. Pseudo-bulbar palsy, abulic-apathetic depression, focal motor or sensory deficits, and extrapyramidal signs may also occur. Notably, most but not all patients with multiple discrete lacunes provide a history of recurrent strokes and stepwise decline.

♦ Often, patients with severe subcortical ischemic disease tend to have confluent areas of white matter disease (leukoaraiosis) rather than multiple discrete lesions (Figure 7-9).

♦ Ischemic white matter disease is a progressive disorder (see Figure 7-9). Progression is greater in the deep white matter and anterior subcortical regions.³¹ The degree of progression is associated with the initial severity of subcortical ischemic changes and the presence of vascular risk factors.³²

♦ Nomenclature is confusing when describing these disorders. Subcortical arteriosclerotic encephalopathy (also known as Binswanger’s disease despite the questionable resemblance of modern descriptions of this condition with the original report by Otto Binswanger in 1894)³³ is a commonly used term, but its definition in the literature is far from uniform. Actually, the most accepted pathological and radiological correlate of subcortical arteriosclerotic encephalopathy in more recent classifications is diffuse white matter changes rather than multiple lacunes.³⁴

♦ Pathologically, the most severe cases of multiple lacunar infarctions have been classified as lacunar state (état lacunaire of Pierre Marie). These cases are commonly associated with dementia and for some authors constitute the pathological substrate for true multi-infarct dementia.

♦ Small subcortical infarctions in the deep gray nuclei appear to correlate much better with cognitive decline than small white matter infarctions.³⁵

♦ We ascribe to the use of the comprehensive term “subcortical ischemic vascular disease”³⁶ to describe the clinicoradiological syndrome involving cognitive decline affecting predominantly executive functions, dysbasia, upper motor neuron signs, and bladder incontinence and associated with multiple lacunar infarctions, more diffuse and confluent white matter changes, or both.

♦ In practice, neuroimaging (especially MRI) is crucial in establishing this diagnosis.

Figure 7-8 Computed tomography scan of the brain revealing bilateral small subcortical infarctions (arrowheads) and extensive periventricular and deep white matter changes (arrows) in a patient who presented for evaluation of progressive cognitive impairment and dysbasia.

Figure 7-9 Multiple examples of patients with worsening degrees of ischemic white matter disease, from isolated discrete lesions to confluent extensive leukoaraiosis, as seen on fluid-attenuated inversion recovery sequence of magnetic resonance imaging.

SILENT INFARCTIONS, WHITE MATTER DISEASE, AND DEMENTIA

Case Vignette

A 78-year-old woman with treated hypertension was brought to the neurological consultation by the family because of concerns about cognitive decline. The patient was a retired teacher who had been excellent at multitasking, but over the previous couple of years, she had been noticed to have increasing difficulties performing regular chores at her house. She only acknowledged some difficulties with concentration. In addition, both she and her family reported worsening gait balance. On examination, the patient had fairly pronounced cognitive problems, particularly on executive functions. Her gait was frankly apraxic. Although she denied ever having had a stroke, MRI of her brain revealed extensive white matter changes indicative of subcortical ischemia (Figure 7-10).

Figure 7-10 Fluid-attenuated inversion recovery sequence of brain magnetic resonance imaging disclosing extensive and confluent white matter hypertintensities in an elderly patient with diagnosis of vascular dementia.

♦ Silent brain infarctions and white matter changes increase the risk of dementia in the elderly population.^5,³⁷ To some degree, the type of cognitive difficulties can be fairly reliably predicted by the location of ischemia on MRI: thalamic infarcts are predominantly associated with memory loss and nonthalamic infarcts with psychomotor slowing.⁵

♦ The volume of white matter hyperintensities (often collectively referred to as leukoaraiosis) on T2-weighted or FLAIR sequences of MRI correlate with decreased cognitive performance in populations of nondemented subjects.³⁸ Furthermore, extensive white matter changes have a negative impact on executive performance in patients with documented lacunar strokes,³⁹ and the degree of white matter hyperintensities is independently related to poststroke cognitive decline.⁴⁰

♦ However, in individual cases, the severity of white matter disease on neuroimaging may not correlate with the degree of cognitive and functional deficits. The coexistence of underlying Alzheimer’s disease pathology in patients with more cognitive impairment may explain this apparent discrepancy between radiological and clinical findings.⁴¹

♦ The extent of white matter disease is much better visualized with MRI than CT scan (Figure 7-11).

♦ It may be important to discriminate the degree of periventricular versus subcortical white matter changes. There is some evidence that periventricular white matter changes may be less detrimental than deep subcortical or more superficial white matter lesions.⁴²

♦ The clinician should always personally review the MRI scan when trying to interpret the contribution of white matter changes to the clinical status of a patient. Outside of study protocols applying strict grading criteria, the description of the severity of white matter changes is subjective and often deceiving.

♦ White matter hyperintensities are also associated with increased risk of future stroke independently of traditional vascular risk factors.^43,⁴⁴