Intracranial Atherosclerosis

Current Concepts
Juan F. Arenillas, MD, PhD

AbstractThe most relevant ideas discussed in this article are described here. Intracranial atherosclerotic disease (ICAD)
represents the most common cause of ischemic stroke worldwide. Its importance in whites may have been
underestimated. New technical developments, such as high-resolution MRI, allow direct assessment of the intracranial
atherosclerotic plaque, which may have a profound impact on ICAD diagnosis and therapy in the near future. Early
detection of ICAD may allow therapeutic intervention while the disease is still asymptomatic. The Barcelones Nord and
Maresme Asymptomatic Intracranial Atherosclerosis Study is presented here. The main prognostic factors that
characterize the patients who are at a higher risk for ICAD recurrence are classified and discussed. The best treatment
for ICAD remains to be established. The Stenting Versus Aggressive Medical Management for Preventing Recurrent
Stroke in Intracranial Stenosis Study is currently ongoing to address this crucial issue. These and other topics will be
discussed at the Fifth International Intracranial Atherosclerosis Conference (Valladolid, Spain, autumn 2011). (Stroke.
2011;42[suppl 1]:S20-S23.)
Key Words: acute stroke intracranial stenosis intracranial atherosclerotic disease prevention treatment

Intracranial Atherosclerotic Disease: A Major
Cause of Stroke
Intracranial atherosclerotic disease (ICAD) is characterized
by the development, progression, and complication of athero-
sclerotic lesions affecting intracranial large arteries. ICAD
represents the most common cause of ischemic stroke among
patients of Asian ancestry.1,2 Moreover, atherosclerosis is
also more prone to affect intracranial compared with extracra-
nial arteries in Hispanics and Africans.3 Thus, it has been
claimed that ICAD may be the most common cause of stroke
worldwide.4 Accordingly, as shown in the Figure, ICAD has
become a rapidly evolving research field in the last 2 decades.
ICAD may account for 8% to 10% of all ischemic strokes
in whites.3,5 Nevertheless, the real impact of ICAD on whites
may be greater than expected. A study conducted by a French
group in 339 autopsies of patients who died because of an
ischemic or hemorrhagic stroke showed a strikingly high
prevalence of both intracranial plaques and intracranial ste-
noses.6 As will be discussed later on, intracranial stenosis
represents only the most advanced stage of ICAD, and, as
suggested by this work, nonstenotic ICAD may turn to be
much more common than stenotic ICAD.
Intracranial Atherosclerotic Plaque Imaging
Our traditional understanding of ICAD is based on the
detection of hemodynamically relevant intracranial stenoses.
The main limitations of this approach are as follows: (1) it
may be restricted to the most advanced stage of ICAD alone;
(2) it is unable to differentiate atherostenoses from stenoses
caused by other entities; and (3) it may not be able to provide
information about the histopathologic composition and activ-
ity of the intracranial atherosclerotic plaque. This last point
seems extremely relevant, because symptomatic intracranial
atherosclerotic plaques are characterized not only by a higher
degree of luminal stenosis but also by a richer content in lipid,
intraplaque hemorrhage and inflammatory cell infiltration, all
of which are well-known determinants of plaque instability in
the extracranial vasculature.7
In contrast to this classical approach to ICAD, newer
technical developments, such as high-resolution MRI and
intravascular ultrasound, allow direct assessment of intracra-
nial atherosclerotic plaques. The main implications of this
focus on intracranial atherosclerotic plaque imaging are
shown in Table 1. This new concept could have a dramatic
impact on the way we will diagnose and treat ICAD in the
near future. For instance, intravascular ultrasound has shown
intraplaque hemorrhage in vivo in symptomatic ICAD, a
finding that supports the hypothesis that intracranial athero-
sclerotic plaques can become symptomatic after complication
by intraplaque hemorrhage analogous to coronary artery
plaques.8 In line with this observation, 3T high-resolution
MRI direct thrombus imaging also allows characterization of
intraplaque hemorrhage in vivo and identification of other

Received July 17, 2010; accepted August 24, 2010.

From the Stroke Unit, Department of Neurology, Hospital Clnico Universitario, Valladolid, Spain.
This article is based on a presentation held by the author at the symposium, Recent Developments and Future Directions in Stroke Management and
Prevention, which took place in Barcelona, Spain, on May 25, 2010, during the European Stroke Conference.
Correspondence to Juan F. Arenillas, Stroke Unit, Department of Neurology, Hospital Clnico Universitario Valladolid, Avda Ramon y Cajal 3, 47003
Valladolid, Spain. E-mail juanfarenillas@gmail.com
2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.110.597278

S20
 Arenillas Intracranial Atherosclerosis S21

Table 1. New Concept: Intracranial Atherosclerotic

Plaque Imaging
Traditional: Angiographic and New Concept: Intracranial
Hemodynamic Assessment Plaque Imaging
Transcranial Doppler and duplex; High-resolution MRI, high
magnetic resonance angiography; magnetic field (3T) preferable;
computed tomography angiography intravascular ultrasound
Identification and gradation of Imaging and characterization of
intracranial stenosis intracranial atherosclerotic plaque
Diagnosis of advanced (stenotic) Allows detection of nonstenotic
ICAD intracranial atheroma
Useful in clinical decision May help establish the role of
making in patients with nonstenotic intracranial atheroma
symptomatic ICAD in stroke of undetermined origin
Figure. Intracranial stenosis: articles published. The growing
interest in intracranial atherosclerotic disease is illustrated on Detects intracranial stenoses of May have the power to confirm
this bar diagram. Bars represent the number of articles pub- different histopathological nature the atherosclerotic nature of
lished in the English literature from 1985 to nowadays by every (including partially recanalized intracranial stenoses
5-year period. Medline search terms: intracranial stenosis. Lim- emboli)
its: English.
Unable to directly assess Able to detect intraplaque
plaque instability; microembolic hemorrhage and other
components within the atherosclerotic plaque. Moreover,
9
signal detection as surrogate characteristics of unstable
high-resolution MRI could provide surrogate markers of marker plaques
atherosclerotic plaque activity in vivo, thereby leading to Noninvasive; widely available; Noninvasive; less available; still
improvements in risk stratification and treatment of ICAD. rapid disposal of clinically limited clinical value; requires
Finally, direct plaque imaging may allow detection of nonste- valuable images extensive postprocessing
notic plaques affecting intracranial arteries missed by mag- Allows assessment of May allow monitoring of
netic resonance angiography as the probable cause of brain intracranial stenosis progression atherosclerotic plaque dynamics
infarctions of undetermined origin.10 and in-stent restenosis and help guide therapy (medical
vs endovascular)
Primary Prevention: Asymptomatic ICAD Data are in contrast with our traditional view of ICAD based on the detection
Atherosclerotic lesions develop silently over years until they of intracranial stenosis.
suddenly become symptomatic. Therefore, early detection of
ICAD may allow therapeutic intervention while the disease is determined by means of transcranial color-coded Duplex and
still asymptomatic. However, the natural history of asymp- subsequent MR angiography confirmation. Preliminary re-
tomatic ICAD is still largely unknown, especially in whites. sults were presented at the 2009 International Stroke Confer-
In this setting, several transcranial Doppler studies in an ence, showing a prevalence of asymptomatic ICAD of 9% in
asymptomatic population have been conducted in Asia.1113 the first 157 subjects studied. Recruitment took place from
The prevalence of asymptomatic intracranial stenosis ranged March 2007 until June 2010.
from 5.9% to 24.5%. Age, hypertension, and diabetes melli-
tus emerged as the most relevant factors associated with Symptomatic ICAD: New Predictors
asymptomatic ICAD, and interestingly the odds ratio for of Recurrence
hypertension was higher than the one for diabetes mellitus in Symptomatic ICAD is burdened with a high clinical recurrence
the Chinese studies. rate. The annual recurrence rates for any ischemic stroke
To clarify the prevalence and natural history of asymptom- reported in the Warfarin-Aspirin Symptomatic Intracranial Dis-
atic ICAD in whites, we designed a population-based study in ease (WASID) Trial were as high as 15% and 14% in the aspirin
the metropolitan area of Barcelona, the Barcelones Nord and and warfarin arms, respectively.15 Moreover, most subsequent
Maresme Asymptomatic Intracranial Atherosclerosis Study.14 strokes in patients with symptomatic intracranial artery stenosis
The main aims of the Barcelones Nord and Maresme Asymp- occurred in the same arterial territory, were nonlacunar, and
tomatic Intracranial Atherosclerosis Study are as follows: (1) nearly half of them were disabling.16 Therefore, it seems
to determine the prevalence of asymptomatic ICAD in a crucial to identify those prognostic factors that characterize
moderate-high vascular risk population; (2) to study its high-risk patients to stratify preventive therapies. These
prognostic impact on the risk of experiencing future major prognostic factors could be classified in 2 main categories,
ischemic events; and (3) to identify clinical, biological, and local factors that confer vulnerability to the intracranial
genetic predictors of the development, progression, and atherosclerotic plaque itself (vulnerable intracranial stenosis)
clinical expression of this condition. Study subjects were and systemic factors and basic pathways that render the
obtained from an initial sample of 1503 individuals randomly patient more prone to ICAD recurrence (vulnerable patient).17
selected from a population of 600 000 inhabitants. Main entry Probably the latest contributions in this field, not collected in
criteria were age 50 years, no past history of cerebrovas- the referred book chapter, are the observation of racial
cular or ischemic heart disease, and moderate-to-high vascu- differences in recurrence risk in the WASID cohort, with
lar risk. Presence and severity of intracranial stenoses were black patients having a higher risk than whites,18 and the
S22 Stroke January 2011

Table 2. Main Predictors of ICAD Recurrence
Vulnerable Intracranial Stenosis
Severity of intracranial stenosis
(70% lumen reduction)
Concomitant intracranial and
extracranial stenosis
Disease extent: No. of intracranial
stenoses
Symptomatic vs asymptomatic
intracranial stenosis
Progression of intracranial
stenoses
Intracranial stenosis causing
hemodynamic compromise
Detection of microembolic signals
Composition of atherosclerotic
plaque: inflammation, lipid core,
neovascularization, intraplaque
hemorrhage
Vulnerable ICAD Patient
Diabetes mellitus associated with
greater ICAD extent in whites
Deficient vascular risk factor
control
Metabolic syndrome and insulin
resistance may have a greater
effect on intracranial vs
extracranial athero
Sex: women (WASID)
Race: black (WASID)
Failure of antithrombotic therapy
Inflammation: leukocyte count,
C-reactive protein, adhesion
molecules
Endogenous fibrinolysis
inhibitors: high plasminogen
activator inhibitor 1
Inhibited endogenous angiogenic
response
Genetic factors: C-reactive
protein gene C1444T
polymorphism
early recurrence risk remains to be proven.24 The trial of
Cilostazol-Aspirin Therapy Against Recurrent Stroke With
Intracranial Artery Stenosis is currently ongoing to test
whether combined cilostazol-aspirin therapy is superior to
aspirin alone in the prevention of recurrent stroke in symp-
tomatic ICAD. Previously, the multicenter double-blind,
placebo-controlled Trial of Cilostazol in Symptomatic Intra-
cranial Arterial Stenosis showed that progression of symp-
tomatic intracranial stenosis was significantly lower in the
cilostazol-plus-aspirin group versus in the placebo-plus-
aspirin group.25
Continuous progress in intracranial angioplasty and stent-
ing has led to high rates of technical success. However, as has
been reviewed extensively, adverse event rates vary widely,
in-stent restenosis is common, and the impact of stent devices
on long-term outcome has not been clarified.26 To address
this critical issue, the Stenting Versus Aggressive Medical
Management for Preventing Recurrent Stroke in Intracranial
Stenosis (www.clinicaltrials.gov) is currently ongoing.
In conclusion, ICAD is the most common cause of ische-
mic stroke worldwide, but its optimal treatment has not been
established. ICAD has become a fascinating and rapidly
evolving research field, with relevant advances in basic
mechanisms, imaging, and treatment. These and other topics
will be discussed at the Fifth International Conference on
Intracranial Atherosclerosis, which will be held in Valladolid
in autumn 2011.

description of an association between a common polymorphism Sources of Funding

in the C-reactive protein gene and a higher recurrence risk.19
Table 2 summarizes ICAD prognostic factors.
Symptomatic ICAD: Best Treatment
The optimal preventive therapy for symptomatic ICAD re-
mains yet to be clarified. Although the WASID Trial was not
designed to evaluate the importance of risk factor control in
symptomatic ICAD, the results of some WASID substudies
strongly suggest that this stroke subgroup may benefit from
aggressive risk factor management.20 Contrary to what had
been postulated classically, the lower the blood pressure
values are kept during follow-up, the more reduced is the
recurrence risk.21 Regarding lipid management, it remains
controversial whether ICAD patients may benefit from in-
tense low-density lipoprotein cholesterol reduction, as shown
by the Stroke Prevention by Aggressive Reduction in Cho-
lesterol Levels Study, because the location of the symptom-
atic vessel was not assessed in the that study.22 Moreover, a
recent study failed to show a beneficial effect of 20 mg of
simvastatin daily on the evolution of asymptomatic middle
cerebral artery stenosis over 2 years.23 Given this profound
impact of risk factor control, the benefit of future therapies
for this disease should be proven on top of optimal risk factor
management.
Following the results of the WASID Trial, antiplatelets are
the antithrombotic drug of choice for ICAD patients. Recent
studies have shown that double antiplatelet therapy is more
effective than single therapy in reducing microembolic sig-
nals caused by a symptomatic intracranial stenosis, but the
clinical benefit of this association in terms of diminishing
The Barcelons Nord and Maresme Intracranial Atherosclerosis
Study was founded by a grant by the Spanish Ministry of Health and
Social Policy (FIS PI07/0393).
Disclosures
J.F.A. received an honorarium from Ferrer Grupo in concept of this
lecture.
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