REVIEW ARTICLE

Cerebral Small Vessel

Disease

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
By Natalia S. Rost, MD, MPH, FAAN, FAHA; Mark Etherton, MD, PhD
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ABSTRACT
PURPOSE OF REVIEW: This article reviews the clinical significance and
neuroimaging characteristics of cerebral small vessel disease and the
impact on neurologic disease and current and potential therapeutic
approaches.

RECENT FINDINGS: Cerebral small vessel disease is increasingly prevalent and

CITE AS:
CONTINUUM (MINNEAP MINN)
2020;26(2, CEREBROVASCULAR
DISEASE):332–352.
Address correspondence to
Dr Natalia S. Rost, J. Philip Kistler
Stroke Research Center,
Massachusetts General
Hospital, 175 Cambridge St,
Ste 300, Boston MA 02114,
nrost@partners.org.
highly heterogeneous in neuroimaging and clinical presentation. Small
subcortical infarcts, lacunes, cerebral microbleeds, cortical microinfarcts,
and white matter hyperintensity of presumed vascular origin represent the
major neuroimaging markers of small vessel disease. Increasing small
vessel disease burden is associated with risk of incident stroke and
dementia, as well as other neuropsychiatric symptoms. Current research
strategies are targeting elucidation of the mechanisms of small vessel
disease pathogenesis and pursuing clinical trials of therapeutic agents to
reduce the clinical manifestations of cerebral small vessel disease.
SUMMARY: Cerebral small vessel disease is common in aging adults and

RELATIONSHIP DISCLOSURE:
represents a major risk factor for multiple acute and chronic neurologic
Dr Rost serves as an assistant diseases. Increased awareness of cerebral small vessel disease as a
editor for Stroke and has modifiable risk factor holds potential for reducing neurologic disease
received personal compensation
for serving on the scientific morbidity and mortality across diverse populations in the United States
advisory boards for Omniox and worldwide.
and Sanofi Genzyme and as a
consultant for Abbvie Inc.
Dr Rost has received research/
grant support as a principal
investigator for the National INTRODUCTION

O
Institute of Neurological
Disorders and Stroke (R01
NS082285, R01 NS086905, and
U19 NS115388) and publishing
royalties as a contributor to
UpToDate, Inc. Dr Etherton has
received a research grant from
the American Heart Association
(17CPOST33680102).
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Drs Rost and Etherton report no
disclosures.
© 2020 American Academy
of Neurology.
ne of the most important objectives of the clinical stroke
evaluation is characterizing the specific stroke subtype that the
patient has experienced, including the individual risk factors
contributing to the particular stroke event and, based on that,
developing a personalized secondary stroke prevention program.
Cerebral small vessel disease encompasses a multitude of clinical (acute lacunar
infarct, intraparenchymal hemorrhage) and neuroimaging (white matter
hyperintensities of presumed vascular origin, cerebral microbleeds, enlarged
perivascular spaces, cortical microinfarcts, and brain atrophy) manifestations as
a result of focal or diffusely diseased microvasculature.1 Small vessel disease is
prevalent among healthy aging adults and patients diagnosed with acute
ischemic stroke or intraparenchymal hemorrhage. As a major cause of vascular
cognitive impairment and dementia, late-life depression, urinary incontinence,
and impaired gait in older adults, small vessel disease is also responsible for

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significant cognitive and functional disability in the United States and KEY POINTS
worldwide.1 A growing list of genetic variants and lifetime environmental
● Small vessel disease is
exposures to traditional vascular risk factors such as hypertension, chronic prevalent among healthy
hyperglycemia, tobacco abuse, chronic kidney disease, and elevated blood aging adults and patients
homocysteine levels are linked to the severity of small vessel disease. diagnosed with acute
In this article, the definition and phenotypic heterogeneity of small vessel ischemic stroke or
intraparenchymal
disease manifestations, diagnostic utility of neuroimaging in the quantification of
hemorrhage.
small vessel disease in clinical and subclinical cerebrovascular disease, and
pathophysiologic considerations of small vessel disease syndromes are discussed. ● Small vessel disease
Personalized approaches to small vessel disease treatment during the acute is a multifaceted
hospitalization for stroke are also presented, as well as long-term management cerebrovascular syndrome
that is composed of distinct
strategies aimed at reducing the development of small vessel disease–related clinical, neuropathologic,
sequelae. and neuroimaging findings.

SMALL VESSEL DISEASE AND THE SPECTRUM OF CEREBRAL ● Brain MRI plays an
essential role in the
MICROVASCULAR CHANGES diagnosis and
Small vessel disease is a multifaceted cerebrovascular syndrome that is composed characterization of the
of distinct clinical, neuropathologic, and neuroimaging findings. Small vessel small vessel disease
disease affects the smaller caliber vessels of the brain, including arterioles spectrum.
(perforating, diameter <0.1 mm), capillaries, and venules, and results in acute
and chronic, often progressive/accumulating injury to the white and gray matter.
Small vessels are key in maintaining cerebral tissue perfusion to the deep and
superficial brain structures, isolated nerves (vasa nervorum), and vasculature
proper (vasa vasorum). Small vessels are also instrumental in supporting the
metabolic demand of the structures they supply, as well as serving as the essential
interface with the central nervous system through the blood-brain barrier. The
mechanisms of interaction between cerebral microvasculature and the brain
parenchyma are currently under intense investigation.2 It is widely believed that
the neurovascular unit plays a key role in overall brain health and resilience to
acute insults (eg, stroke) or chronic exposures initiating pathologic cascades
leading to neurodegeneration and dementia.
The pathophysiology of small vessel disease has been subject to a recent
renaissance, as the neuropathologic features of diseased cerebral vasculature in
various small vessel disease syndromes have received detailed characterization
from high-resolution MRI techniques developed over the past 2 decades.3 In 1965,
C. Miller Fisher described detailed clinicopathologic correlations in classic
ischemic lacunar stroke syndromes that revealed evidence of (1)
arteriolosclerosis, or thickening of and damage to the arteriolar wall, also referred
to as lipohyalinosis and (2) obstruction of the origins of penetrating arteries by
the parent large artery’s intimal plaque (FIGURE 5-1).4 Most of the small vessel
disease subtypes discussed in this chapter involve the arterial circulation and
result from intrinsic rather than extrinsic mechanisms of flow obstruction.
Ultimately, arteriolar narrowing or occlusion leads to ischemia, which can
present as small (lacunar) infarction. In addition, microvasculature (both
arterioles and venules) can be affected by abnormal deposition of amyloid-β
(Aβ) within the vessel walls in a condition called cerebral amyloid angiopathy.
The accumulation of Aβ results in gradual vessel wall degeneration and,
ultimately, breach of integrity/rupture leading to asymptomatic
microhemorrhages (cerebral microbleeds) or lobar intraparenchymal
hemorrhage. Less frequently, genetic disorders are also associated with small

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CEREBRAL SMALL VESSEL DISEASE

FIGURE 5-1
Neuroimaging examples of key small vessel disease subtypes. A, Fluid-attenuated inversion
recovery (FLAIR) image showing mild periventricular white matter hyperintensities and a
chronic lacune of the right lentiform nucleus (arrow) with cavitation. B, Gradient recalled
echo (GRE) image showing a right frontal nontraumatic lobar hemorrhage and cortical
superficial siderosis in the right parietal lobe (arrow). C, T2-weighted image showing
enlarged perivascular spaces of the basal ganglia (arrow). D, FLAIR image showing global
brain atrophy and confluent white matter hyperintensities. E, Susceptibility-weighted image
(SWI) showing multiple lobar cerebral microbleeds in the right temporal and left temporal
and occipital lobes; the arrow highlights one lobar cerebral microbleed. F, High-resolution
diffusion-weighted image (DWI) demonstrating a cortical microinfarct (arrow). The inset
shows the magnified view of left hemisphere cortical microinfarct.

vessel disease due to abnormal intramural deposits as seen in CADASIL (cerebral

autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy) or diffuse microangiopathy due to abnormal collagen
structure causing white matter hyperintensities and cerebral microbleeds in the
recently described COL4A1/COLA4A2 syndromes.
Brain MRI plays an essential role in the diagnosis and characterization of the
small vessel disease spectrum (TABLE 5-1). Numerous MRI techniques enable
in-depth visualization of brain tissue and vessel status, and these techniques are
constantly evolving and becoming extensively available to both clinicians and
researchers. Inconsistency in the techniques and terminologies used for

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characterizing small vessel disease prompted an international consortium,
STandards for Reporting Vascular changes on nEuroimaging (STRIVE), to
propose standardized terms for the MRI features of small vessel disease.5 The
most frequently used conventional and advanced MRI techniques used in
cerebrovascular disease are those that specifically assess brain structure,
including basic T1-weighted and T2-weighted imaging, T2-fluid-attenuated
inversion recovery (FLAIR), T2*-gradient recalled echo (GRE), susceptibility-
weighted imaging (SWI), and those that evaluate the function of water molecule
diffusion (diffusion-weighted imaging [DWI]) and blood flow (perfusion-
weighted imaging).
With these techniques, the main small vessel disease manifestations include
(1) acute lacunar or small subcortical infarct detected on DWI, (2) chronic
lacunes detected on T2/FLAIR, (3) white matter hyperintensities (also known as
leukoaraiosis) detected on T2/FLAIR, (4) enlarged perivascular spaces detected
on T2, (5) cerebral microbleeds detected on GRE/SWI, (6) intraparenchymal
hemorrhage detected on GRE/SWI, (7) cortical microinfarcts detected on
DWI/T2/FLAIR, and (8) cortical superficial siderosis detected on GRE/SWI
(FIGURE 5-1). Additional MRI-based features of small vessel disease exist,
including, for example, diffuse microstructural white matter integrity loss
(detected on diffusion-tensor imaging) and brain atrophy; however, these
remain under intense research investigations and are outside of the scope of this
article’s discussion for current diagnosis and management of small vessel disease
in neurology practice.

Lacunar Infarcts and Recent Small Subcortical Infarcts

These small lesions (<15 mm in largest diameter) result from an ischemic event in
the territory of the smallest perforating vessels in the arterial tree and, by

Neuroimaging Features of Cerebral Small Vessel Disease TABLE 5-1

Size
Lesion (mm) MRI Features

Lacune 3–15 Acute—diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery

(FLAIR)/T2: hyperintense; T1: hypointense; GRE/SWI: isointense
Chronic—DWI, FLAIR, and T1: hypointense; T2: hyperintense; gradient recalled echo
(GRE)/ susceptibility-weighted imaging (SWI): isointense

Recent small subcortical ≤20 DWI and FLAIR/T2: hyperintense; T1: hypointense; GRE/SWI: isointense
infarcts

White matter Variable DWI and GRE/SWI: isointense; FLAIR/T2: hyperintense; T1: hypointense
hyperintensities

Enlarged perivascular ≤2 DWI and GRE/SWI: isointense; FLAIR and T1: hypointense; T2: hyperintense
spaces

Cerebral microbleeds ≤10 DWI, FLAIR, T2, and T1: isointense; GRE/SWI: hypointense

Cortical superficial Variable DWI, FLAIR, T2, and T1: isointense; GRE/SWI: hypointense
siderosis

Cortical microinfarcts 0.2–3 DWI and FLAIR/T2: hyperintense; T1: hypointense; GRE/SWI: isointense

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CEREBRAL SMALL VESSEL DISEASE

definition, are subcortical (either located in the deep gray matter such as the
basal ganglia or thalamus or in the hemispheric, brainstem, or cerebellar white
matter).6 When acute, these infarcts appear hyperintense on DWI, with
corresponding hypointense signal on apparent diffusion coefficient (ADC)
sequence, and increased signal on T2/FLAIR imaging (“T2 shine through”) and
reduced signal on T1-weighted imaging compared with the normal surrounding
gray or white matter (CASE 5-1). Recent generally refers to lesions associated with
clinical symptoms occurring in the previous few weeks. The terminology recent
small subcortical infarcts has been proposed as the new consensus term replacing
the historical term lacune because not all of these infarcts cavitate.5
Acute lacunar infarct size is often larger than the original lacune size described
in the clinicopathologic correlations (chronic lacunes), likely because of
associated edema; furthermore, those small vessel infarcts involving
lenticulostriate perforators (single or multiple) may result in acute lesions greater
than 20 mm in diameter and originate from atherothrombotic (or embolic)
occlusion of their ostia at the proximal segment (M1) of the middle cerebral
arteries, causing striatocapsular infarcts, or thalamocapsular infarcts involving
the anterior choroidal artery distribution. Other common vascular territories
involved in lacunar infarction include the recurrent artery of Heubner (branch of
the anterior cerebral artery), thalamoperforators (branches of the posterior
cerebral artery), and paramedian pontine perforators (branches of the basilar
artery).
In addition to these classic lacunar infarct locations, small infarcts that are
apparent on acute (DWI) and chronic (T2/FLAIR) MRI in the subcortical
supratentorial and infratentorial distribution (eg, in the corona radiata,
cerebellum, or brainstem other than pons) often result from occlusion of the
smallest caliber vessels. Although these small subcortical infarcts do not have
classic clinicopathologic correlates and their etiology is often questioned (ie,
intrinsic small vessel disease versus embolism or in situ thrombosis), these are
considered one of the small vessel disease manifestations and should be included
in etiologic classifications in neurology practice. Of note, chronic lacunes can
be visualized on neuroimaging as CSF-containing spaces (lacus is Latin for lake),
are 3 to 15 mm in diameter, and are often asymptomatic, or “silent” brain infarcts.
The propensity to cavitate varies among the lacunar infarcts based on the
assessment method and chronicity of the lesions. Furthermore, multiple
noncavitated small subcortical ischemic lesions may contribute to the appearance
of diffuse white matter hyperintensities on T2/FLAIR MRI or leukoaraiosis (on
CT), or nonspecific white matter changes in the brainstem.

White Matter Hyperintensity of Presumed Vascular Origin

The term white matter hyperintensities refers to the radiographic appearance of
the diffuse, largely symmetrical microvascular pathology that is specifically
described in the bihemispheric supratentorial distribution on the T2/FLAIR MRI.
The original neuroimaging reference to the same pathology on CT by Vladimir
Hachinski as leukoaraiosis describes a similar underlying disease process (leuko
for white and araiosis for rarefaction),9 but the detailed description of this small
vessel disease manifestation resulted from systematic MRI analysis. Over the
nearly 4 decades of study, white matter hyperintensity is known to be one of the
most well-characterized features of the small vessel disease neuroimaging
spectrum; it is a validated biomarker and an established risk factor for stroke and

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 A 64-year-old woman presented to a local emergency department after CASE 5-1
discovering weakness of her left face, arm, and leg on waking. She had a
history of poorly controlled hypertension and smoking.
Initial evaluation was notable for a National Institutes of Health Stroke
Scale score of 6 (1 point for dysarthria, 2 points for left facial weakness,
2 points for left arm weakness, and 1 point for left leg weakness). She was
not eligible for IV alteplase because she was last known well beyond
4.5 hours. Her admission blood pressure was 183/100 mm Hg. She was
admitted to the inpatient stroke service for further evaluation and
workup. Brain MRI showed an acute infarct involving the right lentiform
nucleus and internal capsule and moderate white matter hyperintensity
burden (FIGURE 5-2). Her blood pressure was allowed to autoregulate
(“permissive hypertension”) for the first 24 hours before alterations to
her antihypertensive regimen were made to achieve a long-term systolic
blood pressure goal of <130 mm Hg for secondary stroke prevention.7
She was also started on aspirin 81 mg daily. Atorvastatin 80 mg daily was
added for secondary stroke prevention for a low-density lipoprotein
level of 135 mg/dL per the SPARCL (Stroke Prevention by Aggressive
Reduction in Cholesterol Levels) trial.8 Lastly, she was counseled on
tobacco cessation.

FIGURE 5-2
Imaging of the patient in CASE 5-1. Axial diffusion-weighted MRI (A) shows an acute infarct
involving the right lentiform nucleus and internal capsule, and axial fluid-attenuated
inversion recovery (FLAIR) MRI (B) shows moderate white matter hyperintensity burden.

This case exemplifies how common microvascular risk factors such as COMMENT
hypertension and tobacco use can contribute to small vessel disease,
which can manifest as acute ischemic (lacunar) stroke. In this patient
population, the importance of optimizing vascular risk factors for
secondary stroke prevention is paramount.

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CEREBRAL SMALL VESSEL DISEASE
TABLE 5-2
Disease
CADASIL (cerebral autosomal
dominant arteriopathy with
subcortical infarcts and
leukoencephalopathy)
CARASIL (cerebral autosomal
recessive arteriopathy with
subcortical infarcts and
leukoencephalopathy)
Familial cerebral amyloid
angiopathy
HANAC (hereditary angiopathy
with nephropathy, aneurysms,
and muscle cramps)
Fabry disease
Homocystinuria
MELAS (mitochondrial
encephalomyopathy, lactic
acidosis, and strokelike
syndrome)
HDLS (hereditary diffuse
leukoencephalopathy with
spheroids)
RVCL (retinal vasculopathy
with cerebral leukodystrophy)
Axenfeld-Rieger syndrome
a
Modified with permission from Giese AK, Rost NS.14 © 2017 Springer International Publishing AG.
338
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Monogenic Forms of Cerebral Small Vessel Diseasea
Genetic Basis (Inheritance)
NOTCH3 (autosomal
dominant [AD])
HTRA1 (autosomal
recessive [AR])
APP (amyloid precursor
protein), CST3 (cystatin C),
ITM2B (integral membrane
protein 2B), TTR
(transthyretin) (AD)
COL4A1, COL4A2 (collagen
type IV A) (familial and
sporadic)
GLA
(α-galactosidase)
(X-linked)
CBS (cystathionine
β-synthase) (AR)
Multiple mitochondrial
genes (maternal
inheritance)
CSF1R (Colony-stimulating
factor 1 receptor) (AD)
TREX1 (AD)
FOXC1, PITX2 (AD)
Neuroimaging Findings Clinical Manifestations
Extensive white matter Small vessel more common
hyperintensities with than territorial strokes,
anterior temporal intraparenchymal
predominance, cerebral hemorrhage (rare), dementia,
microbleeds, brain atrophy depression, migraine with
aura
Extensive white matter Small vessel more common
hyperintensities, brain than territorial strokes,
atrophy dementia, early-onset diffuse
alopecia, spondylosis
Extensive white matter Lobar intraparenchymal
hyperintensities, lobar hemorrhage, dementia
cerebral microbleeds and
cortical superficial
siderosis, brain atrophy
Extensive white matter Retinal arteriolar tortuosity
hyperintensities, cerebral and hemorrhages, neonatal
microbleeds, intracranial stroke and porencephaly,
aneurysms intraparenchymal
hemorrhage, nephropathy
White matter Small vessel stroke,
hyperintensities dementia, small fiber
neuropathy, angiokeratomas,
renal and cardiac failure
White matter Stroke, premature
hyperintensities atherosclerosis, lens
dislocation, Marfanlike
features, cognitive
impairment and mental
retardation
Extensive white matter Stroke, mitochondrial
hyperintensities myopathy, lactic acidosis,
developmental delay,
sensorineural hearing loss,
seizures
Extensive white matter Dementia, personality and
hyperintensities behavioral changes,
parkinsonism, seizures
Extensive white matter Stroke, progressive visual
hyperintensities loss, nephropathy
White matter Stroke, retinal arteriolar
hyperintensities, tortuosity, cerebellar
subcortical infarcts malformations
APRIL 2020
intraparenchymal hemorrhage (incident and recurrent), vascular cognitive KEY POINT
impairment and dementia, mortality, and functional disability among healthy
● White matter
aging adults and in patients with acute ischemic stroke.10,11 In addition to being a hyperintensity is known to
common radiographic manifestation of small vessel disease, white matter be one of the most well-
hyperintensities are also thought to be a link in the underlying cerebrovascular characterized features of
disease pathway that contributes to impaired mechanisms of poststroke the small vessel disease
neuroimaging spectrum; it
recovery.10 A preexisting burden of white matter hyperintensities is associated
is a validated biomarker
with loss of white matter structural integrity, which in turn leads to impaired and an established risk
functional connectivity and the overall capacity of the brain to withstand an factor for stroke and
acute insult and to increase the odds of favorable poststroke outcome, known as intraparenchymal
hemorrhage (incident and
the brain’s effective reserve.12
recurrent), vascular
Based on the topography, two distinct categories of white matter cognitive impairment and
hyperintensities have been described: periventricular white matter dementia, mortality, and
hyperintensities (contiguous with the ventricular system) and deep white matter functional disability among
hyperintensities (located in subcortical white matter, noncontiguous with the healthy aging adults and in
patients with acute ischemic
ventricles or periventricular white matter hyperintensities, and including stroke.
isolated, punctate white matter hyperintensity lesions colloquially known as
UBOs or unidentified bright objects), giving rise to the continuing discussion
regarding the mechanisms underlying white matter hyperintensity
heterogeneity. Furthermore, histopathologic correlates of white matter
hyperintensities vary by topography, including areas of demyelination with
venous congestion resulting from noninflammatory periventricular venous
collagenosis, mild to moderate subependymal gliosis, and discontinuity of the
ependymal lining (nonischemic) in periventricular white matter
hyperintensities, as well as progressive myelin loss, fibrohyalinotic evolution of
arterioles, occurrence of dilated perivascular spaces, and ultimately axonal loss
and reactive gliosis in deep white matter hyperintensities.13
While age is the most robust determinant of white matter hyperintensity
severity and progression, a complex interaction between genetic factors and
lifetime exposures to vascular risk factors such as hypertension, diabetes
mellitus, tobacco smoking, hyperlipidemia, and alcohol abuse, to name a few,
plays a significant role. White matter hyperintensity burden is greater in patients
with ischemic stroke and intracerebral hemorrhage, as well as patients with
genetic conditions such as CADASIL, Fabry disease, COL4A1 disorder, familial
cerebral amyloid angiopathy, and MELAS (mitochondrial encephalomyopathy,
lactic acidosis, and strokelike syndrome) caused by mitochondrial DNA
mutations (TABLE 5-214). In CADASIL, an autosomal dominant condition caused
by mutations of the NOTCH3 gene (chromosome 19),15 the microangiopathy
involving abnormal fibrous arterial wall thickening and intramural inclusions
detected as granular osmophilic material on electron microscopy might represent
a basic model for understanding the pathogenesis of sporadic white matter
changes.
The underlying mechanisms of disease leading to white matter hyperintensity
development and progression have been under investigation for more than
3 decades.16 The most established hypothesis focuses on the ischemic (vascular)
origins of white matter hyperintensities and is supported by the findings of the
pathologic-radiographic correlation studies, which underscore the patterns of
periventricular white matter vascularization as an arterial borderzone
(watershed) area and presumed white matter susceptibility to hypoxic-ischemic
damage resulting from a systemic or focal cerebral hypoperfusion. Instead, deep

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CEREBRAL SMALL VESSEL DISEASE

CASE 5-2 A 66-year-old woman presented to an emergency department with

sudden-onset headache and weakness of the left upper and lower
extremities, more pronounced in her leg. She had a history of
hyperlipidemia treated with simvastatin.
Emergent head CT showed a large intraparenchymal hemorrhage
involving the right medial frontal lobe. Her prothrombin time/
international normalized ratio (INR) was 1.0, and her platelet count was
254,000/mm3. She was admitted to the neurocritical care unit for further
management and close neurologic monitoring. Blood pressure was
intensively controlled for the first 48 hours with a systolic blood pressure
goal of <140 mm Hg. A repeat head CT was performed 6 hours after the
original CT to confirm stability of the hemorrhage. Subsequent brain MRI
with gradient recalled echo sequences revisualized the large frontal
hematoma and showed evidence of right parietal cortical superficial
siderosis (FIGURE 5-3A) and multiple lobar cerebral microbleeds in the right
temporal and left occipital lobes (FIGURE 5-3B). A diagnosis of probable
cerebral amyloid angiopathy was made based on the modified
Boston criteria.

FIGURE 5-3
Imaging of the patient in CASE 5-2. Axial gradient recalled echo (GRE) images show the large
right frontal hematoma and evidence of right parietal cortical superficial siderosis (A) and
multiple lobar cerebral microbleeds in the right temporal and left occipital lobes (B).

COMMENT This case highlights the practical application of previously published

clinical and neuroimaging criteria (the modified Boston criteria) to make a
diagnosis of probable cerebral amyloid angiopathy. This individual
presented with a spontaneous lobar intraparenchymal hemorrhage and
brain MRI also showing lobar cerebral microbleeds in multiple lobes and
cortical superficial siderosis, thus satisfying the modified Boston
diagnostic criteria for probable cerebral amyloid angiopathy.

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white matter hyperintensity is thought to be caused by the pathologic changes in KEY POINT
the territorial end arterioles (such as lenticulostriates or thalamoperforators),
● In cerebral amyloid
which are susceptible to the effects of chronic hypertension, hypoperfusion, and angiopathy, several
other intrinsic small vessel disease states leading to lacunar infarcts, deep hemorrhagic manifestations,
intraparenchymal hemorrhage, and diffuse ischemic changes in the territories including acute
supplied by these microvessels. However, atherosclerosis of the larger intraparenchymal
hemorrhage, subclinical
perforating arteries tends to result in more sizeable, albeit still clearly small
macrohemorrhages,
vessel, infarctions that present as classic clinical lacunar syndromes. Conversely, cerebral microbleeds,
diffuse intrinsic microvascular arteriopathy that is prevalent and manifest cortical subarachnoid
throughout the brain as endothelial dysfunction and increased blood-brain hemorrhage, and cortical
superficial siderosis, have
barrier permeability leads to leakage of plasma material into the vessel wall and
been described.
perivascular space and inflammation. The result is loss of structural integrity of
the white matter, both at the microscopic level (early, often seen with advanced
diffusion MRI techniques) and macroscopic level (late, often irreversible, visible
on T2/FLAIR sequences), producing periventricular or patchy/confluent deep
white matter hyperintensities. The only nonischemic etiology of white matter
hyperintensities is known for the immediate periventricular component (“caps”
and “halos” in periventricular white matter hyperintensities), which are thought
to emerge from the disruption of ependymal lining linked to increased water
reabsorption and CSF leakage associated with abnormal transependymal flow.

Hemorrhagic Small Vessel Disease Subtypes

In recent years, the body of knowledge regarding hemorrhagic manifestations of
small vessel disease has dramatically increased, mostly based on studies of
sporadic and familial cerebral amyloid angiopathy, a distinct prototype of small
vessel disease that demonstrated a high degree of clinicopathologic and
radiographic correlations.
In cerebral amyloid angiopathy, several hemorrhagic manifestations,
including acute intraparenchymal hemorrhage, subclinical macrohemorrhages,
cerebral microbleeds, cortical subarachnoid hemorrhage, and cortical superficial
siderosis, have been described.17 These manifestations result from the primary
pathology of the Aβ-peptide deposits in the vascular wall, ultimately leading to
loss of vascular wall integrity (rupture) and a bleeding event. The specific
hemorrhagic phenotype is thought to be related to the underlying distribution of
vascular amyloid deposits (cerebral amyloid angiopathy tends to favor cortical
vessels, including the cerebellar cortex and vermis) and the size and type of
vessel affected (eg, arteriole, venule). In addition, cerebral amyloid
angiopathy–related hemorrhages are more likely to arise in posterior brain
regions for yet unclear reasons. Because of the extensive involvement of the
leptomeningeal vessels, cerebral amyloid angiopathy–related hemorrhage often
extends into the subarachnoid space and, in the subclinical form, is detected as
cortical superficial siderosis (CASE 5-2). In 2018, the Boston criteria for diagnosis
of cerebral amyloid angiopathy were modified from the original form based on
the recent radiographic insights into this prototypical cerebral small vessel
disease (TABLE 5-3), serving as a guide for the future diagnostic and therapeutic
developments.18 A rare but distinct subset of cerebral amyloid angiopathy,
cerebral amyloid angiopathy–related inflammation, can manifest with acute to
subacute cognitive decline, seizures, headache, and focal neurologic deficits.
Brain MRI generally shows confluent, asymmetric white matter hyperintensities
and many cerebral microbleeds.

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CEREBRAL SMALL VESSEL DISEASE

In addition to cerebral amyloid angiopathy, hemorrhagic forms of small vessel

disease such as cerebral microbleeds are prevalent on MRI scans of healthy aging
adults (approximately 6%), individuals with vascular risk factors such as
hypertension, and patients with symptomatic cerebrovascular disease including
ischemic stroke (approximately 30%) and intraparenchymal hemorrhage
(approximately 60%). Cerebral microbleeds are punctate deposits of
hemosiderin due to blood extravasation from the diseased microvasculature.19
Due to the magnetic susceptibility phenomenon exhibited by hemosiderin,
cerebral microbleeds can be detected on such sequences as T2*-weighted GRE or
SWI. Evolution of susceptibility-weighted MRI available for clinical use
enhanced the routine ability to detect cerebral microbleeds but also increased the
variability in interpretation and research applications involving this form of
small vessel disease.
Most cerebral microbleeds are 2 to 5 mm or, rarely, up 10 mm in diameter
(accounting for detection bias and “blooming artifact” on SWI) and may occur in
clusters. The topographic location of cerebral microbleeds has been used as a

TABLE 5-3 Modified Boston Criteria for Diagnosis of Cerebral Amyloid Angiopathya,b

Pathology Available
◆ Definite cerebral amyloid angiopathy
◇ Full postmortem
→ Lobar intraparenchymal hemorrhage
→ Severe cerebral amyloid angiopathy with vasculopathy
◆ Probable cerebral amyloid angiopathy with supporting pathology
◇ Pathologic tissue
→ Cerebral amyloid angiopathy in specimen (biopsy or evacuated hematoma)
◇ Neuroimaging data
→ Lobar intraparenchymal hemorrhage, cerebral microbleeds, or cortical superficial
siderosis
No Pathology Available
◆ Probable cerebral amyloid angiopathy
◇ Age ≥55 years
◇ Neuroimaging data
→ Multiple lobar intraparenchymal hemorrhages or cerebral microbleeds
→ Single lobar intraparenchymal hemorrhage and cortical superficial siderosis
◆ Possible cerebral amyloid angiopathy
◇ Age ≥55 years
◇ Neuroimaging data
→ Single lobar intraparenchymal hemorrhage, cerebral microbleeds, or cortical
superficial siderosis

a
Modified with permission from Greenberg SM, Charidimou A, Stroke.18 © 2018 Wolters Kluwer Health.
b
In the absence of any other diagnostic lesion or cause of hemorrhage.

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diagnostic clue for the underlying etiology. For example, cortical cerebral KEY POINT
microbleeds located at the gray-white matter junction or throughout the
● Cortical microinfarcts
occipital, parietal, temporal, or frontal lobe cortex (lobar) are usually associated are silent and usually
with cerebral amyloid angiopathy. Subcortical (deep) cerebral microbleeds undetectable on
including the basal ganglia, thalamus, brainstem, and cerebellum are often conventional neuroimages.
described as a pathognomonic finding in chronic arterial hypertension. Cerebral
microbleeds that occur in both lobar and deep areas of the brain may indicate
mixed pathology or, in the case of the cerebellum, an undetermined pathology of
underlying hemorrhagic small vessel disease. Cerebral microbleed mimics may
include iron or calcium deposits, cavernous malformations, hemorrhagic
transformation of small infarcts, and vascular flow voids. Other hemorrhagic
manifestations of small vessel disease, including cortical subarachnoid
hemorrhage and cortical superficial siderosis, result from bleeding events that
occur in the microvasculature intrinsic to the superficial cortical layers or
extrinsic to these layers (leptomeningeal) and represent acute versus chronic
sequelae of vessel rupture. In most cases, these hemorrhagic small vessel disease
manifestations are asymptomatic, although they can be associated with syndromes
of focal cortical involvement, such as cortical spreading depression or seizures.

Enlarged Perivascular Spaces

One of the more recently recognized manifestations of small vessel disease,
enlarged perivascular spaces, is a pathologic variant of the normal physiologic
structures called Virchow-Robin spaces that surround the walls of vessels (arteries,
arterioles, veins, and venules) as these traverse the subarachnoid spaces through
the brain surface and parenchyma.20 In recent years, understanding of the
functional role of perivascular spaces has greatly increased including their role in
“toxic” solute drainage from the brain through the extracellular spaces, in lieu of
lymphatic drainage of the nervous system, as well as facilitation of immunologic
processes. Enlarged perivascular spaces (état criblé) appear as elongated or
punctate, usually less than 3 mm, lesions surrounding perforating arterioles and
are frequently noted in basal ganglia, hemispheric white matter (centrum
semiovale), thalamus, and hippocampus. On neuroimaging, enlarged
perivascular spaces are similar in appearance to CSF, ie, hypodense on CT
and hyperintense on T2-weighted images/hypointense on FLAIR; however,
T1-weighted magnetization-prepared rapid gradient echo (MP-RAGE) became
one of the more reliable MRI sequences for enlarged perivascular space detection.
These lesions are usually symmetric and appear well demarcated (FIGURE 5-4).

Cortical Microinfarcts
Given the advances in MRI techniques and resolution of in vivo imaging of the
brain, cortical microinfarcts emerged as a novel entity of small vessel disease.
Like the majority of the small vessel disease lesions, cortical microinfarcts are
silent and usually undetectable on conventional neuroimages; however, they
have been verified in a series of MRI-neuropathologic correlation studies. DWI is
highly sensitive for detection of acute microinfarcts21; however, lesions may
appear larger than they actually are due to the “blooming artifact” and
misclassified as “lacunar” or “small vessel” infarcts. Microscopically, they can
be detected by light microscopy as regions of cerebral cortical tissue necrosis,
with a mean diameter ranging from 0.2 to 2.9 mm, with or without cavitation, or
with other characteristics that earn these lesions the term microinfarct.22

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CEREBRAL SMALL VESSEL DISEASE

FIGURE 5-4
Neuroimaging examples of enlarged perivascular spaces. Axial T2-weighted brain MRI
showing enlarged perivascular spaces at the level of the basal ganglia and centrum
semiovale. A and B, Several representative enlarged perivascular spaces (red arrows) are
captured in cross-section. C and D, Several representative enlarged perivascular spaces
(blue arrows) are captured longitudinally.

Brain Atrophy
Neuroimaging evidence of diffuse brain atrophy is recognized as another marker
of small vessel disease. Generally characterized by symmetric decreased total
brain volume, increased CSF spaces, and enlarged sulci, brain atrophy is strongly
associated with other small vessel disease neuroimaging markers, such as white
matter hyperintensity burden and lacunar stroke, and correlates with cognitive
dysfunction.23

CLINICAL SYNDROMES
The clinical ramifications of small vessel disease can be extremely heterogeneous,
ranging from insidious in onset, resulting in late-stage clinical presentation, to
sudden-onset acute clinical syndromes. It is increasingly recognized that by the

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nature of the multitude of neuroimaging manifestations and variable locations of KEY POINTS
cerebral involvement small vessel disease is associated with many diverse clinical
● Small vessel disease is the
syndromes and diseases. most common cause of
vascular cognitive
Vascular Cognitive Impairment and Dementia impairment and dementia.
Small vessel disease is the most common cause of vascular cognitive impairment
● Small vessel disease
and dementia. Vascular cognitive impairment and dementia are associated
represents a significant risk
with small vessel disease through several mechanisms, including cerebral factor for ischemic stroke,
hypoperfusion (principally of the deep white matter), strategic infarcts in specifically small vessel
eloquent brain regions, and recurrent or multiple infarcts. Moreover, the small occlusive mediated infarcts
vessel disease subtypes of cerebral microbleeds, white matter hyperintensities, (lacunar stroke), and
hemorrhagic stroke.
lacunes, recent small subcortical infarcts, and cortical microinfarcts have all been
demonstrated to increase the risk of vascular cognitive impairment and dementia ● In adults older than
(CASE 5-3).24 Cognitive decline caused by small vessel disease typically manifests 55 years of age, cerebral
as problems with executive function, processing speed, attention, and memory. amyloid angiopathy
represents the most
Compounding these cognitive issues are two additional factors. First, small common etiology of
vessel disease is also associated with increased risk of depression and anxiety, spontaneous, nontraumatic
apathy, and sleep disturbances (discussed later in this article). There is also lobar intraparenchymal
significant overlap between small vessel disease pathology and Alzheimer hemorrhage.
disease–type pathology, co-occurring in greater than 50% of reported cases but
● Apathy, depression,
also in other neurodegenerative disorders.25 parkinsonism, anxiety,
hallucinations, and sleep
Stroke disturbances have all been
Small vessel disease represents a significant risk factor for ischemic stroke, reported in patients with
small vessel disease.
specifically small vessel occlusive mediated infarcts (lacunar stroke), and
hemorrhagic stroke. Among more than 20 acute lacunar stroke syndromes
described by C. Miller Fisher, the most common are pure motor hemiparesis,
pure sensory stroke, mixed sensorimotor stroke, ataxic hemiparesis, and
dysarthria-clumsy hand (TABLE 5-4).26 These clinical stroke syndromes are
determined based on the involvement/location of the affected perforating
arteriole in relation to the corticospinal tract (at the level of the internal capsule
or pons), thalamus, or the pontocerebellar fibers. Beyond the dramatic acute
stroke clinical presentation, many patients with small vessel disease are also
found to have experienced silent brain infarction, a consequence of a lacunar
stroke in a noneloquent region of the brain with less overt clinical symptoms.
Importantly, secondary effects of these acute subcortical infarcts include remote
cortical thinning due to degeneration of connecting white matter tracts.27
Small vessel disease is also a well-established risk factor for both lobar and
nonlobar intraparenchymal hemorrhage. In the case of nonlobar
intraparenchymal hemorrhage, which is classically associated with chronic
exposure to microvascular risk factors, namely hypertension, the development of
Charcot-Bouchard aneurysms of the lenticulostriate arterioles predisposes to risk
of nonlobar intracerebral hemorrhage. In adults older than 55 years of age,
cerebral amyloid angiopathy represents the most common etiology of
spontaneous, nontraumatic lobar intraparenchymal hemorrhage.

Neuropsychiatric Symptoms
The neuropsychiatric manifestations of small vessel disease are diverse. Apathy,
depression, parkinsonism, anxiety, hallucinations, and sleep disturbances have
all been reported in patients with small vessel disease.28–30 Emphasizing the

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CEREBRAL SMALL VESSEL DISEASE

CASE 5-3 A 78-year-old man with a history of hypertension on lisinopril/

hydrochlorothiazide was referred to the neurology clinic for memory
difficulties. He and his family reported 12 months of short-term memory
problems and difficulty managing his personal finances and household
affairs.
Formal neuropsychological testing was notable for impaired executive
function, processing speed, and short-term memory. Elemental
neurologic examination was otherwise normal without evidence of
parkinsonism or gait abnormalities. The patient had no evidence of
depression on a screening test. Laboratory testing to rule out treatable
causes of dementia was negative.
Brain MRI showed confluent periventricular white matter hyperintensities
(FIGURE 5-5A), enlarged perivascular spaces in the basal ganglia and
centrum semiovale (FIGURE 5-5B), and silent infarction of the right corona
radiata (FIGURE 5-5C). A presumptive clinical diagnosis of major
neurocognitive disorder with high suspicion for a component of vascular
cognitive impairment was made.

FIGURE 5-5
Imaging of the patient in CASE 5-3. Axial fluid-attenuated inversion recovery (FLAIR) MRI
shows confluent periventricular white matter hyperintensities (A) and enlarged perivascular
spaces in the basal ganglia and centrum semiovale (B); the arrow highlights one enlarged
perivascular space. Axial diffusion-weighted image (C) shows a silent infarction of the right
corona radiata.

COMMENT This case exemplifies the often-insidious clinical trajectory of small vessel
disease, in which some individuals present with gradual neuropsychiatric
symptoms or cognitive decline (ie, mood disturbances and cognitive
dysfunction) and are found to have neuroimaging evidence of severe small
vessel disease. Going forward, early and sustained optimization of small
vessel disease risk factors, such as hypertension in this case, is critical for
primary prevention of small vessel disease–related neurologic dysfunction
including stroke, functional and cognitive decline, and dementia.

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influence of the location of the small vessel disease lesions on clinical phenotype,
cerebral microbleeds in the thalamus have been shown to be positively associated
with increased rates of poststroke emotional lability.31

Urinary Symptoms
In patients with small vessel disease, urinary disturbances have also been
reported. LADIS (the Leukoaraiosis And DISability Study) of 639 individuals
with small vessel disease showed a high prevalence of urinary symptoms,
including nocturia, urinary frequency, urgency, and incontinence.32
Furthermore, in this study, increased white matter hyperintensity burden was
associated with increased urinary urgency.33

Gait Disturbances
Abnormalities in multiple parameters of gait have been reported in individuals
with small vessel disease. White matter hyperintensity burden and lacunes have
been demonstrated to be independently associated with reduced gait velocity,
stride length, and cadence.33 Similarly, an increasing cerebral microbleed burden
has also been reported to be associated with gait abnormalities.

CURRENT TREATMENT STRATEGIES

Despite the debilitating clinical sequelae of small vessel disease, there is currently
no approved small vessel disease–specific treatment to mitigate its long-term
consequences. As such, in patients presenting with acute syndromes due to small
vessel disease, such as ischemic stroke or intraparenchymal hemorrhage,
immediate attention should be paid to preventing irreversible brain injury. From
an acute ischemic stroke standpoint, these efforts should comprise emergent
evaluation for thrombolytic therapy, prevention/minimization of penumbral
loss, and risk factor modification for secondary stroke prevention.

Common Lacunar Stroke Syndromes TABLE 5-4

Lacunar Stroke
Syndrome Clinical Featuresa Neuroanatomic Localization

Pure motor stroke Contralateral hemiparesis, no Corticospinal tract: basis pontis,

sensory symptoms posterior limb of the internal capsule,
corona radiata

Pure sensory stroke Contralateral hemisensory Ventral posterolateral nucleus of the

loss, no motor symptoms thalamus

Mixed sensorimotor Contralateral hemiparesis Thalamocapsular

stroke and hemisensory loss

Dysarthria-clumsy Dysarthria, contralateral Basis pontis, genu of the internal

hand syndrome hand weakness capsule

Ataxic hemiparesis Contralateral hemiparesis, Basis pontis, internal capsule

ataxia of the contralateral
arm and leg

a
Absence of any cortical signs (ie, aphasia, neglect).

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CEREBRAL SMALL VESSEL DISEASE

In the case of intraparenchymal hemorrhage, excluding a vascular

malformation and ongoing bleeding, reversing any coagulopathy, and managing
hypertension are essential. The data on optimal blood pressure in acute ischemic
stroke, however, are mixed, and the current guidelines, therefore, only
recommend avoiding hypotension in patients not treated with thrombolytic
therapy.34 Of note, the capsular warning syndrome is a well-recognized
phenomenon in patients with lacunar stroke whereby “stuttering” or a crescendo
of the severity of neurologic deficits can occur in the early stages of the stroke.35
In patients with minor ischemic stroke, as is often the case with lacunar
strokes, short-term (21-day course recommended when initiated up to 3 days
after stroke) dual antiplatelet therapy with aspirin and clopidogrel is efficacious
for reducing the rate of recurrent ischemic stroke.36,37 Otherwise, antiplatelet
monotherapy in conjunction with medical optimization of any pertinent vascular
risk factors is important for secondary stroke prevention. Emphasizing the
importance of individual vascular risk factor optimization in patients with acute
symptomatic lacunar infarction, the SPS3 (Secondary Prevention of Small
Subcortical Strokes) trial randomly assigned 3020 patients to systolic blood
pressure goals of 130 to 149 mm Hg or <130 mm Hg.7 No difference was observed
in the rates of the primary end point, defined as all strokes; however, recurrent
intraparenchymal hemorrhage was significantly reduced in the intensive blood
pressure arm (hazard ratio, 0.37; 95% confidence interval [CI], 0.15 to 0.95;
P=.03).
In the outpatient setting, the evidence for candidate therapeutic strategies in
small vessel disease is largely based on secondary analyses of randomized
controlled trials of vascular risk factor modification in recurrent stroke
prevention or vascular cognitive impairment, such as the SPS3 trial. Given the
strong association of hypertension with various neuroimaging markers of small
vessel disease, intensive treatment of hypertension has been investigated in
relation to small vessel disease burden. A meta-analysis of four clinical trials of
blood pressure reduction in ischemic stroke secondary prevention found that
blood pressure reduction was associated with less white matter hyperintensity
progression.38 Similarly, a longitudinal study of patients with minor ischemic
stroke demonstrated that approximately one-third of patients had a decreased
white matter hyperintensity burden at 1 year, and those individuals had larger
reductions in blood pressure and fewer recurrent strokes.39 Building on these
observations, the MIND (Memory and Cognition IN Decreased Hypertension)
substudy of SPRINT (Systolic Blood Pressure Intervention Trial), a randomized
controlled trial of 9361 adults with hypertension, reported that intensive blood
pressure treatment (systolic blood pressure <120 mm Hg versus <140 mm Hg)
reduced the risk of developing mild cognitive impairment or probable dementia
(20.2 versus 24.1 cases per 1000 person-years; hazard ratio, 0.85; 95% CI, 0.69 to
0.95).40 Importantly, the SPRINT MIND study was halted prematurely, resulting
in fewer than expected cases of dementia, and the effects of intensive blood
pressure management on neuroimaging markers of small vessel disease have not
yet been reported. As such, intensive treatment of hypertension seems promising
for treatment of small vessel disease; however, future randomized controlled
trials are needed.
The statin family of medications, routinely prescribed for secondary stroke
prevention of ischemic stroke, also has been shown to have some relationship
with white matter hyperintensity burden. In particular, statins have shown a

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signal for potentially slowing the progression of white matter hyperintensities KEY POINTS
after stroke; however, further research is necessary.
● Intensive treatment of
Beyond antihypertensive and statin therapy, based on their promising hypertension seems
mechanism(s) of action, several pharmacologic agents approved for other promising for treatment of
indications either have been previously studied or are in the process of being small vessel disease.
evaluated as therapeutics for small vessel disease. Specifically, various agents
● Given the multifactorial
that improve blood-brain barrier integrity, induce vasodilation, exert anti-
benefits of smoking
inflammatory effects, or reduce endothelial dysfunction have been targeted. cessation, diet, and aerobic
Cilostazol, a phosphodiesterase-3 inhibitor that is frequently used in the exercise in secondary stroke
treatment of peripheral arterial disease, is one example that has appealing effects prevention, these lifestyle
on blood-brain barrier permeability and inflammation. By reducing blood-brain modifications should be
emphasized in all patients
barrier injury and inducing vasodilation, nitric oxide donors are also being with stroke regardless of
evaluated in patients with small vessel disease. The LACI-1 (Lacunar small vessel disease burden.
Intervention Trial-1) is an ongoing phase 2a dose-escalation, prospective,
randomized trial of isosorbide mononitrate and/or cilostazol in patients with
lacunar stroke.41 Secondary aims of LACI-1 include assessing the effects of
isosorbide mononitrate and/or cilostazol on cerebrovascular reactivity, platelet
function, blood pressure, and arterial stiffness. Lastly, a small substudy of the
VITATOPS (VITamins TO Prevent Stroke) trial, which treated patients with
recent stroke or transient ischemic attack with folate, vitamin B6, and
vitamin B12, showed no significant difference in white matter hyperintensity
volume in the overall population (359 patients); however, white matter
hyperintensity burden was reduced with folate/vitamin B6/vitamin B12
supplementation in patients with severe small vessel disease.42
Regarding dietary and lifestyle modifications, smoking/tobacco abuse is a
relatively well-established risk factor for small vessel disease progression.
Conflicting reports on a relationship between aerobic exercise and white
matter hyperintensity burden have been described, with several studies
showing a benefit for aerobic exercise and others showing no change.
Adherence to the Mediterranean diet has also been associated with reduced
white matter hyperintensity burden in a cross-sectional analysis of the
Northern Manhattan Study. Given the multifactorial benefits of smoking
cessation, diet, and aerobic exercise in secondary stroke prevention, these
lifestyle modifications should be emphasized in all stroke patients regardless of
small vessel disease burden.
For patients with cerebral amyloid angiopathy, treatment strategies depend
on the clinical context. In cases of cerebral amyloid angiopathy–related
intraparenchymal hemorrhage, these cases should be managed like other cases
of intraparenchymal hemorrhage. Antiplatelet and anticoagulant agents are
generally avoided in patients with cerebral amyloid angiopathy given the high
risk of recurrent intraparenchymal hemorrhage. However, in patients with prior
intraparenchymal hemorrhage and atrial fibrillation, the data are mixed, and
clinical trials are currently underway exploring the benefit of anticoagulation
with a direct oral anticoagulant in individuals with atrial fibrillation and prior
intraparenchymal hemorrhage. The second tenet of cerebral amyloid angiopathy
management is treatment of hypertension. This is based on several observational
studies and secondary analysis of the PROGRESS (Preventing Strokes by
Lowering Blood Pressure in Patients With Cerebral Ischemia) trial, which
showed lower rates of intraparenchymal hemorrhage recurrence with blood
pressure lowering among patients with cerebral amyloid angiopathy.

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CEREBRAL SMALL VESSEL DISEASE

FUTURE RESEARCH DIRECTIONS

Future research in the field of small vessel disease should emphasize several
important avenues. First, additional investigations into the mechanism(s) of
small vessel disease development, with attention to each of the small vessel
disease subtypes, are necessary and should emphasize the roles of blood-brain
barrier/endothelial dysfunction, inflammation, abnormal cerebral perfusion and
vasoreactivity, and glymphatic system (a macroscopic waste clearance system)
function. Secondly, further longitudinal studies of small vessel disease subtype
progression in relation to detailed assessment of qualitative and quantitative
measures of vascular risk factors will further inform on the mechanisms of small
vessel disease pathogenesis. Lastly, ongoing and future randomized clinical trials
of novel pharmacologic agents targeting purported key pathways in small vessel
disease development are necessary in both poststroke and aging populations with
different outcome measures.

CONCLUSION
Small vessel disease represents a clinically relevant risk factor for various types of
acute and chronic neurologic disease and is associated with a diverse spectrum of
neuroimaging manifestations. Recognition of the clinical significance of small
vessel disease in individuals and the risk that small vessel disease poses for
development of various neurologic diseases represents the first step in caring for
patients with this disease. At present, intensive treatment and optimization of the
modifiable microvascular risk factors, such as hypertension, smoking, and
diabetes mellitus, as well as favorable lifestyle modifications represent the best
approach to preventing secondary complications of small vessel disease. Future
studies of novel pharmacologic agents for treatment of small vessel disease
and its purported mechanism(s) of injury are underway and hold promise for
offering new therapeutic strategies to reduce disability associated with this disease.

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