Illustrative Teaching Case
Section Editors: Sophia Sundararajan, MD, PhD, and Shadi Yaghi, MD
Symptomatic Intracranial Atherosclerosis
With Impaired Distal Perfusion
A Case Study
Katarina Dakay, DO; Shadi Yaghi, MD
Case Description
An 82-year-old woman with a history of hypertension pre-
sented to the emergency department with a 1-week history of
3 episodes of word-finding difficulty and right arm weakness
lasting for a few minutes each without any known triggers or
Downloaded from http://stroke.ahajournals.org/ by guest on January 17, 2018
associated neurological symptoms.
On arrival, her blood pressure was 174/84 mm Hg. Her
general and neurological examination showed mild expres-
sive aphasia. Neuroimaging was immediately undertaken with
computerized tomographic angiogram of the brain and neck,
demonstrating high-grade proximal left M1 stenosis without
cervical artery stenosis (Figure 1). She then underwent mag-
netic resonance imaging (MRI) of the brain with perfusion
imaging with rapid processing of perfusion and diffusion
(RAPID), which demonstrated delayed perfusion in the left
middle cerebral artery territory and small left hemispheric
infarcts (Figure 2, top). She was started on aspirin, clopido-
grel, and high-intensity statin therapy and admitted to the
stroke unit. A transthoracic echocardiogram was unremark-
able, her glycosylated hemoglobin was 5.7%, and low-density
lipoprotein was 131 mg/dL. Her stroke was attributed to intra-
cranial atherosclerosis. She was discharged on dual antiplate-
let therapy and high-intensity statin therapy with persistent
mild expressive aphasia.
Two weeks after discharge, she represented with right
hemiplegia and severe near-global aphasia. Her blood pressure
was 130/82 mm Hg. Computerized tomographic angiogram of
the head and neck was stable. A repeat brain MRI with RAPID
showed expansion of infarcts to involve the left corona radiata
(Figure 2, bottom). Because of the large hypoperfused penum-
bra on MRI and suspected pressure-dependent examination,
decision was made to augment cerebral blood flow, and she
was placed on norepinephrine with a goal of systolic blood
pressure >180 mm Hg, which led to regaining of speech; how-
ever, her right hemiplegia persisted. She was then started on
oral midodrine and fludrocortisone, her home blood pressure
medications were held, and she was slowly weaned off nor-
epinephrine after 48 hours. During her hospital stay, her blood
pressure goal was initially liberalized to 160 to 180 mm Hg
Received September 19, 2017; final revision received October 19, 2017; accepted October 20, 2017.
From the Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI.
Correspondence to Shadi Yaghi, MD, Department of Neurology, Warren Alpert Medical School of Brown University, 353 Eddy St, APC 530, Providence,
RI 02903. E-mail shadiyaghi@yahoo.com
(Stroke. 2018;49:e10-e13. DOI: 10.1161/STROKEAHA.117.019173.)
© 2017 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
e10
systolic and then 140 to 160 mm Hg systolic. Her examination
subsequently stabilized after 1 week with mild-to-moderate
global aphasia and severe right hemiparesis. Follow-up brain
MRI RAPID showed improvement in the perfusion deficit
(Figure 2), and she was discharged to a skilled nursing facility.
On discharge, her blood pressure goal was liberalized to nor-
motension with a goal of ≤140 mm Hg systolic. The patient’s
recurrent symptoms were felt to be attributable to a pressure-
dependent examination, often referred to as misery perfusion.
Discussion
Intracranial atherosclerotic disease (ICAD) is an important
stroke mechanism, accounting for 9% to 17% of all strokes.1
Certain demographic and clinical factors predispose to intra-
cranial atherosclerosis; the incidence seems to be the highest
in blacks and those of Asian descent, with whites having the
lowest incidence. Additionally, hypertension, diabetes melli-
tus, hyperlipidemia, and age are associated with the risk of
developing ICAD. Angiography is considered the gold stan-
dard for diagnosis of ICAD; however, noninvasive tests, such
as computerized tomographic angiography, magnetic reso-
nance angiography, and transcranial Doppler ultrasound, are
often used.1
ICAD can cause strokes by way of 3 mechanisms:
artery-to-artery embolism, flow failure or hypoperfusion,
and branch-atheromatous disease; of these, artery-to-artery
embolism seems to be the most common.2 Studies have
shown a relatively high risk of recurrent cerebrovascular
events in patients with symptomatic ICAD. The SAMMPRIS
study (Stenting Versus Aggressive Medical Management for
Preventing Recurrent Stroke in Intracranial Stenosis) showed
that the risk of recurrent events is ≈12% at 1 year and 20%
at 2 years from the initial event.3 However, the SAMMPRIS
trial excluded patients with worsening deficits during the 24
hours preceding stent placement. So it did not address the
subpopulation of patients with worsening neurological symp-
toms, despite medical therapy, such as our patient during her
second admission. Other studies have shown that the highest
risk of recurrence or worsening in patients with intracranial or
DOI: 10.1161/STROKEAHA.117.019173
 Dakay and Yaghi   A Patient With a Left M1 Stenosis   e11
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Figure 1. Computed tomographic angiogram demonstrates criti-
cal left proximal middle cerebral artery (M1) stenosis.
extracranial large-vessel atherosclerotic disease is in the first
few days after the initial event.4,5
Perfusion-based imaging has been recently used to aid
with acute stroke treatment decisions in patients with emer-
gent proximal large-vessel anterior circulation intracranial
occlusion. At our institution, we use RAPID—a software,
which computes quantitative perfusion maps and can calcu-
late the ratio of ischemic infarct on diffusion weighted imag-
ing to the hypoperfused penumbra.6 Recent data demonstrates
the benefit from mechanical thrombectomy using perfusion-
based imaging selection with RAPID software beyond 6 hours
from symptom onset.7 This may also be the case in patients
with ICAD where there has been increased use of perfusion
imaging to predict stroke risk with a recent study showing an
increased risk of recurrent stroke in patients with impaired
distal blood flow.8 In addition to perfusion, 1 study demon-
strated that absent or poor collaterals portended a high risk of
stroke recurrence rate, whereas rapid filling of collateral ves-
sels was relatively protective against stroke recurrence.9
To date, aggressive medical treatment with antiplate-
let agents, statins, and risk-factor modification remains the
treatment of choice for patients with symptomatic ICAD.1
Aggressive medical treatment, however, may help stabilize
atherosclerotic plaques and reduce the risk of embolization,
but it is unlikely to significantly and acutely improve blood
flow to tissue at risk and prevent neurological deterioration.
In fact, impaired distal blood flow detected by noninvasive
imaging has been shown to predict stroke risk in patients with
extracranial and ICAD, despite medical therapy.8
Hence, patients with symptomatic ICAD and impaired
blood flow remain a therapeutically challenging subgroup.
Although small trials and case reports have demonstrated
the clinical phenomenon of vasopressor-responsive flow
failure, there are no randomized clinical trials studying this
phenomenon.10 Given that pressure dependence is theoreti-
cally predicated on the presence of a penumbra, it is possible
that the widespread implementation of perfusion imaging
may help identify patients in whom a higher blood pressure
target may be beneficial. Induced hypertension, however, is
not an ideal treatment because the duration and blood pres-
sure target are widely variable among patients and there are
potential significant adverse events from prolonged use of
vasopressors. In the SAMMPRIS trial, blood pressure lower-
ing appeared to be safe and was included as part of the medi-
cal management arm.
Furthermore, patients with symptomatic ICAD and
unfavorable perfusion may benefit from revascularization
therapy beyond aggressive medical management alone. This
has already been suggested regarding treatment of extracra-
nial large-artery stenosis in a pooled analysis of completed
randomized trials of carotid endarterectomy. In patients with
ICAD, the 2 prior randomized trials that assessed interven-
tions for intracranial atherosclerotic stenosis, SAMMPRIS3
and VISSIT (Vitesse Intracranial Stent Study on Ischemic
Therapy),11 did not select patients based on perfusion status.
In SAMMPRIS, the periprocedural complication rate was
≈15% in the first 30 days. Recently, results from the WEAVE
(Wingspan Stent System Post Market Surveillance Study) reg-
istry of symptomatic ICAD showed a relatively low risk of
periprocedural complications (≈5% at 30 days) with stenting
when compared with the reported rates in the SAMMPRIS
study (NCT02034058). The authors attribute this to increased
operator experience with the device and perhaps because
of a submaximal angioplasty alone strategy. Because of the
high recurrence risk in patients with symptomatic ICAD
and impaired perfusion, these patients may be a distinctive
group in whom the safety of revascularization and reperfu-
sion against the risk of neurological deterioration in medically
treated patients may be studied.
In addition to endovascular treatment, surgical revas-
cularization by way of external carotid to internal carotid
bypass through connecting the superficial temporal artery
to the middle cerebral artery has been studied but failed to
benefit patients with severe middle cerebral artery stenosis.12
More recent studies have explored indirect bypass by way
of encephaloduroarteriosynangiosis, wherein the superficial
temporal artery is transposed directly onto the brain, allow-
ing it to form collaterals. Preliminary studies of this proce-
dure in patients with moyamoya have been more promising
than with atherosclerotic disease, where small prospective
trials have shown no benefit.13,14
Our patient had minor neurological symptoms but had
evidence of impaired distal blood flow on the initial brain
MRI RAPID and exhibited neurological deterioration, despite
aggressive medical treatment. Clinical trials investigating the
safety of reperfusion treatment in this patient population are
needed with an ultimate goal to reduce the risk of neurologi-
cal deterioration in patients with symptomatic ICAD causing
impaired distal blood flow.
 e12  Stroke  January 2018
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Figure 2. The patient’s sequential rapid processing of perfusion and diffusion (RAPID) magnetic resonance imaging (MRI) demonstrates
the evolution of the perfusion deficit. The top of the figure shows the initial RAPID MRI with punctate left hemispheric infarcts and
delayed perfusion in the left middle cerebral artery territory with 61-mL volume of brain tissue with T max >6-s delay. Middle of figure
shows second RAPID MRI with infarct expansion and 61-mL volume of brain tissue with T max >6-s delay. The bottom of the figure
shows the last RAPID MRI after blood pressure augmentation showing stable left hemispheric infarcts without areas of brain tissue with
T max >6-s delay. ADC indicates apparent diffusion coefficient.
 Dakay and Yaghi   A Patient With a Left M1 Stenosis   e13
TAKE-HOME POINTS
• Intracranial atherosclerosis can cause stroke by
artery-to-artery embolism, branch artery atheroscle-
rosis, or hypoperfusion.
• Stenting is not routinely recommended for symptom-
atic intracranial atherosclerosis because of increased
risk of stroke compared with medical management.
• Antiplatelet therapy, blood pressure control, and
treatment of hyperlipidemia are recommended for
intracranial atherosclerosis.
• A small subset of patients with severe intracranial
stenosis may demonstrate pressure dependence or
deterioration with lowering of blood pressure beyond
a threshold value.
• Pressure dependence can be demonstrated clinically
and is treated with augmentation of blood pressure
until it can be weaned without deterioration.
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• Clinical trials investigating the safety of reperfusion
treatment in this patient population are needed with
an ultimate goal to reduce the risk of neurological
deterioration in patients with symptomatic intracra-
nial atherosclerotic disease causing impaired distal
blood flow.
Disclosures
None.
Acknowledgments
K. Dakay contributed in the preparation of manuscript and literature
review and Dr Yaghi in preparation of manuscript, literature review,
and critical review.
References
1. Banerjee C, Chimowitz MI. Stroke caused by atherosclerosis of the
major intracranial arteries. Circ Res. 2017;120:502–513. doi: 10.1161/
CIRCRESAHA.116.308441.
2. López-Cancio E, Matheus MG, Romano JG, Liebeskind DS,
Prabhakaran S, Turan TN, et al. Infarct patterns, collaterals and likely
causative mechanisms of stroke in symptomatic intracranial atheroscle-
rosis. Cerebrovasc Dis. 2014;37:417–422. doi: 10.1159/000362922.
3. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, et
al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical
therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993–
1003. doi: 10.1056/NEJMoa1105335.
4. Yaghi S, Rostanski SK, Boehme AK, Martin-Schild S, Samai A, Silver
B, et al. Imaging Parameters and recurrent cerebrovascular events in
patients with minor stroke or transient ischemic attack. JAMA Neurol.
2016;73:572–578. doi: 10.1001/jamaneurol.2015.4906.
5. Sangha RS, Naidech AM, Corado C, Ansari SA, Prabhakaran S.
Challenges in the medical management of symptomatic intracranial
stenosis in an urban setting. Stroke. 2017;48:2158–2163. doi: 10.1161/
STROKEAHA.116.016254.
6. Straka M, Albers GW, Bammer R. Real-time diffusion-perfusion mis-
match analysis in acute stroke. J Magn Reson Imaging. 2010;32:1024–
1037. doi: 10.1002/jmri.22338.
7. McTaggart RA, Yaghi S, Sacchetti DC, Haas RA, Hemendinger M,
Arcuri D, et al. Mechanical embolectomy for acute ischemic stroke
beyond six hours from symptom onset using MRI based perfusion imag-
ing. J Neurol Sci. 2017;375:395–400. doi: 10.1016/j.jns.2017.02.044.
8. Amin-Hanjani S, Pandey DK, Rose-Finnell L, Du X, Richardson
D, Thulborn KR, et al; Vertebrobasilar Flow Evaluation and Risk of
Transient Ischemic Attack and Stroke Study Group. Effect of hemo-
dynamics on stroke risk in symptomatic atherosclerotic vertebrobasi-
lar occlusive disease. JAMA Neurol. 2016;73:178–185. doi: 10.1001/
jamaneurol.2015.3772.
9. Liebeskind DS, Cotsonis GA, Saver JL, Lynn MJ, Turan TN, Cloft HJ,
et al; Warfarin-Aspirin Symptomatic Intracranial Disease (WASID)
Investigators. Collaterals dramatically alter stroke risk in intracranial
atherosclerosis. Ann Neurol. 2011;69:963–974. doi: 10.1002/ana.22354.
10. Regenhardt RW, Das AS, Stapleton CJ, Chandra RV, Rabinov JD,
Patel AB, et al. Blood pressure and penumbral sustenance in stroke
from large vessel occlusion. Front Neurol. 2017;8:317. doi: 10.3389/
fneur.2017.00317.
11. Zaidat OO, Fitzsimmons BF, Woodward BK, Wang Z, Killer-
Oberpfalzer M, Wakhloo A, et al; VISSIT Trial Investigators. Effect of
a balloon-expandable intracranial stent vs medical therapy on risk of
stroke in patients with symptomatic intracranial stenosis: the VISSIT
randomized clinical trial. JAMA. 2015;313:1240–1248. doi: 10.1001/
jama.2015.1693.
12. EC/IC Bypass Study Group. Failure of extracranial-intracranial arterial
bypass to reduce the risk of ischemic stroke. Results of an international
randomized trial. The N Engl J Med. 1985;313:1191–1200.
13. Komotar RJ, Starke RM, Otten ML, Merkow MB, Garrett MC, Marshall
RS, et al. The role of indirect extracranial-intracranial bypass in the treat-
ment of symptomatic intracranial atheroocclusive disease. J Neurosurg.
2009;110:896–904. doi: 10.3171/2008.9.JNS17658.
14. Agarwalla PK, Stapleton CJ, Phillips MT, Walcott BP, Venteicher
AS, Ogilvy CS. Surgical outcomes following encephaloduroarterio-
synangiosis in North American adults with moyamoya. J Neurosurg.
2014;121:1394–1400. doi: 10.3171/2014.8.JNS132176.
KEY WORDS: aspirin ◼ blood pressure ◼ humans ◼ hypertension ◼ troponin
 Symptomatic Intracranial Atherosclerosis With Impaired Distal Perfusion: A Case Study
Katarina Dakay and Shadi Yaghi

Stroke. 2018;49:e10-e13; originally published online November 22, 2017;

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doi: 10.1161/STROKEAHA.117.019173
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