Stroke in Asia Book 3

TBC
STROKE IN ASIA
E D I T E D B Y SUWANWELA AND NAVARRO

ASIAN STROKE ADVISORY PANEL
EDITED BY
NIJASRI C. SUWANWELA
JOSE C. NAVARRO
STROKE IN ASIA
EDITION
SECOND
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www.wiley.com
978-4-939028-28-1 SECOND EDITION

Stroke management for Asian patients
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0003172485.INDD 2 8/21/2017 11:39:30 AM
Stroke management
for Asian patients
EDITED BY
Nijasri C. Suwanwela, MD
Division of Neurology, Department of Medicine
Faculty of Medicine, Chulalongkorn University
Bangkok, Thailand
Jose C. Navarro, MD, MSc

Institute of Neurosciences
St. Luke’s Medical Center, José R. Reyes Memorial Medical Center
University of Santo Tomas
Manila, Philippines
0003172485.INDD 3 8/21/2017 11:39:31 AM

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Library of Congress Cataloging‐in‐Publication Data
PB: 978-4-939028-28-1
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1 2017
0003172485.INDD 4 8/21/2017 11:39:31 AM

Contents
Foreword, vii
Authors, ix
Asian stroke advisory panel members, xii
PART I Acute ischemic stroke management and complications

1 Multimodality imaging in acute stroke, 3
Byung‐Woo Yoon, Han‐Yeong Jeong, and Chang Hui-Meng
2 Intravenous thrombolysis and endovascular treatment, 22
Nijasri C. Suwanwela and Nguyen Huy Thang
3 General management of stroke, 31
Kazuo Minematsu and Deepak Arjundas
4 The stroke unit, 39
Jose C. Navarro and Jeyaraj D. Pandian
5 Antithrombotics for acute stroke, 50
Tsong‐Hai Lee and Hou‐Chang Chiu
6 Acute surgical interventions in stroke, 58
Chang Hui‐Meng and Joseph Erroll V. Navarro
7 Acute complications after stroke, 78
Sardar M. Alam and Jose C. Navarro
PART II Long term stroke care and complications

8 Risk factor management for primary and secondary stroke
prevention, 91
Kay-Sin Tan and Ester S. Bitanga
9 The role of antiplatelets for stroke prevention, 107
Xinyi Leng, Nijasri C. Suwanwela, and Lawrence K.S. Wong
10 The role of anticoagulants for stroke prevention in atrial fibrillation, 116
Eun‐Jae Lee and Sun U. Kwon
11 Stroke rehabilitation, 124
Yohanna Kusuma and Lyna Soertidewi Kiemas
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vi Contents
12 Alternative and complementary treatments for stroke, 139

N. Venketasubramanian Ramani and Jeyaraj D. Pandian
13 Stroke‐related dementia, 152
Shinichiro Uchiyama and N. Venketasubramanian Ramani
14 Central nervous system infections and stroke in Asia, 170
Jeyaraj D. Pandian and Nijasri C. Suwanwela
Index, 187
ftoc.indd 6 08/25/2017 11:04:43 AM

Foreword
More than half the world’s population resides in Asia. The region also contains
many of the most dynamic economies, which are directing increasing proportions
of their gross domestic product toward improving health outcomes. As the
leading cause of death in many parts of Asia, stroke therefore attracts more
attention than most because of its unacceptable burden upon societies and
families. The volume edited by Nijasri Suwanwela and Jose Navarro is therefore
timely, as is its focus on treatment given the burgeoning number of proven inter-
ventions that have been introduced over the last few decades.
There have always been quite specific issues in stroke management pertain-
ing to Asia. We know that hemorrhagic stroke is more common in Asia com-
pared to other parts of the world and therefore deserves attention in terms of
prevention and management post event. Intracranial atherosclerosis is also more
common in this region with less emphasis on extracranial vascular disease as a
cause of stroke. Hence, an understanding of its epidemiology and most of the
experience in managing this condition comes from Asia. Unfortunately
rheumatic valvular disease also continues to be prevalent in Asian societies and
contributes to the burden of embolic stroke. These quite singular Asian stroke
issues have always extended to their specific management. It was no accident
that many of the most important clinical trials that have established management
strategies around blood pressure lowering, thrombolytic agents, and antiplatelet
usage have been conducted largely in Asia or at least have benefited from
significant contributions from this region. These include studies of blood p ressure
lowering such as PROGRESS and ENCHANTED and use of low‐dose thrombolytic
therapy also in the latter.
Notably, the use of cilostazol as an effective antiplatelet agent for secondary
stroke prevention was pioneered in Asia.
The emergence of dynamic groups and organizations such as the Asian Stroke
Advisory Panel (ASAP) which led to the publication of Stroke in Asia and now its
natural complementary volume, Stroke Management for Asian Patients, reflects the
enormous advances in our understanding of stroke and its management in both
Asia and elsewhere. The recent formation of the Asia‐Pacific Stroke Organisation
(APSO) as the major Asian professional body now balances similar organizations
in other continents under the umbrella of the World Stroke Organization. The
APSO Annual Scientific Meeting promises to be one of the major stroke
gatherings on the global calendar in the years to come.
vii
0003172487.INDD 7 08/25/2017 11:33:33 AM

viii Foreword
This volume covers all aspects of stroke management from prevention

through to acute management and rehabilitation. The contributions are
extremely readable and reflect the distinguished array of authors from most
regions of Asia. Overall, the book represents the energy, quality, and commit-
ment of those leading the critical task of managing one of the most important
conditions in Asia today. It is a pleasure to introduce this volume to you and
recommend it to all those involved in the modern multidisciplinary teams
managing stroke today.
Geoffrey A. Donnan
Past‐President, World Stroke Organization
Director, The Florey Institute of Neuroscience and Mental Health
Melbourne, Australia
0003172487.INDD 8 08/25/2017 11:33:33 AM

Authors
Editors in‐chief
Sardar M. Alam, FRCP (Edin)

Consultant Neurologist
Northwest General Hospital & Research Centre
Hayatabad, Peshawar, Pakistan
Deepak Arjundas, MD, DM

Senior Consultant Neurologist and Stroke Specialist
Mercure Hospital, Vijaya Hospital, and Apollo Hospital
Chennai, Tamil Nadu, India
Ester S. Bitanga, MD, FPNA

Senior Consultant Neurologist
Department of Neurology
The Medical City
Ortigas Avenue, Pasig City
Philippines
Chang Hui-Meng, MD
Senior Consultant, Department of Neurology
National Neuroscience Institute, Singapore General Hospital campus
Adjunct Associate Professor, Duke‐NUS Graduate Medical School
Hou‐Chang Chiu, MD
Professor of Medicine
Department of Neurology, Shin‐Kong WHS Memorial Hospital
College of Medicine, Fu‐Jen Catholic University
Taipei, Taiwan
Han‐Yeong Jeong
Lyna Soertidewi Kiemas, MD

Medical Board Chairman,
National Brain Centre, Jakarta,
Indonesia
Yohanna Kusuma, MD, Cert. Neurosonology ASN(USA)& WFN‐NSRG

Head of Neurosonology and Acute Stroke Service
National Brain Centre (Rumah Sakit Pusat Otak Nasional)
Jakarta, Indonesia
ix
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x Authors
Sun U. Kwon, MD, PhD

Professor
Department of Neurology, University of Ulsan College of Medicine
Seoul, Korea
Eun‐Jae Lee, MD, PhD

Professor
Department of Neurology, University of Ulsan College of Medicine
Seoul, Korea
Tsong‐Hai Lee, MD, PhD

Professor of Neurology
Stroke Center and Department of Neurology, Linkou Chang Gung Memorial Hospital
College of Medicine, Chang Gung University
Taoyuan, Taiwan
Xinyi Leng, MBBS, MMed, PhD

Research Assistant Professor
Department of Medicine & Therapeutics, The Chinese University of Hong Kong
The Prince of Wales Hospital
Shatin, Hong Kong SAR, China
Kazuo Minematsu, MD, PhD

Director‐General of the Hospital
National Cerebral and Cardiovascular Center
National Cardiovascular Center
Osaka, Japan

Institute of Neurosciences
St. Luke’s Medical Center, José R. Reyes Memorial Medical Center
Manila, Philippines
Joseph Erroll V. Navarro, MD, FAFN

Chief‐of‐Section, Neurosurgery and Spine services
José R. Reyes Memorial Medical Center
Clinical Consultant, Section of Neurosurgery
Manila, Philippines
Jeyaraj D. Pandian, MD, DM, FRACP

Professor and Head
Department of Neurology, Head of Research
Betty Cowan Research & Innovation Centre, Christian Medical College
Ludhiana Punjab, India
0003172487.INDD 10 08/25/2017 11:33:33 AM

Authors xi
N. Venketasubramanian Ramani, MBBS, MMed, FAMS, Cert Neurosonology,

MSc, DLSHTM, MHlthSci, FRCP
Consultant Neurologist
Raffles Neuroscience Centre, Raffles Hospital
Singapore
Faculty of Medicine
Chulalongkorn University
Bangkok, Thailand
Kay-Sin Tan, MBBS, FRCP, FAMM

Professor and Senior Consultant Neurologist
Division of Neurology, Department of Medicine, Faculty of Medicine
University of Malaysia
Kuala Lumpur, Malaysia
Nguyen Huy Thang, MD

Senior Stroke Consultant
The People’s 115 Hospital General
Secretary of Vietnam Stroke Association
Ho Chi Minh City, Vietnam
Shinichiro Uchiyama, MD, PhD, FAHA, FESO

Professor, Clinical Research Center for Medicine
International University of Health and Welfare
Director, Center for Brain and Cerebral Vessels
Sanno Hospital and Sanno Medical Center
Tokyo, Japan
Lawrence K.S. Wong, MBBS, MHA, MD, MRCP, FHKAM, FRCP

Professor
Department of Medicine & Therapeutics, The Chinese University of Hong Kong
The Prince of Wales Hospital
Shatin, Hong Kong SAR, China
Byung‐Woo Yoon, MD, PhD, FAHA

Professor
Department of Neurology
Seoul National University College of Medicine
Seoul National University Hospital
Seoul, Korea
0003172487.INDD 11 08/25/2017 11:33:33 AM

Asian stroke advisory
panel members
Sardar M. Alam
CEO, Consultant Neurologist
Northwest General Hospital & Research Centre
Phase V, Hayatabad, Peshawar, Pakistan
Deepak Arjundas
Senior Consultant Neurologist and Stroke Specialist
Mercure Hospital, Vijaya Hospital, and Apollo Hospital
Chennai, Tamil Nadu, India
Ester S. Bitanga
Professor, College of Medicine‐University of
the Philippines Manila
Department of Neurosciences
Philippine General Hospital
Taft Avenue, Ermita
Manila, Philippines
Chang Hui-Meng
National Neuroscience Institute
Singapore
Hou‐Chang Chiu
Professor of Medicine, Department of Neurology
Shin‐Kong WHS Memorial Hospital
College of Medicine, Fu‐Jen Catholic University
Taipei, Taiwan
Yi‐Ning Huang
Professor, Department of Neurology
First Hospital of Peking University
Beijing, China
Sun U. Kwon
Asan Medical Center
University of Ulsan College of Medicine
xii
0003172487.INDD 12 08/25/2017 11:33:33 AM

Asian stroke advisory panel members xiii
Lyna Soertidewi Kiemas

Rumah Sakit Pusat Otak Nasional,
JL. M.T. Haryono – Cawang
Jakarta, Indonesia
Sze Haur Lee

National Neuroscience Institute
Singapore
Tsong‐Hai Lee
Professor of Neurology,
Stroke Center and Department of Neurology
Linkou Chang Gung Memorial Hospital,
College of Medicine, Chang Gung University
Taoyuan, Taiwan
Kazuo Minematsu
Director‐General of the Hospital
National Cerebral and Cardiovascular Center
National Cardiovascular Center
Osaka, Japan
Jusuf Misbach
Rumah Sakit Pusat Otak Nasional,
JL. M.T. Haryono – Cawang
Jakarta, Indonesia
Jose C. Navarro
Institute of Neurosciences,
St. Lukes Medical Center
Jose R Reyes Medical Center
Manila, Philippines
Yongchai Nilanont
Associate Professor, Chairman of Neurology
Siriraj Hospital, Mahidol University
Bangkok, Thailand
Jeyaraj D. Pandian
Professor and Head, Department of Neurology
Head of Research, Betty Cowan Research & Innovation Centre
Christian Medical College, Ludhiana
Punjab, India
0003172487.INDD 13 08/25/2017 11:33:33 AM

xiv Asian stroke advisory panel members
N. Venketasubramanian Ramani
Consultant Neurologist, Raffles Neuroscience Centre
Raffles Hospital
Singapore
Nijasri C. Suwanwela
Faculty of Medicine, Chulalongkorn University
Bangkok, Thailand
Kay‐Sin Tan
Professor and Senior Consultant Neurologist
Department of Medicine, Faculty of Medicine
University of Malaya
Kuala Lumpur, Malaysia
Nguyen Huy Thang

Senior Stroke Consultant, The People’s 115 Hospital
General Secretary of Vietnam Stroke Association
Ho Chi Minh City, Vietnam
Le Van Thinh
Clinical Professor of Neurology
Head of Neurology Department of Bach Mai Hospital
President of Hanoi Neurology Association
Bach Mai University Hospital
Hanoi, Vietnam
Shinichiro Uchiyama
Professor, Clinical Research Center for Medicine,
International University of Health and Welfare,
Director, Center for Brain and Cerebral Vessels,
Sanno Hospital and Sanno Medical Center
Tokyo, Japan
Lawrence K.S. Wong

Professor, Department of Medicine & Therapeutics
The Chinese University of Hong Kong
The Prince of Wales Hospital, Shatin
Hong Kong SAR, China
Byung‐Woo Yoon
Seoul National University Hospital
Seoul, Korea
0003172487.INDD 14 08/25/2017 11:33:33 AM

PAR T I
Acute ischemic stroke
management and
complications
0003172488.INDD 1 8/21/2017 11:45:48 AM

0003172488.INDD 2 8/21/2017 11:45:48 AM
CHAPTER 1
Multimodality imaging in acute

stroke
Byung‐Woo Yoon, Han‐Yeong Jeong, and Chang Hui-Meng
Introduction
Neuroimaging plays an important role in the diagnosis and management of

patients with acute stroke. Recently, advanced stroke treatment with intra-
venous or intra‐arterial treatment makes the role of multimodal imaging
even more crucial. Furthermore, advanced computed tomography (CT) and
magnetic resonance imaging (MRI) techniques are able to define the poten-
tially salvageable ischemic penumbra, thereby allowing better selection of
patients likely to benefit from therapy. This chapter reviews the role of CT
and MRI with multimodality for the evaluation of patients presenting with
acute stroke syndrome.
Computed tomography (CT)
Computed axial tomography (CAT) or CT scanning was invented in the 1980s.

The early generation CT scanners had a pencil beam (collimated) X‐ray source
with a one‐dimensional array of detectors opposite and obtained images one
slice at a time. Scans obtained using this older technique were laborious and
slow, and patients had to hold their breath for every slice. Spiral or helical CT
scanners feature a fan beam X‐ray source on one side of the gantry, and detec-
tors on the opposite side of the gantry. The gantry, with its X‐ray source and
detectors, rotates continuously in the same direction as the patient bed is moved
through, hence the name helical or spiral CT.
Early spiral CT scanners had a single row of detectors on the gantry, and were
known as single slice CT scanners. With multislice CT scanning, this single row
of detectors is replaced by multiple rows of detectors, enabling simultaneous
acquisition of images during a single turn. Multislice CT scanning is also known
as multidetector CT, multidetector‐row CT, and multisection CT. These scanners
Stroke Management for Asian Patients, First Edition. Edited by Nijasri C. Suwanwela and Jose C. Navarro.
© 2017 John Wiley & Sons Australia, Ltd. Published 2017 by John Wiley & Sons Australia, Ltd.
0003172471.INDD 3 8/22/2017 10:11:20 AM

4 Stroke management for Asian patients
acquire data rapidly as they scan a fairly large volume very quickly. The advan-
tages are many: (i) the entire study can be performed with patients holding their
breath once, reducing motion artifacts; (ii) rapid image acquisition allows for
more optimal use of intravenous contrast enhancement; and (iii) it allows for
higher resolution in the same study time. The data obtained from multislice CT
are also ideal for 3D imaging such as CT angiography.
Brain CT is the mainstay of imaging in acute stroke, being widely available in
many hospitals. The following types of CT imaging modalities are commonly
used in the diagnostic evaluation of stroke:
1 Non‐contrast CT (NCCT) or non‐enhanced CT (NECT).
2 CT angiography (CTA) and CTA‐source images.
3 CT perfusion (CTP) image.
A simple NCCT image, with a multislice CT scanner, can be acquired in as
little as 2 minutes. The addition of CTA and CTP will increase the time, up to 10
minutes, but provides further information about large vessel occlusions and
even collateral flows. However, iodine contrast will need to be administered.
The goals of CT in the acute setting are:
1 To exclude intracranial or subarachnoid hemorrhage, which would preclude
thrombolysis.
2 To exclude other intracranial pathologies that may mimic a stroke, such as
tumor.
3 To identify “early” features of infarction.
With the addition of CTA and/or CTP, the following information is often
available as well:
1 Site and extent of vascular occlusion.
2 Presence and extent of collaterals.
3 Mechanism and etiology of stroke.
The pros and cons of CT imaging compared to MRI are summarized in
Table 1.1.
Table 1.1 Advantages and disadvantages of CT in acute ischemic stroke.
Advantages Disadvantages
Widely available in hospitals, relatively Not sensitive to detect acute small infarcts
inexpensive, 24‐hour rapid access and posterior fossa infarcts
Shorter acquisition time Exposure to ionizing radiation
Less vulnerable to motion artifacts Risk of iodine contrast-related problems renal
toxicity and thyroid problems
Identification of acute intracranial and Low detection rate of chronic small bleeds
subarachnoid hemorrhages
Suitable for ventilated patients and patients
with metallic implants
0003172471.INDD 4 8/22/2017 10:11:20 AM

Multimodality imaging in acute stroke 5
Non‐contrast CT (NCCT) scan

On NCCT, acute blood products appear hyperdense, therefore acute intracranial
hemorrhage (ICH) and subarachnoid hemorrhage can be rapidly diagnosed [1].
However the identification of acutely ischemic tissue can be challenging.
Detection depends, in part, on the duration and size of ischemia or infarct and
the vascular territory involved.
Radiological signs of infarction reflect the development of cytotoxic edema in
the ischemic brain. However, the detection of these signs is quite variable, being
influenced by size of infarct and time from symptom onset. Over the first few
hours, the following signs may be discernable:
•• Loss of gray‐white differentiation.
•• Loss of distinction among the nuclei of the basal ganglia.
•• Blending of the densities of the cortex and underlying white matter in the
insula.
•• Sulcal effacement.
•• Asymmetrical ventricular compression.
As mentioned earlier, the ability of observers to detect these signs can be quite
variable, depending on the size of the infarct and the time between symptom
onset and imaging. For strokes imaged within 3 hours, the detection rate ranged
from 31%, where all types of acute strokes were included, to 75% when using
the Alberta Stroke Program Early CT Score (ASPECTS), in patients with acute
anterior circulation ischemia alone [2,3]. The rate of detection correlates with the
clinical severity of the infarct and time from stroke onset [2–4]. In Asia, there are
not many reports about this. A single Thai hospital described 47% early infarct
signs on CT scan in patients considered for thrombolysis within 4.5 hours [5].
The presence of an acute thrombus in a large vessel can cause a “hyperdense”
signal along the involved vessel. Any vessel can be occluded, but when seen along
the middle cerebral artery (MCA), the term “dense or hyperdense MCA sign” is
used when the MCA stem is viewed longitudinally (Fig. 1.1), or “dot sign” when a
distal occluded branch of the MCA is viewed along its cross section, usually within
the Sylvian fissure. The frequency of detection in acute stroke varies. The hyper-
dense MCA sign has been described in up to about 44% of patients who presented
with acute MCA territory infarct in the West [6,7]. Other studies have noted that
the MCA dot sign is more commonly seen than the dense MCA sign [8].
Estimation of the extent of ischemia with NCCT: ASPECTS

The use of a systematic scoring system, such as the ASPECTS, on NCCT may help
the end user to more accurately quantify the extent of ischemic tissue [9].
ASPECTS is used to quantify the extent of infarct in the MCA territory only. Two
CT planes of the brain are assessed, and from these 10 areas are scored: three
points for subcortical structures (caudate, lentiform nucleus, and internal cap-
sule), four points at the level of the basal ganglia (one point for insular cortex,
one point each for M1, M2, and M3 regions), three points at the level of just
0003172471.INDD 5 8/22/2017 10:11:20 AM

(A) (B)
Fig. 1.1 Non‐contrast CT (NCCT) of a 74‐year‐old female who developed right hemiparesis

1.5 hours before imaging (A) dense MCA sign; (B) sulcal effacement. Images courtesy of
Byung‐Woo Yoon.
(A) (B)
Fig. 1.2 Alberta Stroke Program Early CT Score (ASPECTS) on a non‐contrast CT. Ten defined
regions of the MCA distribution are identified at ganglionic (A) and supraganglionic (B) levels:
the caudate nucleus (C), the lentiform nucleus (L), the internal capsule (IC), the insular
cortex (I), and M1 to M6. Images courtesy of Byung‐Woo Yoon.
rostral to the basal ganglia (one point each for M4, M5, and M6 regions). A point
is subtracted for every area that has an early ischemic sign so an ASPECTS of 10
is normal (at least in the area of the MCA) and 0 means the whole territory of
the MCA shows early ischemic signs (Fig. 1.2).
0003172471.INDD 6 8/22/2017 10:11:22 AM

0.5
0.4
Probability of excellent outcome

0.3
0.2
0.1
0
0 2 4 6 8 10
Baseline ASPECTS score
Fig. 1.3 Baseline Alberta Stroke Program Early CT Score (ASPECTS) as predictor of an

excellent outcome (functional independence) in patients experiencing an acute ischemic
stroke. A higher baseline score is associated with a greater probability of an excellent
outcome. Source: reference [11].
The ASPECTS is a strong predictor of functional outcome. Several studies

have confirmed the prognostic value of ASPECTS [3,10]. Patients with low
ASPECTS are unlikely to achieve an independent functional outcome [11]
(Fig. 1.3). The extent of early ischemic change using ASPECTS is also associated
with the risk for thrombolysis‐related hemorrhagic transformation [12]. In the
Japan alteplase clinical trial, patients with low ASPECTS had an increased risk of
thrombolysis‐related symptomatic intracranial hemorrhage within 36 hours [13].
Despite its promise, the data suggest that ASPECTS of NCCT does not identify
patients who may benefit from intravenous thrombolysis. Several reports showed
that the ASPECTS of baseline NCCT scans were not associated with a statistically
significant modification of intravenous tissue plasminogen activator (tPA) treat-
ment effect [14]. However, the ASPECTS modifies the effectiveness of intra‐arterial
thrombolysis in patients with MCA occlusion. An ASPECTS below 4 is associated
with increased risk of hemorrhagic transformation and poor outcomes after intra‐
arterial thrombectomy [15]. For this reason, patients with an ASPECTS lower
than 6 were excluded from enrollment in many recent positive thrombectomy
trials [16–18].
CT angiography (CTA)
CTA is performed by administering a bolus injection of iodinated contrast intra-
venously. The helical CT scan is obtained in the arterial phase to capture the
arrival of dye into the brain. The scanning typically starts from the aortic arch
and continues up to a level above the circle of Willis.
0003172471.INDD 7 8/22/2017 10:11:22 AM

CTA is important in the evaluation of acute stroke and the detection of intrac-
ranial large vessel stenosis and occlusion. This imaging technique has high sen-
sitivities of 92–100% and specificities of 82–100% for the detection of intracranial
occlusion and thrombus, when compared with conventional angiography [19].
CTA also has high sensitivity (76–100%) and specificity (93–100%) for identifi-
cation of high‐grade (70–99%) carotid artery stenosis [20].
During CTA, contrast dye fills the brain microvasculature in the normal per-
fused tissue and appears as increased signal intensity on the raw images (also
called CTA source images). In contrast, dye does not fill in ischemic brain regions
that are less accessible and have poor collateral flow. The CTA source images give
a qualitative picture of cerebral blood volume, and the regions of hypoattenuation
on CTA source images are predictive of ischemic areas. CTA source images are
more sensitive than NCCT scans for the detection of early brain infarction [21].
CT perfusion (CTP) imaging

CTP images are acquired during rapid intravenous administration of iodinated con-
trast medium. Repeated scanning of the same portion of the brain parenchyma is
obtained during the passage of the contrast medium. Thereby time–concentration
curves can be drawn for each pixel in the image and, through deconvolution
methods, perfusion parameters can be calculated [22] (Fig. 1.4). A simplified
explanation of the different parameters is as follows (Fig. 1.5).
Time to peak (TTP) refers to the time to the apex of the time‐concentration
curve. It reflects the time it takes until the contrast reaches the brain tissue,
Normal
TTP
CBV = CBF × MTT

Maximum slope
of the curve
(CBF)
Area under the
curve (CBV)
Concentration
MTT
Infarct
Time (sec)
Fig. 1.4 Time–concentration curve demonstrating the relationship of different perfusion

parameters in normal tissue and during infarction. TTP, time to peak; MTT, mean transit time;
CBF, cerebral blood flow; CBV, cerebral blood volume. Source: modified from reference [23].
0003172471.INDD 8 8/22/2017 10:11:22 AM

TTP MTT CBF CBV
Fig. 1.5 Pre‐contrast CT, CT angiogram, and CT perfusion (TTP, MTT, CBF, CBV) in a
74‐year‐old woman with acute infarction in left middle cerebral artery (MCA) territory and
occlusion of left MCA. Red colors in the left MCA territory on TTP and MTT maps indicate
increased time parameters. Blue colors in the left MCA territory on CBF and CBV maps
indicate decreased blood flow and blood volume. TTP, time to peak; MTT, mean transit time;
CBF, cerebral blood flow; CBV, cerebral blood volume. Images courtesy of Byung‐Woo Yoon.
and is the most sensitive marker for cerebral ischemia. In an ischemic tissue,
TTP is increased as it takes more time for the contrast agents to reach an ischemic
area compared to normal tissue. Mean transit time (MTT) is average time
required for blood flow to enter the artery and maintain the inside of the cere-
bral artery; this is also prolonged in an ischemic area. Cerebral blood flow (CBF)
reflects the blood supply to the brain tissue in a given time and is derived from
the gradient of the wash in of the time‐concentration curve. Cerebral blood
volume (CBV) is the volume of blood present at a given moment in a distinct
brain area and is calculated from the area under the time–concentration curve.
The relation between these parameters is MTT = CBV/CBF.
The goal of CTP is to assess the extent of the infarction core (irreversibly
damaged brain tissue) and the penumbra. The penumbra is the part surrounding
the infarction core that is still viable if reperfusion is achieved. There are differ-
ent approaches for estimating the penumbra on CTP. The most common one is
to presume that areas with significantly low CBV represent the infarction core,
whereas areas with solely reduced CBF and/or TTP are considered as the penum-
bra. Thus the mismatch area comparing CBV and CBF represents roughly the
penumbral area. The usefulness of multimodal CT with CTP image as a diagnos-
tic tool for acute stroke is proven in many countries of Asia including Malaysia
and the United Arab Emirates [24,25].
0003172471.INDD 9 8/22/2017 10:11:22 AM

Magnetic resonance imaging (MRI)
Although CT is the most commonly used modality for acute stroke imaging, MRI
has advantages over CT imaging for two major reasons [26]. First, MR imaging
demonstrates higher sensitivity and specificity for the detection of hyperacute
ischemia. Diffusion‐weighted imaging (DWI) provides the most sensitive way to
detect acute infarction, and perfusion imaging can help in delineation of ischemic
penumbra. The second reason is the absence of radiation exposure. This is espe-
cially important for patients who need repeated CT scans or interventions at risk
of an accumulated radiation dose.
Brain MRI protocols are usually composed of conventional T1 and T2
sequences with the following components: (i) parenchymal imaging including
DWI, fluid‐attenuated inversion recovery (FLAIR), and gradient‐echo imaging;
(ii) magnetic resonance angiogram (MRA); and (iii) magnetic resonance
perfusion imaging. Each of these components and their clinical applications are
discussed as follows (Fig. 1.6).
Diffusion‐weighted imaging (DWI)

DWI detects the rate of water diffusion at the location between two closely spaced
radiofrequency pulses. To assemble diffusion and relaxation effects on imaging, one
may obtain quantitative images of the diffusion coefficient, or more exactly the
apparent diffusion coefficient (ADC). The mobility of water is highly dependent on
its cellular environment. In acute stroke, swelling of the ischemic brain parenchy-
mal cells due to cytotoxic edema leads to decreased water diffusion. As a result, the
infarcted tissue demonstrates increased DWI and decreased ADC signals.
DWI is the most sensitive and specific technique for early detection of an
acute ischemic lesion of the brain within 3–30 minutes of onset, far beyond
NCCT or standard MR imaging sequencing [27]. DWI is superior to NCCT for the
diagnosis of acute ischemic stroke in patients presenting within 12 hours of
symptom onset, and baseline DWI volume may be useful for predicting stroke
severity in anterior territory stroke and clinical outcome measures [28]. In addi-
tion, a DWI sequence may enable discrimination of an acute stroke lesion from
an asymptomatic or recurrent lesion.
However, DWI contains an additional component of T2 effect, and increased
T2 signal due to vasogenic edema can create a high signal intensity lesion on DWI
images. This so‐called “T2 shine through effect” can be overcome by comparison
with an ADC map. Vasogenic edema may cause increased DWI signal due to T2
shine through effect, but increased ADC signal is seen on ADC maps. Other
neurological disease (i.e., diffuse axonal injury, Creutzfeldt–Jakob disease) may
also show high intensity lesions on DWI, mimicking acute ischemic stroke [29].
Therefore, considering clinical presentation and performing follow‐up images
may be beneficial for diagnosis.
0003172471.INDD 10 8/22/2017 10:11:22 AM

0003172471.INDD 11
DWI
TTP
ADC
MTT
FLAIR
CBF
CBV
Fig. 1.6 MRI, MR perfusion, and MRA in a 71‐year‐old man with acute infarction in right middle cerebral artery territory and occlusion of right proximal
internal carotid artery. Images courtesy of Byung‐Woo Yoon. Left: DWI, apparent diffusion coefficient (ADC), FLAIR images are shown. There is a small
acute infarction in the right inferior frontal gyrus and insula on a background of chronic infarction in the right centrum semiovale seen on FLAIR images.
Middle: Dynamic susceptibility contrast perfusion weighted image; TTP, MTT, CBF, CBV. There is a large perfusion deficit that indicates delayed
perfusion and hypoperfusion respectively. Right: Contrast‐enhanced MRA shows diminutive flow signal in the high cervical segment and occlusion of the
C1 segment of the right internal carotid artery.
8/22/2017 10:11:23 AM
Gradient‐echo (GRE) imaging/susceptibility‐weighted

imaging (SWI)
GRE imaging is T2*‐weighted imaging and is very sensitive to the inhomogene-
ous magnetic field induced by iron in the blood or blood breakdown products
[30]. Newer SWI sequences have an even greater sensitivity to intravascular and
extravascular blood [31]. For this reason, GRE MRI can detect acute or chronic
ICH and can be used to identify asymptomatic ICH, cerebral microbleeds (CMBs),
superficial siderosis, and traumatic brain injury. GRE MRI is as accurate as CT for
the detection of acute hemorrhage and more sensitive than CT for the detection
of chronic hemorrhage [1] (Fig. 1.7).
GRE MRI is also superior to CT for the detection of chronic small bleeding
lesions, called CMBs, which may be the sequelae of amyloid angiopathy or
chronic hypertension. CMBs appear as focal signal loss on GRE imaging resulting
from hemosiderin deposits from prior small bleeds [32]. Compared with a con-
ventional sequence, the GRE image not only improves the detection rate of
CMBs, but also reveals the progression of the bleeding lesion. Thus, it allows
more accurate detection of progression of hematoma or hemorrhagic transfor-
mation of preceding infarction [33].
Acute thrombotic occlusion in the intracranial vasculature may appear as an
intravascular hypointense signal on GRE imaging [34]. This finding is called the
susceptibility vessel sign and is analogous to the dense MCA sign of CT imaging
(Fig. 1.8).
GRE SWI
Fig. 1.7 Multiple cerebral microbleeds (arrows) seen on gradient‐echo (GRE) and

susceptibility‐weighted imaging (SWI) maps. SWI is more sensitive than GRE. Images courtesy
of Byung‐Woo Yoon.
0003172471.INDD 12 8/22/2017 10:11:23 AM

SWI MRA
Fig. 1.8 Clot presented on susceptibility‐weighted imaging (SWI) (arrow) and occlusion of left
middle cerebral artery presented on magnetic resonance angiography (MRA). Images courtesy
of Byung‐Woo Yoon.
Fluid‐attenuated inversion recovery (FLAIR) imaging

FLAIR imaging is a T2‐weighted sequence in which the cerebrospinal fluid
(CSF) signal is suppressed. CSF appears as a dark signal on FLAIR instead of as
a bright signal on traditional T2‐weighted MRI. FLAIR is useful to detect blood
or gadolinium‐based contrast agents in the CSF, and therefore can readily
identify subarachnoid hemorrhage and subdural hemorrhage [35].
FLAIR helps to determine the age of the infarction. In general, acute ischemic
stroke within the first 6 hours of onset produces no sign on FLAIR. Thereafter
hyperintensity lesions evolve on FLAIR imaging due to vasogenic edema [36]. In
a case in which timing of stroke onset is unknown or symptoms first noted on
awakening (wake‐up stroke), a DWI lesion without a matching hyperintensity
on FLAIR helps to determine whether the infarcts lie within the thrombolytic
time window [37].
In patients with acute ischemic stroke, portions of the intracranial arterial
tree can appear hyperintense on FLAIR. This hyperintense vessel sign indicates
slow blood flow distal to the site of acute arterial obstruction. This slowdown in
blood flow is attributable to anterograde flow through an incomplete occlusion,
or flow via leptomeningeal collaterals [38].
Perfusion‐weighted imaging (PWI)

Different MRI techniques are available for measurements of cerebral perfusion,
but dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) tech-
niques are the common methods. The major difference between the two methods
is the use of a contrast agent.
0003172471.INDD 13 8/22/2017 10:11:24 AM

Perfusion MRI with contrast agent

The DSC imaging technique is very similar to the CTP technique. A series of
susceptibility‐weighted images (T2*) are obtained every 1–2 seconds during an
injection of intravenous contrast. As this gadolinium contrast agent passes
through the cerebral circulation, MRI T2* signal intensity in the surrounding
brain tissue alters by the paramagnetic effect of the contrast [39]. The time–
concentration curve can be obtained from the change of signal intensity. As
in CTP imaging, various perfusion parameters can be calculated from the
time‐concentration curves (Fig. 1.9).
MTT, which is the average time required for blood flow to enter and remain
inside of the cerebral artery, is used to estimate vulnerable brain tissue which may
progress to infarction. MTT shows the widest range of perfusion deficits com-
pared to other parameters, and is therefore likely to overestimate areas at risk
[29]. TTP describes the time at which CBF reaches the highest value in the target
tissue. Since a delay in TTP can occur in a patient with carotid artery stenosis, TTP
can overestimate the hypoperfused area in an acute infarction. CBF is determined
by cerebral perfusion pressure, the dilatation of blood vessels, and blood viscosity,
and is most directly related to the viability of the infarcted tissue [29]. An area
DWI TTP
MTT CBF CBV
Fig. 1.9 Various perfusion‐weighted image parameters. DWI, diffusion‐weighted imaging; TTP,

time to peak; MTT, mean transit time; CBF, cerebral blood flow; CBV, cerebral blood volume.
Images courtesy of Byung‐Woo Yoon.
0003172471.INDD 14 8/22/2017 10:11:24 AM

Table 1.2 A simple representation of typical changes in perfusion parameters

in certain conditions. TTP, time to peak; MTT, mean transit time; CBF, cerebral
blood flow; CBV, cerebral blood volume. Source: modified from reference [42].
TTP MTT CBF CBV
Normal — — — —
Compensated low cerebral perfusion pressure ↑ ↑ — ↑
Underperfused ↑ ↑(↓) ↓ ↑(↓)
Infarction ↑ ↑ ↓ ↓
Post‐ischemic hyperperfusion ↓(↑) ↑↓ ↑ ↑
with normal CBF and delayed MTT or TTP indicates an area with blood flow
maintained by blood vessel dilatation. CBV is measured by the whole blood
quantity within the target area. The areas of decreased CBV correlate with the
final size of the cerebral infarction [40]. In general, tissue at risk of infarction will
have normal or decreased CBF, normal or elevated CBV, and elevated MTT and/
or TTP. Infarcted tissue will have decreased CBF and CBV with elevated MTT and
TTP [41] (Fig. 1.4, Table 1.2).
Perfusion MRI without contrast agent

Arterial spin labeling (ASL) is an additional technique for measuring cerebral
perfusion that does not require a paramagnetic contrast agent. ASL utilizes the
spins of endogenous water protons as a tracer by magnetically labeling the blood
entering the brain [43]. ASL is rarely used in the acute stroke setting because of
its low signal‐to‐noise ratio, relatively long imaging times, and difficulty in dis-
tinguishing between reduced blood flow and delayed transit times [42]. However,
ASL is promising for patients in whom a contrast agent is contraindicated.
Magnetic resonance angiography (MRA)

MRA gives information about the intracranial and extracranial vasculature. MRA
is used for not only detection of arterial stenosis or occlusion, but also identification
of cerebral aneurysm. Two MRA techniques are routinely used in clinical practice:
time‐of‐flight MRA (TOF‐MRA) and contrast‐enhanced MRA (CE‐MRA).
TOF‐MRA technique does not require injection of contrast medium, and the
vascular signal depends on the direction and velocity of blood flow. TOF‐MRA
can be an alternative for patients who are not suitable to receive contrast agents.
However, TOF‐MRA tends to overestimate the degree of stenosis. TOF‐MRA is
useful in diagnosing proximal vessel occlusions but is not suitable for more distal
or smaller branch occlusions [44].
In CE‐MRA, the vascular anatomy is outlined by a bolus injection of contrast
medium. CE‐MRA has the advantage of visualization from the aortic arch through
to distal branches with higher spatial resolution and faster acquisition time [45].
0003172471.INDD 15 8/22/2017 10:11:24 AM

Clinical application of multimodal MRI in acute stroke

Diagnosis of acute ischemic core
Acute ischemic lesions can be identified with high accuracy using DWI imaging.
The lesions appear as hyperintense areas on DWI and as correlative hypointense
areas on ADC maps, even within 3 minutes of stroke onset [29]. The pattern of
DWI lesions also provides information on the underlying mechanism of stroke.
Multiple lesions in the unilateral anterior circulation or small, scattered lesions
in one vascular territory are related to large artery sclerosis [46]. Perforating
infarcts, pial infarcts, or borderzone infarcts are distinctive patterns for intracra-
nial atherosclerosis [47]. Multiple lesions within different vascular territories on
DWI may indicate an embolic stroke mechanism [48].
Multimodal MRI can identify the age of acute infarcts (Fig. 1.10). According
to the signal changes of DWI and ADC maps, acute ischemic lesions can be
divided into hyperacute lesions (high DWI and low ADC) and subacute lesions
(normalized ADC). Chronic lesions appear in the normalized DWI and ADC
[49]. The presence of multiple lesions of varying ages identified by DWI suggests
active early recurrences over time and higher risk of future ischemic events.
Diagnosis of ischemic penumbra

PWI can be used to identify the extent of ischemic penumbral tissue, whereas DWI‐
depicted lesions represent the ischemic core [29]. Therefore, areas with PWI–DWI
mismatch have been considered representative of salvageable tissue that requires
active treatment (Fig. 1.11). Previously, PWI–DWI mismatch was used for patient
selection in several clinical trials focusing on acute stroke treatment [50–52]. The
ischemic penumbra is expected to have CBV within normal ranges, moderate
reduction in CBF, and moderately increased MTT. Perfusion deficit noted on PWI
time maps (MTT, TTP) encompasses both delayed perfusion caused by arterial
occlusion and flow through collateral circulation. In contrast, CBF and CBV maps
DWI T2 or FLAIR
ADC
24 hours 10 days 3 weeks
Fig. 1.10 The change of signal intensities of different MRI parameters after the onset of
ischemic stroke. DWI, diffusion‐weighted imaging; FLAIR, fluid‐attenuated inversion
recovery; ADC, apparent diffusion coefficient. Source: reference [49].
0003172471.INDD 16 8/22/2017 10:11:24 AM

DWI PWI MRA
Fig. 1.11 PWI–DWI mismatch. Images courtesy of Byung‐Woo Yoon.
Table 1.3 Evolution of MRI findings of intracerebral hemorrhage. Source: reference [53].
Time Hemoglobin state T1‐weighted T2‐weighted
Hyperacute 0–6 hours Oxyhemoglobin (intracellular) Iso – hypo Hyper

Acute 6 hours to 3 days Deoxyhemoglobin (intracellular) Iso – hypo Hypo
Early 3 days to 1 week Methemoglobin (intracellular) Hyper Hypo
subacute
Late subacute 1 week to 1 month Methemoglobin (extracellular) Hyper Hyper
Chronic >1 month Hemosiderin and ferritin Hypo Hypo
provide information about amount of blood flow to specific regions of the brain,
although the arterial source of perfusion may not be evident. The mismatch
between the tissue volume with time delay and the tissue volume with hypoperfu-
sion on CBF/CBV may be a good representation of collateral flow [26].
Detection of hemorrhagic stroke

Intracerebral hemorrhage (ICH)
The pattern of ICH on T1‐ and T2‐weighted sequences evolves over time from
acute to chronic stage (Table 1.3). GRE and SWI are highly sensitive to hemor-
rhage, and the hypointensity signal appearance of such hemorrhage is present at
all stages. As mentioned above, GRE has been shown to be as accurate as CT for
the detection of acute intracranial hemorrhage, and is superior to CT in the detec-
tion of chronic hemorrhage [1]. MRI is an excellent technique for distinguishing
ischemic and hemorrhagic stroke for consideration of reperfusion therapy.
Hemorrhagic transformation (HT)

HT is a frequent, often asymptomatic event that occurs after acute ischemic stroke.
HT is presumed to occur in the infarcted brain area due to the extravasation of
blood components. Imaging data indicative of a large infarction and early ischemic
0003172471.INDD 17 8/22/2017 10:11:25 AM

signs on CT are considered to increase the incidence of HT. A large initial DWI
lesion or low ADC value has been suggested as an independent predictor of HT
after intravenous thrombolysis [54]. Extremely low or absent apparent CBV may
increase the risk of HT [55]. The presence of focal FLAIR hyperintensity within
acute infarcts is also associated with an increased risk of symptomatic HT [56].
Cerebral microbleeds (CMBs)

GRE is sensitive for detection of chronic CMBs, which may be the sequelae of
chronic hypertension or amyloid angiopathy. The clinical importance of CMBs is
unclear. Although CMBs are prevalent in patients with spontaneous ICH and
ischemic stroke, the presence of CMBs on GRE does not appear to increase the
risk of HT after thrombolysis [57].
Summary
A brain CT or MRI scan is urgently recommended for all patients with suspected
acute stroke syndrome. DWI MRI is more sensitive than NCCT for detecting
acute ischemic stroke. NCCT or GRE MRI shows similar accuracy in the diagno-
sis of acute ICH. Multimodal CT or MRI combined with brain parenchymal, vas-
cular, and perfusion imaging could identify ischemic penumbra that might be
restored with reperfusion therapy. Overall, MRI is diagnostically superior to CT
for acute stroke syndrome, but has limited accessibility in some hospitals, and
can be costly and time‐consuming.
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0003172471.INDD 21 8/22/2017 10:11:25 AM

CHAPTER 2
Intravenous thrombolysis
and endovascular treatment
Nijasri C. Suwanwela and Nguyen Huy Thang
In patients with acute ischemic stroke, revascularization strategies have proven

to be effective if given within a certain time window. The “time is brain” concept
has been accepted for emergency stroke management. Pharmacological reca-
nalization by intravenous thrombolysis with recombinant tissue plasminogen
activator (rtPA) is the established treatment for acute ischemic stroke patients
presenting within 4.5 hours of stroke onset. However, in a significant number of
patients, intravenous thrombolysis with rtPA is ineffective due to a low rate of
recanalization, especially for proximal occlusions and a large thrombus burden.
Endovascular mechanical revascularization is an evolving treatment option
enabling clot disruption or extraction. The safety and efficacy of several new
endovascular devices have been successfully demonstrated in acute ischemic
stroke patients.
Intravenous thrombolysis
Definition
Thrombolytic therapy is the method that uses a drug to lyse or dissolve throm-
bus, which is the main cause of ischemic stroke. This results in restoration of
blood flow in the underperfused area of the brain. The only drug that is approved
for acute ischemic stroke treatment is rtPA.
Rationale of treatment
Initially, the medication was shown to be effective when started within 3 hours
after stroke onset [1]. More recent evidence has demonstrated rtPA treatment
can still show benefit when treatment is initiated within 4.5 hours [2]. However,
the benefit of this therapy is extremely time sensitive. The treatment is more
22
0003172472.INDD 22 8/22/2017 10:14:49 AM

Intravenous thrombolysis and endovascular treatment 23
effective when given early. When treatment is initiated <1.5 hours, and 3–4.5 hours
of symptom onset, the odds ratio for disability‐free outcome compared with pla-
cebo is 2.6 and 1.3, respectively [3]. Nowadays, it is generally accepted that
stroke is a medical emergency.
Evidence base in Western and Asian countries

Intravenous thrombolysis is available for acute stroke management in most
Asian countries. However, compared to the Western world, the treatment has
not been widely applied, especially among developing countries [4]. Although
the rate of thrombolysis in Asia is increasing, there are still great discrepancies
between the developed and developing countries. In a recent study among the
12 countries in Asia that are members of the Asian Stroke Advisory Panel,
intravenous thrombolysis was available in all countries. During 2012, when the
survey was performed, more than 17 000 patients received intravenous throm-
bolysis for acute stroke in these countries, with the highest number of patients
in Japan [5]. However, to our knowledge, thrombolysis is still currently not
available in some countries, such as Laos.
The major barrier to giving intravenous thrombolysis is the relatively
short therapeutic window, which requires public awareness, effective pre-
hospital evaluation, and rapid transportation to the hospital. Access to acute
neuroimaging facilities as well as special setting of emergency management
is also required. Moreover, in some remote areas, shortage of knowledgea-
ble and experienced stroke personnel together with the cost of the medica-
tion contributes to the lower rate of thrombolysis. In the early years of
treatment, there was also a fear of serious complications, especially intracer-
ebral hemorrhage, which was believed to be more common among the Asian
population [6,7]. Thailand was the first to start treatment in 1996 and
reported the first case series. Even though the stroke presented in this series
was more severe when compared to the original National Institute of
Neurological Disorders and Stroke (NINDS) study, the results showed simi-
lar efficacy and hemorrhagic outcomes, thus encouraging treatment in the
Asian population [8].
According to the World Stroke Organization, awareness, access, and action
are key for effective management of stroke. Awareness of the symptoms of
stroke and the need for urgent management have been emphasized in many
Asian countries throughout various public activities such as the World Stroke
Day campaign. However, public awareness is still poor in many developing
countries. In one study, only one‐third of acute stroke patients who arrived at
the emergency room realized that their symptoms were caused by stroke [9].
A study from Japan demonstrated that intensive interventions by distribution
of leaflets and booklets and holding lectures are useful for strengthening the
association between correct knowledge of early stroke symptoms and intention
to call an ambulance [10].
0003172472.INDD 23 8/22/2017 10:14:49 AM

Mode of transportation to the hospital is another factor determining the time of

hospital arrival. An advanced emergency medical service is established in most
developed countries, whereas in many developing countries patients still need to
make their own way to hospital. For example, in India, only 12% of patients with
acute stroke used an ambulance whereas 50% went by personal cars and 17%
used rickshaws [11]. In contrast, stroke is the second most common condition after
trauma to activate the helicopter medical service in Fukushima, Japan [12]. Mobile
stroke units equipped with CT scanners are available in some centers. However,
their use in crowded cities with heavy traffic in Asia is still questionable.
Hospital set‐up for rapid stroke management is another important factor in
increasing the number of patients suitable for thrombolysis. Team cooperation—
from emergency medical service to emergency room personnel, imaging facilities,
labs, pharmacists, nurses, and physicians knowledge about thrombolysis—is key.
Due to the limited number of neurologists in some Asian countries, in many
centers thrombolysis is given by non‐neurologists such as emergency room
physicians, general practitioners, and internists. According to the national survey
from Taiwan from 2003 to 2010, approximately one‐fourth of patients received
rtPA from non‐neurologists or neurosurgeons [13].
Establishment of comprehensive stroke centers can help to direct patients
to institutions that can effectively deliver thrombolysis in timely manner. For
example, in South Korea, organization of government‐initiated comprehen-
sive stroke centers resulted in a doubling in the cases of thrombolysis in the
country in 4 years and reduction of mean door‐to‐needle time from 62 to 41
minutes [14]. Unfortunately, this level of expertise is not available at some
urban and most rural centers in Asia, resulting in underuse of rtPA in these
hospitals. This gap can be attributed to limited resources to set up stroke cent-
ers, insufficient availability of stroke specialists, and long distances between
remotely located patients and centrally located stroke specialists. Telemedicine
or telestroke involves the use of communication technology to provide physi-
cians in remote areas with timely access to stroke expertise. It has become
widely used as a standard practice in some European and U.S. centers for aid-
ing acute stroke treatment. There is definitely a need for a telestroke network
in Asia [15,16] and some centers have started their networks with varying
levels of technology [17].
According to the meta‐analysis of thrombolysis for stroke treatment from 18
publications in Asia, the mean age of the subjects in each study ranges from 53 to
79 years and the onset to treatment time ranged from a mean of 130 to 73 minutes.
A significantly higher proportion of cardioembolic stroke was noted [18].
Dose
Variable dosages of intravenous rtPA were used for thrombolysis in Asia. In our
recent study among members of the Asian Stroke Advisory Panel, the dosage of
0.9 mg/kg was most commonly used. However, in Japan, Pakistan, and Vietnam,
0003172472.INDD 24 8/22/2017 10:14:49 AM

0.6 mg/kg was used as a standard-dose [5]. India and the Philippines employed
a variable-dosing regimen determined by several factors including cost saving,
old age, and physicians’ choice. The rationale of using a lower dose in many
Asian centers includes the anticipation of higher rates of rtPA‐related intracra-
nial hemorrhage among Asian patients and the reduction of treatment cost.
In Japan, a low‐dose regimen (0.6 mg/kg) was approved for standard prac-
tice after the Japan Alteplase Clinical Trial (J‐ACT), which was an open
non-randomized study in patients receiving the treatment within 3 hours of
onset. The study demonstrated similar clinical outcomes to the 0.9 mg/kg dose
in the NINDS study but a lower risk of symptomatic intracerebral hemorrhage
[19]. Subsequent registries, SAMURI, J‐ACT II, and J‐MARS, showed the
same results; therefore this low‐dose regimen is established as a standard
treatment in Japan [20–22].
The ENCHANTED study is a randomized double‐blind study comparing two
dosages of rtPA in patients with acute ischemic stroke. The studied patients were
predominantly Asian (43% Chinese and 20% other Asian). The participants
were randomly assigned to receive either a standard-dose of rtPA (0.9 mg/kg,
10% as a bolus and 90% as an infusion over a period of 60 minutes; maximum
dose, 90 mg) or a low-dose (0.6 mg/kg, 15% as a bolus and 85% as an infusion
over a period of 60 minutes; maximum dose, 60 mg). The median age was 68 and
median NIH stroke scale was eight. The majority of the studied patients had large
vessel atherosclerosis (40%); cardioembolic and lacunar stroke were found in 20%
each. The study did not show the noninferiority of low‐dose to standard‐dose
rtPA with respect to death and disability at 90 days. However, there were signifi-
cantly fewer symptomatic intracerebral hemorrhages in the low‐dose group (1.0
vs 2.1% by SITS‐MOST criteria, p value 0.01) [23].
Recommendations
Intravenous thrombolysis is the standard treatment for acute ischemic stroke
in Asia. It is proven to be effective with an acceptable complication rate. The
treatment is recommended in the national guidelines of most Asian countries.
To make this treatment available, efforts should be made to increase public
awareness and improve physicians’ knowledge and hospital stroke care facilities.
Telemedicine is another method that should aid treatment.
Endovascular treatment
Definition
Endovascular therapy is an intra‐arterial method that uses catheter‐guided
devices to assist restoration of blood flow in an occluded vessel. This is accom-
plished by providing a thrombolytic agent directly to the clot and/or removing
the clot mechanically from the site of vessel occlusion.
0003172472.INDD 25 8/22/2017 10:14:49 AM

Rationale of treatment
Intravenous alteplase administered within 4.5 hours after symptom onset is
the reperfusion therapy with proven efficacy in patients with acute ischemic
stroke. However, the limitations of this therapy include the narrow therapeutic
time window and contraindications such as recent surgery, coagulation abnor-
malities, and a history of intracranial hemorrhage. Moreover, intravenous
alteplase appears to be much less effective in cases with proximal occlusions
of the major intracranial arteries, which account for more than one‐third of
cases of acute anterior circulation stroke. Clinical evidence has confirmed that
effective recanalization of these large vessels is strongly associated with improved
functional outcomes.
Initial work on endovascular treatment (EVT) of acute ischemic stroke was
published in the 1980s. Since then, the endovascular techniques for acute
ischemic stroke treatment have tremendously improved, advancing from
intra‐arterial administration of thrombolytic drugs to first‐generation mechani-
cal thrombectomy devices (MERCI clot retriever and Penumbra clot aspiration)
and more recently to second‐generation mechanical thrombectomy devices
(stent retrievers).

Recently, five randomized controlled trials of endovascular treatment of
acute ischemic stroke with primarily stent retrievers (MR CLEAN, EXTEND‐
IA, ESCAPE, SWIFT‐PRIME, and REVASCAT) have reported that endovascular
treatment, when added to standard stroke treatment (mostly involving IV
rtPA), shows increased favorable outcomes (modified Rankin score [mRS]
0–2) in selected stroke patients with proximal arterial occlusions compared to
standard care alone.
The MR CLEAN study (Multicenter Randomized Clinical Trial of Endo
vascular Treatment for Acute Ischemic Stroke in the Netherlands) is the first
randomized controlled trial that proved the efficacy of mechanical thrombec-
tomy. MR CLEAN enrolled 500 patients in 16 medical centers in the Netherlands
with acute ischemic stroke caused by a proximal intracranial occlusion in
the anterior circulation (distal intracranial carotid artery, MCA [M1 or M2], or
anterior cerebral artery [A1 or A2]) established with computed tomography
angiography (CTA), magnetic resonance angiography (MRA), or digital sub-
traction angiography and a score of ≥2 on the National Institutes of Health
Stroke Scale (NIHSS). There were 445 patients (89.0%) who received intrave-
nous rtPA before randomization; 233 patients were assigned to intra‐arterial
treatment (IAT), and the other 267 patients were treated with usual care alone.
The onset time to groin puncture was 260 minutes (interquartile range, 210–313
minutes), a stent retriever was used in 81.5%, and thrombolysis in cerebral
infarction (TICI) grade 2b/3 recanalization was achieved in 59%. The results
showed an absolute difference of 13.5% (95% CI, 5.9–21.2) in the rate of
0003172472.INDD 26 8/22/2017 10:14:49 AM

functional independence (mRS score 0–2) in favor of the intervention (32.6%

vs 19.1%). There were no significant differences in mortality or the occurrence
of symptomatic intracranial hemorrhage (sICH).
The ESCAPE (Endovascular Treatment for Small Core and Anterior Circulation
Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times)
trial included 316 patients with disabling acute ischemic stroke (NIHSS score >5)
who could be randomized up to 12 hours after the onset. Non enhanced CT
and CTA (preferably multiphase) were performed rapidly with a target door‐
to‐imaging time of 25 minutes to identify participants with a small infarct core
(by Alberta Stroke Program Early CT Score [ASPECTS] 6–10 or CT perfusion), an
occluded proximal intracranial artery in the anterior circulation (internal carotid,
M1 MCA, or ≥2 M2s), and moderate to good collateral circulation defined as
“the filling of 50% or more of the middle cerebral artery pial arterial circula-
tion on CTA (preferably on multiphase CTA).” The result showed that the rate
of a 90‐day good outcome was higher in the intervention group (53.0 vs 29.3%;
p < .001), with a common odds ratio of 2.6 (95% CI 1.7–3.8; p < .001) in favor of
intervention. A lower mortality rate was observed in the intervention group
(10.4 vs 19.0%; p = .04). There was no significant difference in the rates of sICH
(3.6 vs 2.7%; p = .75). ESCAPE provides evidence for rapid endovascular treat-
ment plus standard care in proximal intracranial arterial occlusion with a small
infarct core and moderate‐to‐good collateral circulation.
The EXTEND‐IA trial (Extending the Time for Thrombolysis in Emergency
Neurological Deficits—Intra‐Arterial) obtained advanced perfusion‐imaging crite-
ria to select patients suitable for endovascular treatment. Seventy participants
who were eligible for randomization had to present with acute anterior proximal
occlusion within 4.5 hours and evidence of salvageable tissue and small infarct
core (<70 ml) on CT perfusion. They were randomized to receive either intrave-
nous rtPA only or intravenous rtPA plus endovascular therapy with a stent
retriever. The trial was halted after assigning 70 patients because of efficacy.
The reperfusion rate at 24 hours was higher in the endovascular group than in
the control group (100 vs 37%; p < .001). Endovascular therapy also showed
greater early neurological improvement at 3 days (80 vs 37%; p = .002) and also
higher functional independence at 90 days (71 vs 40%; p = .01). No differences
in mortality and sICH were observed.
The SWIFT PRIME study (Solitaire™ with the Intention for Thrombectomy
as Primary Endovascular Treatment for Acute Ischemic Stroke) randomized 196
patients with acute ischemic stroke and NIHSS scores of 8–29 who received
intravenous rtPA within 4.5 hours of onset and had CTA or MRA confirmation of
intracranial ICA, M1, or carotid terminus occlusion. Participants were randomized
1:1 to treatment with intravenous rtPA alone or to treatment with intravenous
rtPA followed by neurovascular thrombectomy with the use of a stent retriever.
After the results of the MR CLEAN trial and the passing of stopping boundaries
in the ESCAPE trial were announced, a decision was made to conduct the first
0003172472.INDD 27 8/22/2017 10:14:49 AM

interim efficacy analysis a little earlier than originally planned. The results
showed a reduced disability rate at 90 days and a higher rate of functional
independence in the intervention group (60 vs 35%, p < .001). The two groups
had no significant differences in 90‐day mortality (9 vs 12%; p = .50) or sICH
(0 vs 3%; p = .12).
The REVASCAT trial (Endovascular Revascularization with Solitaire Device
Versus Best Medical Therapy in Anterior Circulation Stroke within 8 Hours)
enrolled 206 anterior proximal occlusion patients within 8 hours of symptom
onset at four centers in Spain to receive either medical therapy alone or endo-
vascular therapy (with stent retriever) plus medical therapy. Endovascular ther-
apy showed a common odds ratio for 90‐day mRS improvement of 1.7 (95%
CI 1.05–2.8) compared with the control group.
Current status of endovascular thrombectomy in Asia

Among five randomized controlled studies, only three subjects were enrolled
from one participating Asian country. Thus, studies and clinical data specific to
Asia are still limited. Moreover, there are few publications about EVT from Asia.
The Clinical Research Center for Stroke‐Fifth Division (CRCS‐5), a prospective
registry involving 15 Korean hospitals, showed that 2.0% of patients with acute
stroke underwent EVT alone, and 2.6% had EVT combined with intravenous
thrombolysis between April 2008 and November 2013. Among patients who
received reperfusion therapy, 32.5% had good outcome (mRS 0–1) at 3 months.
In the (RESCUE)‐Japan Registry, patients with acute large artery occlusion
were registered from 84 Japanese hospitals between July 2010 and June 2011,
when the MERCI was the only approved thrombectomy device. Acute EVT was
performed in 23% of the overall patients, 65% of the alteplase‐failed patients,
and 35% of the potential candidates for EVT who were ineligible for intravenous
thrombolysis. Both clinical and vascular outcomes were relatively better in
patients receiving EVT than in those without EVT in both alteplase‐failed and
alteplase‐ineligible patients.
In a report of seven patients in Thailand with successful recanalization by the
Solitaire or Penumbra system, five had a good outcome with mRS 0–1.
In Vietnam, a case series study that included 30 consecutive patients with
proximal intracranial occlusion showed significant benefits in patients who
received intra‐arterial reperfusion procedures using a Solitaire stent retriever
compared with those who received intravenous thrombolysis alone.
Recommendation
Endovascular therapy is an effective treatment in acute ischemic stroke patients
with documented occlusion of the proximal circulation. It is a new standard of
care for acute ischemic stroke management. However, a large limitation of EVT
in Asia is the high prevalence of intracranial atherosclerosis, we still need more
evidence from real-world EVT data collection in Asia.
0003172472.INDD 28 8/22/2017 10:14:49 AM

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2391–6.
15. Imai T, Sakurai K, Hagiwara Y, Mizukami H, Hasegawa Y. Specific needs for telestroke
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0003172472.INDD 30 8/22/2017 10:14:49 AM

CHAPTER 3
General management of stroke

Kazuo Minematsu and Deepak Arjundas
Most patients with acute ischemic stroke (AIS) should be carefully treated in a
hospital having a stroke unit (SU) and specializing in the management of stroke.
Such a hospital has been called a primary stroke center (PSC) or comprehensive
stroke center (CSC). Although the availability of stroke units varies throughout
Asian countries, the number has increased during the past 10 years. At present,
patients with AIS can be treated in the setting of an SU (or stroke care unit, SCU)
with thrombolytic/thrombectomy treatment, antiplatelet/anticoagulant therapy,
and/or neuroprotective agents in some countries including Japan. These specific
treatments for AIS are described and discussed in other chapters.
In this section, the importance of appropriate medical care will be reviewed
with particular reference to general care: respiration, blood pressure, nutrition
and brain edema, prevention of complications, and so on.
General conditions
Respiration
Maintaining adequate blood oxygen level is an essential component of stroke
management, particularly in patients with impaired consciousness. Hypoxia may
occur in cases of airway obstruction, aspiration pneumonia, atelectasis, hypoven-
tilation, and so on. A secured airway and appropriate management of ventila-
tion are strongly recommended for AIS patients in whom a respiratory disorder
causes disturbance of consciousness. If ventilation is unsatisfactory or secretions
are uncontrollable, an endotracheal tube should be placed, with frequent suc-
tion of secretions. If intubation is necessary for longer than 3 days, tracheostomy
can be considered.
In the presence of hypoxia that is confirmed by blood gas determination,
supplemental oxygen should be provided to maintain oxygen saturation >94%.
While it was not statistically significant, the survival rate was slightly better in a
31
0003172473.INDD 31 8/22/2017 10:16:57 AM

group of severe stroke patients given oxygen therapy [1]. Routine oxygen
administration cannot be recommended for mild to moderate stroke patients
without obvious hypoxia because of the lack of scientific evidence.
Patients with acute stroke often have sleep apnea syndrome (SAS). Induction
of continuous positive airway pressure (CPAP) ventilation may result in neuro-
logical recovery and good clinical outcome, and therefore can be used in AIS
patients who have moderate to severe SAS [2].
Blood pressure
In general, cerebral blood flow (CBF) is maintained constant in the normal brain
when blood pressure (BP) changes acutely within a limited range, so-called
“autoregulation” of CBF. In AIS patients, however, CBF autoregulation often
fails, and therefore acute lowering of BP to a normal level may induce hypoper-
fusion and further ischemia, particularly within or around the ischemic brain
lesions. This is the most important issue for the management of BP in AIS
patients. An ideal BP range in AIS patients may depend on the stroke subtype
and comorbidity, but has not yet been determined scientifically.
Elevated BP is common in AIS patients. It may be attributable to the secondary
effects of premorbid hypertension, hypoxemia, intracranial hypertension, pain,
stroke‐associated stress, filling of the bladder, and so on. Systolic BP may often
decrease by 20–30% within 24 hours without hypotensive therapy [3].
For the first days and weeks after AIS onset, antihypertensive therapy can
carefully be used only when hypertension persists with a systolic BP of >220 mmHg
or a diastolic BP of >120 mmHg, or if concurrent aortic dissection, acute myocar-
dial infarction, heart failure, or renal failure is present [4]. The reasons for this
recommendation are as follows: (i) the autoregulation of CBF is impaired in and
around the ischemic lesion, where regional CBF changes passively as BP changes;
(ii) in most cases, elevated BP decreases considerably within 1–2 weeks without
hypotensive therapy; (iii) enlargement of the infarct size caused by rapid lower-
ing BP has been reported; and (iv) effects of lowering BP were tested in AIS
patients but no scientific conclusions have yet been provided.
Intravenous antihypertensive therapy can be recommended for patients
scheduled to receive intravenous rtPA therapy when systolic BP is >185 mmHg
or diastolic BP is 110 mmHg or higher [4,5]. BP should be stabilized at the lower
level before beginning treatment with intravenous rtPA and maintained below
180/105 mmHg for at least the first 24 hours after intravenous rtPA treatment.
In AIS patients who were administered antihypertensive agents before stroke
onset, the agents may be restarted carefully after the first 24 hours from AIS onset [6].
Hypovolemia should be corrected with intravenous normal saline. Cardiac
arrhythmias that might be reducing cardiac output should also be treated. If
marked hypotension or shock is present, its cause should be determined urgently.
AIS patients with BP lower than normal are at high risk of expansion of infarct
volume and therefore they may have a poor clinical outcome. Rapid correction
0003172473.INDD 32 8/22/2017 10:16:57 AM

General management of stroke 33
of hypovolemia and restoration of cardiac output are important measures during

the first hours for such cases.
Nutrition
Nutritional state should always be evaluated in AIS patients because undernutri-
tion is often observed (6–60%) and predicts poor clinical outcome [7]. Nutrition
supplementation should be given to ensure adequate calories and protein intake
for patients with malnutrition, but not for those without [8,9].
Hyperglycemia is relatively common and may increase infarct size in AIS
[10]. It is reasonable to treat hyperglycemia to achieve blood glucose levels
in the range of 140–180 mg/dl and closely monitor to avoid hypoglycemia.
Hypoglycemia may also be related to poor clinical outcome. When blood glucose
is <60 mg/dl, it should immediately be corrected to achieve normoglycemia.
Fluid balance
AIS patients tend to develop fluid and electrolyte disturbance. Dehydration often
worsens the ischemic process, due to an increase in blood viscosity and hypoten-
sion, and predisposes to recurrent cardioembolic stroke [11].
Early after stroke onset, dehydration is usually hyperosmolar, which may be
caused by decreased oral intake of water due to disturbed consciousness or dys-
phagia. Loss of electrolytes, caused by vomiting, diarrhea, and hyperhidrosis,
and decreased intake of salt, leads to hypoosmolar or mixed‐type dehydration.
This may result from inappropriate infusion of hypoosmolar fluids.
Electrolyte imbalance may occur because of dysphagia, decreased sensation
of thirst due to brain damage, inappropriate administration of parenteral fluids,
use of diuretics, and coexisting diseases such as congestive heart failure, liver
cirrhosis, nephrotic syndrome, and so on. A premorbid cardiac or renal disorder
often makes the correction of fluid and electrolyte abnormalities difficult.
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH),
characterized by hyponatremia but with excessive urinary loss of sodium, may
occur in AIS patients. Hypernatremia is most commonly caused by administra-
tion of osmotic diuretics and/or decreased intake of water. Massive hemispheric
infarction with brain herniation may be associated with diabetes insipidus.
When oral intake is impossible or prohibited, 1500–2000 ml of fluids should be
infused intravenously or through tube feeding. Excessive infusion of fluids may
cause cardiac failure and pulmonary congestion. Rapid correction of hyponatremia
is contraindicated to avoid the development of central pontine myelinolysis.
Brain edema
Brain edema and elevated intracranial pressure (ICP) is one of the most impor-
tant and serious problems in the ischemic process of the brain and may result in
brain herniation and death. Overhydration, particularly with hypoosmolar fluids,
worsens brain edema and further elevates ICP.
0003172473.INDD 33 8/22/2017 10:16:57 AM

Intravenous administration of hypertonic glycerol (10%) can be used for

the treatment of the acute phase of large cerebral infarcts accompanying an
elevated ICP [12,13]. However, the true effect of acute glycerol administration
on long‐term survival and functional outcome has not yet been demonstrated.
The use of mannitol (20%) can be considered in AIS, but there is no adequate
scientific evidence [14].
Management of complications
Complications in general, including infection

Various complications may develop during the course of AIS, and they are frequent
in elderly patients with pre‐stroke morbidity. They include respiratory infection
(12–22%), urinary tract infection (16–24%), falling (22–25%), and decubitus
ulcer (18–21%) [15,16]. These complications often result in an increase of
mortality or deterioration of functional outcome. Early initiation of vigorous
physiotherapy or respiratory rehabilitation during the acute phase can reduce
the development of pneumonia. Prophylactic use of antibiotic agents should be
avoided for preventing infections in AIS patients.
Gastrointestinal bleeding
Gastrointestinal (GI) bleeding occurs in 1.5–3% of patients with acute stroke, in
half of whom it was severe [17]. An endoscopic study revealed that gastric
changes were noted in 52% of 177 patients with acute stroke [18]. Use of
steroids and long‐term nasogastric tube feeding were correlated with gastric
changes. Antithrombotic and thrombolytic therapies may cause life‐threatening
GI bleeding in AIS patients with a history of gastric ulcer.
Prophylactic use of intravenous anti‐ulcer agents, such as H2 receptor antago-
nists, is recommended in AIS patients, especially in those with a history of peptic
ulcer or those being treated with antiplatelet, anticoagulant, and thrombolytic
agents, although there is no study of stroke patients exclusively.
Deep venous thrombosis and pulmonary thromboembolism

Deep venous thrombosis (DVT) and subsequent pulmonary thromboembolism
(PTE) occur in 11–75% and 3–16%, respectively, of AIS patients, being a major
source of mortality and morbidity. However, studies from Asian populations
suggest a lower prevalence of DVT when compared to Caucasians [19,20].
Venous stasis associated with paralysis of the lower extremity, bedridden status,
hypercoagulability, and endothelial damage of a catheterized vein are strongly
associated with the development of DVT.
PTE patients may present with variable and nonspecific symptoms and signs,
including pleuritic pain, hemoptysis, dyspnea, tachypnea, and tachycardia. Massive
PTE often causes cardiogenic shock or sudden death. Once the diagnosis of DVT
0003172473.INDD 34 8/22/2017 10:16:57 AM

or PTE is made, anticoagulation or thrombolytic therapy should immediately be

started. These therapies, however, may be hazardous because of bleeding
complications. Blood tests of markers of blood coagulation activation and
fibrinolysis, and duplex and Doppler ultrasonographic examinations of the veins
in the lower extremities are recommended in high‐risk AIS patients. For the
diagnosis of PTE, echocardiographic signs of acute right ventricular pressure
overload, and mismatch in pulmonary perfusion–ventilation scintigrams are
useful. Echocardiographic and chest computed tomographic studies may detect
thrombi in the heart or the main pulmonary arteries.
Physiotherapy for paretic legs soon after stroke onset is essential for the
prevention of DVT and PTE. Prophylactic subcutaneous injection of heparin or
low‐molecular‐weight heparin is recommended for the prevention of DVT and
PTE for AIS patients having severe paralysis of the lower extremities. Because of
a risk of intracranial and extracranial hemorrhage, routine administration
cannot be recommended to AIS patients [20,21]. Aspirin and dextran are not
recommended for the prevention of DVT and PTE.
Step‐by‐step compression stockings are not recommendable for the preven-
tion of DVT, because sufficient scientific evidence of these therapies is lacking
[22,23]. Intermittent pneumatic compression is recommendable for the preven-
tion of DVT and PTE in AIS, based on results in a recent large‐scale clinical trial
[22,24].
Fever
Central hyperthermia often causes poor clinical outcome in patients with acute
stroke [25]. Use of an antipyretic is recommended to lower elevated body
temperature in patients with acute stroke. However, the scientific evidence for
normothermia therapy is inadequate [26].
Hypothermic treatment can be considered in treatment of AIS, although
adequate scientific evidence is unavailable at present [25]. Mild hypothermic ther-
apy using acetaminophen has shown no clinical benefit in AIS patients [27,28].
Seizure
Seizure after stroke is not rare (approximately 10%) and may be related to poor
clinical outcome and death during hospitalization [29]. Prophylactic treatment
for several days may be given to elderly patients with large hemorrhagic infarcts
involving the cortex, because seizures may worsen the ischemic process by
increasing cerebral oxygen demand. Routine prophylactic use of anticonvul-
sants, however, is not recommended for AIS patients without seizures.
Seizures that occur within the initial 14 days are called early seizures, have a
reported incidence of 2.5–5.7%, hardly ever recur, and do not affect the outcome.
In contrast, seizures may recur in patients who develop a seizure more than
14 days after onset (delayed seizure) and may well progress to symptomatic epi-
lepsy, therefore continuous antiepileptic treatment is recommended in such cases.
0003172473.INDD 35 8/22/2017 10:16:57 AM

Dysphagia
Dysphagia carries the risk of causing aspiration pneumonia and worsening
clinical outcome; therefore, an appropriate evaluation is essential before starting
oral intake of water, meals, or drugs. Patients with brainstem infarcts, multiple
infarcts, and large infarcts are high‐risk groups for dysphagia. For patients with
possible dysphagia, a water‐swallowing test is useful as a simple screening test at
the bedside. To evaluate swallowing state more accurately, a videofluoroscopic
(VF) swallow examination is recommended. When a patient is determined to be
at high risk for aspiration, an appropriate mode of delivering nourishment
(nasogastric tube or percutaneous endoscopic gastrostomy) and prevention of
aspiration is recommended.
Headache
Headache occurs in approximately one‐third of patients immediately after the
stroke onset. There is, however, no relationship between headache and the size
or location of the lesion of ischemic stroke. Headache as an accompaniment of
stroke often disappears in a short period of time, but non‐narcotic analgesics can
be used when the headache is severe.
Other medical therapies for acute ischemic stroke
Hyperbaric oxygen therapy

The number of randomized controlled trials investigating the efficacy of hyper-
baric oxygen therapy in AIS patients is too small to provide sufficient scientific
evidence supporting its efficacy [30].
Hemodilution
Hemodilution therapy can be considered for the treatment of AIS. However,
therapy using plasma expanders or extracorporeal circulation has not been dem-
onstrated to be effective for AIS.
References
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A quasi‐randomized controlled trial. Stroke 1999;30:2033–7.
2. Minnerup J, Ritter MA, Wersching H, et al. Continuous positive airway pressure ventilation
for acute ischemic stroke: A randomized feasibility study. Stroke 2012;43:1137–9.
3. Oliveira‐Filho J, Silva SC, Trabuco CC, et al. Detrimental effect of blood pressure reduction
in the first 24 hours of acute stroke onset. Neurology 2003;61:1047–51.
4. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with
acute ischemic stroke. A guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke 2013;44:870–947.
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5. Minematsu K, Toyoda K, Hirano T, et al. Guidelines for the intravenous application of
recombinant tissue‐type plasminogen activator (alteplase), the second edition, October
2012: a guideline from the Japan Stroke Society. J Stroke Cerebrovasc Dis 2013;22:
571–600.
6. Robinson TG, Potter JF, Aord GA, et al. Effects of antihypertensive treatment after acute
stroke in the Continue or Stop Post‐Stroke Antihypertensive Collaborative Study (COSSACS);
a prospective, randomized, open, blinded‐endpoint trial. Lancet Neurol 2010;9:767–75.
7. Yoo SH, Kim JS, Kwon SU, et al. Undernutrition as a predictor of poor clinical outcomes in
acute ischemic stroke patients. Arch Neurol 2008;65:39–43.
8. Dennis MS, Lewis SC, Warlow C. Routine oral nutritional supplementation for stroke
patients in hospital (FOOD): a multicenter randomized controlled trial. Lancet 2005;365:
755–63.
9. Rabadi MH, Coar PL, Lukin M, et al. Intensive nutritional supplements can improve
outcomes in stroke rehabilitation. Neurology 2008;71:1856–61.
10. Wagner KR, Kleinholz M, de Courten‐Myers GM, Myers RE. Hyperglycemic versus normo-
glycemic stroke: Topography of brain metabolites, intracellular pH, and infarct size. J Cereb
Blood Flow Metab 1992;12:213–22.
11. Yasaka M, Yamaguchi T, Miyashita T, et al. Predisposing factors of recurrent embolization in
cardiogenic cerebral embolism. Stroke 1990;21:1000–7.
12. Yu YL, Kumana CR, Lauder IJ, et al. Treatment of acute cortical infarct with intravenous
glycerol. A double‐blind, placebo‐controlled randomized trial. Stroke 1993;24:1119–24.
13. Righetti E, Celani MG, Cantisani T, et al. Glycerol for acute stroke. Cochrane Database Syst Rev
2004;(2):CD000096.
14. Bereczki D, Liu M, Prado GF, Fekete I. Cochrane report: A systematic review of mannitol
therapy for acute ischemic stroke and cerebral parenchymal hemorrhage. Stroke
2000;31:2719–22.
15. Davenport RJ, Dennis MS, Wellwood I, Warlow CP. Complications after acute stroke. Stroke
1996;27:415–20.
16. Langhorne P, Scott DJ, Robertson L, et al. Medical complications after stroke: a multicenter
study. Stroke 2000;31:1223–9.
17. Davenport RJ, Dennis MS, Warlow CP. Gastrointestinal hemorrhage after acute stroke.
Stroke 1996;27:421–4.
18. Kitamura T, Ito K: Acute gastric changes in patients with acute stroke. 1. With reference to
gastroendoscopic findings. Stroke 1976;7:460–3.
19. Yi X, Lin J, Han Z, et al. The incidence of venous thromboembolism following stroke and its
risk factors in eastern China. J Thromb Thrombolysis 2012;34:269–75.
20. Chua K, Kong KH, Chan SP. Prevalence and risk factors of asymptomatic lower extremity
deep venous thrombosis in Asian neurorehabilitation admissions in Singapore. Arch Phys
Med Rehabil 2008;89:2316–23.
21. Sandercock PA, Counselle C, Kamal AK. Anticoagulants for acute ischaemic stroke.
Cochrane Database Syst Rev 2008;(4):CD000024.
22. Dennis M, Sandercock PA, Reid J, et al. Effectiveness of thigh‐length graduated compres-
sion stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a
multicenter, randomized controlled trial. Lancet 2009;373:1958–65.
23. Naccarato M, Chiodo Grandi F, Dennis M, Sandercock PA. Physical methods for preventing
deep vein thrombosis in stroke. Cochrane Database Syst Rev 2010;(8):CD001922.
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sion in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS
3): a multicenter, randomized controlled trial. Lancet 2013;382:516–24.
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26. Dippel DW, van Breda EJ, van Gemert HM, et al. Effect of paracetamol (acetaminophen) on
body temperature in acute ischemic stroke: a double‐blind, randomized phase II clinical
trial. Stroke 2001;32:1607–12.
27. Kasner SE, Wein T, Piriyawat P, et al. Acetaminophen for altering body temperature in
acute stroke: A randomized clinical trial. Stroke 2002;33:130–4.
28. den Hertog HM, van der Worp HB, van Gemert HM, et al. The Paracetamol (Acetaminophen)
In Stroke (PAIS) trial: a multicenter, randomized, placebo‐controlled, phase III trial. Lancet
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29. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multi-
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stroke. Cochrane Database Syst Rev 2005;(3):CD004954.
0003172473.INDD 38 8/22/2017 10:16:57 AM

CHAPTER 4
The stroke unit

Jose C. Navarro and Jeyaraj D. Pandian
Introduction
Currently there are very few evidence‐based interventions available for acute
ischemic stroke and these are: aspirin (ASA), intravenous recombinant tissue
plasminogen activator (IV rtPA), mechanical thrombectomy, decompressive
hemicraniectomy, stroke units (SUs), and, for hemorrhagic strokes, blood pres-
sure (BP) lowering in the acute phase. These options have been recommended
in almost all stroke guidelines following a high level of evidence. However,
the applicability to the community of these different interventions for acute
stroke varies. Thrombolysis, both intravenously and intra‐arterially with rtPA
and mechanical thrombectomy, has been shown to be very effective; however,
utilization in the community has been limited because of the short time window
for triage and treatment [1,2]. On the other hand about 80% of acute stroke
patients are qualified to be admitted to an SU and this has shown to reduce
mortality and morbidity [3,4]. SUs are hospital‐based infrastructures that enable
and facilitate the complex process of organized treatment of stroke patients [5].
An SU is defined as “a geographic location within the hospital where stroke
patients are exclusively managed by coordinated multidisciplinary team which
includes stroke physician, nurses, therapists, social workers etc.” [6].
In spite of the significant benefits of SU care [7] its widespread implementa-
tion seems to be not well utilized in the community. The purpose of this chapter
is to review the basic aspects of SUs and most importantly to offer solutions
to the common obstacles seen during the implementation of SUs. It must also
be emphasized that an SU is the backbone of the whole organization of stroke
services [8].
In the 1950s, the earliest studies on the establishment of an appropriate
organizational model for stroke management with emphasis on aspects of
rehabilitation were reported [5]. It was in the 1970s that the idea of the SU was
suggested for the first time. Initially, these units were patterned after coronary
39
0003172474.INDD 39 8/22/2017 10:19:40 AM

Table 4.1 “Landmarks” in the history of stroke unit care, adapted with permission from

Stroke Units: an Evidence Based Approach [6].
1950 First published reports of organized stroke care [18]

1962 First published RCT of a system of stroke rehabilitation [19]
1970 Reports (no RCT) of stroke intensive care units [9]
1980 First large (>300 patients) RCT of a stroke unit shows only short‐term benefits [20]
1985 RCT of a mobile stroke team [21]
1988 King’s Fund Consensus Conference statement criticizes stroke services [22]
1990 Small systematic review suggests possible benefit of stroke unit care [23]
1991 RCT of stroke unit provides convincing evidence of benefit [16]
1993 First RCT on an acute unit (intervening only in the first few days) [24]
1993 Systematic review (10 RCTs) suggesting stroke unit care may prevent premature deaths [25]
1995 Pan American Consensus Meeting supports organized stroke unit care [26]
1997 Updated systematic review (18 RCTs) shows a reduction in dependency [27,28]
RCT, randomized controlled trial.
care units, with facilities for monitoring and for the administration of intensive
therapy. The results were very variable and did not show a clear reduction in
mortality, although a reduction in complication rates was noted [9–13].
In the 1980s, the concept of the SU evolved to include acute‐phase treatment
and early functional rehabilitation and early return to the community. This
probably is the frontrunner of the multidisciplinary team approach in the man-
agement of stroke patients. In the 1990s, interest in SUs was renewed following
the publication of several studies comparing SUs with general medical wards
that demonstrated the benefits in terms of mortality, functional recovery, and
reduction in rates of chronic institutionalization [14–17]. Table 4.1 shows the
historical “landmark” evolution of the SU.
Numerous definitions have been given for a stroke unit, from a team of phy-
sicians with certain specialty being consulted in the whole hospital to a special
area in the hospital managing stroke cases. The Helsingborg declaration (2006)
defines an SU as “a unit with dedicated beds offering an approach to inpatient
care through multidisciplinary care by a dedicated stroke team” [8].
According to this definition there are several potential advantages of a stroke
unit for the benefit of the patients. Several categories of SU have also been
defined, mainly based on admission policy. There are two major types of stroke
units: (i) acute admission units that admit patients within 1 week of stroke onset,
and (ii) delayed admission units that admit patients at least 1 week after stroke
onset and that mainly focus on rehabilitation [29,30].
The following are examples of acute admission units [28]:
1 Intensive care units (ICUs) are dedicated SUs with facilities such as ventilators
and intensive invasive and non‐invasive monitoring equipment. The units
focus on the very acute care of a selected group of acute stroke patients, but
have little or no focus on rehabilitation.
0003172474.INDD 40 8/22/2017 10:19:40 AM

The stroke unit 41
2 Acute stroke units (ASUs) are dedicated SUs that accept patients acutely but
discharge them early (within 7 days). Once stabilized, the patient is trans-
ferred to the general neurology ward, where the diagnostic–therapeutic pro-
cess continues up until discharge from hospital or transfer to rehabilitation or
to geriatric units. They have a modest focus (at best) or none on rehabilitation.
The units usually do not have intensive care facilities, but usually have facili-
ties for non‐invasive monitoring of vital signs.
3 Combined acute/rehabilitation SUs are dedicated SUs that accept stroke
patients acutely for acute treatment, combined with early mobilization and
rehabilitation for an average period of at least 1–2 weeks.
4 Mixed acute units are units that treat stroke patients and patients with other
diagnoses. These units accept patients acutely. Some units have a program of
care similar to that of ASUs or combined SUs.
Benefits of the stroke unit
Numerous studies have been published establishing the benefit of SU care across
all ages, gender, type of stroke, and severity. However, in spite of the reported
benefits of SU care, the number of established SUs is still quite low even in
well‐developed countries. This scarcity is well observed in the developing
countries such as in Asia, especially in rural areas.
Early reports of intensive stroke management did not show any benefit for
patients with acute stroke. An appraisal of stroke intensive care was done in
1970 from a center in North America. Its objectives, physical plan, nurse training
and staffing, and the operation of the unit were discussed. Patients admitted to
this stroke intensive care unit (SICU) were compared with those from two other
community hospitals that served as control. Despite intensive care for these
stroke patients in the acute phase, with trained personnel, the study did not show
any benefit in terms of mortality reduction [31]. In another study evaluating
the benefit of stroke intensive care in a municipality hospital with four‐bed
stroke intensive care, the mortality was not reduced among patients admitted
for stroke intensive care [32]. These two studies on intensive care management
of stroke patients did not seem to show reduced death rate, however the work
done by Drake in 1973 reported otherwise. He described the outcome of patients
managed at three community hospitals before and after the institution of the
neurovascular care unit (NCU) [33]. This paper showed a significant decline in
mortality of non‐hemorrhagic stroke. This reduction in deaths was attributed to
the reduction of complication‐related deaths.
The first large randomized controlled trial (RCT) was carried out in 1980,
comparing elderly patients with acute stroke admitted to the SU and medical
units. A significant number of patients discharged from the SU were assessed as
independent (78 out of 155) compared with patients from the medical ward
0003172474.INDD 41 8/22/2017 10:19:40 AM

(40 out of 152) [20]. Subsequent papers reported almost identical results in
reduction of mortality and improvement of outcome among patients admitted to
the SU [34,35].
Two meta‐analyses and systematic reviews have been performed comparing
organized inpatient SU with general/neurology ward care. The first collaborative
review performed in 1997 consisted of 19 trials with a total of 2006 patients
included for analysis. It showed a significant reduction in death, death or
dependency, and death or institutionalization [28]. In terms of absolute out-
come rates, the number needed to treat (NNT) to prevent one death is 22. It is
necessary to treat 14 patients for one to be able to live at home, thus reducing
disability. Patients in the SU have a relatively shorter period of confinement
compared to non‐SU patients. In spite of the fact that there are certain limita-
tions such as the non‐uniformity in personnel and structural set‐up, the impor-
tant components of an SU are in place in participating SUs. Multidisciplinary
team care with nursing integration, comprehensive rehabilitation, and interest
of personnel in stroke medicine and stroke care have significantly improved the
outcome in the SU.
The other meta‐analytic study on organized inpatient care for stroke was car-
ried out in 2013 by the Cochrane Collaboration group. This study excluded quasi‐
randomized trials to avoid further bias in the analysis. It included 28 trials
involving 5855 patients and compared SU care with an alternative service. Stroke
unit care was shown to reduce the odds of death at 1‐year follow‐up (odds
ratio [OR] = 0.87, 95% confidence interval [CI] = 0.69–0.94, p = .005), the odds
of death or institutionalized care (OR = 0.78, 95% CI = 0.68–0.89, p = .0003), and
the odds of death and dependency (OR = 0.79, 95% CI = 0.68–0.90, p = .0007).
Furthermore it also showed that these benefits for patients admitted to an SU
were independent of patients’ age, sex, initial stroke severity, and stroke type.
This meta‐analysis has further reinforced whatever benefit was seen in the col-
laborative systematic review of RCT of organized stroke care in the SU in 1977.
Applicability of the stroke unit
Despite the numerous data supporting the benefits of SU care for patients with
acute stroke, it seems that its implementation has not permeated to the majority
of hospitals in some countries or is only limited to big medical centers. It is rather
unfortunate that this “easy” to implement strategy for organizing a stroke ser-
vice is mostly neglected. Some physicians clamor more for IV thrombolysis with
obvious disregard to the establishment of SUs.
Gilligan and colleagues analyzed the eligibility of stroke patients for different
specific treatments available in the hospital and in the general population. The
results were then extrapolated to the general population. It was shown that 83%
would be candidates for management in a specialized SU, 40% for treatment
0003172474.INDD 42 8/22/2017 10:19:40 AM

The stroke unit 43
7% Mechanical thrombectomy
NNT 5
10% Intravenous thrombolysis
NNT 16
10 40% Aspirin
8
NNT 83
6
4
2
0 80% Stroke units
IV Thrombolysis Aspirin Stroke units NNT 18
% death or dependence avoided
Target population
Fig. 4.1 Applicability and effectiveness of treatment for acute stroke patients. Modified from
Fuentes and Díez‐Tejedor [36].
with aspirin in the first 48 h, and only 10% for IV thrombolysis with rtPA in the
first 3 h. These data indicated that greater benefit to the community is achieved
with SU care. However, all these therapeutic measures should be accessible to
acute stroke patients, and access to the SU needs to be considered a priority [4].
Following the work of Fuentes and Díez‐Tejedor, the applicability of all
modalities for acute stroke treatment was analyzed and the benefit of such treat-
ment was presented in terms of NNT [36] (Fig. 4.1). Almost 80% of the target
population who developed acute stroke were eligible to be admitted at the
SU with an NNT of 18. About 40% of acute stroke patients could be given aspirin
with an NNT of 83. Only 10% of acute ischemic stroke patients would qualify for
IV thrombolysis; however, it has a low NNT of 16. The newer technique of
mechanical thrombectomy could be applicable to about 5–10% of patients with
large vessel occlusion and a NNT of 5 [37]. Obviously, strategies requiring exten-
sive personnel such as thrombolysis and mechanical thrombectomy may only be
applicable to a small number of patients. However, the benefit is much greater
than SU and aspirin.
How to organize/develop a stroke unit

in a resource‐limited setting
Incorporation of SUs into healthcare development at a national, regional, or

local level seems to be difficult in many developing countries where most of the
population is likely to depend on publicly funded healthcare [14]. Stroke unit
care is a complex intervention requiring the interplay of several interrelated
components [38]. However, setting up an SU mainly involves a reorganization
of services without necessarily demanding greater resources overall. Thus, its
0003172474.INDD 43 8/22/2017 10:19:41 AM

implementation in the developing world where there are restricted healthcare

resources should be emphasized [39]. Stroke units generally make more effi-
cient use of existing staff and beds than do other care units, and might therefore
eventually increase the resources available to the hospital.
The key component in the implementation of an SU is likely to be enthusias-
tic leadership from a clinician who is willing to act as a champion for develop-
ment [40]. Clinicians should establish the need for an SU in their own hospitals
and should establish the case for such development. This establishment will
need an understanding of the local healthcare system and the pressures under
which it operates. Furthermore, clinicians should engage and persuade key deci-
sion‐makers at an early stage. Clinicians should decide which model of SU care
is most appropriate for their setting and should try to adopt it as closely as pos-
sible. A gradual approach might lead to less resistance than would a sudden
change. Involvement of staff in changes and decision‐making can be useful to
move forward changes in practice. Many nursing and therapy staff value oppor-
tunities for multidisciplinary teamwork. Training or learning and the potential to
improve patient care in an SU should be encouraged among the staff. After an
SU is established, monitoring of its effect is important [41].
The steps in setting up an SU in any hospital [39] are as follows:
1 Find a physician, preferably a neurologist with interest or training in stroke,
to run the stroke service and in particular the stroke unit.
2 Set up a multidisciplinary stroke team comprising members of professions
interested or trained in the various aspects of stroke care.
3 Encourage all physicians treating stroke patients to participate in the stroke
unit.
4 Conduct team ward rounds.
5 Convince the hospital authorities to cohort stroke patients geographically.
6 Establish protocols in patient management to guide junior doctors and nurses
in day‐to‐day management. These protocols should be tailored to the health-
care setting, practices, spectrum of diseases, available services, and financial
resources of the patients and the community.
7 Support the stroke unit with easy access to neuroimaging (CT brain, angiog-
raphy) and neurosurgical consultancy services, preferably on a 24 h basis.
8 Carry out frequent and continuous audit and review of the services. Integral
to the development of stroke units is the continuous striving for quality
improvement using clinical practice guidelines. Furthermore, the training of
nursing and therapy staff is a prerequisite to allow a common understanding
of SU practices, such as multidisciplinary team working.
The presence of a multidisciplinary team, comprising medical, nursing, physio-
therapy, occupational therapy, speech therapy, and social work staff, who coor-
dinate their work through regular meetings, is an essential feature of SU care.
This teamwork includes holding formal multidisciplinary team meetings at least
once a week, and close linking of nursing practice with other multidisciplinary
0003172474.INDD 44 8/22/2017 10:19:41 AM

The stroke unit 45
activities. These meetings introduce the patients to the team and provide a forum
for multidisciplinary assessment, identification of problems, and setting of
short‐term and long‐term recovery goals. Stroke units typically include early
active involvement of carers in the rehabilitation process and usually have a
program of ongoing education and training [42,43].
Stroke units in Asia
Unfortunately there are not many studies on SUs in Asia. This is probably another
indication of the failure in organization of stroke services. In 1997, a report on the
establishment and operation of an SU in a tertiary hospital in Singapore was pub-
lished [39]. As a component of the program, the SU consists of an eight‐bed
stroke intensive care unit with a four‐bed high dependency care area. Aside from
the minimum equipment required in an SU, the unit is also equipped with some
highly specialized tools to monitor blood flow and intracranial pressure. Both
neurologists and neurosurgeons are involved in the management of stroke
patients. Guidelines and a stroke care pathway were developed and observed
by the staff of the unit. A critical comparison with stroke patients admitted to
general or neurology wards was not reported in this paper.
A study from Beijing assessed the effectiveness of SU compared with gen-
eral ward care among early stroke patients and it showed benefit for SU.
Patients were assessed utilizing the Barthel Index, NIHSS, and Oxford Handicap
scale. Patients treated in a special SU were able to return to normal activities
and had better social abilities and less neurologic disability [44]. Additionally,
the effect of SU care on Chinese stroke patients was reported from an estab-
lished comprehensive SU [45]. Following a group‐matched assembly of
patients, 188 patients from the SU and 177 from the general ward were
recruited and followed up at 28 and 120 days. Additionally, the length of hos-
pitalization was also compared. This study showed a reduction in mortality of
patients between SU patients and general ward stroke patients, 3.3% vs 17.2%
at 28 days and 5% vs 24.7% at 120 days. Furthermore the length of hospitali-
zation was shorter among patients admitted to the SU compared to the general
ward (37.1 days vs 69.3 days).
A report on stroke care services in India was published in 2013 [46]. The only
study done in India comparing SU care with conventional medical treatment
showed a reduction in mortality and complications, and a higher proportion
of patients were initiated on secondary prevention strategies including access
to rehabilitation services [47]. In India, SUs are largely present in urban
private hospitals but now there are a few states in the country where SUs are
being implemented in government hospitals. The physicians are being trained
by neurologists to run these SUs in government medical college hospitals.
Thrombolysis also is being delivered using a hub and spoke model [48].
0003172474.INDD 45 8/22/2017 10:19:41 AM

The latest meta‐analysis of the effectiveness of SU care in resource‐limited set-

tings has clearly shown a benefit [41].
A clinical trial in the Philippines comparing stroke patients admitted to
the SUs and general/neurology wards (Clinicaltrial.gov #03000959) is being
carried out. Twelve centers from the Philippines will be recruiting 1000 patients.
Twelve hospitals are participating. The primary outcome measure is mortality
at 3 months, and the secondary outcome will be modified Rankin scale score at
3 months.
Medical expertise in stroke care might be limited by a shortage of trained staff.
Capacity could be increased by provision of training for physicians to develop
knowledge and skills in stroke care and the development and implementation of
practical protocols that can be used by generalist doctors and that could improve
the medical care of most patients with stroke [49]. These protocols should include
on admission, diagnostic assessment, investigations, management of risk factors,
and prevention and management of complications.
Access to diagnostic imaging and supporting investigations is clearly impor-
tant when antithrombotic treatments, such as thrombolysis and anticoagulation,
are considered.
A key feature of SU care is early systematic identification of dysphagia and
appropriate management of feeding and fluids to prevent aspiration pneumonia.
Findings from the largest randomized trial so far [50] showed a reduction in
medical complications related to swallowing, chest infections, and death after
the implementation of early intervention for swallowing, including active
therapeutic approaches and dietary modification.
Early mobilization is thought to be a key component of management in acute
SUs and is the subject of a large ongoing multicenter trial [51]. A key component
when nursing patients with acute stroke is the prevention of pressure‐related
injuries [41,52].
Early and efficient discharge planning is a key characteristic of effective SU
care. This planning includes early assessment of discharge needs, identifica-
tion of recovery goals, discharge planning involving the patient and their
family, and (ideally) early rehabilitation input in the home. Findings from
systematic reviews of discharge planning [52] and early supported discharge
services [53,54] indicate the importance of these processes in high‐quality
stroke care.
Conclusion
A significant role is played by the SU in the organization of stroke services. The

establishment of an SU does not require any major infrastructure and staff need
only reorientation of stroke knowledge. Team effort is crucial in management,
and everyone involved in the SU should strictly observe protocol and the care
0003172474.INDD 46 8/22/2017 10:19:41 AM

The stroke unit 47
pathway. Following the applicability of different stroke management strategies,

the majority of patients with stroke regardless of age, sex, severity, and type
would benefit from SU care. In closing we quote Dr LR Caplan “There is no
longer doubt that stroke units work” [55].
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0003172474.INDD 49 8/22/2017 10:19:41 AM

CHAPTER 5
Antithrombotics for acute stroke

Tsong‐Hai Lee and Hou‐Chang Chiu
Definition and rationale of treatment
Stroke is one of the leading causes of death in the world and the leading cause
of adult disability. In 1996, the U.S. Food and Drug Administration approved the
first treatment for acute ischemic stroke, intravenous recombinant tissue plasmi-
nogen activator (rtPA). Later that year, the National Institute of Neurologic
Disorders and Stroke (a branch of the National Institutes of Health) convened a
consensus conference on the Rapid Identification and Treatment of Acute
Ischemic Stroke, setting goals for acute stroke care in the United States. Since
then, it has been recognized that time is brain and urgent management of acute
ischemic stroke can improve functional outcome and reduce stroke mortality.
After the treatment of rtPA and the more recent endovascular revascularization
in acute ischemic stroke, the use of antithrombotics is the treatment of choice.
Physicians who are able to understand the pathophysiology of stroke, the basis
and rationale for treatment, and the therapeutic approaches to the disease pro-
cess can largely improve the outcome of acute stroke.
Mechanism of antithrombotics
Several antiplatelet agents have been used for stroke prevention. Among them,
aspirin is an established drug in the regimen for the prevention of myocardial
infarction and ischemic stroke and is probably the oldest synthetic drug in phar-
macopoeias today. Aspirin inhibits the cyclo‐oxygenase enzyme in the platelets
leading to reduced formation of prostaglandin G2, the precursor of thrombox-
anes, to inhibit thrombotic reaction [1]. Clopidogrel is a novel adenosine diphos-
phate (ADP)‐selective agent whose anti‐aggregating properties are several times
higher than those of ticlopidine. Clopidogrel is active only after intravenous or
oral administration, and no circulating activity has been found in the plasma of
50
0003172475.INDD 50 8/22/2017 1:08:11 PM

Antithrombotics for acute stroke 51
treated animals or human volunteers. The anti‐aggregating property of clopidogrel

is caused by inhibition of the binding of ADP to its platelet receptors, and more
specifically to the low-affinity receptors, whereas the high-affinity binding sites
are unaffected by clopidogrel [2]. Cilostazol is an antiplatelet agent that acts as a
specific inhibitor of 3′,5′‐cyclic adenosine monophosphate (cAMP) phosphodies-
terase in platelets and vascular endothelium [3–5]. Cilostazol can induce nitric
oxide (NO) production by activation of endothelial NO synthase via a cAMP/PKA‐
and PI3K/Akt‐dependent mechanism. It improves endothelial function and inhib-
its inflammatory reactions. Ticagrelor, a direct‐acting, potent, fast‐acting P2Y12
inhibitor, is the first drug of the chemical class called cyclopentyltriazolopyrimi-
dine, which has a reversible P2Y12 receptor inhibitory effect. Preclinical and
early‐phase clinical studies have shown ticagrelor to be characterized by a rapid,
greater, and consistent antiplatelet effect with a favorable safety profile [6].
Single antiplatelet therapy

Among antiplatelet drugs, aspirin is the most widely studied in the treatment of
acute ischemic stroke. In 1997, the results of the Chinese Acute Stroke Trial
(CAST) [7] and International Stroke Trial (IST) [8] suggested that aspirin, if
given 160 or 300 mg within 48 h after acute stroke onset, can produce a small
but real reduction of about 10 deaths or recurrent strokes per 1000 during the
first few weeks after acute ischemic stroke, and there is no increased risk of
intracranial hemorrhage. The meta‐analysis of both trials [9] suggests that if
aspirin can be started as early as possible after the onset of ischemic stroke,
stroke risk is significantly decreased. This benefit could be due to the reduced
risk of recurrent stroke. However, in terms of 6‐month mortality and functional
outcome, there was no significant difference between aspirin and placebo
groups. It is recommended that aspirin should be prescribed as early as possible
after ischemic stroke onset.
However, there is limited evidence for other antiplatelet treatments in the
prevention of acute ischemic stroke. For those patients with acute ischemic
stroke or transient ischemic attack (TIA) who were already taking aspirin regu-
larly or had aspirin allergy or intolerance, a previous study found the bolus
administration of 300–600 mg clopidogrel within 25 h after stroke onset may
result in a lower median score on the National Institutes of Health Stroke Scale
(NIHSS) at 24 h than the NIHSS at baseline, and there was no neurological dete-
rioration or hemorrhagic transformation [10]. However, this study enrolled a
small number of 20 patients, and the potential for risk reduction in early recur-
rent stroke needs to be studied in future large trials.
The efficacy and safety of cilostazol in acute stroke have also been compared
in 447 patients with NIHSS score ≤15 within 48 h of onset. These patients
0003172475.INDD 51 8/22/2017 1:08:11 PM

were randomly assigned to cilostazol (200 mg/day) or aspirin (300 mg/day) for

90 days [11]. The primary endpoint of a modified Rankin Scale (mRS) score of
0–2 at 90 days was achieved in 76% with cilostazol and in 75% with aspirin,
supporting the non‐inferiority of cilostazol to aspirin (p = .0004). Cardiovascular
events were no different between the cilostazol (3%) and aspirin (4%, p = .41)
groups. Although adverse events were more common in cilostazol than aspirin
groups but insignificant (cilostazol vs aspirin: 91% vs 85%, p = .055), the fre-
quencies of bleeding complications (11% vs 13%, p = .43) or drug discontinua-
tion (10% vs 7%, p = .32) were no different. This study suggests that cilostazol is
comparable to aspirin in its efficacy and safety and can be feasible in the treat-
ment of acute ischemic stroke.
Another randomized controlled trial has been conducted to investigate the
effect of cilostazol on progressing non‐cardioembolic ischemic stroke within 24 h
after onset. In 510 patients, the rate of progressing stroke was 3.2% in the
cilostazol group and 6.3% in the control group (p = .143), suggesting a trend of
cilostazol to prevent against acute progressing stroke but this was insignificant
[12]. Nevertheless, these two cilostazol trials have the limitation of relatively
small patient numbers and more evidence is needed.
The SOCRATES trial studied the outcome in patients with acute ischemic
stroke or TIA treated with aspirin or ticagrelor. The results showed that when
compared to aspirin, ticagrelor demonstrated no superiority in reducing the rate
of composite event of stroke, myocardial infarction, or death at 90 days (hazard
ratio [HR] = 0.89, 95% confidence interval [CI] = 0.78–1.01, p = .07). Also, there

was no significant interaction in terms of the efficacy of ticagrelor vs aspirin with

respect to race—Asian and non‐Asian [13]. In the Asian subgroup analysis
with the outcome study assessed in a prespecified exploratory analysis, the
primary endpoint event defined as the time from randomization to the first
occurrence of any event from the composite event of stroke (ischemic or hemor-
rhagic), myocardial infarction, or death, was found in 9.6% of the ticagrelor
group compared to 11.6% of the aspirin group (HR = 0.81, 95% CI = 0.67–0.99,

nominal p = .04). Ischemic stroke occurred in 8.9% of the ticagrelor group vs

10.8% of the aspirin group (HR = 0.81, 95% CI = 0.66–0.99, nominal p = .04).
The primary endpoint event rate was 10.6% in the Asian subgroup, numerically
higher than the 5.7% in the non‐Asian group (nominal p < .01). Results were
similar for the outcome of ischemic stroke. As to the safety outcomes in Asian
patients, the rate of PLATO (Platelet Inhibition and Patient Outcomes)‐defined
major bleeding was similar between the ticagrelor and aspirin groups (0.6% vs
0.8%; HR = 0.76, 95% CI = 0.36–1.61, p = .47) and also major or minor bleeding
events were similar between the ticagrelor and aspirin groups (2.4% vs 1.9%;
HR = 1.22, 95% CI = 0.78–1.91, nominal p = .39). There is consistent safety of
ticagrelor vs aspirin among patients in and outside Asia (p for interaction = .76).
There is also consistent efficacy and safety of ticagrelor vs aspirin in Asian patients
and non‐Asians with acute stroke or TIAs. The event rates were numerically
0003172475.INDD 52 8/22/2017 1:08:11 PM

higher in the Asian patients, and there was a trend toward a lower HR in reduc-
ing risk of the composite event of stroke, myocardial infarction, or death in the
ticagrelor group among the Asian patients [14].
Dual antiplatelet therapy

The effect of dual antiplatelet therapy in acute ischemic stroke treatment has
also been studied. The EARLY trial compared acute ischemic stroke patients who
were randomly assigned to receive dual antiplatelet therapy (25 mg aspirin plus
200 mg extended‐release dipyridamole twice daily) or monotherapy (100 mg
aspirin once daily) for 7 days. After 7 days, all patients were given aspirin plus
extended‐release dipyridamole for up to 90 days. The results showed that 56%
of patients in the aspirin plus early extended‐release dipyridamole group and 52%
in the aspirin plus later extended‐release dipyridamole group had no or mild dis-
ability at day 90 (difference = 4.1%, 95% CI = −4.5 to 12.6, p = .45). The compos-
ite safety and efficacy endpoint of vascular adverse events (non‐fatal stroke, TIA,
non‐fatal myocardial infarction, and major bleeding complications) and mortal-
ity was also no different between the two groups (HR = 0.73, 95% CI = 0.44–1.19,
p = .20). The study suggested that initiation of aspirin plus early extended‐release
dipyridamole within 24 h of stroke onset is likely to be as safe and effective in
preventing disability as is later initiation after 7 days [15].
Two clinical trials used the combination therapy of aspirin plus clopidogrel in
acute ischemic stroke. The FASTER trial in Caucasians randomly assigned patients
with TIA or minor stroke to clopidogrel (300 mg loading dose then 75 mg daily)
or placebo, and simvastatin (40 mg daily) or placebo. All patients were also given
aspirin and followed for 90 days: 7.1% of patients on clopidogrel and 10.8% of
patients on placebo had a stroke within 90 days (risk ratio = 0.7 [95% CI = 0.3–
1.2]; absolute risk reduction = −3.8% [95% CI = −9.4 to 1.9]; p = .19). Two patients
on clopidogrel and none on placebo had intracranial hemorrhage (absolute risk
increase 1.0% [95% CI = −0.4 to 2.4]; p = .5). The FASTER trial suggests that imme-
diate use of clopidogrel plus aspirin after TIA or minor stroke might have the
potential to reduce the risk of stroke, and the hemorrhagic risks of the combina-
tion of aspirin and clopidogrel do not seem to offset this potential benefit [16].
Another clinical trial, the CHANCE study in China, compared combination
therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg,
followed by 75 mg/day for 90 days, plus aspirin at a dose of 75 mg/day for
the first 21 days) with placebo plus aspirin (75 mg/day for 90 days) in preven-
tion of subsequent stroke in patients within 24 h after the onset of minor
ischemic stroke or high‐risk TIA. The CHANCE study showed that stroke
occurred in 8.2% of patients in the clopidogrel–aspirin group and 11.7% in
the aspirin group (HR = 0.68, 95% CI = 0.57–0.81, p < .001). Seven patients
(0.3%) in the clopidogrel–aspirin group and eight (0.3%) in the aspirin group
(p = .73) had moderate or severe hemorrhage, and the rate of hemorrhagic
stroke was 0.3% in each group. The CHANCE study suggested that the dual
0003172475.INDD 53 8/22/2017 1:08:11 PM

antiplatelet therapy of clopidogrel and aspirin is superior to aspirin alone in

reducing the risk of stroke at 90 days and does not increase the risk of hemorrhage
among patients with TIA or minor stroke [17].
Clopidogrel (300 mg for the first day, then 75 mg daily) plus aspirin (75–160 mg
daily) vs aspirin alone (75–160 mg daily) for 7 days has also been examined in the
CLAIR trial in patients with TIA or acute ischemic stroke who had symptomatic
large artery stenosis in the cerebral or carotid arteries. Fourteen of 45 patients in
the dual antiplatelet group and 27 of 50 patients in the monotherapy group were
found to have at least one microembolic signal on transcranial Doppler within
7 days of symptom onset (relative risk reduction = 42.4%, 95% CI = 4.6–65.2,
p = .025). Adverse events were similar in the two groups. No patient in either
group had intracranial or severe systemic hemorrhage, and only two patients in
the dual therapy group had minor hemorrhages. This CLAIR study suggested that
combination therapy with clopidogrel and aspirin is more effective than aspirin
alone in reducing microembolic signals in patients with predominantly intra
cranial symptomatic stenosis [18].
The above dual antiplatelet studies, EARLY [15], FASTER [16], CHANCE [17],
and CLAIR [18], suggest that combination treatment may be a safe strategy to
prevent recurrent stroke in patients with mild acute ischemic stroke who are not
eligible for thrombolytic therapy [15–18]. The most recent CHANCE study also
showed that early and short‐term use of aspirin plus clopidogrel within 24 h after
mild acute ischemic stroke or TIA can effectively reduce 90‐day recurrent stroke
risk when compared to aspirin alone [17].
The POINT trial is still ongoing and aims to determine whether clopidogrel
plus aspirin vs aspirin alone taken <12 h after symptom onset of TIA or minor
ischemic stroke can be more effective in preventing major ischemic vascular
events at 90 days. All participants who received open‐label 162 mg aspirin daily
for 5 days followed by 81 mg daily are randomized to clopidogrel (600 mg load-
ing dose followed by 75 mg/day) or matching placebo. The primary efficacy out-
come is the composite of new ischemic vascular events—ischemic stroke,
myocardial infarction, or ischemic vascular death—by 90 days. The primary
safety outcome is major hemorrhage, which includes symptomatic intracranial
hemorrhage [19]. The POINT study can offer more detailed information about
the effects of dual antiplatelets in acute ischemic events.
Thrombolysis with intravenous rtPA is the standard approved treatment for
acute ischemic stroke. After recanalization by rtPA, 14–34% of patients may have
reocclusion, presumably owing to platelet activation. Early administration of anti-
platelet therapy after rtPA may help to reduce the risk of reocclusion and improve
outcome. A multicenter, randomized, open‐label trial with blind‐endpoint assess-
ment randomly assigned patients with acute ischemic stroke to 300 mg i ntravenous
aspirin within 90 min after the start of rtPA treatment or to no aspirin treatment
between July 29, 2008, and April 20, 2011. In both groups, the oral antiplatelet
was given 24 h after rtPA treatment. The trial was terminated prematurely because
0003172475.INDD 54 8/22/2017 1:08:12 PM

of an excess of symptomatic intracranial hemorrhage (sICH) and no evidence of

benefit in the aspirin group, with a favorable outcome in 54.0% of aspirin group
vs 57.2% of the standard treatment group (absolute difference = −3.2%, 95%
CI = −10.8 to 4.2; crude relative risk = 0.94, 0.82–1.09, p = .42). sICH occurred more
often in the aspirin group (4.3%) than in the standard treatment group (1.6%,
absolute difference = 2.8%, 95% CI = 0.2–5.4, p = .04). This study suggests that
early administration of intravenous aspirin in patients with acute ischemic stroke
treated with rtPA does not improve outcome at 3 months and may increase the
risk of sICH [20].
Conclusion
From the above evidence, it is suggested that within 48 h after acute ischemic
stroke onset, an initial higher dose of aspirin may be beneficial to cause a signifi-
cant reduction in mortality and adverse events. These benefits may come from the
prevention of early stroke recurrence. Evidence also shows that in patients with
high‐risk TIA and mild acute ischemic stroke, the short‐term use of aspirin plus
clopidogrel may not only help to prevent stroke recurrence but also be less likely
to increase the occurrence of intracerebral hemorrhage and major bleeding events
(Table 5.1).
Table 5.1 Comparison of antiplatelet treatment in acute ischemic stroke.
Category Study design Conclusions References
CAST and Aspirin vs placebo (40 000 Early aspirin is of benefit and its prompt use [7–9]
IST patients) should be routinely considered for all patients
with suspected acute ischemic stroke, mainly
to reduce the risk of early recurrence
Clopidogrel 600 mg clopidogrel bolus Lower NIHSS median score at 24 h than the [10]
(20 patients) NIHSS at baseline
Cilostazol Cilostazol vs aspirin (447 Cilostazol is comparable to aspirin in its [11]
patients) efficacy and safety and can be feasible in
the treatment of acute ischemic stroke
SOCRATES Aspirin vs ticagrelor Ticagrelor is not superior to aspirin in [13,14]
(13 199 patients) reducing the rate of stroke, myocardial
infarction, or death at 90 days
EARLY Aspirin + early dipyridamole Aspirin + early dipyridamole is as safe and [15]
vs + later dipyridamole after effective as later dipyridamole after 7 days
7 days (543 patients) in preventing disability
FASTER Aspirin + clopidogrel Aspirin + clopidogrel might have the potential [16]
vs + placebo (392 patients) to reduce the risk of stroke, but insignificant
CHANCE Aspirin + clopidogrel Aspirin + clopidogrel is superior to aspirin [17]
vs + placebo (5170 alone to reduce the risk of stroke at 90 days
patients) and does not increase the risk of hemorrhage
0003172475.INDD 55 8/22/2017 1:08:12 PM

Recommendations
1 Within 48 h of the onset of acute ischemic stroke, aspirin (160–300 mg) should
be considered to prevent the recurrence of ischemic stroke, if there is no con-
traindication to antiplatelet treatment.
2 Even after 48 h of the onset of acute ischemic stroke, aspirin should still be
considered for the prevention of stroke recurrence.
3 For TIA with ABCD2 score ≥4 or mild acute ischemic stroke with NIHSS ≤3,
consider the use of combination therapy with aspirin and clopidogrel for 21
days, then continue clopidogrel to a total of 90 days.
4 For acute ischemic stroke patients who have contraindications to aspirin or
have aspirin failure, clopidogrel may be considered.
5 In acute ischemic stroke, the use of aspirin with extended‐release dipyridamole
(25 mg/200 mg BID) may help to reduce poor outcome.
6 For acute ischemic stroke patients who are not eligible for aspirin treatment,
cilostazol (200 mg BID) may be considered based on safety concerns and ben-
efit in reducing vascular events.
7 In acute ischemic stroke, the use of intravenous rtPA should be given prior-
ity, and the use of antiplatelet therapy should not interfere with the use of
rtPA.
8 Antiplatelet therapy should not be used within 24 h after thrombolytic therapy,
to prevent bleeding risk.
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1. Talbodec A, Berkane N, Blandin V, et al. Aspirin and sodium salicylate inhibit endothelin
ETA receptors by an allosteric type of mechanism. Mol Pharmacol 2000;57(4):797–804.
2. Savi P, Nurden P, Nurden AT, Levy‐Toledano S, Herbert JM. Clopidogrel: a review of its
mechanism of action. Platelets 1998;9(3–4):251–5.
3. Hashimoto A, Miyakoda G, Hirose Y, Mori T. Activation of endothelial nitric oxide synthase
by cilostazol via a cAMP/protein kinase A‐ and phosphatidylinositol 3‐kinase/Akt‐depend-
ent mechanism. Atherosclerosis 2006;189(2):350–7.
4. Jung WK, Lee DY, Park C, et al. Cilostazol is anti‐inflammatory in BV2 microglial cells by
inactivating nuclear factor‐kappaB and inhibiting mitogen‐activated protein kinases. Br J
Pharmacol 2010;159(6):1274–85.
5. Ito H, Hashimoto A, Matsumoto Y, Yao H, Miyakoda G. Cilostazol, a phosphodiesterase
inhibitor, attenuates photothrombotic focal ischemic brain injury in hypertensive rats.
J Cereb Blood Flow Metab 2010;30(2):343–51.
6. Capodanno D, Dharmashankar K, Angiolillo DJ. Mechanism of action and clinical develop-
ment of ticagrelor, a novel platelet ADP P2Y12 receptor antagonist. Expert Rev Cardiovasc Ther
2010;8(2):151–8.
7. CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo‐
controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet
1997;349(9066):1641–9.
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8. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a ran-
domised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with
acute ischaemic stroke. Lancet 1997;349(9065):1569–81.
9. Chen ZM, Sandercock P, Pan HC, et al. on behalf of the CAST and IST collaborative groups.
Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40 000
randomized patients from the Chinese Acute Stroke Trial and the International Stroke Trial.
Stroke 2000;31(6):1240–9.
10. Suri MF, Hussein HM, Abdelmoula MM, Divani AA, Qureshi AI. Safety and tolerability of
600 mg clopidogrel bolus in patients with acute ischemic stroke: preliminary experience.
Med Sci Monit 2008;14(10):I39–I44.
11. Lee YS, Bae HJ, Kang DW, et al. Cilostazol in Acute Ischemic Stroke Treatment (CAIST
Trial): a randomized double‐blind non‐inferiority trial. Cerebrovasc Dis 2011;32(1):65–71.
12. Shimizu H, Tominaga T, Ogawa A, et al. Cilostazol for the prevention of acute progressing
stroke: a multicenter, randomized controlled trial. J Stroke Cerebrovasc Dis 2013;22(4):449–56.
13. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus aspirin in acute stroke or
transient ischemic attack. N Engl J Med 2016;375(1):35–43.
14. Wang Y, Minematsu K, Wong KS, et al. Ticagrelor in acute stroke or transient ischemic attack
in asian patients: from the SOCRATES Trial (Acute Stroke or Transient Ischemic Attack
Treated With Aspirin or Ticagrelor and Patient Outcomes). Stroke 2017;48(1):167–73.
15. Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended‐
release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of
symptom onset (EARLY trial): a randomised, open‐label, blinded‐endpoint trial. Lancet
Neurol 2010;9(2):159–66.
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ment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a
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17. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient
ischemic attack. N Engl J Med 2013;369(1):11–19.
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embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR
study): a randomised, open‐label, blinded‐endpoint trial. Lancet Neurol 2010;9(5):489–97.
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minor ischemic stroke (POINT) trial: rationale and design. Int J Stroke 2013;8(6):479–83.
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acute ischaemic stroke: a randomised controlled trial. Lancet 2012;380(9843):731–7.
0003172475.INDD 57 8/22/2017 1:08:12 PM

CHAPTER 6
Acute surgical interventions

in stroke
Chang Hui‐Meng and Joseph Erroll V. Navarro
Introduction
Stroke continues to be a major global problem in the twenty‐first century, with

an estimated 6.7 million deaths in 2012 [1]. Unfortunately, disproportionately
more deaths and disabilities occur in low- and middle-income countries [1–3].
Economic status is a strong predictor of the mortality and disability that follows
stroke [2,3]. Furthermore, while the incidence of hemorrhagic stroke has fallen
in high-income countries, it continues to be a problem in developing or lower
income countries [2,3]. In the Interstroke study, 23% of the 2104 strokes in Asia
were hemorrhagic strokes [4]. This was similar to South America (26%) and
lower than Africa (34%) but double that of high-income countries (9%) [4].
Early mortality from hemorrhagic strokes are almost double that seen in ischemic
strokes (25–48% vs 13–30%) [2]. While significant advances have been made
with non‐surgical treatments for stroke, especially endovascular clot retrieval in
acute ischemic stroke, surgery still has a role in acute strokes, and this chapter
will elaborate on such options by stroke subtype.
Hemicraniectomy in malignant middle

cerebral artery infarction
Malignant middle cerebral artery (MCA) infarction occurs in 10% of supratentorial

ischemic strokes and carries a very high mortality rate (80%) [5–8]. Death
and devastating neurologic sequelae result from refractory progressive swelling
of the infarct, compartmentalized increased intracranial pressure, brain shifts,
and subsequent extension of ischemia to adjoining vascular territories [9].
Despite mainstay medical intervention such as osmotic therapy, sedation, hyper-
ventilation, and barbiturates, mortality and morbidity remains high and carries
58
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Acute surgical interventions in stroke 59
significant limitations. It is because of these limitations that decompressive

hemicraniectomy or hemicraniectomy became an alternative strategy. Briefly,
this entails the removal of the cranium and opening of the dura over the involved
edematous hemisphere [5]. It prevents further deterioration by normalizing
intracranial pressure, restoring an already compromised flow in the ischemic
penumbra and other vascular territories, and returning the midline position of
the brainstem and diencephalon [9].
Hemicraniectomy can increase survival. Vahedi et al. demonstrated that
hemicraniectomy more than doubled the chances of survival, from 29% to 78%
[5]. These results were consistent with Back et al., who reported that death at 6
months and 12 months, were significantly reduced with an odds ratio (OR) of
0.19 (95% confidence interval [CI] of 0.10–0.37) and OR of 0.17 (95% CI of
0.10–0.29), respectively, in favor of hemicraniectomy [6]. Alexander et al., in a
pooled analysis with GRADE approach, showed that hemicraniectomy increased
the likelihood of survival compared to best medical treatment by two times (rel-
ative risk [RR] = 2.05, 95% CI = 1.54–2.72, p < .00001) [10]. Hemicraniectomy
resulted in a 49% absolute risk reduction in death; in other words, for every 10
hemicraniectomized patients, 5 will escape death. This translates into a number
needed to treat of 2 to avoid one fatality [9].
Certain factors that help to prognosticate good outcome in terms of sur-
vival and quality of life remain controversial. Landmark publications from
Europe, namely the DESTINY 8 and DECIMAL 9 trials, reported their results
in March 2007, and concluded that hemicraniectomy was only beneficial for
patients under 60 years old who had the surgery performed within 48 h of
stroke onset. Enrollment had been restricted only to this particular subset of
patients. The DESTINY and DECIMAL trials clearly demonstrated that hemi-
craniectomy was beneficial for younger patients in whom early intervention
can be given. But questions remain about those who are older, aged 60–80
years. In addition, what is the impact of such radical surgery on the quality of
life? Because of this, Clinicians are left to determine if such surgery will be
beneficial for elderly patients.
Age
This is the most common factor that both clinicians and patients (relatives)
consider before making a decision. The struggle stems from the fact that older
patients have far worse functional outcomes after hemicraniectomy [11].
Both the DESTINY and DECIMAL trials recommended that hemicraniectomy
was only beneficial for patients <60 years old. This was paralleled by Gupta
et al., who found that younger age was the only clinical determinant of sur-
vival with good functional outcome [12]. A pooled analysis by Vahedi also
favored younger age; however, the majority of trials excluded patients who
were older than 60 years old. In a retrospective review of 259 neurosurgical
practices in Japan, Suyama et al. found that hemicraniectomy was performed
0003172476.INDD 59 8/22/2017 10:24:56 AM

in 8.7% of 4092 candidates with malignant MCA infarction [13]. Of the

operated patients, most were elderly; in fact, 80.2% of all hemicraniectomized
patients were over 60 years old. Three‐month modified Rankin Score (mRS)
was available for half of all operated patients, and only 5.2% exhibited favora-
ble outcome (mRS <3), 22.9% had an mRS of 4, 26.9% had an mRS of 5, and
45.1% were dead [13]. A retrospective study of non‐surgical patients with
large hemispherical infarcts offered possible reasons why hemicraniectomy
was performed less often in the elderly [8]. The authors showed that
older aged patients with large hemispherical infarcts had lower mortality.
Patients younger than 70 years tended to die within the first 2 weeks from
fatal cerebral edema, whereas older patients tended to die later, from systemic
complications. Their relatively more atrophied brains afforded protection
from fatal cerebral edema. Hence, hemicraniectomy can be offered sparingly
for older patients. In the absence of conclusive evidence, Alexander et al. rec-
ommended more reliance on patient and family input when considering
hemicraniectomy for patients >60 years old [10].
Timing of surgery
The optimal timing of surgery also remains unresolved. Some surgeons prefer to
operate based on the time from stroke onset, others upon the appreciation of
early signs of deterioration. Both DESTINY and DECIMAL advocated early inter-
vention, which was within 24 hour/s of stroke onset, and not later than 48 hour/s.
They demonstrated good survival as well as functional outcome using this
parameter [14,15]. Alexander et al. recommended that hemicraniectomy be
instituted within 24–48 hour/s of symptom onset and prior to any herniation
symptoms [10]. The concern regarding early timing as the sole indicator for
intervention is the danger of over‐utilization of surgery, with resultant exposure
of patients to unnecessary surgical risk [6]. Vahedi et al., in their pooled analysis,
found that the timing of surgery did not affect outcome. They included in their
analysis studies that initiated hemicraniectomy from as early as 24 hour/s to as late
as 47 hour/s (mean from stroke onset). There was no difference in outcome
found between patients treated on the first day and those treated on the second
day [5]. Back et al., in a meta‐analysis that compared patient inclusion up to
48 hour/s, to up to 96 hour/s, did not show any trend for less benefit from
surgery with later time inclusion. This led them to conclude that benefit
was obtained within 48 hour/s, with a potential to extend intervention up to
96 hour/s [6]. Hao et al., in their small series of 31 patients, also showed no sig-
nificant differences in fatality rate and functional outcome for surgery between
48 hour/s and beyond 48 hour/s [7]. A retrospective review conducted by
Suyama et al. found that in the 36.9% of patients who underwent hemicraniec-
tomy beyond 48 hour/s, the timing of surgery was not an independent factor
affecting 30‐day mortality. Although a trend was observed toward decreased
mortality, however, it did not reach statistical significance [13].
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Early deterioration and signs of cerebral herniation

The common theme in studies for malignant hemispherical stroke was that early
deterioration portended poor outcome. Chen et al. showed that patients with
middle cerebral artery infarct who had Glasgow Coma Scale (GCS) <10 on the first
day were almost five times (HR = 4.76, 95% CI = 1.03–21.89) more likely to develop
a massive infarct, and 42.3% would be dead by 30 days [8]. Suyama et al. found
that midbrain compression independently predicted for 30‐day mortality
(OR = 2.12, 95% CI = 1.16–3.95, p = .01) [13].
Malignant MCA infarct carries a grave prognosis. While decompressive hemi-
craniectomy improves survival, at the least, disabilities from the initial stroke
remain, and this often places a significant burden on the patient, family, and
society. It is a life‐saving procedure that should be offered after consideration of
pertinent information, to ensure that these survivors are not left with severe dis-
abilities. Decompressive hemicraniectomy should be part of comprehensive
stroke care that includes intensive care facilities and multidisciplinary specialties
such as neurosurgery, neuro intensive care, and rehabilitation. A treatment pro-
tocol included in the DESTINY trial literature is one excellent example [14].
Subarachnoid hemorrhage
The incidence of subarachnoid hemorrhage (SAH) in Asia ranges from a low 2.0
per 100 000 population per year in China to as high as 22.7 per 100 000 in Japan,
and increases with age [16,17]. High fatality rates have been described, ranging
from 32% to 67%, but downward trends were observed from the 1960s to 1990s,
probably due to improved diagnosis and care [18,19]. The amount of initial
bleed is the main determinant of patients’ early death, followed by rebleeding
[20]. In addition, the initial neurological condition, especially the level of con-
sciousness, is another important prognostic factor. There are several clinical
grading scales described; the WFNS (World Federation of Neurological Surgeons)
scale that is based on the GCS, and the Hunt and Hess scale are more widely used
scales, with good inter‐rater agreement [21]. Patients with good clinical grade
have better outcomes.
About 70–80% of all SAHs are due to ruptured intracranial aneurysms, and
most of these aneurysms are saccular [22]. In India, a lower rate of aneurysm
identification (less than 40%) with more arteriovenous malformations was
described [23]. However, a later hospital‐based study in Kashmir showed that
aneurysmal rupture was quite prevalent in adults with SAH, 57.8%, followed by
hypertension in 32.8%, with arteriovenous malformations found in only 1.2%
[24]. Arteriovenous malformations were more common in children, contribut-
ing to 65.5% of SAH [24]. Similarly, early studies suggested that aneurysmal
rupture contributed to about half of SAH, followed by arteriovenous malforma-
tions in South‐East Asian countries such as Malaysia, Singapore, Thailand, and
0003172476.INDD 61 8/22/2017 10:24:56 AM

the Philippines, but this has not been consistently borne out by later hospital
publications [25–27]. In Singapore, 75.8% of patients had aneurysmal rupture,
and non‐aneurysmal bleeds were present in 19% [26]. In Thailand, vascular
lesions contributed to 62.6% of cases, with aneurysms making up 57.6% and
non‐aneurysmal SAH 42.4% [27]. In Thailand, unusual tropical infections like
gnathostomiasis also contribute to SAH. The parasitic larva causes bleeding in
the subarachnoid space when it enters and travels through this space [28].
Epidemiologic and treatment data in the Philippines are lacking. Improved
diagnoses and investigations, improved access to healthcare facilities, and better
socioeconomic environment may explain some of these differences and incon-
sistencies reported in the causes of SAH in Asia. Smoking and hypertension are
the most important modifiable risk factors in Asia [29].
SAH is a life‐threatening disease and initial management must be in an
intensive care facility or stroke unit with intensive care facilities, where general
medical and specific neurological parameters can be closely monitored and
appropriately treated. The following neurological complications are common,
and some benefit from early surgical interventions.
Bleeding and rebleeding
The amount of initial bleeding and recurrent bleeding are the two most
important prognostic factors for mortality [20]. Patients who rebleed have a
70% fatality rate, and rebleeding risk was highest in the early period, ranging
from 4% to 13.6% within the first hours to first day of SAH, with elevated blood
pressure contributing to this risk [30,31]. This risk remained high for the first
month, varying around 1–2% per day for the next 4 weeks, and eventually
falling to 3.5% per year during the first decade; even then, such late rebleeds
were still associated with high mortality of 67% [30,32].
Aneurysms can be obliterated by surgical clipping or endovascular coiling.
The International Subarachnoid Aneurysm Trial (ISAT) showed that 10 years
after endovascular coiling for aneurysmal SAH, patients were about 30% more
likely to be alive and independent compared to those who had surgical clipping
(OR = 1.34, 95% CI = 1.07–1.67) [33]. There was a higher risk of late rebleeding
with endovascular coiling, but this was an uncommon event (at 1 year, target
aneurysm rebleed was 0.042% of patients with endovascular coiling vs 0.036%
with clipping) [34]. In addition, patients with endovascular coiling were four
times (17.4% vs 3.8%) more likely to require retreatment, mainly for incom-
plete occlusion of the aneurysm. Late retreatment, at a mean of 20.7 months,
was 6.9 times more likely with endovascular coiling compared to clipping [35].
ISAT patients had mainly saccular aneurysms in the anterior circulation; there
were few posterior circulation aneurysms. The Barrow Rupture Aneurysm
Trial (BRAT) included all SAH, and complete aneurysm occlusion at 6 years was
two times more likely with clipping—96% clipping compared to 48% with
coiling—but despite this, rebleeding rates were still not significantly higher in
0003172476.INDD 62 8/22/2017 10:24:56 AM

the patients with endovascular coiling [36]. In addition, more favorable out-
comes were observed in posterior circulation aneurysms treated with endovas-
cular coiling. So, despite a lower aneurysmal obliteration rate with a higher
retreatment rate, patients with endovascular coiling still had better outcomes
compared to surgical clipping.
The best timing for aneurysm surgery is not clear, as there are few prospec-
tive trials [37]. The arguments for early treatment of ruptured aneurysm include
prevention of rebleeding, reducing the risk of vasospasm by washing out suba-
rachnoid blood, and avoiding conflict with the subsequent management of
vasospasm that tends to set in after a few days. Treatment often involves hyper-
volemia, induced hypertension, intra-arterial vasodilators, and balloon angio-
plasty, which can be dangerous in the presence of an untreated aneurysm.
Current American and European guidelines advocate treatment as early as
possible to reduce the risk of rebleeding, with a preference toward endovascular
coiling over clipping, if the patient is eligible for both procedures [38,39]. A
poor clinical grade on admission, while associated with a worse outcome, is not
a contraindication for aneurysm surgery. However, the final decision would
depend on many factors such as patient factors, aneurysm factors, and the inter-
ventional specialists.
Hydrocephalus
Hydrocephalus is identified in between 15% and 87% of patients in the acute
stage, with an additional 10–48% in the late phase [38]. About a third of these
patients are asymptomatic in the acute stage, and of those who are sympto-
matic, half would improve spontaneously [40,41]. Radiographically, the bicau-
date index on computed tomography (CT) scan is widely used to identify this
condition [42]. The bicaudate index is the ratio of the width of the two lateral
ventricles, at the level of the head of the caudate nucleus, to the diameter of the
brain at the same level (i.e., the distance between the outer tables of the skull
at the same level). Normal values are influenced by age [42]. Serial lumbar
punctures, lumbar drainage, external ventricular drainage, lamina terminalis
fenestration, and ventricular or lumbar–peritoneal shunt have been used to
treat hydrocephalus. There are no trials to determine the most appropriate
modality to use, although in the acute stage lumbar drainage or external ven-
tricular drainage is commonly used. Rebleeding and infections are more likely
to occur, but the risk is low [41,43–45]. Rapid (within 24 h) or gradual (over
96 h) removal of the catheter also had no impact on hospitalization or need for
long‐term shunt placement [46]. Fenestration of the lamina terminalis, per-
formed during early surgery for SAH, was believed to reduce the development
of shunt‐dependent hydrocephalus. However, a meta‐analysis found no such
benefit [47].
Approximately 10–20% of patients will develop shunt‐dependent hydroceph-
alus [48,49]. This is more likely to occur in patients who had poor neurological
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signs at presentation, the elderly, and those who had acute hydrocephalus, intra-
ventricular blood or rebleeding [50].
Raised intracranial pressure

Multiple factors contribute to the development of raised intracranial pressure
(ICP)—diffuse cerebral edema from SAH, acute hydrocephalus, cerebral infarc-
tion, and impaired cerebral autoregulation among others. Increased ICP is
associated with worse outcomes. In one study, good outcomes decreased with
increasing ICP, from 72% of patients with normal ICP, to 63.5% of those with
elevated ICP (20–50 mmHg), down to 33.3% of those with markedly elevated
ICP over 50 mmHg [51]. Raised ICP is also associated with increased mortality
[51,52]. First‐line therapy would be medical management with sedation, pain
control, osmotic therapy, and diuresis. Hyperventilation is generally avoided
because of the risk of inducing vasoconstriction.
ICP is normally 7–15 mmHg in adults who are supine, with pressures over
20 mmHg considered pathological and pressures over 15 mmHg considered
abnormal [53]. Cerebral blood flow is influenced by ICP and cerebral perfusion
pressure (CPP), a relationship that is shown as CPP = mean arterial blood pres-
sure (MAP)—mean ICP.
Ideally, CPP should be maintained somewhere above 50–70 mmHg, either by
reducing ICP or by increasing MAP, preferably with vasoactive agents that do not
affect the cerebral vessels [54,55]. Over a fairly wide range of CPP and MAP,
cerebral blood flow is kept constant by autoregulation, with cerebral vessels con-
stricting or dilating as needed. However, in the damaged brain, this autoregula-
tion is often lost. ICP monitoring can be done by inserting a probe into the
ventricle or against the brain parenchyma. Ventriculostomy, also called an external
ventricular drain (EVD) or ventricular catheter, is the insertion of a catheter into
the cerebrospinal fluid (CSF) space, such as the lateral ventricle. The advantage
of a ventriculostomy is that besides ICP monitoring it also allows for the drainage
of CSF. The parenchymal probes involve the insertion of either a subdural screw
or an epidural sensor, which is the least invasive procedure of the three.
Potential complications with ventriculostomy include intraparenchymal,
intraventricular, or subdural hemorrhage, described in 1–33% of patients, and
infections in 1–12% of patients, the latter more likely with longer duration of
catheter placement [56–58].
Decompressive hemicraniectomy has been used to treat raised ICP, regardless
of underlying cause, with reasonable outcomes reported in up to 50–64% of
patients [59,60]. These are small hospital series, and in the absence of robust
studies and data it is difficult to make any recommendations. In a large German
series, 43 of 787 SAH patients who had raised ICP >20 mmHg received fronto‐
temporo‐parieto‐occipital hemicraniectomy that was at least 15 cm large. Only
16% of these patients had good clinical grade at surgery [61]. Decompressive
hemicraniectomy was performed after aneurysm clipping in two groups (on day
0003172476.INDD 64 8/22/2017 10:24:56 AM

of SAH, mean time to surgery 7.7 h), and in the remaining three groups it was
performed because of persistent elevated ICP, with or without infarction or
rebleeding (mean time to surgery 93.6 h). Twenty‐five to 26% of patients,
respectively, had a favorable outcome (mRS ≤3), irrespective of the underlying
pathology that caused raised ICP. Unfortunately, there was no control group.
However, the authors propose that decompressive hemicraniectomy is a viable
option in selected patients, as historical data show that these patients have an
otherwise dismal outcome.
Vasospasm and delayed cerebral ischemia

Delayed cerebral ischemia (DCI) is a clinical syndrome of focal neurological and/
or cognitive deficits that is attributed to vasospasm. As documented using serial
transcranial Doppler to track blood flow velocities, vasospasm typically develops
4–10 days after SAH, reaches maximum between day 11 and day 20, and normal-
izes over the subsequent 4 weeks [62]. DCI usually occurs in about 30% of SAH
patients, but angiographic vasospasm has been reported in up to 70%, emphasiz-
ing that angiographic vasospasm was not always associated with clinical deficits
[63,64]. While vasospasm is considered to be the main cause of DCI, studies sug-
gest that other mechanisms such as failure of cerebral autoregulation, microvas-
cular vasospasm and thrombosis, and cortical spreading ischemia contribute to
the development of DCI [65,66]. Evidence for this comes from studies that
showed that up to 25% of delayed infarcts did not have vasospasm demonstrated
in the affected vessel [67]. Morbidity and mortality are further compromised by
the occurrence of DCI. Patients who develop cerebral infarction are five times
more likely to have poor outcomes [68].
Medical treatments include the use of nimodipine, “triple H” therapy
(hypervolemia, induced arterial hypertension, and hemodilution), intrathecal
thrombolytic infusions, statins, and magnesium. Of these only nimodipine has
been shown to improve neurological outcomes and is recommended in both
American and European guidelines [38,39,69]. There is early promise for local
delivery of a calcium channel blocker, via polymers loaded with nicardipine,
into the basal cisterns, for the reduction of vasospasm and delayed infarcts and
improved outcomes [70].
In a multicenter phase II study, prophylactic balloon angioplasty within
96 h of SAH did not reduce poor outcomes or hospitalization [71]. However,
less vasospasm was observed in the treatment arm, and these patients were
also less likely to require therapeutic angioplasty. Symptomatic vasospasm
refractory to medical management can be treated with endovascular therapies
such as transluminal balloon angioplasty or infusion of intra‐arterial vasodilat-
ing agents like papaverine or calcium channel blocking agents. Transluminal
balloon angioplasty was more effective than intra‐arterial papaverine or nica-
rdipine, improving outcomes in over 60% of patients compared to around 40%
0003172476.INDD 65 8/22/2017 10:24:57 AM

with drug therapy [72]. Cerebral angioplasty and/or selective intra‐arterial

vasodilator therapies are recommended for refractory vasospasm not responding
to medical therapy [38].
Other neurological complications that occur with SAH, not requiring surgical
intervention, include the development of seizures and hypothalamic‐pituitary
dysfunction, manifesting with frequent metabolic derangements. These are
managed medically.
Intracerebral hemorrhage
Hemorrhagic stroke is twice as common in Asia compared to Western countries

[73]. The proportion of intracerebral hemorrhage (ICH) to SAH is variable, depend-
ing on the country, region, and hospital. In China, 33.6% of strokes were hemor-
rhagic, with ICH almost seven times more common than SAH (23.4% vs 2.4%)
[74]. In Japan, the Akita stroke registry revealed that hemorrhagic stroke, at 37.4%,
was two times higher than Western countries [75]. However, ICH was only two
times more common than SAH (25.8% vs 11.6%) [75]. By comparison, less than
20% of stroke in Singapore was hemorrhagic, but ICH o utnumbered SAH by about
five times (15.5% vs 3.1% in 2014) [76]. Similar to Singapore, in Taiwan ICH was
five times more common than SAH (16.1% vs 2.8%) [77]. In Malaysia, hemor-
rhagic stroke accounted for 20.6% of all strokes [78]. In Indonesia, stroke is the
leading cause of mortality, with hemorrhagic stroke accounting for 32.9% [79].
ICH carries a high mortality with approximately 40.4% dead at 1 month
[73]. Japan has one of the lowest 1‐month mortality rates at about 16.71%.
Twelve to 39% of ICH patients will achieve independent function [73]. There are
several prognostic scores for ICH, the ICH score being one of the most easy and
widely used [80,81]. This is because the prognosis after ICH is influenced by
many factors: location, size and cause of hemorrhage, level of consciousness,
Glasgow coma score, prior use of anticoagulant, to name a few. In addition,
hematoma growth, ventricular and subarachnoid extension, and perihematoma
edema expansion rate are poor prognostic indicators [82].
Similar to SAH, ICH patients are best managed in an intensive care area, or
stroke unit with similar facilities, where neurological parameters and blood
pressure can be closely monitored. Medical therapies for pain, anxiety, high
blood pressure, raised intracranial pressure, and more can be given as needed.
Raised intracranial pressure

Raised ICP occurs because of the initial hematoma, hematoma expansion,
perihematoma edema, or hydrocephalus. Similar to SAH, initial medical

management includes the use of sedation, analgesia, osmotic agents, and

hyperventilation (unlike in SAH, where hyperventilation is generally avoided
because of the risk of exacerbating vasospasm).
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Invasive measuring of ICP allows medical therapies to be titrated to maintain

a cerebral perfusion pressure of 50–70 mmHg, failing which aggressive medical
and surgical options are needed. Similar to SAH, ventriculostomy allows ICP to
be measured and also CSF to be drained if hydrocephalus develops. In addition,
neuromuscular blockage has been used to improve cerebral venous return by
reducing intrathoracic pressures.
Intraventricular hemorrhage
Intraventricular hemorrhage (IVH) is an independent predictor of poor out-
come, with expected mortality between 50% and 80% [83,84]. It occurs in about
40–50% of ICH [85,86]. Hydrocephalus is more likely to occur, especially if
blood involves the third and fourth ventricles [87]. Patients with IVH and hydro-
cephalus have even worse outcomes [85]. A few scores have been devised to
help prognosticate outcomes, such as the IVH score, Graeb (original or modified)
score, and LeRoux score, and a comparison study showed that these were simi-
larly accurate in predicting outcomes, with perhaps the modified Graeb score
having the best prognostic accuracy [83,88–91]. These scores grade the severity
of IVH by assessing the amount and extent of blood in some or all of the follow-
ing ventricles: the lateral, third, and fourth ventricles, and the temporal and
occipital horns. Increasing amount and extent of intraventricular blood carry a
bad outcome [88–91].
Treatment options
1 An external ventricular drain (ventriculostomy) can be used for temporary
drainage of hydrocephalus. Complications that more commonly occur include
catheter occlusion by clotted blood and infections.
2 Intraventricular fibrinolytics. Instillation of fibrinolytics theoretically speeds
up resolution of intraventricular blood, prevents catheter tip obstruction by
clotted blood, and possibly even reduces long‐term risk of developing obstruc-
tive hydrocephalus. Fibrinolytic agents used include urokinase, streptokinase,
and recombinant tissue‐type plasminogen activator (rtPA). In the CLEAR IVH
trial, patients with supratentorial ICH measuring less than 30 ml and massive
IVH received an EVD and were randomized to receive rtPA or normal saline
until CT scan showed resolution of the IVH [92–94]. IVH resolved faster in the
rtPA group (18% per day for rtPA group vs 8% per day for placebo) and the effect
was dose dependent. Although rtPA patients had more bleeding complications
(23% rtPA vs 5% placebo), there were no significant differences in mortality
(19% rtPA vs 23% placebo) [92,93]. Unfortunately, the large confirmatory
CLEAR III trial published in 2017, with 500 patients, showed no net clinical
benefit at 3 months [95]. The rtPA group had lower mortality (18% rtPA vs
29% placebo) but a higher proportion of survivors with modified Rankin
Scale of 5 (17% rtPA vs 9% placebo), so there was no net benefit (48% rtPA
vs 45% placebo) [95]. However, the therapy was safe with no difference in
0003172476.INDD 67 8/22/2017 10:24:57 AM

symptomatic bleeding in both groups. In addition, ventriculitis and serious

adverse events occurred less frequently in the rtPA group, supporting that
intraventricular fibrinolytic therapy was safe, but with no clinical benefit seen
at 3 months [95]. A 2011 meta‐analysis of 316 patients in 12 studies who had
spontaneous supratentorial IVH associated with obstructive hydrocephalus
found that intraventricular fibrinolytics reduced mortality by more than half,
from 46.7% to 22.7% in the intraventricular fibrinolytic group; this effect
was mainly in patients who had received urokinase [96]. An updated 2014
meta‐analysis of 785 patients in 24 studies with non‐traumatic IVH treated
with intraventricular fibrinolysis showed an almost 50% reduction in mortal-
ity (RR of 0.55), 66% increase in good functional outcome (RR of 1.66), and
40% decreased rate of shunt dependence (RR of 0.62), without any increase
in bleeding or ventriculitis [97]. The 2015 American Heart and Stroke
Association guidelines recognize that intraventricular fibrinolytics can proba-
bly be a dministered safely, although the benefits are less certain [98].
3 Neuroendoscopic removal of IVH has also been evaluated in many small trials.
In a 2013 review of 11 trials (eight Chinese) with 680 patients, the mortality
was significantly lower with neuroendoscopic removal and external ventricu-
lar drainage, compared to intraventricular fibrinolytics [99]. Similarly, patients
were more likely to have good functional outcomes and less likely to become
shunt dependent [99]. Other interesting developments include the use of son-
othrombolysis to liquefy the clot, allowing for easier drainage. Ultrasound
energy can be delivered via an ultrasound catheter, inserted through a ven-
triculostomy or guided by magnetic resonance imaging (MRI) [99–101].
Cerebellar hemorrhage
Approximately, 10% of ICH are cerebellar hemorrhages, and these either arise
spontaneously or are related to hypertension [102]. Interestingly, a Japanese
study showed that patients taking prior antiplatelet therapy were more likely
to develop cerebellar hemorrhage, 24% vs 6.4%, and hypothesized that the
cerebellum was susceptible to loss of autoregulation because of the sparse sym-
pathetic innervation [103]. This remains to be confirmed in larger studies. Other
causes include arteriovenous malformations, coagulopathies (antithrombotic
usage or illnesses such as cirrhosis, thrombocytopenia), dural arterio venous fis-
tula, aneurysm, trauma, amyloid angiopathy, or remote cerebellar hemorrhage,
usually from supratentorial procedures [103–105]. Large cerebellar intracranial
hemorrhages lead to brainstem compression, obstructive hydrocephalus (arising
from aqueduct or IV ventricle obstruction), and Cerebellar herniation, either down
through the foramen magnum or up through the tentorium. The timing and rate
of deterioration is often unpredictable: in one series, two‐thirds were responsive
on admission, half were comatose by 24 h, and three‐quarters by 1 week [105]. The
conscious level of patients before surgical decompression had a strong influence
on outcome; unresponsive patients were likely to have a fatal outcome [105–107].
0003172476.INDD 68 8/22/2017 10:24:57 AM

Mortality rates range between 27% and 48% [108]. Compared to cerebellar
infarcts, cerebellar hemorrhages are much more likely to require surgical decom-
pression, because of deterioration from hematoma growth and/or brainstem com-
pression [109]. Many studies have shown that early surgical decompression,
when the patient is still alert, is associated with improved outcomes and mortal-
ity [104,106,109,110]. Suggested treatment algorithms for decision‐making on
evacuation of cerebellar clot and surgical intervention have generally considered
the following factors [108,109,111,112]:
1 patient factors: Glasgow Coma Scale, clinical deterioration, brainstem reflexes;
2 CT scan findings: size of cerebellar clot, presence of hydrocephalus, presence
of regular cisterns.
In general, a patient who is alert (GCS score of 14–15) with a small cerebellar
hematoma <3 cm may be managed conservatively in a stroke unit. Any clinical
deterioration attributable to the hematoma is an indication for surgery. At the
other end of the spectrum, comatose patients who have lost their brainstem
reflexes are also usually managed conservatively because of the dismal prognosis
regardless of surgery.
Patients with GCS ≤13, hematoma >3 cm, hydrocephalus, or absent basal
cisterns are candidates for surgical treatment. Drainage of CSF with an external
ventricular drain by itself is inadequate to manage large cerebellar hematomas
and suboccipital craniectomy is performed.
Supratentorial hemorrhage
Surgical options for evacuation of supratentorial ICH include craniotomy with

clot evacuation under direct visual guidance or minimally invasive evacuation
using either stereotactic aspiration or endoscopic evacuation. Minimally i nvasive
evacuation is generally favored for deeply located bleeds because of the perception
that less brain is damaged. Factors to consider for surgery include the location of
bleed (deep or superficial), size and cause of clot, associated complications such
as hydrocephalus, patient’s neurological condition, age, and comorbidities. With
this information, the surgeon then needs to decide which type of surgical method
is most appropriate.
Early trials of surgery in ICH did not show any advantage, and possible
contributing reasons to this include the inclusion of overly diverse types of
ICH—deep and superficial, with or without associated complications like hydro-
cephalus or intraventricular hemorrhage, underlying vascular malformations,
spontaneous or tumor related, and so forth. The STICH trial looked at patients
with spontaneous lobar hemorrhages, at least 2 cm in diameter, with a minimum
GCS of 5 or more. Patients had to present within 72 h of ICH onset, and early
surgery was performed within 24 h [113]. There was no difference in favora-
ble outcome at 6 months, occurring in 26% in the early surgery group vs 24%
0003172476.INDD 69 8/22/2017 10:24:57 AM

in the conservative therapy group. Mortality was also similar (36% surgical vs
37% conservative). In the pre‐specified subgroup analysis, benefit was seen with
early surgery if the hematoma was lobar, ≤1 cm from the cortex, GCS was ≥9,
and the hematoma was evacuated via craniotomy [113]. However, as the type of
surgery was not pre‐specified, 75% of the procedures had been craniotomies. In
addition, about one‐quarter of patients in the conservative arm eventually had
surgical evacuation and 6% of surgical patients never went for their procedures,
possibly further diluting any beneficial effect for early surgery. A uniformly grim
prognosis was seen in comatose patients, GCS ≤8. As a result of STICH, STICH II
recruited patients with spontaneous lobar hemorrhage ≤1 cm from the cortical
surface of brain with 10 to 100 ml of blood. These patients also had to be con-
scious with motor GCS ≥5 and present within 48 hours [114]. Unfortunately,
poor outcomes occurred similarly in both groups (59% surgery vs 62% con-
servative); mortality was 18% surgery vs 24% conservative, but this did not
reach significance. Again, 21% of patients assigned medical therapy crossed over
to surgery later, which might have affected the results. Patients in the early sur-
gery group were more likely to die from cardiac events and less from intracere-
bral hemorrhage or rebleed. Adding their data to 14 other trials of surgeries in
ICH, the authors showed a significant 26% reduction in unfavorable outcomes
in favor of surgery [114], arguing for surgical evacuation in ICH. However,
uncertainties still remained about when surgery should be performed and who
would benefit. The current data emphasize that routine evacuation of all
supratentorial hemorrhages is not recommended. Surgical evacuation is gener-
ally considered when patients are deteriorating.
Minimally invasive surgery is a promising alternative to standard craniot-
omy as it is less invasive [115–117]. In a 2014 meta‐analysis by Yang, com-
pared to medical therapy, surgical treatment led to significantly lower mortality,
death, and dependency in 3616 patients with ICH from 18 studies [118].
However, when they divided the surgeries into craniotomies and minimally
invasive procedures, the authors found that the benefit was significant only for
minimally invasive procedures, regardless of location of ICH (deep or other-
wise). They did observe a preponderance of minimally invasive procedures
performed for deeply located bleeds, rather than craniotomies, which might
have biased the analysis. The phase II MISTIE trial, published in 2016, used
minimally invasive aspiration followed by rtPA and showed that, while this
was feasible, there was no difference in outcomes compared to standard ther-
apy [119]. The aim was to assess clot dissolution using image‐guided mini-
mally invasive aspiration followed by thrombolysis with rtPA. Patients had
spontaneous ICH with ≥20 ml blood, and a GCS score ≤14 or National Institute
of Health Stroke Scale (NIHSS) ≥6. There were no significant differences for
mortality, brain infection, and symptomatic bleeding. However, asympto-
matic bleeding was more common with rtPA use—22.2% vs 7.1% standard
therapy. Further trials are needed to clearly define the role and use of minimally
0003172476.INDD 70 8/22/2017 10:24:57 AM

invasive surgery compared to craniotomy. Currently the choice of surgical

procedure often depends on the surgeon, and again, its use in patients who are
deteriorating.
While there is a role for acute surgical interventions in stroke, uncertainty exists
over patient selection, type of stroke and complications, and type of procedure
because the multiple trials to date have not provided clear indications. However,
many of the studies have shown that surgical procedures can be performed
safely and are likely to be of benefit in carefully selected patients.
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0003172476.INDD 77 8/22/2017 10:24:57 AM

CHAPTER 7
Acute complications after stroke

Sardar M. Alam and Jose C. Navarro
Stroke is the third most common cause of death after coronary heart disease
and all cancers. It has a huge impact on the family and society because of its
high morbidity and mortality [1]. Medical complications after an acute stroke
tend to be neglected but they occur frequently in 45–96% of cases and are the
leading causes of this high morbidity and mortality [2–4]. There is increasing
evidence that this shortfall has been recognized in both Western and Asian lit-
erature [2–5]. One of the reasons for this wide range in reported prevalence
could be the type and timing of the study as well as the type of center conduct-
ing the study. Acute units would be more likely to report neurological and
infective complications, whereas rehabilitation units would report depression
and contracture [3]. It is widely recognized now that patients in dedicated geo-
graphical units for stroke patients, that is, acute stroke units or hospitals that
have a dedicated multidisciplinary team to look after stroke patients, do better
than patients who are admitted to a general medical or neurological ward [6,7].
The immediate or very early mortality is usually due to the direct conse-
quences of brain damage. The extent and site of brain damage as well as patient’s
age and pre-stroke health affect the early outcome. However, deaths occurring
over the following weeks are mostly due to potentially preventable factors.
Awareness of these factors, their identification, and putting in place preventive
as well as adequate treatment initiatives, especially in organized stroke care, is
effective in reducing the morbidity and mortality of acute stroke and can change
the final outcome of the disorder. Acute complications after stroke consist of:
1 Neurological complications
(a) Recurrent stroke
(b) Hemorrhagic transformation of an ischemic stroke
(c) Expansion of the hematoma after a hemorrhagic stroke
(d) Seizure after a stroke
(e) Confusion
78
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Acute complications after stroke 79
2 Infections after a stroke

(a) Aspiration pneumonia
(b) Chest infections
(c) Urinary tract infections
(d) Phlebitis
3 Gastrointestinal
(a) Dysphagia
(b) Constipation
(c) Paralytic ileus
(d) Bowel incontinence
(e) Dehydration
(f) Upper gastrointestinal bleeding
4 Genitourinary
(a) Urinary retention
(b) Urinary incontinence
5 Thromboembolic
(a) Deep vein thrombosis
(b) Pulmonary embolism
6 Cardiac complications
(a) Myocardial infarction
(b) Cardiac failure
(c) Cardiac arrhythmias
7 Complications due to immobility
(a) Pressure sores
(b) Falls
(c) Fractures
(d) Shoulder pain
8 Long‐term complications
(a) Spasticity
(b) Contractures
(c) Post‐stroke pain
(d) Delirium
(e) Anxiety
(f) Fatigue
(g) Depression
(h) Dementia
(i) Epilepsy
Neurological complications
Early neurological deterioration after an acute stroke is a common occurrence

and is associated with both early and late morbidities and mortalities. The causes
of this deterioration are heterogeneous in nature and include hemorrhagic
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transformation of an ischemic stroke, hematoma expansion of a hemorrhagic

stroke, recurrent stroke, clot progression, seizures, and raised intracranial pres-
sure [8]. There are other non‐neurological factors that must be managed in
order to provide an environment in which the ischemic penumbra survives and
remains viable and is not converted into infarcted tissue thus contributing to a
worse outcome. These factors include hyperglycemia, hyperthermia, hypoxia,
dehydration, and changes in blood pressure. The ischemic penumbra is a poten-
tially reversible phenomenon if managed correctly.
Raised intracranial pressure occurs in posterior circulation strokes with
obstructive hydrocephalus that may require a drainage procedure, in large ves-
sel proximal occlusion such as malignant middle cerebral artery infarction that
may require a hemicraniectomy, as well as in total anterior circulation infarc-
tion. Hemorrhagic transformation may occur spontaneously or due to treat-
ment complications of antiplatelet therapy as well as intravenous thrombolysis
treatment [9].
Atrial fibrillation as well as presence of a cardiac source of thrombus can lead
to early recurrent stroke. Confusion in patients is usually due to metabolic
abnormality or medications.
Early seizures after a stroke occur in 4–6% of patients. Status epilepticus will
require immediate treatment. Most single fits may not require anticonvulsive
treatment. Another 2.5–6.5% of patients will develop late post‐stroke epilepsy
requiring long‐term antiepileptic medication [10,11]. The incidence of post‐stroke
seizures was reported as 1.3% in a study of 10 Asian countries [5] as compared
to 2–5% from other studies [12].
Infections after a stroke
Infections are the most common complication after an acute stroke. They are
one of the leading causes of increased morbidity and mortality both in acute
stroke and as late complications of stroke. Infections are a major contributory
factor to the early neurological deterioration following an acute stroke leading to
increased length of hospital stay and long‐term disability.
Chest and urinary tract are the two most common sites of infections reported
worldwide and from Asian countries’ literature. The Acute Stroke Advisory
Panel (ASAP) study, which is a study from 10 Asian countries, reported a fre-
quency rate of infection in 16.8% of patients [5] compared to 14–46% in other
studies. A study from Peshawar, Pakistan, reported a 46% infection rate; all the
patients were in a general neurology ward [13]. Among the infections, chest
infection is the most common complication followed by urinary tract infection.
The multicenter Indian study showed 21.2% chest infections [14]. The ASAP
study noted the lower rate of infection and attributed this to the fact that patients
admitted to a acute stroke unit had a lower rate than those admitted to a general
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medical or general neurology ward. It was noted that most infections occurred
in the first few days of the stroke with the frequency falling later on.
Chest infections are due to either community-acquired or hospital-acquired
pneumonias; aspiration pneumonias also occur following acute strokes. The risk
factors predisposing to chest infections include reduced level of consciousness,
immobility, dysphagia, nasogastric feeding, confusional state, poor oral hygiene,
dehydration, and poor nutrition. They also include stroke severity and brainstem
stroke as well as mechanical ventilation and the presence of comorbidities. There
is a high incidence of aspiration pneumonia in unwell hospitalized patients with
an impaired swallowing mechanism. It is common not to find the causative orga
nism for the cause of the infection, but almost all organisms have been documented.
All patients must have a chest radiograph and efforts must be made to find the
causative organism. The infection needs to be treated with the appropriate anti
biotic. Studies of routine use of prophylactic antibiotics have shown varied results.
There are a number of recently completed and ongoing clinical trials looking at the
use of prophylactic antibiotics in management of post‐stroke infections [15].
Urinary tract infections (UTIs) are the second most common infections in
patients with an acute stroke. In the ASAP study, UTI was reported in 4.9% of
cases compared to 7–28% from other studies. The frequency of UTI was 10% in
the Peshawar study [13] and 8.7% in a multicenter Indian study [14]. Risk fac-
tors associated with UTI include urinary catheterization, decreased conscious
level, advanced age, diabetes mellitus, and obstructive uropathy.
Recommendations to reduce UTI include adequate hydration, prevention of
constipation, adequate mobility measures, and minimizing the use of indwelling
urinary catheters. Use of aseptic technique in catheterization, use of appropriate
catheters, and early removal of urinary catheters are helpful in reducing the
incidence of UTI.
Gastrointestinal complications after stroke
Dysphagia
Dysphagia is common after stroke. It occurs in large hemispheric strokes as well
as brainstem strokes. Swallowing difficulties lead to aspiration pneumonias,
dehydration in the short term, and undernutrition in the long term. The ASAP
study did not mention dysphagia as a complication but did report aspiration
pneumonia in 2.5% of patients, which was the consequence of swallowing dif-
ficulty. The Peshawar study reported aspiration in 12% of its cases [13].
All patients with an acute stroke should have their swallowing assessed
formally. This is done by the nursing staff and involves a series of questions fol-
lowed by giving a teaspoonful of water followed by a larger volume (39–50 ml)
of water; if swallowing is judged to be safe, fluids and a soft diet are allowed.
Those who have a functional gastrointestinal tract should receive fluids and
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nutrition via the oral route with the help of a nasogastric tube. Intravenous
fluids may be required for adequate hydration, and for some patients parenteral
nutrition is needed. Aspiration pneumonia with nasogastric feeding has been
recognized, especially if assisted feeding is required beyond the first two weeks.
Percutaneous endoscopic gastrostomy has been recognized to be superior to
nasogastric tube feeding and is widely used [16].
Long‐term swallowing difficulties lead to undernutrition and will require
the support of a dietician for advice with food supplements, diet texture modi-
fication, and improving the environment in the ward and home for adequate
nourishment.
Constipation and fecal incontinence

These are common after stroke and occur in 40% of patients. Together with urinary
incontinence they can have a disastrous effect on patients’ psychological, physical,
and social well-being, both in the short term and when participating in rehabili
tation. These distressing symptoms can lead to social isolation in the long run.
Assessment for bowel dysfunction should include abdominal examination,
digital rectal examination, and perianal/groin examination to find the cause of
the problem. Fecal impaction with overflow incontinence may be present. Bowel
problems are usually due to functional impairment after stroke and individual
strategies need to be employed including privacy, appropriate utensils and aids,
stool softeners, bulk‐forming agents, avoiding dehydration, and ensuring that
the patient is not on any medication that would cause constipation.
Upper gastrointestinal bleeding

This has been reported and is due to medication, stress, and other comorbidities.
The Indian study [14] reported 10 cases of gastrointestinal hemorrhage out of the
449 patients recruited. A study from Malaysia reported upper gastrointestinal
hemorrhage in 3.7% [17].
Genitourinary complications
Along with bowel complications, urinary complications are common after

stroke. Communication and mobility problems add to these distressing prob-
lems. Post‐stroke urinary incontinence is widely regarded as a poor prognostic
indicator for functional outcome.
In a review, Brittain et al. reported post‐stroke urinary incontinence in
between 32% and 79% of patients at admission [18]. The ASAP study [5]
reported urinary retention in 5% of inpatients and did not record urinary incon-
tinence. The Peshawar study also reported urinary retention frequency at 4%
and did not record urinary incontinence as a complication [13].
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Persistent urinary incontinence is associated with a poor outcome due to the

inability of the patient to participate in a rehabilitation program. It is also a
marker of large strokes and poor outcome. Patients with urge incontinence are
liable to fall.
Urinary incontinence has a psychological impact on the patient as the com-
plication is distressing for both patient and carer.
Urinary incontinence may be due to overflow incontinence, impaired aware-
ness, urge incontinence, or functional incontinence. All patients with an acute
stroke should have their bladder function assessed and inpatients with urinary
dysfunction should have a detailed examination including digital rectal exami-
nation to exclude fecal impaction.
Treatment strategies should include easy access to a nurse call bell, access to
hand‐held urinals, and the offer of absorbent pads if the patient is unable to hold
a urinal. Interventions such as indwelling urinary catheter should be under-
taken with great care as this is a common cause of UTI and urethral injury.
Penile sheaths should be considered in male patients [19].
Thromboembolic complications
These usually comprise of deep vein thrombosis (DVT) and pulmonary embolism
(PE) and are potentially fatal complications. Venous thrombosis is common after
stroke as there is blood stasis due to lack of the muscle pump in the paralyzed
limb. There is a state of hypercoagulability after an acute stroke. There may be
endothelial damage and along with it dehydration causing increased blood vis-
cosity. Thromboembolic complications can occur any time after an acute stroke
but are more common in the first 7–10 days after an acute stroke. DVT occurs in
both types of strokes, ischemic and hemorrhagic. It is more common in the para-
lyzed limb but may occur bilaterally.
The clinical diagnosis of both DVT and PE is easy when the patient presents
with classical signs and symptoms; however, they may present with nonspecific
symptoms and present as an infection or other diagnosis, and in some cases the
DVT may go unrecognized. All these may happen in a group of patients who
may be dysphasic, confused, drowsy, unconscious, or have a paralyzed limb with
hemianesthesia. Improvement in acute stroke care, particularly in acute stroke
units, has seen a decline in the incidence of these complications. The ASAP study
showed a low risk of both PE and DVT. This low incidence has been noted previ-
ously in Asian patients [20]. The Peshawar study did not record these complica-
tions but the number of patients was small. Studies outside Asia have shown a
varied incidence of 15–75% of DVT and 1–20% of PE [5]. These complications
can occur in hemorrhagic stroke.
DVT may occur below the knee in calf veins, in the pelvic or inferior vena
cava, or in the upper extremity veins.
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These complications are best managed with adequate prevention such as early
mobilization, adequate hydration, use of low molecular weight heparin, intermit-
tent pneumatic compression, and use of the novel anticoagulation drugs.
Diagnosis is assisted by imaging of veins with Doppler ultrasound, contrast
venography, and, in the case of PE, by pulmonary angiography, V/Q (ventilation/
perfusion) scans, pulmonary angiography, computed tomography (CT), pulmo-
nary angiography, or magnetic resonance imaging (MRI) of the embolism. Despite
preventive measures, these complications do occur and require treatment with
heparin, warfarin, low molecular weight heparin, and novel anticoagulants. In
cases where chances of recurrence are high, then inferior vena cava filters need
to be considered.
Every effort should be made to prevent venous thromboembolism, but when
it does occur, it should be treated urgently and adequately.
Cardiac complications
Cerebrovascular disease and cardiovascular disease share common risk factors,

hence cardiac disease and its complications are common after an acute stroke.
Cardiac disease is the most common cause of death in stroke survivors at 1 year.
After neurological causes, cardiac complications are the second most common
cause of mortality, ahead of infections. Prompt recognition of cardiac irregulari-
ties and their treatment improves complication rates and decreases both
morbidity and mortality. Prosser et al. [21] reported cardiac complications in 19%
of post‐stroke patients, with a peak incidence in the first 3 days. These included
acute coronary syndromes, symptomatic heart failure, atrial and ventricular tach-
ycardias and fibrillations, and cardiac arrest.
The ASAP study reported cardiac complications in 5% of their cases, which
included cardiac dysrhythmias and cardiac failure. The Indian study by Pandian
et al. reported only five cases [14]. Investigating and treating acute coronary
syndromes can be challenging in the presence of both ischemic and hemorrhagic
strokes. The timing of treating atrial fibrillation with anticoagulants in presence
of a large ischemic infarction as well as cerebral hemorrhage may cause thera-
peutic dilemmas.
Complications due to immobility
These include pressure sores, falls, fractures, and shoulder pain.

A pressure sore can be defined as “a new or established area of skin and/or
tissue discoloration or damage, which persists after the removal of the pressure
and which is likely to be due to the effects of pressure on the tissues” [22]. Factors
contributing to pressure sores include immobility, obesity, reduced conscious
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level, sensory impairment, neurological deficit, age, malnutrition, dehydration,

incontinence, vascular disease, terminal illness, and acute illness.
The frequency of pressure sores in previous studies ranges from 2% to 21%.
The ASAP study [5] reported a frequency of 2.6% and the Peshawar study [13]
reported a 2% frequency. The variation is due to the size of the studies, whether
prospective or retrospective, and timing of recruitment to the study and length
of follow‐up.
Pressure sores are a significant problem in healthcare in general and an
important post‐stroke complication. When present they prolong hospital stay,
delay rehabilitation, and have a significant psychological effect on both the
patient and caregivers. They are a persistent problem throughout the post‐stroke
period. Pressure sores occur in the acute phase as well as being a late complica-
tion and are a significant cause of morbidity. In stroke patients the common sites
of pressure sores are the sacrum, heels, and malleoli, but sores can occur at any
pressure point.
They occur due to the pressure of the patient’s own body weight c ompressing
the skin and underlying capillaries over a long period without any relief in the
pressure. They also occur when skin rubs against another surface, leading to
the epidermis being stripped away as well as damaging capillaries leading
to ischemia.
The sores are graded I–IV: grade I consists of skin redness, and grade IV is
deep damage up to muscles and tendons [23]. These sores are also complicated
by infection and gangrene. It is important to identify patients at high risk for
developing pressure sores (overweight, unconscious, with vascular disease, etc.).
It is important to prevent pressure sores by providing an appropriate mattress
such as a foam mattress, air mattress, or sheep skin rather than a standard
hospital mattress. The patient has to be repositioned every 4 hours to prevent
pressure necrosis but this has to be tailored according to the individual patient’s
risk analysis and skin condition. Appropriate intervention for adequate hydration
and nutrition should be instituted as well as intervention for adequate skin health
where appropriate. Once a pressure sore occurs, it will require a multidisciplinary
approach including nursing staff, occupational therapist, physiotherapist, and
where appropriate a plastic surgeon.
While there is some evidence that optimal positioning, seating, and pressure
care for patients after a stroke can improve outcome, more research is required
to guide clinicians in these aspects of care.
Falls and fractures are a common and serious but potentially preventable
complication. They occur in 2.4–25% of patients. The ASAP study [5] reported
a 2.4% frequency of falls and Pandian et al. reported a 1.6% [14] frequency of
falls. In the acute stage these falls occur around the bedside or around the toilet,
usually due to decreased conscious level, confusion, and delirium. Falls as a late
complication are common (in up to 75% of elderly patients) and are due to
decreased muscle strength, decreased postural reflexes, impaired vision, postural
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hypotension, urinary incontinence, joint disease, and decreased response time.

Poor balance is common after stroke and leads to falls and their consequences.
Shoulder pain, especially on the side of the neurological deficit, is common
but usually occurs later than the acute phase. It may be associated with shoulder
subluxation. Shoulder pain may be present at rest but is usually present with
movement.
Long‐term complications
The following long‐term complications are causes of considerable morbidity fol-

lowing a stroke episode:
•• spasticity;
•• contractures;
•• post‐stroke pain;
•• delirium;
•• anxiety;
•• fatigue;
•• depression;
•• dementia;
•• seizures.
Conclusion
Despite major advances in stroke care during the last decade, stroke continues to
be a major cause of morbidity and the leading cause of adult physical and mental
disabilities. Complications occurring after a stroke are a major contributory fac-
tor for these. Physicians and caregivers need to be aware of these complications,
to put in strategies to prevent them from occurring, to recognize them promptly
when they occur, and to commence appropriate therapy when they are found.
Acute stroke units and a multidisciplinary team looking after stroke patients and
guiding the caregivers in their continuing care will help in decreasing the mor-
bidity and mortality of this disorder (Table 7.1).
Table 7.1 Take‐home messages.
•• Post‐stroke complications are common.

•• Post‐stroke complications are heterogeneous in nature.
•• Post‐stroke complications are associated with a poor outcome.
•• Most stroke complications are preventable and treatable.
•• Acute stroke units and a multidisciplinary team are the most effective strategy in identifying these
complications and treating them adequately for a more favorable outcome.
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come in a Nigerian stroke unit. Ann Afr Med 2014;13:11–5.
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study. Stroke 2000;31:1223–9.
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a randomized controlled trial. PLoS One 2008;3:e2158.
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19. Mehdi Z, Patel M. Urinary and bladder complications after stroke. In: Bhalla A, Birns J
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PAR T II
Long term stroke care
and complications
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CHAPTER 8
Risk factor management

for primary and secondary
stroke prevention
Kay-Sin Tan and Ester S. Bitanga
Introduction
Stroke is the second leading cause of death in individuals worldwide. The bur-
den of stroke in low‐ and middle‐income countries is substantial. The Global
Burden of Disease study [1] showed that about two‐thirds of the increased rate
in stroke incidence and prevalence occurred in Asia. However, Asia is a diverse
continent with many countries and regions that differ greatly in terms of risk
factors, ethnic composition, income, and available medical resources. Accordingly,
primary as well as secondary prevention strategies are important methods to
reduce the problem. This chapter will address the traditional risk factors as well
as conditions more common in Asia and outline approaches to their manage-
ment. Regional differences and relevant challenges will also be highlighted.
Impact of risk factors—Western and Asian differences
A large, international case–control study (INTERSTROKE) [2] investigated mod-

ifiable risk factors across many regions in the world and included both ischemic
stroke and intracerebral hemorrhage. Previous history of hypertension, lack of
regular physical activity, diet, abnormal waist to hip ratio, psychosocial factors,
smoking, cardiac causes, alcohol consumption, and diabetes mellitus were all
associated with ischemic stroke (91.5%) and intracerebral hemorrhage (87.1%).
There is supporting evidence that Western and Asian populations differ with
respect to major factors that affect the incidence of stroke. Two factors, smoking
and alcohol consumption, showed statistically significant differences between
Western and Asian populations, and the results were as follows (Western/Asian):
2.05 (95% confidence interval [CI], 1.68–2.49)/1.27 (95% CI, 1.04–1.55) [3]
and 0.89 (95% CI, 0.76–1.04)/1.28 (95% CI, 1.07–1.53). Body mass index
(BMI) = 18.5–21.9 kg/m2 showed statistically significant differences only in
91
08.indd 91 08/25/2017 11:03:27 AM

Western populations, 0.96 (95% CI, 0.93–0.99); while systolic blood pressure
(SBP) = 120–139 mmHg showed statistically significant differences only in Asian
populations, 2.29 (95% CI, 1.04–5.09) [4].
Therefore, different interventional approaches can be implemented to reduce
the risk of stroke among high‐risk individuals from different regions and different
ethnic groups.
Gender
Impact
Gender confers unique risk factors in men and women. In Asia, these differences
occur due to variations in stroke awareness, risk factors, and prevailing social
issues that impact stroke care. Asian men have higher overall incidence of
stroke compared to Asian women, while Asian women tend to have poorer
short‐ and long‐term outcomes. Physiological changes found in women make
their risk for ischemic stroke different from men. The differences in immunity,
hormonal changes, and changes due to pregnancy and puerperium impact on the
stroke type and its outcomes [5]. Conventional risk factors such as hypertension,
diabetes mellitus, dyslipidemia, and central obesity by waist‐to‐hip ratio were
found to be more prevalent among Filipino women [6]. In contrast, the results of
a multicenter ischemic stroke series done in Pakistan showed a significantly
higher proportion of hypertension, dyslipidemia, smoking, and severe left ven-
tricular dysfunction among men compared with women [7]. Other important
risk factors for stroke in young women include oral contraceptives, heavy alcohol
consumption, and, rarely, pregnancy and post‐partum strokes [8].
While oral contraceptive use and tobacco and alcohol addictions are less
prevalent among Asian women due to socio‐cultural differences, prior studies
have demonstrated that almost 50% of pregnancy‐related strokes in women
from five Asian countries were due to cortical venous thrombosis [5,9]. Women
are at an increased risk of venous thromboembolism during pregnancy and up
to 8 weeks post-partum. Pregnancy and early puerperium cause transient pro-
thrombotic states, with hypercoagulability worsening after delivery secondary
to volume depletion and trauma. Additional risk factors such as infection, instru-
mental delivery, or caesarean section can be seen during the puerperium.
A case–control study showed that hyperhomocysteinemia was associated with
increased risk of puerperal cerebral venous thrombosis (odds ratio [OR] 10.8;
95% CI 4.0–29.4) [10]. Another study in Pakistan, which aimed to identify dif-
ferent risk factors for stroke in patients of different genders, found that men and
women have similar conventional risk factors for stroke but that hypertension
and atrial fibrillation are more prevalent in women at the onset of stroke. The
prevalence of smoking, drinking alcohol, coronary artery disease, and diabetes is
found to be higher in men [11].
08.indd 92 08/25/2017 11:03:27 AM

Risk factor management for primary and secondary stroke prevention 93
Obesity, on the other hand, was found in 28% of Pakistani women com-
pared to 22% in men [12]. The 2010 National Health and Nutrition Examination
Survey showed that in populations aged 30 and above, hypertension was
more prevalent in men compared to women (30.1% vs 27.7%). Estimates of
stroke‐related differences by gender in China showed an increased dependency
rate at 12 months for women as well as a higher mortality rate at 3, 6, and
12 months compared to men [13]. Overall, there were marked regional differ-
ences in gender‐related comorbidities and clinicians are encouraged to be aware
of local differences in conventional risk factors in order to optimize treatment
and reduce risk factors.
Risk modification
Primary prevention
Gender is a non‐modifiable stroke risk factor, therefore other gender‐specific risk
factors for stroke must be addressed. Risk factors for stroke vary between genders,
thus it is important to identify relevant risk factors [14].
As these cardiovascular risk factors are modifiable, screening and subsequent
treatment are recommended. There should be proper education on the side
effects of oral contraceptives, smoking, and heavy alcohol consumption. Proper
nutrition and exercise should be given priority. During pregnancy, dehydration
should be avoided and infections should be adequately treated.
Secondary prevention
The 2010 EFNS guideline on the treatment of cerebral venous and sinus throm-
bosis recommends that patients without contraindication to anticoagulation
be treated with either body weight‐adjusted subcutaneous low‐molecular‐weight
heparin or with dose‐adjusted intravenous heparin with an at least d oubled acti-
vated partial thromboplastin time. Concomitant intracerebral hemorrhage related
to cerebral venous thrombosis is not a contraindication for heparin. In uncompli-
cated cases, low‐molecular‐weight heparin is preferred. There are insufficient
data about the use of thrombolysis and the optimal duration of oral anticoagula-
tion therapy. Prophylactic antiepileptic therapy may be considered as a therapeutic
option in patients with focal neurological deficits and supratentorial lesions on
admission CT/MRI [15].
Diabetes mellitus
Definition
Diabetes mellitus (DM) is defined as a fasting plasma glucose level of 7.0 mmol/l
(126 mg/dl) or higher, a 2‐hour oral glucose tolerance test glucose level of
11.1 mmol/l (200 mg/dl) or higher, or a history of diabetes, with or without use
of oral antihyperglycemic medication or insulin. An International Expert
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Committee that included representatives of the American Diabetes Association

(ADA), the International Diabetes Federation (IDF), and the European
Association for the Study of Diabetes (EASD) recommended the use of the
HbA1C test to diagnose diabetes, with a threshold of ≥6.5% [16].
Impact
Diabetes and impaired glucose tolerance (IGT) have been acknowledged as
important healthcare challenges among Asian countries. The countries included
in the study are Mauritius, India, Sri Lanka, Bangladesh, Bhutan, Nepal, and the
Maldives. The region is estimated to have more than 72 million adults with dia-
betes and 24.3 million with IGT. This present trend indicates that more than
60% of the world’s population with diabetes will be in Asia. The country in Asia
with the highest diabetes prevalence is Mauritius (14.8%), followed by India
(9.1%). It was estimated that the number of diabetics will exceed 123 million in
2035 [17]. A profile in South Asians showed that diabetes mellitus affects 35%
of the population older than 45 years [12]. Asians have a greater risk of develop-
ing diabetes at earlier ages and with lower BMI. This risk can be aggravated by
rapid socioeconomic development, increasing number of people following a
western diet, and lifestyle changes in Asian countries [18].
The level of pre‐diabetes is an important consideration in assessing stroke
risk. A meta‐analysis of five prospective cohort studies analyzing a pre‐diabetic
population with a fasting glucose of 110–125 mg/dl (6.1–6.9 mmol/l) showed an
increased risk of stroke after adjusting for established cardiovascular risk factors,
while those with impaired fasting glucose of 100–125 mg/dl (or 5.6–6.9 mmol/l)
did not show an increased risk of stroke after adjustment [19]. The risk
of secondary strokes in diabetics was shown to be 2.1–5.6 times the risk in the
non‐diabetic population [20–22].
Risk modification
Primary prevention
Behavioral modifications and pharmacological treatment are recommended for
the control of pre‐diabetes (defined as fasting plasma glucose of 110–125 mg/dl or
6.1–6.9 mmol/l) and DM. A target of hemoglobin A1c (HbA1c) of less than 7% is
a reasonable goal for the general nonpregnant population in preventing micro-
vascular complications (Class I, level A). The same HbA1c target is reasonable for
the prevention of macrovascular complications of DM as well (Class I, level B).
The American Heart Association (AHA) recommends the control of comorbidities
such as hypertension and dyslipidemia in diabetic patients. The use of aspirin for
primary stroke prevention in patients with DM without evidence of atheroscle-
rotic disease is not recommended as it has not been satisfactorily demonstrated
for patients with diabetes. However, aspirin given as primary prevention may be
reasonable in diabetic patients with high cardiovascular disease risk (Class IIb,
level B) [20,21].
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AHA guidelines for the secondary prevention of stroke recommend that all
post‐stroke patients should be screened for DM. HbA1c may be more accurate
compared to other screening tests in the period immediately after stroke (Class
IIa, level C). The AHA also recommends the use of the existing ADA guidelines
for glycemic control in post‐stroke patients with DM or pre‐diabetes. In diabetic
patients with transient ischemic attack (TIA) or stroke, a goal of HbA1c of less
than 7% is recommended to reduce microvascular (Class I, level A), and
possible macrovascular complications (Class IIb, level B). In patients with

cardiovascular disease or those with vascular risk factors, HbA1c should not be
lowered to less than 6.5%. Aspirin, at a dose of 75–162 mg/day, may be used
as a secondary prevention in DM patients with a history of stroke (Class I, level
A) [16,20,21,23].
Hypertension
Definition
Hypertension is the most important modifiable risk factor for stroke. It was noted
to be a more potent risk factor for intracerebral hemorrhagic stroke than for
ischemic stroke [2]. Hypertension, as defined in the JNC‐7 recommendation, con-
sists of a systolic BP (SBP) of 140 mmHg or higher, diastolic BP (DBP) of 90 mmHg
or higher, a previous diagnosis of hypertension, or use of antihypertensive medi-
cation [24]. The latest Joint National Committee (JNC) 8 recommendations
effected no change in the definition, believing them to still be reasonable [25].
Impact
Hypertension affects approximately 1 billion of the world’s population. By 2025, it
is estimated that up to 1.58 billion adults will suffer from its complications [26].
In a 2008 stratified multistage sampling of the entire Philippine population aged
20 years and older, there was a 4.2% increase in the prevalence of hypertension
when compared to the 2003 survey result (20.6% vs 16.4%), suggesting insuffi-
cient effort in the prevention and control of hypertension [6]. The National Health
Survey of Pakistan showed that 33.3% of adults older than 45 years, and 18% of
the population (aged 15 and above) are affected by hypertension. Among those
who are hypertensive, less than 3% have blood pressures controlled to less than
140/90 mmHg [27,28]. A meta‐analysis of prospective cohort studies in Western
and Asian countries indicated that an increasing systolic blood pressure is associated
with increased risk of stroke. The risk of stroke was noted to be greater among par-
ticipants with systolic blood pressure ≥140 mmHg than among patients with diag-
nosed hypertension. From this phenomenon, it was postulated that most individuals
diagnosed with hypertension had received appropriate antihypertensive interven-
tions [3]. It was reported that among the East Asian population, hypertension was
08.indd 95 08/25/2017 11:03:27 AM

seen to be higher in older‐aged men, those with high salt consumption, and popu-
lations in urbanized and medium‐sized cities [18].
Risk modification
Primary prevention
Among all risk factors for stroke, blood pressure is the most amenable to change
in low‐income settings. Only modest equipment and little specialized expertise
are needed in screening programs. Blood pressure is also readily reduced and
controlled by inexpensive medications and nonpharmacologic approaches.
Regular blood pressure monitoring is recommended in adults, particularly in the
elderly and those with other cerebro-and cardiovascular risk factors. Lifestyle
modifications such as a low‐salt, low‐fat diet, exercise, moderate alcohol con-
sumption, and smoking abstinence are recommended. Blood pressure of less than
140/90 mmHg should be targeted, and in patients with comorbidities of d iabetes
and/or renal disease, a lower target blood pressure of 130/90 mmHg is recom-
mended (Class I, level A). Pharmacologic therapy such as specified in JNC 8 and
the European Society of Hypertension/European Society of Cardiology (ESH/
ESC) guidelines are recommended [29].
The absolute target blood pressure levels are still uncertain, and treatment should
be individualized. Some studies have shown the benefit of an average reduction of
10/5 mmHg. Blood pressure less than 140/90 mmHg is considered acceptable (Class
Ia, level B). Treatment with antihypertensive medications is recommended for the
prevention of stroke recurrence in all patients with stroke or transient ischemic
attack (Class IIa, level B). Regular blood pressure monitoring and lifestyle modifica-
tions are recommended to supplement antihypertensive medications [24,29].
A summary of key therapeutic points required

pharmacologically (based on JNC 8) [25]
For the population aged 60 years and older, pharmacologic treatment is recom-
mended for systolic blood pressure ≥150 mmHg and for diastolic blood pressure
≥90 mmHg. For the general population younger than 60 years as well as for the
population ≥18 years old with chronic kidney disease (CKD), treatment is started
at systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg
[25]. Table 8.1 shows the recommended antihypertensive medication for each
population type.
Antihypertensives can be titrated and a second or third drug added in order
to reach goal blood pressure. If the target blood pressure cannot be achieved
using the drugs listed in the recommendation due to the need to add a fourth
drug or because of a contraindication, antihypertensive drugs from other classes
can be used. For cases with difficult to control blood pressure or other compli-
cated cases, referral to a hypertension specialist might be indicated [25].
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Table 8.1 Choice of antihypertensives at initiation according to population characteristic [2].
Population Recommended antihypertensives
General non‐Black population, including Thiazide‐type diuretic, calcium channel blocker

those with diabetes mellitus (CCB), angiotensin‐converting enzyme inhibitor
(ACEI), or angiotensin receptor blocker (ARB).
(Moderate recommendation—Grade B)
General black population, including those Thiazide‐type diuretic, calcium channel blocker
with diabetes mellitus (CCB). (For general black population: Moderate
recommendation—Grade B; for black patients with
diabetes: Weak recommendation—Grade C)
Population ≥18 years old with chronic Angiotensin‐converting enzyme inhibitor (ACEI) or
kidney disease (regardless of race and angiotensin receptor blocker (ARB). (Moderate
diabetic status) recommendation—Grade B)
Caution: Do not use an ACEI and an ARB together in the same patient.
Cigarette smoking and stroke
Impact
The age‐standardized prevalence of daily smoking was 25% for men and 5.4%
for women in 2015. Most countries in the world, including Asian countries, have
achieved significant declines in smoking prevalence in the last decade [30].
The 2009 Philippine Global Adult Tobacco Survey (GATS) revealed that 28.3%
(17.3 million) of Filipinos aged 15 years old and above smoke tobacco;
47.7% (14.6 million) are men and 9.0% (2.8 million) are women [31]. Eighty
percent of them smoke on a daily basis, men and women consuming an average
of 11.3 and 7 cigarette sticks/day, respectively. In a separate survey, from 1994 to
2013, a decreasing proportion of adolescent smokers (less than 1 in 5 individuals)
was observed. Numerous studies have shown that cigarette smoking is an
independent predictor for first ischemic stroke in both men and women. A meta‐
analysis of 22 studies showed that the relative risk (RR) of cerebral infarction
among smokers is approximately double that of the nonsmokers. In the Japan
Public Health Center (JPHC 1) prospective cohort study, the RR for a first stroke
among current smokers, after adjustment for cardiovascular risk factors, was 1.27
(95% CI, 1.05–1.54) for total stroke, 0.72 (95% CI, 0.49–1.07) for intraparenc
hymal hemorrhage, 3.60 (95% CI, 1.62–8.01) for subarachnoid hemorrhage, and
1.66 (95% CI, 1.25–2.20) for ischemic stroke. Similarly, a positive association was
observed between smoking and the risks of lacunar infarction and large‐artery
occlusive infarction, but not embolic infarction [32,33].
Given the strong association between the risk of stroke and smoking, the need
for abstention from smoking (or complete cessation) cannot be overemphasized.
However, no trial to date has examined the effectiveness of smoking cessation for
secondary prevention among individuals with a history of stroke or TIA.
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Recommendations
Primary stroke prevention [21]
1 Smoking cessation for all current smokers is recommended (Class II, level B).
2 Smoking should be banned in public places because second‐hand smoke is
associated with increased risk of CVD (Class II, level B).
3 Effective behavioral and pharmacological treatments should be advised and
encouraged for nicotine dependence (Class IIa, level B).
Secondary stroke prevention [24]

1 Patients with stroke or TIA who have smoked in the past year should be
strongly advised to quit smoking (Class I, level C).
2 Counseling, nicotine products, and oral smoking cessation medications are
effective for helping smokers to quit (Class I, level A).
3 It is reasonable to advise patients after TIA or ischemic stroke to avoid envi-
ronmental (passive) tobacco smoke (Class IIa, level B).
Nicotine dependence treatment [34]

Several behavioral and pharmacologic interventions are used (usually in
combination) for the treatment of nicotine dependence. These include nico-
tine replacement products (e.g., patch, gum, lozenge, nasal spray, and
inhaler), non‐nicotine medications (e.g., antidepressants, varenicline
[Chantix], and clonidine), counseling, rehabilitation, social support groups,
and smoking cessation programs.
Dyslipidemia
Definition
Dyslipidemia can be defined as increased levels of total cholesterol (>240 mg/dl
or 6.2 mmol/l), plasma triglycerides (>200 mg/dl or 5.2 mmol/l), and low‐density
lipoprotein cholesterol (>160 mg/dl or 4.1 mmol/l) and a decreased concen
tration of high‐density lipoprotein cholesterol (<40 mg/dl or 1.04 mmol/l).
Dyslipidemia is a well‐established risk factor for atherosclerotic cardiovascular
diseases (ASCVD) and other comorbid conditions [35].
Impact
Epidemiological evidence suggests a link between high low‐density lipoprotein
cholesterol (LDL‐C) levels and the risk of ischemic stroke over a wide range of
lipid levels. A low HDL cholesterol (HDL‐C) and high lipoprotein (a) levels are
associated with increased risk of stroke [36,37]. On the other hand, hypertriglyc-
eridemia has been correlated with both ischemic stroke and large‐artery athero-
sclerotic (LAA) subtype [38,39].
08.indd 98 08/25/2017 11:03:27 AM

Recommendations
Dietary intake of saturated fats, physical inactivity, obesity, and diabetes all con-
tribute to raise blood cholesterol levels. As such, lifestyle modification is crucial
in risk modification. There is a compelling body of evidence that lipid lowering,
specifically LDL‐C, reduces major cardiovascular events including primary and
secondary stroke. Current evidence shows that lipid‐lowering agents, particu-
larly statins, can halt or reverse atherosclerotic progression in a dose‐dependent
manner. Statins (3‐hydroxy‐3‐methylglutaryl coenzyme A [HMG‐CoA] reduc-
tase inhibitors) are commonly used as first‐line agents for the treatment of
hypercholesterolemia. On the other hand, supporting data regarding the use of
nonstatin agents, including the proprotein convertase subtilisin/kexin type 9
(PCSK) inhibitors for stroke prevention, are not widely available [40]. Thus, the
use of these medications should be carefully considered on the basis of safety
and efficacy.
Primary prevention
Large randomized trials involving HMG‐CoA reductase inhibitors (statins) have
consistently shown them to be beneficial in the prevention of ischemic stroke in
patients with coronary artery disease. Studies such as the Anglo‐Scandinavian
Cardiac Outcomes Trial (ASCOT) and the Heart Protection Study showed a
27–32% reduction in stroke rates in the groups treated with a statin compared
with placebo. Screening for coronary heart disease (CHD) risk factors (cigarette
smoking, hypertension, HDL‐C <40 mg/dl, CHD in a male first‐degree relative
<55 years of age or in a female first‐degree relative <65 years of age, or age ≥45
years in men or ≥65 years in women) and CHD risk equivalents (diabetes or
other forms of atherosclerotic disease) must be carried out. Patients with known
coronary artery disease (CAD) and high‐risk hypertensive patients, even those
with normal LDL cholesterol levels, must be treated with lifestyle measures
(diet modification, weight loss, and physical activity) and a statin (Class I, level
A). A target of LDL‐C <160 mg/dl is recommended for patients with 0–1 CHD
risk factor, LDL‐C <130 mg/dl for those with ≥2 CHD risk factors, and LDL‐C
<100 mg/dl for patients with CHD or CHD risk equivalent [38].
The Canadian Cardiovascular Society [41] recommended screening patients
with the following characteristics for dyslipidemia:
1 Men ≥40 years of age, and women ≥50 years of age or post‐menopausal.
2 All patients with the following conditions, regardless of age:
•• diabetes
•• hypertension
•• current cigarette smoking
•• obesity
•• family history of premature CAD
•• inflammatory diseases such as systemic lupus erythematosus, rheumatoid
arthritis, and psoriasis
08.indd 99 08/25/2017 11:03:27 AM

•• chronic renal diseases (estimated glomerular filtration rate <60 ml/min/1.73 m2)

•• evidence of atherosclerosis
•• HIV infection treated with highly active antiretroviral therapy
•• clinical manifestation of hyperlipidemias (xanthomas, xanthelasmas, and
premature arcus cornealis)
•• erectile dysfunction.
3 Children with a family history of hypercholesterolemia or chylomicronemia [41].
Patients with ischemic stroke or TIA with elevated cholesterol, comorbid CAD,
or evidence of an atherosclerotic origin should be managed with lifestyle modi-
fication, dietary guidelines, and medications such as statins. An LDL‐C target of
<100 mg/dl is recommended for patients with CHD or symptomatic atheroscle-
rotic disease and LDL‐C of <70 mg/dl is advised for very high‐risk patients with
multiple risk factors (Class I, level A).
The ongoing Treat Stroke to Target (TST) trial (ClinicalTrials.gov identifier
NCT01252875) is testing the effects of targeting LDL‐C concentration on reduc-
ing recurrent atherosclerotic stroke risk because the optimum target for LDL‐C
in secondary stroke prevention is uncertain. This trial is scheduled to be com-
pleted in 2019 [23].
Obesity
Definition
Body mass index (BMI) is calculated as the weight in kilograms divided by the
square of the height in meters. Overweight is defined as BMI of 25.0–29.9 kg/m2,
and BMI of 30 kg/m2 or higher is defined as obesity [42]. Overweight in Asians
was defined as BMI ≥23.0 kg/m2 and obese was defined as BMI ≥25.0 kg/m2.
A World Health Organization (WHO) proposal for a lower cut‐off at BMI
>23.0 kg/m2 as overweight for Asians was presented because the proportion of
Asian people with a high risk of type 2 diabetes and cardiovascular disease is
substantial at BMIs lower than the existing WHO cut‐off point for overweight
(>25 kg/m2). However,, available data do not necessarily indicate a clear BMI
cut‐off point for all Asians for overweight or obesity and as a result this target
BMI has not been uniformly adopted in Asian guidelines.
Obesity can also be defined based on the waist‐to‐hip ratio (WHR), which is
measured by dividing waist circumference (measured at the midpoint between
the lowest rib and the iliac crest) by the hip circumference (measured at the
greater trochanter or widest diameter of the hips). Obesity has been categorized
as WHR of 1.0 or higher for men and 0.85 or higher for women [43]. It has also
been noted that morbidity and mortality in Asian populations occurred in p eople
with lower BMIs and smaller waist circumference.
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Impact
The INTERSTROKE study results showed that WHR was associated with increased
risk of all types of stroke [2]. However, in Asia, the impact of BMI on stroke is
more controversial. In China, a prospective cohort study showed that elevated
BMI increased the risk of both ischemic and hemorrhagic stroke incidence and
stroke mortality [44]. On the other hand, in Japan [45], the association between
BMI and stroke incidence observed was different than those previously reported:
low BMI was a risk factor for all stroke and cerebral infarction in men, while high
BMI was a risk factor for all stroke in women.
Risk modification
Primary prevention
Weight reduction is recommended for primary stroke prevention as it results in
the lowering of blood pressure. Recommended methods of weight reduction
include exercise, diet modification, weight loss counseling, and lifestyle inter-
vention. Screening patients with TIA or stroke for obesity through the measure-
ment of BMI is recommended [22].
The following target parameters are recommended:
1 BMI between 18.5 kg/m2 and 24 9 kg/m2.
2 Waist–hip ratio not greater than 1.0 in men and 0.85 in women.
3 Waist circumference not greater than 35 inches in men and 31 inches in
women [22].
Specific national guidelines that can contribute to weight reduction include
vigorous physical activity for ≥10 minutes at a time, ≥20 minutes per day, and ≥3
times a week, or moderate physical activity or walking for ≥10 minutes at a time,
≥30 minutes per day, and ≥5 times a week [14]. Regular physical activity was
associated with a reduced risk of all stroke. Increased consumption of fruit and
fish was associated with reduced stroke risk.
Specific international guidelines for the management of overweight and obe-
sity in adults recommended identifying patients who need to lose weight (via
BMI and waist circumference) and subsequently matching treatment benefits
with the risk profile of individual patients such as dietary measures for weight
loss, lifestyle intervention and counseling, exploration of the option of adding
pharmacotherapy as an adjunct to comprehensive lifestyle intervention, and the
selection of patients who are candidates for bariatric surgical treatment. The
panel recommends an initial goal of a weight loss of 5–10% of baseline weight
within 6 months [46].
There are currently no studies that have been able to demonstrate a decrease in
stroke recurrence with weight reduction. There are studies in Western countries
that demonstrated that overweight and obese patients have a lower rate of mor-
tality and dependency compared to normal weight and underweight patients
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[22,46]. This association, however, was not observed in studies involving Asian
patients. As weight reduction can result in lowering of blood pressure (Class Ia,
level A), lipid indices, fasting plasma glucose, and improved physical endurance,
maintaining a healthy weight is recommended as it has been shown to decrease
the risk of stroke and death [22,29].
Rheumatic heart disease
Definition
Rheumatic heart disease (RHD) results from immunological and inflammatory
damage to one or more cardiac valves after one or more episodes of acute rheu-
matic fever.
Impact
Rheumatic heart disease is common in Asia and is a major risk factor for cardioem-
bolic stroke. A recent study observed that the stroke prevalence in a population of
patients with RHD ranged from 0.37% to 12.6% in Asia over the last 30 years. In
addition, the proportion of RHD in ischemic stroke patients ranged from 3.4% to
23.2% in Asia, while the figures were much lower at 1.8–2.0% in Europe and
Northern America in the past three decades [47].
Six studies reported the case‐fatality rate in stroke patients with RHD; it
ranged from 8.5% to 47.4% in Asia during the last three decades [1]. More recent
data on clinical outcomes of symptomatic RHD taken from a prospective study
in children and adults revealed a case‐fatality rate of 16.9% and a median age
of death at 28.7 years with stroke and congestive cardiac failure affecting 20% of
the cohort. Modifiable predictors for mortality in this study included congestive
cardiac failure, dyspnea, atrial fibrillation, and low level of education [48].
Recommendation
Prevention of stroke from RHD can be accomplished through systematic
programs focused on early detection of acute rheumatic fever and treatment of
RHD. Other strategies to ameliorate the clinical impact and reduce the burden
of RHD are penicillin prophylaxis, oral anticoagulation, timely intervention of
valvular disease, and addressing modifiable predictors described earlier.
Infection and strokes
Definition
The association between infections and acute ischemic stroke is multifaceted.
Infections can result in ischemic stroke while the rate of infection is increased
after ischemic stroke. Infections can cause a stroke through two major direct
08.indd 102 08/25/2017 11:03:27 AM

mechanisms: systemic bacteremia–endocardial infection, resulting in infectious

endocarditis and septic emboli to the brain. Infectious vasculitis in the context of
a meningoencephalitic process can also contribute to vasculopathy leading to
strokes. Thus, infections as a direct cause of ischemic stroke can result in cardi-
oembolic, large vessel or small vessel, lacunar infarctions.
Other recognized infections that contribute to vasculopathy and stroke
include TB meningitis, Japanese B encephalitis, dengue, malaria, neurocysticer-
cosis, and fungal infections of the central nervous system including aspergillosis
and cryptococcosis [49].
HIV infection can result in stroke via several mechanisms, including opportun-
istic infection, vasculopathy, cardioembolism, and coagulopathy. HIV‐associated
vasculopathy describes various cerebrovascular changes, including stenosis and
aneurysm formation, vasculitis, and accelerated atherosclerosis, and might be caused
directly or indirectly by HIV infection, although the mechanisms are controversial.
HIV and associated infections contribute to chronic inflammation. Combination
antiretroviral therapies (cART) are clearly beneficial, but can be atherogenic and
could increase stroke risk. cART can prolong life, increasing the size of the aging
population at risk of stroke. Stroke management and prevention should include
identification and treatment of the specific cause of stroke and stroke risk factors,
and judicious adjustment of the cART regimen [50].
Recommendation
Early recognition and treatment of underlying conditions remains the corner-
stone of management in these uncommon conditions in Asia.
Less common conditions
Uncommon cerebrovascular diseases and systemic conditions resulting in

stroke include moyamoya disease, numerous acquired hypercoagulable
states, and toxic conditions (bee stings, snake envenomation, and scorpion
sting) as described in Chapter 3 of Stroke in Asia [51–57]. Principles of
management include early recognition and treatment of the primary as well
as the underlying condition.
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08.indd 106 08/25/2017 11:03:27 AM

CHAPTER 9
The role of antiplatelets for

stroke prevention
Xinyi Leng, Nijasri C. Suwanwela, and Lawrence K.S. Wong
Definition and rationale of treatment
Stroke is a leading cause of adult disability worldwide. Asian populations bear a

high stroke burden, especially in developing countries. For instance, in a recently
published nationwide survey of 0.5 million adults throughout rural and urban
areas in China, the prevalence of stroke was 1596.0 per 100 000 people and the
incidence was 345.1 per 100 000 person‐years, while ischemic stroke accounted
for around 70% of all strokes [1]. Thus, efficiently preventing recurrent events
in patients with ischemic stroke or transient ischemic attack (TIA) is important
in reducing the stroke burden in Asia and other parts of the world. During the
past decades, antiplatelet therapy has been first‐line medical treatment in second-
ary prevention of ischemic stroke and TIA, applicable in most noncardioembolic
ischemic stroke and TIA, and cardioembolic stroke patients with contraindica-
tions for anticoagulation therapy [2]. In this chapter, we shall briefly summarize
findings of clinical trials testing the efficacy and safety of antiplatelet therapies
for secondary prevention of noncardioembolic ischemic stroke or TIA, if such
trials were conducted predominantly in Asian populations, or subgroup analytic
results of Asian patients were available in multicenter, multi‐ethnicity trials.
Mechanism of action
Commonly used antiplatelet agents in clinical practice or promising antiplatelet

agents currently under investigation in clinical trials for noncardioembolic stroke
include aspirin, clopidogrel, dipyridamole, ticlopidine, cilostazol, and ticagrelor,
or a combination of two or more antiplatelet agents, for instance, aspirin plus
dipyridamole, or aspirin plus clopidogrel. For the mechanisms of action of these
medications, please refer to Chapter 5.
107
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Evidence based in Western and Asian trials
There have been a few large randomized controlled trials (RCTs), predominantly
in Western countries, testing the efficacy and safety of different antiplatelet regi-
mens to prevent recurrent stroke in patients with noncardioembolic ischemic
stroke or TIA. Based on findings from these trials, aspirin alone, aspirin combined
with dipyridamole, or clopidogrel alone, are recommended in clinical guidelines
for secondary prevention in ischemic stroke patients in Western countries [2,3].
Dual antiplatelet therapy of aspirin and clopidogrel may be effective in reducing
stroke recurrence in minor stroke or TIA patients if initiated early and lasting for a
short period [4,5] but may not be suitable for long‐term secondary prevention in
stroke patients due to similar risk of recurrent stroke but increased risk of hemor-
rhagic events as compared with aspirin alone or clopidogrel alone [6–8].
The effects of different antiplatelet regimens in secondary prevention of
ischemic stroke have also been investigated in large, multicenter trials in Asia
over the past decades. Major multicenter RCTs of antiplatelet therapy in ischemic
stroke in Asia are summarized in Table 9.1 in chronological order. For instance,
the Chinese Acute Stroke Trial (CAST), which was completed over 20 years ago,
is among the largest RCTs in the world. It has demonstrated the beneficial effect
of aspirin over placebo in reducing the risk of death, dependency, and nonfatal
strokes in over 20 000 acute ischemic stroke patients [9]. More recently, the
Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular
Events (CHANCE) trial, another large, multicenter RCT, has proved in acute
minor stroke or high‐risk TIA patients that early‐initiated, short‐term aspirin
and clopidogrel treatment may reduce the risk of recurrent stroke but not
significantly increase the bleeding risk, as compared to aspirin monotherapy [4].
A subsequent meta‐analysis further supported early use of such dual antiplatelet
therapy for preventing stroke in these patients [5]. The beneficial effect of
aspirin and clopidogrel in preventing early recurrent stroke is supported by
another multicenter RCT conducted in Asia, the Clopidogrel plus Aspirin for
Infarct Reduction in acute stroke/TIA patients with large artery stenosis and
microembolic signal (CLAIR) trial, which indicated that aspirin combined with
clopidogrel may reduce microemboli in the first few days after an acute ischemic
stroke attributed to extracranial or intracranial arterial stenosis [10].
The antiplatelet regimen of aspirin plus dipyridamole, which has been
rigorously tested in Caucasians [11–13] and is recommended as first‐line
antiplatelet regimen in secondary prevention of ischemic stroke patients in
Western guidelines [2,3] was not proved to be superior or noninferior to aspirin
therapy in Asians based on limited evidence. For instance, the Japanese Aggrenox
(extended‐release dipyridamole plus aspirin) Stroke Prevention vs Aspirin
Programme (JASAP) study was inconclusive regarding the noninferiority of
extended‐release dipyridamole plus aspirin vs aspirin in preventing ischemic
stroke in stroke patients with additional vascular risk factors [14].
0003172479.INDD 108 8/22/2017 1:16:09 PM

0003172479.INDD 109
Table 9.1 Multicenter, randomized controlled trials on antiplatelet therapy in secondary prevention of ischemic stroke in Asia.
Trial Country Sample Treatment groups and Patient Primary HR or OR or risk Main findings
and centers size dosages characteristics outcome event; reduction (95% CI) of
duration of A vs B for primary
A B follow‐up outcome event
CAST 1997 China, 413 21 106 Asp Placebo IS within 2 days of All‐cause death; 14% risk reduction Aspirin started early in hospital and
[9] centers (160 mg od) onset; 4 weeks continued for a few weeks reduced
mean age 63 years; risks of death, dependency, and
63% males nonfatal strokes in acute ischemic
stroke patients, as compared to
placebo
CSPS 2000 Japan, 183 1095 Cilo Placebo IS within 1–6 Recurrent Significant relative risk Cilostazol is safe and effective in
[24] centers (100 mg bd) months; ischemic stroke; reduction 41.7% preventing recurrent ischemic
mean age 65 years; 1–5 years (9.2–62.5%); p = .015 stroke after an ischemic stroke
66% males
TOSS 2005 South Korea, 135 Cilo (100 mg Placebo + Asp IS within 2 weeks Progression of the Incidence of primary Cilostazol plus aspirin may prevent
[19] 5 centers bd) + Asp (100 mg od) with symptomatic index intracranial outcome: 6.7% vs progression of symptomatic MCA
(100 mg od) intracranial stenosis; stenosis; 28.8% in the two stenosis, but there was no
mean age 62 years; 6 months groups; p = .008 difference in the clinical outcomes
61% males between the two groups
CASISP China, 720 Cilo Asp IS within 1–6 Any recurrent HR 0.62 (95% CI There was no significant difference
2008 [25] multicenter (100 mg bd) (100 mg od) months; stroke; 0.30–1.26); p = .185 between the two medications in
mean age of 60 12–18 months preventing any recurrent stroke in
years; IS patients within the first 6
69% males months, while cilostazol was more
effective than aspirin in the long
term (6–18 months)
CSPS II Japan, 278 2757 Cilo Asp IS in the past 26 Any recurrent HR 0.743 (0.564– Cilostazol may be more effective
2010 [26] centers (100 mg bd) (81 mg od) weeks; stroke; 0.981); p = .0357 than aspirin in preventing recurrent
mean age 64 years; 1–5 years stroke after an ischemic stroke,
70% males and safer than aspirin with fewer
hemorrhagic events
(Continued )
8/22/2017 1:16:09 PM
Table 9.1 (Continued)
0003172479.INDD 110
ARCC South Korea, 244 Cilo (100 mg Asp Aspirin users with IS; Incidence of Incidence of primary Aspirin and cilostazol might be a
2010 [17] 5 centers bd) + Asp (100 mg od) mean age of aspirin resistance; outcome: 8.8% vs treatment option in ischemic stroke
(100 mg od) 62 years; 4 weeks 10.9%; p = .578 patients with aspirin resistance
68% males
CLAIR Asia, 98 Asp (75–160 mg Asp Minor IS or TIA Presence of Relative risk reduction Dual antiplatelet therapy of
2010 [10] multicenter od) + Clop (75–160 mg within 7 days with microembolic 42.4% (4.6–65.2%); clopidogrel and aspirin is superior
(300 mg loading od) extra‐ or intra‐ signals on day 2; p = .025 to aspirin alone in reducing
then 75 mg od) cranial stenosis; 7 days microembolic signals in patients with
mean age 58 years; cervico‐cerebral arterial stenosis
78% males (predominantly intracranial stenosis)
JASAP Japan, 1294 ER‐DP (200 mg Asp Ischemic stroke Recurrent HR 1.47 (0.93–2.31) The study was inconclusive
2011 [14] multicenter bd) + Asp (81 mg od) within 1 week to 6 ischemic stroke; regarding the noninferiority of
(25 mg bd) months with at least over 1 year ER‐DR plus aspirin vs aspirin alone
two additional in preventing recurrent ischemic
vascular risk factors stroke in stroke patients with
(aged over additional vascular risk
50 years); factors
mean age 66 years;
72% males
TOSS‐II East Asia, 20 457 Cilo (100 mg Clop (75 mg Acute IS within Progression of the Incidence of primary There was no significant difference
2011 [20] centers bd) + Asp od) + Asp 2 weeks with index intracranial outcome: 9.3% vs in preventing progression of
(75–150 mg od) (75–150 mg symptomatic stenosis; 15.5% in the two intracranial stenosis or new
od) intracranial stenosis; 7 months groups; p = .092 ischemic lesions between the two
mean age 65 years; antiplatelet regimens in acute
51% males ischemic stroke attributed to
intracranial stenosis
8/22/2017 1:16:09 PM
0003172479.INDD 111
CAIST South Korea, 458 Cilo Asp Acute IS within mRS of 0–2; Incidence of primary Cilostazol was not inferior to aspirin
2011 [27] 12 centers (100 mg bd) (300 mg od) 48 hours; 90 days endpoint: 76% vs 75% for patients to achieve a favorable
mean age 63 years; One‐sided 95% CI of functional outcome at 3 months
61% males the proportion after an ischemic stroke, and
difference: –6.15 to bleeding complications were not
7.22%; p = .0004 significantly different between the
two regimens
Shimizu Japan, 55 510 Cilo None Acute IS within Progressing stroke Rates of progressing Cilostazol failed to show significant
2013 [28] centers (100 mg bd) 24 hours; in the acute stroke: 3.2% vs effects in preventing acute stroke
mean age of phase, and mRS 6.3%; p = .143. progression, and it might not
66 years; 0–1; Rates of mRS 0–1 at 3 improve the 3‐month functional
67% males 90 days months: 74.5% vs outcome, while it did not increase
72.7%; p = .687 the risk of intracranial hemorrhage
CHANCE China, 114 5170 Clop (300 mg Asp Minor IS or TIA Any stroke; HR 0.68 (0.57–0.81); In minor stroke or TIA patients,
2013 [4] centers load then (75 mg od) within 24 hours of 90 days p < .001 clopidogrel plus aspirin is superior
75 mg od) + Asp for 3 m onset; to aspirin alone for reducing the
(75–300 mg mean age 62 years; risk of stroke and does not increase
load then 66% males the risk of hemorrhage
75 mg od) for
21 days; Clop
alone (75 mg
od) on D22–90
CATHARSIS Japan, 163 Cilo (100 mg Asp IS within 2 weeks to Progression of the OR 2.14 (0.50–9.18); Cilostazol with aspirin and strict
2015 [29] multicenter bd) plus Asp (100 mg od) 6 months with symptomatic p = .31 risk factor control may be effective
(100 mg od) symptomatic intracranial in preventing progression of
intracranial stenosis; stenotic lesion; symptomatic intracranial stenosis.
mean age 68 years; 2 years Cilostazol with aspirin was more
66% males effective than aspirin alone in
preventing any new vascular event
while it did not significantly
increase the risk of bleeding
(Continued )
8/22/2017 1:16:09 PM
0003172479.INDD 112
PICASSO South Korea, 1512 Cilo (200 mg Asp (100 mg IS or TIA within 180 Co‐primary Incidence of primary Cilostazol was not inferior to
2017 Hong Kong, od), with or od), with or days and history of endpoints:1) safety endpoint: 0.61% aspirin in preventing overall
[18,21] the without without intracranial safety endpoint of vs 1.20% per person‐ vascular events in patients prone
(2 by 2 Philippines; Probucol Probucol hemorrhage or hemorrhagic year; p = .09 to intracranial hemorrhage. In
factorial 67 centers (250 mg bd) (250 mg bd) imaging evidence of stroke; and 2) Primary efficacy particular, cilostazol was superior
design) previous intracranial efficacy endpoint outcome: HR 0.80 to aspirin in preventing any stroke
hemorrhage of a composite of (0.60–1.05); p = .004 for (HR 0.67, 95% CI 0.46–0.96;
major vascular noninferiority p = .027). However, the risk of
events, including myocardial infarction was higher
stroke, myocardial in those treated with cilostazol
infarction, and than aspirin (9 events vs 2 events;
vascular death; p = .032).
2 years (mean) For overall safety, incidence of
intracranial hemorrhage was not
significantly different between those
assigned to cilostazol or aspirin
Medications: Asp, aspirin; Clop, clopidogrel; Cilo, cilostazol; ER‐DP, extended‐release dipyridamole.
Titles of the trials: CAST, Chinese Acute Stroke Trial; CSPS & CSPS II, Cilostazol Stroke Prevention Study I & II; TOSS & TOSS II, Trial of Cilostazol in Symptomatic Intracranial Arterial
Stenosis I & II; CASISP, Cilostazol versus Aspirin for Secondary Ischaemic Stroke Prevention; ARCC, Overcoming Biological Aspirin Resistance through Cilostazol Combination trial;
CLAIR, Clopidogrel plus Aspirin for Infarct Reduction in acute stroke/TIA patients with large artery stenosis and microembolic signal; CAIST, Cilostazol in Acute Ischemic Stroke
Treatment trial; CHANCE, Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events; CATHARSIS, Cilostazol‐Aspirin Therapy Against Recurrent Stroke with
Intracranial Artery Stenosis trial; PICASSO, PreventIon of CArdiovascular Events in iSchemic Stroke Patients With High Risk of Cerebral HemOrrhage.
Other abbreviations: mRS, modified Rankin Scale; HR, hazard ratio; OR, odds ratio; CI, confidence interval; IS, ischemic stroke; TIA, transient ischemic attack.
8/22/2017 1:16:09 PM
The role of antiplatelets for stroke prevention 113
Cilostazol is an antiplatelet agent that is frequently investigated in stroke

patients in Asian countries. Quite a few multicenter RCTs have been conducted
to test the effects of cilostazol vs placebo, cilostazol vs aspirin, cilostazol plus
aspirin vs aspirin, or cilostazol plus aspirin vs clopidogrel vs aspirin. Please refer
to the brief summary of these trials and the main findings in Table 9.1. Overall,
cilostazol (combined with aspirin or not) is as effective as, or superior to aspirin,
in preventing recurrent stroke after an ischemic stroke, while the bleeding risk
might be lower, or at least not different, in those treated by cilostazol rather than
aspirin [15,16]. Thus, cilostazol may be a safe alternative to aspirin in secondary
prevention of ischemic stroke, especially in those prone to bleeding or with aspi-
rin resistance [15,17,18]. In addition, cilostazol may be more effective in pre-
venting progression of symptomatic intracranial arterial stenosis, an important
cause of ischemic stroke in Asians [19,20]. However, the most recent evidence
from a multicenter RCT, PreventIon of CArdiovascular Events in iSchemic Stroke
Patients With High Risk of Cerebral HemOrrhage (PICASSO), indicated that
ischemic stroke or TIA patients with a history of intracranial macro‐ or micro‐
bleeding treated with cilostazol might be at a higher risk of myocardial infarction
than those treated with aspirin, although the risk of any stroke was significantly
lowered with cilostazol compared with aspirin [18,21]. The effects of cilostazol
in Asian patients need further verification in order to clarify certain groups of
stroke patients who would benefit most from such an antiplatelet regimen. On
the other hand, the efficacy and safety of cilostazol were seldom investigated in
Caucasians, which may be worth testing in pilot studies [15].
Some new antiplatelet agents may be promising in secondary prevention
of ischemic stroke in Asian patients, for example, ticagrelor. Although it has
demonstrated no superiority to aspirin in reducing the rate of stroke, myocar-
dial infarction, or death at 90 days among 13 199 ischemic stroke or TIA
patients throughout the world (hazard ratio [HR], 0.89; 95% confidence
interval [CI], 0.78–1.01; p = .07) [22], it has shown slightly significant benefit
in the 3858 subjects from Asian countries (HR 0.81; 95% CI, 0.67–0.99;
p = .04), probably due to high prevalence of intracranial atherosclerosis, rela-
tively poor baseline patient care, and the overall higher rate of endpoint
events in Asian patients [23]. The effect of ticagrelor in Asian stroke patients
warrants further investigation.
Recommendations
1 Antiplatelet therapy should be used for long‐term prevention of recurrent

stroke or other vascular events after a noncardioembolic ischemic stroke or
TIA.
2 Aspirin or clopidogrel should be considered as initial treatment in secondary
prevention of patients with ischemic stroke or TIA.
0003172479.INDD 113 8/22/2017 1:16:09 PM

3 The effects of aspirin plus dipyridamole vs other antiplatelet regimens in

secondary prevention for Asian patients with ischemic stroke or TIA are based
on limited evidence.
4 Dual antiplatelet therapy of aspirin and clopidogrel should be considered in
the early phase after a minor ischemic stroke or high‐risk TIA to prevent
recurrent stroke, but long‐term aspirin plus clopidogrel may increase the risk
of hemorrhagic events as compared with aspirin alone or clopidogrel alone.
5 Cilostazol may be a safe alternative to aspirin to prevent stroke in Asian
ischemic stroke patients, especially in those prone to bleeding or those with
intracranial atherosclerosis, but it may increase the risk of myocardial infarc-
tion in ischemic stroke patients with a history of intracranial hemorrhage.
Further verification is needed.
6 The effect of ticagrelor in preventing recurrent stroke or other vascular events
in Asian stroke patients warrants further investigation.
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0003172479.INDD 115 8/22/2017 1:16:09 PM

CHAPTER 10
The role of anticoagulants

for stroke prevention in
atrial fibrillation
Eun‐Jae Lee and Sun U. Kwon
Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice
and is associated with an increased risk of stroke [1]. Although the prevalence of
AF in Asians (1%) is lower than in Caucasians (1−2%) [2,3], AF in Asia may be
more burdensome than in Western countries, because Asia is the most popu-
lated area in the world [4]. Moreover, the growing rate of AF prevalence in
Asians actually exceeds that in non‐Asians. Therefore preventing stroke, one of
the most devastating complications of AF, in Asian patients is crucial. However,
Asian AF patients have clinically distinct characteristics and may require differ-
ent preventive strategies (e.g., nonvitamin K oral anticoagulants, NOACs). In
this chapter, we will briefly review the characteristics of AF‐related stroke and
anticoagulation in Asians, and discuss anticoagulation strategies in these patients.
Characteristics of Asian patients with atrial fibrillation
Risk factors and characteristics in clinical practice

Risk factors for occurrence of stroke in AF patients are congestive heart failure,
hypertension, diabetes, and previous stroke/transient ischemic attack; these
factors, with age, comprise the CHADS2 score [5], which is a clinical prediction
rule to predict stroke risk. The mean/median CHADS2 scores in Asian AF patients
are 2.0−3.2 [6–12], and these are comparable to those in non‐Asian patients
[4,13,14]. The major difference in risk factors is the prevalence of previous stroke
or TIA, which is much higher in Asians [4,13].
Asian AF patients are more likely to have lower body weight (or less obesity)
and creatinine clearance (CrCl) than non‐Asian AF patients [6,15–17]. These
trends were consistently shown in four randomized controlled trials (RCTs) of
NOACs (RE‐LY, ROCKET AF, ARISTOTLE, and ENGAGE AF‐TIMI 48) [9,18–20].
116
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The role of anticoagulants for stroke prevention in atrial fibrillation 117
In these trials, the difference of body weight between Asians and non‐Asians
was 16−20 kg, and mild‐to‐moderate renal impairment (30−80 ml/min) was
more frequent in Asians. These findings are notable because CrCl, which is influ-
enced by body weight, significantly affects the metabolism of NOACs.
Stroke and systemic embolism

Although Asian AF patients have comparable CHADS2 scores with non‐Asian
AF patients, their risks of stroke and systemic embolism seem different. A rea-
sonable approach to compare the risk of stroke between the ethnicities would
be to explore the data from large clinical trials that included AF patients with
similar conditions in both Asian and non‐Asian countries. Throughout major
NOAC trials, Asian patients generally had higher risks of stroke and systemic
embolization for both warfarin and NOAC groups [8–12].
Although it is not very clear why Asians are more likely to develop stroke, sev-
eral possible explanations have been suggested. First, in the cited clinical trials, the
proportions of patients with previous stroke or TIA were higher in Asian patients
(Asians vs non‐Asians, RE‐LY: 24% vs 10%; ROCKET AF: 65% vs 54%; ARISTOTLE:
29% vs 18%). Given that previous stroke/TIA is the strongest predictor for future
stroke among all the CHADS2 or CHA2DS2‐VASc scores [21,22], a higher rate of
stroke events in Asians may be plausible. In addition, Asian patients had a level
of international normalized ratio (INR) <2.0 more frequently than non‐Asians
[8–12]. This is partly because Asian physicians tend to target a relatively low INR
because of the fear of hemorrhagic complications (see Warfarin‐related bleeding
risk and INR control) [13]. In particular, the Japanese guidelines recommend an
INR of 1.6−2.6 for patients with AF older than 70 years [23]. Finally, in patients
with AF, stroke does not come from cardiogenic embolism alone, and AF‐unrelated
mechanisms may be at play. Remarkably, patients with AF‐unrelated stroke were
likely to experience recurrent strokes even with adequate anticoagulation, and
most of these recurrent events were AF‐unrelated strokes [24]. Asians have
macro‐ and microangiopathies more frequently than non‐Asians [25] and there-
fore may have a higher risk of experiencing AF‐unrelated stroke.
Warfarin‐related bleeding risk and INR control

Asians are also at higher risk of warfarin‐related intracranial hemorrhages, com-
pared to non‐Asians [26]. Cerebral small vessel diseases, such as lacunar infarct
and microbleeds, which are known to increase the risk of hemorrhages on anti-
coagulation, are more common in Asians [27,28]. According to a recent study,
the risk of warfarin‐associated intracranial hemorrhage in Asians was higher
than in other ethnic groups regardless of comparable INR levels. The hazard
ratio for intracranial hemorrhage was four for Asians, and two for Hispanics and
blacks, compared to whites [26].
In addition, poor INR control in Asian AF patients is also problematic
[8–13]. Asians are generally fond of receiving complementary treatment such as
10.indd 117 08/25/2017 11:03:55 AM

herbal medication and health supplement foods. According to reports from East
Asia, 30−40% of stroke patients also took herbal remedies after discharge [13].
These behaviors may induce unexpected significant interactions between the
complementary medication and warfarin, resulting in poor INR control in Asian
patients. However, in Western countries, stroke patients rarely used alternative
medicine [29]. Genetic factors may also affect the control of INR. The frequen-
cies of genetic polymorphisms associated with warfarin metabolism and action
(e.g., CYP2C9 and VKORC1) are different according to ethnicity [30–32]. These
differences in genetic frequencies between Asians and non‐Asians may also
partly explain poor INR control with warfarin treatment.
In summary, warfarin treatment in Asian AF patients is worrisome considering
the risk of intracranial bleeding and the poor INR control. Therefore, NOAC
treatment deserves attention in these patients.
Nonvitamin K oral anticoagulant (NOAC)

treatment in Asians
Clinical trials in Asian populations

Recent large RCTs have consistently shown that NOACs are at least as effective
and safe as warfarin for stroke prevention in AF patients. Because Asian AF
patients carry distinct clinical characteristics compared to Caucasian AF patients,
subgroup analyses in Asians in these trials also have been conducted to explore
the uniqueness of therapeutic responses to NOACs [9,18–20]. Characteristically,
overall incidence rates of stroke and of major bleeding were both higher in Asian
patients than in non‐Asians (Table 10.1). The excess of bleeding in Asians was
more profound among warfarin users than among NOAC users.
Benefits from NOACs over warfarin in reducing stroke or systemic embolism
and hemorrhagic stroke/major bleeding were comparably shown across Asian
and non‐Asian subgroups (Table 10.1). Generally, Asian patients tended to have
a lower hazard ratio of using NOACs over warfarin, as compared with non‐Asian
patients. In particular, the efficacy of dabigatran in decreasing major bleeding,
including hemorrhagic strokes, was more prominent in Asians than in non‐Asians
[9]. In addition, although non‐Asian NOAC users showed signals of increased
risk of myocardial infarction or gastrointestinal bleeding, Asian NOAC users did
not [9]. Therefore, NOAC treatment can be more beneficial in Asians than in
non‐Asians, especially in regard to bleeding risk.
Dose of NOAC treatment

According to post hoc analyses of RCTs, determinants of major bleeding in NOAC
users were older age, prior stroke, prior gastrointestinal bleeding/anemia, aspirin
use, renal dysfunction, and multiple cerebral microbleeds [33–35]. For frail
patients with these conditions, giving a reduced dose of NOACs can be a good
10.indd 118 08/25/2017 11:03:55 AM

10.indd 119
Table 10.1 Results of clinical trials: Asians and non‐Asians.
Asians Non‐Asians Interaction p
NOAC Warfarin Hazard ratio NOAC Warfarin Hazard ratio

Annual rate Annual rate (95% CI) Annual rate Annual rate (95% CI)
RE‐LY (dabigatran)a
Stroke or systemic embolism 1.39% 3.06% 0.45 (0.28−0.72) 1.06% 1.48% 0.72 (0.56−0.92) .09
Major bleeding 2.17% 3.82% 0.57 (0.38−0.84) 3.52% 3.53% 1.00 (0.87−1.16) .008
ARISTOTLE (apixaban)
Major bleeding 2.02% 3.84% 0.53 (0.35−0.80) 2.15% 3.00% 0.72 (0.62−0.99) .17
ROCKET‐AF (rivaroxaban)
Major bleeding 20.90% 20.70% 1.01 (0.79−1.30) 14.50% 14.10% 1.03 (0.96−1.11) .87
ENGAGE AF (edoxaban)b
Major bleeding 2.86% 4.80% 0.61 (0.41−0.89) 2.74% 3.29% 0.83 (0.73−0.96) .12
a
Dabigatran 150 mg bid.
b
Edoxaban higher doses.
08/25/2017 11:03:55 AM
treatment strategy. The ENGAGE AF‐TIMI 48 study demonstrated the usefulness

of lower‐dose NOACs. In this study, low‐dose (30 vs 60 mg) edoxaban was asso-
ciated with a 41% increase in ischemic stroke but there was a 53% reduction in
hemorrhagic stroke, preserving an overall benefit of edoxaban over warfarin
[36]. The RE‐LY trial also demonstrated similar results: the reduced dose of dabi-
gatran increased the rate of stroke or systemic embolism while significantly
decreasing the rate of major bleeding [8]. Because Asian AF patients commonly
have the above‐mentioned predisposing conditions, it may be reasonable to con-
sider using a reduced dose of NOACs in Asians.
The J‐ROCKET‐AF study examined the efficacy of 15 mg rivaroxaban, instead
of 20 mg, in Japanese patients. This study demonstrated a noninferiority of the
reduced dose of NOAC over warfarin in the primary efficacy endpoints, and less
frequent intracranial hemorrhages in the NOAC users [37]. The recent Taiwan
national health insurance data showed that nearly 90% of patients actually took a
reduced dose of dabigatran [38]. Remarkably, the magnitude of effect for the
outcome was comparable between two doses of dabigatran (110 and 150 mg),
suggesting that using a reduced dose of NOAC may be feasible even in the real
world. A recent meta‐analysis of RCTs of NOACs showed that standard‐dose
NOACs are more effective and safer than warfarin in Asians than in non‐Asians,
and low‐dose NOACs can also be an effective and safe alternative to warfarin [39].
Perspectives
We suggest that NOACs may be considered the first choice of anticoagulant in
Asian AF patients. A lower bleeding tendency and stable pharmacokinetics of
NOACs may be great advantages in Asian patients, who are at higher risk of warfa-
rin‐related cerebral hemorrhages and poorer control of INR. In addition, use of
NOACs for secondary prevention may be more encouraged. Patients with stroke
have higher risks of recurrent thromboembolism and bleeding than those without
stroke. Therefore, the usefulness of NOACs may be more marked in patients who
have already experienced a stroke. Finally, the efficacy of a reduced dose of a NOAC
should be verified in more detail in Asian patients. Routine use of low‐dose NOACs
rather than standard dose may be more beneficial in this fragile group of patients.
Conclusion
Asians have a huge burden of AF, and distinct clinical characteristics in terms of
risk factors and the risk of ischemic/hemorrhagic strokes. Warfarin treatment, a
standard regimen of anticoagulation, is associated with a number of clinical limi-
tations in Asians and therefore difficult to maintain adequately. Available data
reviewed herein suggest that NOACs may be a reasonable treatment option for
Asian patients. Further research is needed to establish the safety and efficacy of
NOACs in more detail in Asians with AF and stroke.
10.indd 120 08/25/2017 11:03:55 AM

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35. Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation
receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke
and Other Thromboembolic Events in Atrial Fibrillation): predictors, characteristics, and
clinical outcomes. J Am Coll Cardiol 2014;63:2141–7.
36. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial
fibrillation. N Engl J Med 2013;369:2093–104.
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37. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in Japanese patients
with atrial fibrillation ‐ the J‐ROCKET AF study. Circ J 2012;76:2104–11.
38. Chan YH, Yen KC, See LC, et al. Cardiovascular, bleeding, and mortality risks of dabigatran
in Asians with nonvalvular atrial fibrillation. Stroke 2016;47:441–9.
39. Wang KL, Lip GY, Lin SJ, Chiang CE. Non‐vitamin K antagonist oral anticoagulants for
stroke prevention in Asian patients with nonvalvular atrial fibrillation: meta‐analysis.
Stroke 2015;46:2555–61.
10.indd 123 08/25/2017 11:03:55 AM

CHAPTER 11
Stroke rehabilitation
Yohanna Kusuma and Lyna Soertidewi Kiemas
Background
The burden of stroke is particularly serious in Asia because mortality is higher

than in Europe or North America. The mortality and case fatality has been
declining in northern and eastern countries such as Korea, Japan, and Taiwan,
and in urbanized areas of China. This is attributable to both risk factor control
and progress in stroke care. The extremely low birth rate and relatively insecure
social health system markedly increase the burden on care givers. In southern
Asian countries, such as India, Pakistan, Bangladesh, and Indonesia, risk factors
such as hypertension, diabetes, obesity, and cigarette smoking have become
increasingly prevalent and are poorly controlled, which has resulted in high
stroke fatality and mortality. Throughout Asia, the most urgent priority should
be primary stroke prevention through promotion of a healthy lifestyle, for
example low salt intake, regular physical exercise, and stopping smoking.
Government sectors should take a stronger initiative to accomplish this. If not,
the rapidly aging population and stroke burden will shrink economies and desta-
bilize society, not only in Asia but also globally. Unless appropriate efforts are
initiated promptly, this may result in problems worldwide [1–3].
Access to tertiary stroke care is limited: the use of tissue plasminogen activa-
tor is rare and there is a lack of stroke neurologists and neurointerventionist and
diagnostic tools. In addition, public and care‐giver awareness of stroke risk fac-
tors and their management fall short of expectations, while the interest of gov-
ernments and policy makers in stroke is suboptimal. Developments in
interventions and management of acute stroke to reduce stroke burden and
stroke‐related mortality in South Asia should have a substantial impact at the
global level. Education of the public and care givers has additional positive ben-
efits in broadening stroke awareness [1–3].
124
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Stroke rehabilitation 125
The disability suffered by stroke patients is a burden on stroke survivors and

their families. We should establish the goals of rehabilitation and how they can
be improved in the management of stroke patients.
The goals of stroke rehabilitation
Rehabilitation for stroke patients is progressive and goal orientated, aiming to

enable patients with their impairments to achieve and improve quality of life
in terms of physical, social, communication, emotional, and functional activity
level [3,4].
There are many factors that may influence this, as recognized in the
International Classification of Functioning, Disability and Health (ICF), which
has two parts, each of which has two components (Table 11.1) [3,5].
The key recommendations of rehabilitation should be prioritized for imple-
mentation in stroke patients (Table 11.2). The grade of recommendation relates
to the strength of evidence [4,5].
Stroke patients should receive well‐organized, coordinated, interpersonal
care for post‐acute rehabilitation. The multidisciplinary team should include
appropriate‐level and well‐trained nurses, physiotherapists, occupational thera-
pists, and speech and language therapists as well as social workers. The coordi-
nation of all professionals is needed to improve the patient’s outcome. A
combined joint meeting to discuss the progression of stroke survivors should be
held at least every week to resolve difficulties and create the agenda for
rehabilitation.
Early rehabilitation will expedite the recovery process. Even when the
patient is still in the ward, the team can provide any rehabilitation suitable for
stroke patients [3,6–8].
Management and prevention strategies [3]

The goal of rehabilitation is to manage all the steps necessary for rehabilitation.
The impairments and limitations of the patient need to be identified to deter-
mine what are the best and most applicable rehabilitation techniques to help the
stroke survivor to reduce and improve their disability.
Table 11.1 Components of the International Classification of Functioning,

Disability and Health. Reproduced with permission from [4].
Part 1 Functioning and disability Part 2 Contextual factors
Body functions and structures Environmental factors

Activities and participation Personal factors
0003172481.INDD 125 8/21/2017 12:24:44 PM

Table 11.2 Key recommendations for rehabilitation of stroke patients. Reproduced with permission from [4].
0003172481.INDD 126
Organization of services Management and prevention strategies Multidisciplinary
team membership
recommendations
Stroke patients requiring admission to hospital should be Stroke patients should be mobilized as early as possible after stroke Multidisciplinary
admitted to a stroke unit staffed by a coordinated team working
multidisciplinary team with a special interest in stroke care.
Rehabilitation should be provided in a generic
rehabilitation ward on an individual basis
The core of rehabilitation services should be delivered by a Personal activities of daily living (ADL) training by occupational therapists is recommended as part of Early active
multidisciplinary team and include appropriate levels of an inpatient stroke rehabilitation program involvement of
nursing, medical, physiotherapy, occupational therapy, patients and care
speech and language therapy, and social work staff givers
Patients and care givers should have an early active Treadmill training may be considered to improve gait speed in people who are independent in Specialist training
involvement in the rehabilitation process walking at the start of treatment and education
The aim of treatment is to have an immediate improvement on walking speed, efficiency, or gait
pattern or weight bearing during stance. Patients should be assessed for suitability for an ankle foot
orthosis (AFO)
Physiotherapists should not limit their practice to one “approach” but should select interventions
according to the individual needs of the patient
Gait‐oriented physical fitness training should be offered to all patients assessed as medically stable
and functionally safe to participate. The goal of treatment is to improve functional ambulation
Rehabilitation should include repetitive task training, where it is assessed to be safe and acceptable
to the patient. The aim of treatment is to improve gait speed, walking distance, functional
ambulation, or sit‐to‐stand‐to‐sit
Where considered safe, every opportunity to increase the intensity of therapy for improving gait
should be pursued
Splinting is not recommended for improving upper limb function
8/21/2017 12:24:44 PM
Stroke patients may experience a range of barriers to recovery of normal

activities and participation. Impairments may be caused directly by the stroke or
by complications of the stroke.
The recommendations in management and prevention are [3,4,9,10]:
•• Early mobilization.
•• Therapeutic positioning.
•• Personal activities of daily living (ADL) training.
Early mobilization
A systematic review of randomized controlled trials (RCTs) identified a trial
where very early mobilization was provided <48 hours after stroke [4,11].
There were significantly fewer nonserious adverse events in the very early
mobilization group compared with the control group. The evidence was insuffi-
cient to support the introduction (or removal) of very early mobilization
(<48 hours after stroke) [4,7].
On the other hand, a survey of stroke unit trials indicated that early mobili-
zation was one of the components of stroke unit care. Current evidence suggests
that earlier mobilization provides more benefit [7]. Even though earlier mobili-
zation has a positive impact, the patient’s condition needs to be the overriding
consideration.
Therapeutic positioning
The aims are to try to promote optimal recovery by modulating muscle tone, to
provide appropriate sensory information and increasing spatial awareness, and
to prevent complications such as pressure sores, contractures, pain, and respira-
tory problems and assist safer eating [12].
From a survey of physiotherapists, the most commonly recommended posi-
tions were sitting in an armchair as recommended, followed by side lying on the
unaffected side, then side lying on the affected side. Sitting in a wheelchair and
lying supine were less commonly recommended [12].
The evidence supports reducing hypoxia in the acute stroke phase
(72 hours) by sitting the patient in an upright position but this depends on the
patient’s condition. The reason for sitting the patient in this position is that
higher oxygen saturation readings were obtained [13].
Activities of daily living (ADL) interventions

An RCT has shown that personal ADL training provided by occupational thera-
pists as part of an inpatient integrated stroke rehabilitation program was
significantly more effective than a stroke rehabilitation program with no

occupational therapy and was effective in improving independence in

community-based patients with stroke. The duration of therapy was 3 hours/
day for 8 weeks [14,15].
0003172481.INDD 127 8/21/2017 12:24:44 PM

The impairments and limitations after stroke

and strategic rehabilitation
Aphasia, dysphasia, apraxia for speech

Therapy should be led and assessed by specialist speech and language therapists
working collaboratively and closely with family, care givers, and friends. They
need to teach methods of communicating such as gestures and writing, as well
as coaching the stroke survivor to develop communication skills in order to
maximize the person’s potential development [16].
Arm, hand, or leg weakness and spasticity

Exercise aims to increase soft tissue length and passive range of movement.
Appropriate therapies include electrical stimulation, constraint‐induced move-
ment therapy, and walking therapies (e.g., treadmill with or without body
weight support, electromechanical gait training, electrical stimulation of the
lower limb).
Approximately 60% of stroke patients who have hemiparesis will develop
joint contractures or spasticity on the affected side, which may cause pain.
Sometimes patients apply a resting hand splint to the affected area; however, the
effectiveness of hand splinting is not well established [17–22]. In contrast, botu-
linum toxin injections to the wrist and finger flexors may be beneficial [17,23]
(Table 11.3).
Table 11.3 Common impairments, limitations, and complications after stroke. Reproduced

with permission from [4].
Common impairments after Common activity limitations Common complications for

a first ever stroke stroke patients
•• Aphasia •• Bathing •• Anxiety

•• Apraxia of speech •• Communication •• Confusion
•• Arm/hand/leg weakness •• Dressing and grooming •• Depression
•• Cognitive impairment •• Eating and drinking •• Emotionalism
•• Dysarthria •• Participation restrictions •• Falls
•• Dysphagia (e.g., returning to work) •• Fatigue
•• Facial weakness •• Psychological (e.g., •• Infection (especially urinary
•• Gait, balance, and decision‐making) tract and chest)
coordination •• Sexual function •• Malnutrition/undernutrition
problems •• Toileting •• Pain
•• Perceptual impairments, •• Transferring •• Pressure sore/skin break
including visuospatial •• Urinary and/or fecal •• Recurrent stroke
dysfunction incontinence •• Shoulder pain
•• Sensory loss •• Walking and mobility •• Shoulder subluxation
•• Upper limb impairment •• Spasticity
•• Visual problems •• Venous thromboembolism
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In the early post‐stroke period, the hemiplegic shoulder needs to be posi-

tioned in maximum external rotation for 30 minutes each day, either in bed or
in a chair; this rehabilitation should be useful for preventing stroke contracture
[24,25].
Cognitive impairment
The stroke patient should be screened for cognitive deficit. Once identified, carry
out a detailed assessment using reliable, valid, and responsive tools before
designing a treatment program [16].
Dysphagia
A swallowing test should be performed swallowing therapy offered at least 3
times a week for stroke patients who are able to follow and participate as long as
they continue to make functional gains. Therapy includes compensatory strate-
gies, exercise, and postural advice. Effective therapy can decrease the risk of aspi-
ration pneumonia. Meanwhile, nutritional support needs to be provided [16].
Facial weakness
Facial weakness can make speech, eating, facial expression, and general facial
movement difficult or impossible for stroke victims.
Smiling
Begin exercise immediately after a stroke; all facial exercises will be difficult. Start
slowly, focusing on the brain–muscle connection. Practicing and using the mus-
cles are keys to regaining mobility. Instructions to the patient should include [26]:
•• Smile, or try to smile, without showing your teeth.
•• Next, smile showing your teeth.
•• Slowly smile, parting your lips deliberately into a smile.
•• Pucker your lips like you are going to blow a kiss.
•• Use equal muscle strength on both sides of your face.
•• Repeat this sequence until full mobility returns.
Vowel sounds
More than one‐fourth of all stroke patients have language impairments.
Post‐stroke exercises can help to overcome them. Have the patient start by
making vowel sounds [26].
Eyebrows
Exercises for people whose strokes result in Bell’s palsy, a dysfunction of the
facial nerve that results in loss of facial muscle control [26]:
•• Raise and lower your eyebrows, keeping a slow, steady rhythm.
•• Next, raise your eyebrows, hold for 10–15 seconds, lower your brows, and
repeat.
0003172481.INDD 129 8/21/2017 12:24:44 PM

•• Focus on performing the exercises correctly.

•• Use short exercise sessions, and perform the exercises several times during
the day.
Eyes
Exercising the eyes is another way for stroke patients to work facial muscles [26]:
•• Open and close your eyes slowly without moving your brows.
•• Try to close your affected eye slowly without moving your eyebrow down-
ward or your lips upward.
•• Winking is an effective facial exercise after a stroke. Wink only one eye, if pos-
sible, and then alternate winking with each eye. Open your eyes as wide as
possible, hold them open and then rest.
Nose
Instruct the patient [26]:
•• To exercise your nose, wrinkle it and sniffle.
•• Next, flare your nostrils, hold them open and then release.
•• Repeat these motions slowly several times throughout the day.
Gait, balance, and coordination problems (e.g., mobility)

Recommendations are summarized in Table 11.4.
Ankle foot orthoses

There were positive results of ankle foot orthoses on the outcomes of walking
speed, efficiency, gait pattern, and weight bearing [27–34].
The aim of treatment is to have an immediate improvement in walking
speed, efficiency, or gait pattern or weight bearing during stance. Patients should
be assessed for suitability for an ankle foot orthosis by an appropriately qualified
health professional [27–34].
Table 11.4 Summary of recommendations for gait, balance, and mobility problems.
Recommended Consider Not recommended Insufficient evidence
•• Ankle foot orthoses •• Treadmill training in •• Routine treadmill •• Routine

•• Individualized people who are training electrostimulation
interventions independent in •• Routine •• Walking aids
•• Gait‐oriented physical walking electromyography
fitness training •• Functional electrical biofeedback
•• Repetitive task training stimulation for •• Balance platform
•• Muscle strength drop‐foot training with
training to improve •• Electromechanical- visual feedback
muscle strength assisted gait training
•• Increased intensity of
rehabilitation
0003172481.INDD 130 8/21/2017 12:24:44 PM

Approach of intervention
Use of a mixture of components of neurophysiological treatments such as Bobath,
Brunnstrom, Rood, and proprioceptive neuromuscular facilitation approaches
showed more benefit compared with placebo or only one approach [35].
Physical fitness training

Gait‐oriented physical fitness training should be offered to all patients assessed
as medically stable and functionally safe to participate, when the goal of treat-
ment is to improve functional ambulation [36–38].
Repetitive task training

The evidence is that repetitive training is effective at improving disability in
stroke patients especially gait speed, functional ambulation, sit‐to‐stand‐to‐sit,
and walking distance [39].
Rehabilitation should include repetitive task training, where it is assessed to
be safe and acceptable to the patient, when the aim of treatment is to improve
gait speed, walking distance, functional ambulation, or sit‐to‐stand‐to‐sit [39].
Muscle strengthening
Systematic reviews revealed that there were benefits of muscle strengthening
[40,41]. On the other hand, there is insufficient association between muscle
strength and functional outcome. Muscle strengthening is recommended when
the specific aim of treatment is to improve muscle strength.
Intensity of intervention
The benefits of increasing the intensity of intervention have been seen from
systematic reviews. The average duration of therapy was approximately 45 min-
utes for physiotherapy plus 14 minutes of occupational therapy daily [36,42,43].
Where considered safe, every opportunity to increase therapy for improving gait
should be pursued.
Treadmill training
Conventional interventions are more effective, however, treadmill training may
provide benefit for those who are already independent in walking [44,45].
Treadmill training is not recommended as a routine gait‐training intervention
after stroke but may be considered in order to improve gait speed in people who
are independent in walking at start of treatment.
Electromyographic biofeedback
Two systematic reviews found no significant benefits to the use of electromyo-
graphic biofeedback [46,47].
It is not recommended as a routine treatment for gait, balance, or mobility
problems after stroke.
0003172481.INDD 131 8/21/2017 12:24:44 PM

Upper limb function [4]

Constraint induced movement therapy (CIMT)
CIMT interventions showed improvement in upper limb function but there was
no evidence for long‐term benefit [48–51]. Individuals need to be carefully
selected for CIMT: they should have at least 10 degrees of finger extension and
intact balance and cognition.
Mental practice
A small number of RCTs and observational studies suggest that mental practice
may have an impact on the recovery of upper limb function post stroke [52,53].
Thus, it may be considered as an adjunct to normal practice to improve upper
limb function after stroke.
Electromechanical devices
Systematic reviews have demonstrated improvement in upper limb function
with the use of electromechanical devices or robotics. This equipment is superior
compared with other interventions [54,55]. These devices may be considered for
improvement of arm motor function and motor strength in selected patients
where the necessary equipment is already available and healthcare professionals
are competent in the use of the equipment.
Visual problems [3]

All stroke patients should be screened and examined for visual problems
including visual field defects, eye movement problems, and visuospatial
neglect. In addition, cataract due to aging, trauma, or radiation exposure is
another cause of visual problems. If the cause of visual problems is low visual
acuity, hemianopia, or ocular pathology, healthcare professionals should
ensure that the patient has and correctly uses eyewear to avoid the risk of fall-
ing. Poor visual acuity has a negative impact on rehabilitation of people with
stroke [56,57].
Post‐stroke spasticity [4]

Spasticity is intermittent or sustained involuntary hyperactivity of the skeletal
muscles associated with an upper motor lesion [58,59]. Clostridium botulinum
toxin type A can be used to reduce spasticity, pain, or joint contracture interfer-
ing with physical function as demonstrated by a systematic review that used the
Modified Ashworth Scale and Global Assessment Scale to measure upper limb
spasticity when comparing Clostridium botulinum toxin type A with placebo [60].
Clostridium botulinum toxin type A may be considered for use to relieve spasticity
following stroke where it is causing pain.
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Pain [4]
Pain is most commonly associated with the musculoskeletal ramifications of
paralysis and immobility and often involves the hemiplegic shoulder. This
condition can develop many months after stroke and be related to move-
ment. Central post‐stroke pain can also occur, as can headache. Pain should
be assessed using a validated pain assessment tool and treated appropriately.
Amitriptyline, lamotrigine, or carbamazepine should be considered for
central post‐stroke pain.
Disturbances of mood and emotional behavior [4]

The onset of mood disturbances may be correlated with psychosocial and physi-
cal factors [61,62]. The use of an antidepressant and an education program
based on psychological principles is preferred treatment. However, routine pre-
scription of antidepressants to prevent post‐stroke depression is not recom-
mended [63]. Psychological principles from motivational interviewing and
problem solving should be incorporated into education programs for people
who have had a stroke.
Determining candidates suitable for outpatient

rehabilitation
In order to be considered for outpatient rehabilitation, patients need to meet the

following criteria:
1 The patient should meet the criteria for rehabilitation candidacy, medical sta-
bility, and rehabilitation readiness as defined in Table 11.5.
2 The patient’s current medical, personal care, or rehabilitation needs can be
met in the community.
3 The patient can attend therapy alone or, if assistance is required (i.e., for feed-
ing or toileting), a care giver is available to attend therapy sessions.
4 The patient can tolerate and organize their own transportation (where neces-
sary) to and from the program. People with communication difficulties such
as aphasia may require assistance with transport organization.
Characteristics to consider in planning rehabilitation of stroke patients
include:
1 Initial stroke severity.
2 Location, etiology, and type of stroke (ischemic versus hemorrhagic).
3 Functional deficits and functional status.
4 Types of therapy required based on assessment of deficits (e.g., occupational ther-
apy, physiotherapy, speech and language physiotherapy, and others as required).
5 Cognitive status, e.g., ability to learn and actively participate in rehabilitation.
6 Time from stroke symptom onset.
0003172481.INDD 133 8/21/2017 12:24:44 PM

Table 11.5 Eligibility and admission criteria for stroke rehabilitation. Reproduced

with permission from [64].
General inclusion criteria for stroke rehabilitation General exclusion

criteria for stroke
rehabilitation
1 All acute or recent stroke patients (<1 year post stroke) or patient >1 1 Severe cognitive
year post stroke who requires: impairment
•• inpatient or outpatient interprofessional rehabilitation to achieve preventing the
functional goals that will prevent hospital admission and/or improve patient from
independence learning and
•• interdisciplinary rehabilitation assessment, treatment, or review from participating in
staff with stroke experience/expertise therapy
•• and whose stroke etiology and mechanisms have been clarified and
appropriate prevention interventions started
2 The patient is medically stable: 2 The patient already
•• A confirmed diagnosis of stroke has been identified, although the receives treatment
mechanism or etiology may not be initially clear; these situations elsewhere and
should not cause delays in access to rehabilitation needs are
•• All medical issues and/or comorbidities have been addressed; being met
•• At the time of discharge from acute care, acute disease processes
and/or impairments are not precluding active participation in the
rehabilitation program
•• Vital signs are stable
•• All medical investigations have been completed or a follow‐up plan is
in place at time of referral and appointments made by time of
discharge from acute care
3 The patient demonstrates at least a minimum level of function, which 3 Behavior is
includes: inappropriate
•• sufficient stamina to participate in the program demands/schedule putting self or
•• ability to follow at minimum one‐step commands, with communication others at risk (i.e.,
support if required aggressive, etc.)
•• Sufficient attention, short‐term memory, and insight to progress
through the rehabilitation process
4 The patient demonstrates by their post‐stroke progress the potential to 4 Terminal illness
return to premorbid/baseline functioning or to increase post‐stroke with expected
functional level with participation in a rehabilitation program short survival
5 Goals for rehabilitation can be established and are specific, measurable, 5 Not willing to
attainable, realistic, and timely participate in
program
6 The patient or substitute decision‐maker has consented to treatment in
the program and demonstrates willingness and motivation to
participate in the rehabilitation program (exceptions: patients with
reduced motivation/initiation secondary to diagnosis, e.g., depression)
7 The patient is ready to participate in rehabilitation:
•• Meets the criteria of medical stability as defined in the guideline
above and meets the minimum tolerance level of the rehabilitation
program as defined by its admission criteria
•• There are no behavioral issues limiting the patient’s ability to
participate at the minimum level required by the rehabilitation
program
0003172481.INDD 134 8/21/2017 12:24:44 PM

Additional characteristics include:

1 Medical stability.
2 The goals can be identified by the patient and/or healthcare team in order to
increase independence in all activities of daily living.
3 Adequate tolerance and endurance to actively participate in stroke rehabilita-
tion therapy.
4 Age and pre‐stroke frailty.
5 Existing comorbidities such as dementia, palliative care status for another
medical condition/terminal illness.
6 Care-giver availability for patients with severe impairment is important.
Summary
The aim of stroke rehabilitation is to enable the person with their post‐stroke
limitations to reach their optimal physical, cognitive, emotional, social, activity,
and functional level by using all the modalities in stroke rehabilitation. The
rehabilitation process should be started soon after the initial stroke event, once
the patient is medically stable and the goal and aims of the rehabilitation have
been identified.
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0003172481.INDD 138 8/21/2017 12:24:44 PM

CHAPTER 12
Alternative and complementary
treatments for stroke
N. Venketasubramanian Ramani and Jeyaraj D. Pandian
Introduction
Stroke is a major cause of death and disability in Asia. Despite the availability
of numerous evidence‐based therapeutic interventions, many survivors remain
disabled. Stroke survivors, dissatisfied with lack of recovery, may seek other
treatments, including alternative and complementary treatments [1].
Definition
The National Center for Complementary and Alternative Medicine (NCCAM)
defines complementary and alternative medicine (CAM) as covering “a broad
range of healing philosophies (schools of thought), approaches, and therapies
that mainstream Western (conventional) medicine does not commonly use,
accept, study, understand, or make available” [2].
Utilization of complementary and alternative medicine

Numerous CAM are used in Asia after stroke. These include:
•• Acupuncture
•• Moxibustion
•• Cupping
•• Herbs
•• Homeopathy
•• Massage
•• Yoga, tai chi
•• Reiki
•• Prayer
The use of CAM is almost 100% in China [3]. Among users in India,
59.3% of stroke survivors use ayurvedic massage, 15% herbal medicines,
139
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13.3% homeopathy, 2.7% witchcraft, 2.7% acupuncture, and 8.5% opium

intake [4]. In Malaysia, 40.4% of users use acupuncture, 40.4% massage,
and 11.5% traditional Chinese medicine [5].
In India, those who seek alternative treatments have severe stroke, limb
weakness, dysphagia, dyslipidemia, hypertension, hemorrhagic stroke, or poor
outcome (modified Rankin score [mRS] >2) [4]. In Malaysia, they are those with
poor functional status or severe stroke on hospital discharge [6].
Acupuncture
Acupuncture is based on the principle that there are patterns of energy flow
(qi) through the body that are essential for health, and that disease is due to
disruptions of this flow. Acupuncture points are located on meridians through
which qi runs. Acupuncture corrects imbalances of flow at points close to
the skin.
In a recent meta‐analysis of 25 trials involving 2224 stroke patients, acupunc-
ture was found to be superior to control by clinical efficacy rates (odds ratio [OR]
4.04, 95% confidence interval [CI] 2.93–5.57, p <.001) (Fig. 12.1), Fugl‐Meyer
assessment (mean difference [MD] 11.22, 95% CI 7.62–14.82, p <.001), Barthel
index score (MD 12.84, 95% CI 9.85–15.82, p <.001), and neurological deficit
score (MD −2.71, 95% CI −3.84 to −1.94, p <.001) [7].
A Cochrane systematic review of 14 trials involving 1208 acute stroke
patients undergoing acupuncture vs sham or open control showed that fewer
patients were dead or dependent (OR 0.66, 95% CI 0.43–0.99), and fewer dead
or institutionalized (OR 0.58, 95% CI 0.35–0.96) [8]. There was a difference
favoring acupuncture in the mean change of global neurological deficit score
during the treatment period (standard mean difference [SMD] 1.17, 95% CI
0.30–2.04).
A systematic review and meta‐analysis of 38 trials of acupuncture during
stroke rehabilitation showed that acupuncture was favorable compared with
controls (OR 4.33, 95% CI 3.09–6.08) [9]. However, there was heterogeneity in
randomization, modes of delivery, method of control, study source country,
reporting of randomization, poor study quality, and publication bias.
One randomized clinical trial and three controlled clinical trials compared
acupressure with routine care vs no treatment in patients with stroke. While
significant effects of acupressure were seen on improving patient function and
symptoms, there were methodological limitations and a high risk of bias [10].
Aromatherapy acupressure (using lavender, rosemary, and peppermint) com-
pared to acupressure alone significantly improved motor power post treatment
compared to pre treatment in both groups (p <.005), but there was no intergroup
difference [11].
0003172482.INDD 140 8/21/2017 12:26:49 PM

0003172482.INDD 141
Experimental Control Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight M-H. Fixed. 95% CI M-H. Fixed. 95% CI
Du 2013 28 30 24 30 4.1% 3.50 [0.65, 18.98]
Feng 2007 26 30 19 30 6.4% 3.76 [1.04, 13.65]
Guo 2007 37 46 26 42 13.5% 2.53 [0.97, 6.60]
Huang 2008 34 40 26 40 9.9% 3.05 [1.03, 9.02]
Li 2009 30 31 24 32 1.9% 10.00 [1.17, 85.59]
Lin 2009 33 37 15 19 5.4% 2.20 [0.48, 10.00]
Liu 2001 118 120 34 40 2.2% 10.41 [2.01, 53.95]
Tong 2013 40 44 31 42 7.3% 3.55 [1.03, 12.22]
Wu 2001 41 50 32 50 14.6% 2.56 [1.02, 6.46]
Wu 2011 35 40 25 40 7.9% 4.20 [1.35, 13.06]
Yang 2008 46 50 35 46 7.4% 3.61 [1.06, 12.31]
Zhang 2008 42 45 23 45 3.9% 13.39 [3.62, 49.58]
Zhang 2009 35 40 27 40 8.6% 3.37 [1.07, 10.61]
Zhu 2005 35 40 21 40 6.7% 6.33 [2.06, 19.49]
Total (95% CI) 643 536 100.0% 4.04 [2.93, 5.57]

Total events 580 362
Heterogeneity: Chi2 = 8.73, df = 13 (P = 0.79); l2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 8.51 (P < 0.00001)
Favours experimental Favours control
Fig. 12.1 Clinical efficacy rate of acupuncture. Reproduced with permission from reference [7].
8/21/2017 12:26:49 PM
Moxibustion
Moxibustion involves the burning of mugwort, a small, spongy herb, to facilitate

healing. In direct moxibustion, a small, cone‐shaped amount of moxa is placed
on top of an acupuncture point and burned. In indirect moxibustion, one end of
a lighted moxa stick is held close to the area being treated, or an acupuncture
needle is inserted into an acupoint and the tip of the needle wrapped in moxa
and ignited. The aim of moxibustion is to stimulate the flow of qi.
Out of nine randomized clinical trials, three randomized clinical trials involving
142 subjects reported favorable effects of moxibustion plus standard care on
motor function vs standard care alone (SMD 0.72, 95% CI 0.37–1.08, p <.0001)
[12]. Three randomized clinical trials comparing effects of moxibustion on activities
of daily living alone failed to show favorable effects of moxibustion.
Cupping
During cupping, plastic or glass cups are used to apply suction and heat to
meridian points on the body. The aim is to rejuvenate meridians, thereby
improving the flow of qi.
Superior effects were found in two randomized controlled trials when
compared to acupuncture in hemiplegic shoulder pain and high upper‐limb
myodynamia after stroke. Other randomized controlled trials failed to show
favorable effects of cupping when compared to acupuncture and warm needling
in patients with hemiplegic hand edema. The two studies reported favorable
effects of cupping on aphasia and intractable hiccup after stroke. However, most
of the included trials compared the effects with unproven evidence and thus
were not informative [13,14].
Chinese herbal medicine
Chinese medicine is based on the principle that disease is due to a disharmony

between the ying and yang within. Herbs are aimed at restoring the balance, and
not just treating the symptoms of disease. The medicines, of plant or animal
origin, are classified based on their nature (hot, warm, cool, cold, or neutral) and
flavor (acrid/pungent, sweet, bitter, sour, salty, or none), with each medicine
having specific or mixed functions.
A meta‐analysis of 191 trials included 19 338 patients on 22 traditional
Chinese patented medicines for ischemic stroke; there were 120 definite or
possible randomized controlled trials, 71 controlled clinical trials, and three
randomized, double‐blind, placebo‐controlled trials [15]. The secondary outcome
showed “marked improvement in neurological deficit” (Fig. 12.2). The apparent
benefits were of about the same magnitude for all the medicines studied. Of the 22,
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0003172482.INDD 143
Review: TCPM for ischemic stroke
Comparison: 01 TCPM vs control (no TCPM)
Outcome: 02 Neurological deficit improvement after treatment
Study TCPM Control Peto OR Weight Peto OR

or sub-category n/N n/N 95% Cl % 95% Cl
Acanthopanax 501/532 402/495 4.13 3.39 [2.33, 4.93]

Da Huo Luo 27/30 26/30 0.24 1.37 [0.29, 6.56]
Dan Shen 674/739 434/616 7.59 4.02 [3.05, 5.30]
Deng Zhan Hua Su 221/234 172/220 2.00 4.04 [2.35, 6.92]
Deng Zhan Xi Xin 121/138 86/138 1.97 3.85 [2.23, 6.63]
Ginkgo biloba 1026/1118 744/961 9.91 3.11 [2.44, 3.96]
Ligustrazine 731/894 496/758 11.87 2.35 [1.88, 2.93]
Mai Luo Ning 1141/1252 750/1132 14.77 4.55 [3.73, 5.55]
Milk vetch 2128/2316 1477/1905 19.73 3.16 [2.66, 3.75]
Nao Xin Tong 181/190 107/131 1.09 4.34 [2.09, 9.02]
Nao Xue Kang 70/80 55/79 1.02 2.88 [1.35, 6.13]
Puerarin 460/514 345/473 5.61 3.00 [2.18, 4.14]
Qing Kai Ling 268/292 206/278 3.03 3.53 [2.27, 5.47]
Shen Mai 194/205 141/184 1.76 4.49 [2.53, 7.98]
Sheng Mai 106/119 85/118 1.41 2.96 [1.56, 5.63]
Shu Xue Tong 21/24 14/24 0.37 4.25 [1.20, 14.97]
Wei Nao Lu Tong 205/260 93/160 3.10 2.73 [1.77, 4.21]
Xiao Shuan Tong Luo 160/168 57/74 0.72 7.08 [2.89, 17.36]
Xing Nao Jing 35/42 16/36 0.67 5.45 [2.15, 13.82]
Xue Se Tong 592/643 424/564 6.06 3.55 [2.60, 4.84]
Xue Shuan Tong 141/152 88/106 0.95 2.65 [1.21, 5.79]
XueShuanXinMaiLing 399/412 309/354 2.02 3.91 [2.29, 6.69]
Total (95% Cl) 10354 8836 100.00 3.39 [3.14, 3.65]

Total events : 9402 (TCPM), 6527 (Control)
Test for heterogeneity. Chi? = 31.25, df = 21 (P = 0.07), I? = 32.8%
Test for overall effect: Z = 31.34 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10

Favours control Favours TCPM
Fig. 12.2 Neurological deficit improvement with traditional Chinese medicine. Reproduced with permission from Ref. [15].
8/21/2017 12:26:49 PM
eight drugs (milk vetch, mailuoning, Ginkgo biloba, ligustrazine, Danshen agents,
xuesetong, puerarin, and Acanthopanax) had relatively more studies and patient
numbers. The apparent benefit on neurological impairment is likely to be
attributable to bias from poor methodology rather than to a real treatment effect;
methodological quality of included trials was “generally poor.”
A more recent review of 22 randomized controlled trials of ischemic stroke and
four of hemorrhagic stroke involved 2214 patients [16]. An overall therapeutic
efficacy (OR 3.39, 95% CI 1.81–6.37) was seen among hemorrhagic stroke. Among
ischemic stroke, rates of cure were also higher (OR 2.22, 95% CI 1.66–2.97); over-
all therapeutic efficacy was high (OR 3.31, 95% CI 2.54–4.31).
The well‐conducted multicenter CHInese Medicine NeuroAiD Efficacy on
Stroke recovery—Extension (CHIMES‐E) involving 1100 Asian patients showed
that MLC601 (NeuroAiD™), given over the initial 3 months after a stroke, is supe-
rior to placebo in improving functional outcome for up to 2 years among subjects
with cerebral infarction of intermediate severity. Odds of mRS of 0–1 were 1.49 (95%
CI 1.11–2.01) at 6 months, 1.41 (95% CI 1.05–1.90) at 12 months, 1.36 (95% CI
1.0–1.83) at 18 months, and 1.29 (95% CI 0.96–1.74) at 24 months [17]. The effect
was even greater among those with poor prognostic factors—female gender, advanced
age, more severe stroke, and longer onset‐to‐treatment time [18].
Avurveda
Ayurveda, Sanskrit for “life knowledge,” originated in the Indian subcontinent.

It is based on the principle that the body has channels (srotas) which transport
fluids, and that unhealthy channels and imbalances in the three elemental
substances (doshas) cause disease. Ayurveda uses plant‐based treatments, animal
products, minerals, alcoholic beverages or opium holistically, addressing physical,
mental, and personality aberrations.
In one publication, 50 patients with middle cerebral artery stroke on standard
allopathic medications were randomized to physiotherapy or Ayurveda treat-
ment [19]. Improvement was seen in heart rate and blood pressure variability
and baroreflex sensitivity; no mention was made of neurologic or functional
recovery. A case study of a woman with post‐stroke aphasia undergoing a regi-
men of different body manipulations, yogic breathing techniques, and ingestion
of coconut oil demonstrated improvement in language, visual attention, and
some mood measures [20].
Homeopathy
Hippocrates may have originated homeopathy around 400 BC, when he pre-
scribed a small dose of mandrake root to treat mania, knowing that in much
larger doses it produces mania. But modern homeopathy may have been created
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Alternative and complementary treatments for stroke 145
in 1796 by Samuel Hahneman. The doctrine is that “like cures like” (similia
similibus curentur): a substance that causes the symptoms of a disease in people
who are healthy would cure similar symptoms in those who are sick. Homeopathy
is based on the principle that underlying causes of disease are phenomena called
miasms, and homeopathic preparations address miasms. The preparations are
manufactured using a process of homeopathic dilution: a chosen substance is
repeatedly diluted in alcohol or distilled water, each time with the containing
vessel being bashed against an elastic material (usually a leather‐bound book).
Dilution continues past the point where no molecules of the original substance
remain. Homeopathy is holistic—the totality of the patient’s symptoms, personal
traits, physical and psychological state, and life history are considered.
It was reported that high‐quality multivitamin/multimineral supplements in
patients with undernutrition may improve outcomes with minimal long‐term
risk [21]. Natural agents such as the antioxidant alphalipoic acid, certain tradi-
tional Asian herbal mixtures, and some homeopathically prepared remedies
show promise for reducing infarct size and associated impairments. However,
the evidence does not favor recommendation of most of these treatments from
a public health policy perspective.
Massage
From the Chinese words tui (“to push”) and na (“to lift and squeeze”), tui‐na uses
range of motion and traction, with the stimulation of acupressure points to open
the body’s defensive chi (wei qi) and get the energy moving in the meridians and
the muscles.
A prospective, multicenter, blinded, randomized, placebo‐controlled inter-
vention trial included 90 patients with post‐stroke spasticity: 45 were in the
tui‐na therapy group, 45 in the control group [22]. All received conventional
rehabilitation. The control group received placebo tai‐na (gentle rubbing) for
20–25 minutes per limb, once per day, 5 days per week for a total of 4 weeks. The
tui‐na group had a significantly greater reduction in Modified Ashworth Scale in
only four muscle groups than the control did (elbow flexors, p = .026; wrist flex-
ors, p = .005; knee flexors, p = .023; knee extensors, p = .017). Improvements
were sustained at 3 months follow‐up. There was no significant difference
between the two groups in Fugl‐Meyer assessment (p = .503) and modified
Barthel Index (p = .544).
Marma massage is based on the principle that the body’s life force (prana)
moves along channels; these channels have points (marma) where flesh, veins,
arteries, tendons, bones, and joints meet. Marma massage promotes flow of
prana. A pilot nonrandomized controlled trial compared standard care with
standard care plus marma massage therapy in 172 post‐stroke patients undergo-
ing rehabilitation in a nested qualitative study [23]. Effectiveness data showed
0003172482.INDD 145 8/21/2017 12:26:50 PM

no significant differences in changed scores. The secondary outcome measure of

score differences of the Motricity Index at 6 and 12 weeks and the trunk control
test at 6 weeks suggested a possible greater improvement in the intervention
group (p <.05, p <.01 respectively). Most patients believed the massage was
beneficial. Some reported pain, but all would choose it again.
Thai massage combines acupressure, Indian Ayurvedic principles, and assisted
yoga postures. Traditional Thai massage was compared against conventional
physical therapy programs in treating muscle spasticity, functional ability, anxi-
ety, depression, and quality of life in 50 Thai stroke patients with spasticity [24].
At week 6, the percentage of patients whose modified Ashworth Scale score
had decreased by at least one grade was not statistically different. Both groups
experienced a significant increase in functional ability and quality of life, but
no difference was found between the groups. Anxiety and depression scores
showed a decreasing trend in the Thai massage group.
A prospective cohort study investigated if traditional Thai massage, herbal
treatments, and physical therapies could improve activities of daily living, mood
and sleep patterns, and pain intensity of 62 stroke patients during rehabilitation
[25]. The Barthel Index significantly improved by 6.1 points after 1 month (p <.01)
and by 14.2 points after 3 months (p <.01). Emotion significantly improved by 0.7
points after 1 month (p <.01) and by 0.9 points after 3 months (p <.01). Pain
significantly improved by 0.5 points after 1 month (p <.01) and by 0.5 points
after 3 months (p <.01). Sleep significantly improved by 0.5 points after 1 month
(p <.01) and by 0.6 points after 3 months (p <.01).
Urut is a Malay massage to relax tense and tired muscles and tone up flabby
muscles. A 32‐year‐old Malay woman with post‐partum stroke received 14 urut
Melayu sessions [26]. She improved tremendously in speech and fine motor
skills, and regained activities of daily living. In another study of 17 patients with
stroke brought about by hypertension and post delivery, urut Melayu was sought
by patients, having “positive experiences” [27].
Yoga
Yoga is a Sanskrit word meaning “listen.” Originating in India, it uses postures

(asanas), focused concentration on specific body parts, and breathing techniques
(pranayama) to integrate the body with the mind and the mind with the soul.
There are many types of yoga. In addition to physical exercise, it also has a medi-
tative and spiritual core. The ultimate goal of yoga is liberation (moksha).
In a systematic review of five randomized controlled clinical trials, four single
case studies, and one qualitative research study of yoga for stroke rehabilitation,
improvements were seen in cognition, mood, and balance, and reductions in stress
[28]. However, modifications to different yoga practices make comparison between
studies difficult, and a lack of controlled studies precludes any firm conclusion.
0003172482.INDD 146 8/21/2017 12:26:50 PM

A subsequent trial to assess efficacy of 10‐week yoga against no treatment for

motor function, mental health, and quality of life outcomes in 22 persons
with chronic post‐stroke hemiparesis showed no significant improvements in
objective motor function measures [29]. However, improvement in quality
of life associated with perceived motor function (p = .0001) and perceived
recovery (p = .072).
Tai chi
Tai chi, an abbreviation of tai chi chuan meaning “supreme ultimate boxing,” is a
graceful form of exercise with slow focused movements and breathing to
promote serenity and inner peace.
A focused review of five randomized controlled trials in post‐stroke rehabilita-
tion showed improved balance in three studies, and no improvement in mobility
in three studies, but three trials showed improvements in quality of life and
mental health [30]. Heterogeneity did not allow a meta‐analysis.
In a later single‐blind randomized controlled trial of effect of a 12‐week tai
chi (TC) intervention on physical function and quality of life among older
stroke survivors, yang‐style 24‐posture short‐form (n = 53), strength and range
of movement exercises (SS) (n = 44), or usual care (UC) (n = 48) were admin-
istered for 12 weeks [31]. TC participants had two‐thirds fewer falls than the
SS and UC groups (χ2 = 5.6, p = .06). TC (p = .02) and SS (p <.01) groups had
significantly better aerobic endurance over time, though not the UC group
(t48 = 1.58, p = .12).
In another recent study of the effects of therapeutic tai chi on balance, gait,
and quality of life in chronic stroke patients, general physical therapy and TC
exercise were compared against only general physical therapy [32] among
chronic stroke patients. Ten different movements were performed for 60 minutes,
twice per week, for 6 weeks. Both groups showed a significant improvement in
sway length and sway velocity, but only the TC group showed a significant result
for the functional reach test, the dynamic gait index, the 10‐m walking test, and
the timed up‐and‐go test. The TC group showed also a significant improvement
in physical function, pain, vitality, general health, mental health among eight
items in the 36‐item short form survey (SF‐36).
Reiki
“Palm healing” or “hands‐on healing” is a combination of rei (“soul, spirit”)

and ki (“vital energy”). It was developed in 1922 by Japanese Buddhist Mikao
Usui. It is based on chi (qi), a universal life force. It is based on the principle
that transferring qi through the palms of the practitioner encourages healing.
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The therapist channels energy into the patient by means of touch, to activate
the natural healing processes of the patient’s body and restore physical and
emotional well‐being.
Nine randomized clinical trials assessed functional recovery after ischemic
stroke [33]. No intergroup differences compared with sham were found. Trial
data for any one condition were scarce; independent replications were not
available for each condition. Most trials suffered from methodological flaws such
as small sample size, inadequate study design, and poor reporting.
Prayer
The Latin word precar means to ask earnestly, to beg, or to entreat. Prayer is an
invocation or act that seeks to activate a rapport with a target of worship through
deliberate communication. It may be directed toward a deity, spirit, animal,
essential element, object, or deceased person.
Among 132 consecutive inpatients in stroke rehabilitation, those with
over‐threshold mood scores (based on the Hospital Anxiety and Depression
Scale [HAD]) had significantly lower religious beliefs (based on Royal Free
Interview [RFI] scores) (OR 0.95, 95% CI 0.92–0.98) [34]. The strength of
religious belief was felt to influence the ability to cope after a stroke event,
with stronger religious beliefs acting as a possible protective factor against
emotional distress.
In a pilot study of the role of religion and spirituality on functional recov-
ery after a recent stroke, 112 consecutive stroke inpatients in a 2‐month
standard rehabilitation program received the RFI and HADS [35]. When
functional status was measured by the Functional Independence Measure,
no association was found between faith and recovery of functional independ-
ence; religiousness as a “coping strategy” was not associated with functional
recovery in this study.
In a cross‐sectional analysis of 63 individuals evaluated in outpatient settings
(32 stroke, 31 healthy controls), the SF‐36 General Mental Health scale was
significantly correlated with only the Brief Multidimensional Measure of
Religiousness/Spirituality Religious and Spiritual Coping scale (r = 0.43; p <.05)
[36]. Spiritual belief that a higher power will assist in coping with illness/
disability was associated with better mental health following stroke, but neither
religious nor spiritual factors were associated with physical health outcomes.
Spiritual beliefs may protect individuals with stroke from experiencing e motional
distress.
Prayer had a positive effect on care givers. Through spirituality, the care
givers felt well‐being and were connected and comforted in difficult times
related to caring [37]. Spirituality gave care givers hope and sustenance, and
helped them express themselves more fully during a difficult time of change
[38]. Religion had significant correlations with care givers’ depression [39].
0003172482.INDD 148 8/21/2017 12:26:50 PM

Table 12.1 Summary of outcomes of complementary and alternative interventions in stroke.
Intervention Study type Comparator Positive findings
Acupuncture Meta‐analysis Control Superior by clinical efficacy rates,

Fugl‐Meyer assessment, Barthel index,
neurological deficit score
Acupuncture Systematic review Sham or open Fewer dead or dependent, fewer dead
(acute stroke) control or institutionalized
Moxibustion Systematic review Standard care Favorable effects on motor function
Cupping Systematic review Acupuncture Superior hemiplegic shoulder pain and
high upper limb myodynamia
Chinese herbal Meta‐analysis Control Improvement of neurological deficit
medicine
Ayurveda Clinical trial Physiotherapy Improved heart rate, blood pressure
variability
Homeopathy Comment Nil “Shows promise”
Massage
Tui‐na Randomized Placebo tai‐na Reduced Ashworth scale in four groups
controlled trial
Marma Controlled trial Standard care Better motricity index
Thai Trial Physiotherapy No difference
Urut Case series Nil “Positive experience”
Yoga Systematic review Control Improved cognition, mood, balance
Tai chi Focused review Control Improved balance
Reiki Systematic review Control Nil
Religious belief Cross‐sectional Nil Better coping
Conclusion
There is a wide range of complementary and alternative treatments used by

disabled stroke survivors. The evidence behind such interventions ranges from
case reports to meta‐analyses of randomized controlled trials (Table 12.1).
Acupuncture reduces death or disability. Moxibustion improves motor function.
Herbal remedies may improve neurological deficit. Tui‐na massage may reduce
spasticity while marma massage may improve motricity. Yoga and tai chi may
improve mood and balance. Religiosity improves coping. Overall, other than
for acupuncture, the evidence for benefit is weak. More research is needed by
well‐conducted randomized controlled trials to determine the role of alternative
and complementary treatments for stroke.
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0003172482.INDD 151 8/21/2017 12:26:50 PM

CHAPTER 13
Stroke‐related dementia
Shinichiro Uchiyama and N. Venketasubramanian Ramani
Cognitive problems are a known complication of stroke. This chapter reviews

the definition, epidemiology, clinical features, and management of cognitive
impairment seen in stroke patients.
Definition
There are a number of definitions for vascular dementia. The more widely
used ones are according to the International Statistical Classification of Diseases
and Related Health Problems, 10th Revision (ICD‐10) [1], National Institute
of Neurological Disorders and Stroke and Association Internationale pour
la Recherché et l’Enseignement en Neurosciences (NINDS–AIREN) [2],
and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
(DSM‐IV) [3].
ICD‐10 uses the following criteria:
1 Dementia—decline in memory and/or other cognitive abilities for at least
6 months; preserved awareness of the environment; decline in emotional
control or motivation, or a change in social behavior.
2 Vascular dementia—the above, plus unequal distribution of deficits in higher
cognitive functions, with some affected and others relatively spared; clinical
evidence of focal brain damage; evidence from the history, examination, or
tests, of a significant cerebrovascular disease, which may reasonably be judged
to be etiologically related to the dementia.
Vascular dementia may be further subclassified into vascular dementia
of acute onset, multi‐infarct dementia, subcortical vascular dementia, mixed
cortical and subcortical vascular dementia, other vascular dementia, vascular
dementia, unspecified (Table 13.1).
152
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Stroke‐related dementia 153
Table 13.1 Subtypes of vascular dementia.
Vascular dementia type Criteria
Vascular dementia of acute (i) The general criteria for vascular dementia must be met
onset (ii) The dementia develops rapidly (i.e., usually within 1 month,
but within no longer than 3 months) after a succession of
strokes, or (rarely) after a single large infarction
Multi‐infarct dementia (i) The general criteria for vascular dementia must be met
(ii) The onset of the dementia is gradual (i.e., within 3–6
months), following a number of minor ischemic episodes.
Comments: It is presumed that there is an accumulation
of infarcts in the cerebral parenchyma. Between the
ischemic episodes there may be periods of actual clinical
improvement
Subcortical vascular dementia (i) The general criteria for vascular dementia must be met
(ii) A history of hypertension
(iii) Evidence from clinical examination and special investigations
of vascular disease located in the deep white matter of
the cerebral hemispheres, with preservation of the cerebral
cortex
Mixed cortical and subcortical Mixed cortical and subcortical components of the vascular
vascular dementia dementia may be suspected from the clinical features, the
results of investigations (including autopsy), or both
Other vascular dementia —
Vascular dementia, unspecified —
NINDS–AIREN uses the following criteria:

•• Probable vascular dementia—includes all of the following:
1 Dementia—cognitive decline from a previously higher level of functioning
and manifested by impairment of memory and of two or more cognitive
domains; deficits should be severe enough to interfere with activities of
daily living not due to physical effects of stroke alone.
2 Cerebrovascular disease (CVD)—presence of focal signs on neurologic
examination, and evidence of relevant CVD by brain imaging.
3 A relationship between the above two disorders, manifested or inferred by
the presence of one or more of the following: (a) onset of dementia within
3 months following a recognized stroke; (b) abrupt deterioration in cogni-
tive functions; or (c) fluctuating, stepwise progression of cognitive deficits.
•• Possible vascular dementia—dementia with focal neurologic signs in patients in
whom brain imaging studies to confirm definite CVD are missing; or in the
absence of clear temporal relationship between dementia and stroke; or in
patients with subtle onset and variable course (plateau or improvement) of
cognitive deficits and evidence of relevant CVD.
•• Definite vascular dementia—(a) clinical criteria for probable vascular dementia;
(b) histopathologic evidence of CVD obtained from biopsy or autopsy;
0003172483.INDD 153 8/22/2017 1:18:23 PM

(c) absence of neurofibrillary tangles and neuritic plaques exceeding those

expected for age; and (d) absence of other clinical or pathologic disorder
capable of producing dementia.
DSM‐IV uses the following criteria:
(A) The development of multiple cognitive deficits manifested by both:
1 Memory impairment (impaired ability to learn new information or to
recall previously learned information).
2 One or more of the following cognitive disturbances:
(a) aphasia (language disturbance)
(b) apraxia (impaired ability to carry out motor activities despite intact
motor function)
(c) agnosia (failure to recognize or identify objects despite intact sensory
function)
(d) disturbance in executive functioning (i.e., planning, organizing,
sequencing, and abstracting).
(B) The cognitive deficits in criteria A1 and A2 each cause significant impairment
in social or occupational functioning and represent a significant decline from
a previous level of functioning.
(C) Focal neurological signs and symptoms or neuroimaging evidence indicative
of cerebrovascular disease that are judged to be etiologically related to the
disturbance.
All definitions exclude delirium and other reversible causes of cognitive
dysfunction.
The different definitions have a different sensitivity and specificity in
the diagnosis of vascular dementia [4]. The prevalence rate of post‐stroke
vascular dementia is lowest when the NINDS–AIREN criteria are used, and
highest when the DSM‐III and the ICD‐10 Neurological Adaptation (ICD‐10‐NA)
criteria are applied. The NINDS–AIREN criteria require evidence of cerebro-
vascular disease in imaging, whereas the DSM‐III and ICD‐10‐NA do not
require such direct evidence. In most studies on post‐stroke cognitive decline,
the diagnoses lack neuropathological verification, leading to some degree of
uncertainty.
The severity of cognitive symptoms could be assessed using the Clinical
Dementia Rating Scale [5]. This is a 5‐point scale that starts at 0,* assessing six
domains of cognitive and functional performance: memory, orientation, judg-
ment and problem solving, community affairs, home and hobbies, and personal
care. The scores are summed, and dementia is rated as follows:
0 = normal
0.5 = very mild dementia
1 = mild dementia
*A score of 0 means that the person does not have dementia. A score of one is very mild demen-
tia, whereas 3 is severe. The score may fall if cognitive function improves, especially just after
acute stroke, or may increase if another stroke occurs that further worsens cognitive function.
0003172483.INDD 154 8/22/2017 1:18:23 PM

2 = moderate dementia
3 = severe dementia
There are a number of tools that may be used to screen for cognitive impair-
ment. These include the Mini‐Mental State Examination (MMSE) [6], Montreal
Cognitive Assessment (MoCA) [7], and the Frontal Assessment Battery (FAB)
[8]. In a systematic review of 21 papers regarding 12 screening tools, only the
MoCA and MMSE met all psychometric and clinical utility criteria for any level
of cognitive impairment [9]. However, the MMSE was most accurate to screen
for dementia (cut‐off score 23/24). The Informant Questionnaire for Cognitive
Decline in the Elderly (IQCODE) and short‐IQCODE, which comprises 16 of the
26 items in the original IQCODE, were useful when the patient was unable to
respond and an informant’s view was required. Overall, the MoCA was the most
valid and clinically feasible screening tool to identify stroke survivors with a
wide range of cognitive impairments who warrant further assessment.
Epidemiology
In a systematic review, studies on pre‐stroke and post‐stroke dementia published

between 1950 and May 1, 2009 were included if they were about patients with
symptomatic stroke, were reported on a series of consecutive eligible patients or
volunteers in prospective cohort studies, included all strokes or all ischemic
strokes, measured dementia by standard criteria, and followed up patients for at
least 3 months after stroke [10].
There were 73 papers that described 22 hospital‐based and 8 population‐based
eligible cohorts (7511 patients). The pooled prevalence of pre‐stroke dementia was
higher (14.4%, 95% confidence interval [CI] = 12.0–16.8) in hospital‐based studies
than in population‐based studies (9.1%, 95% CI = 6.9–11.3) (Fig. 13.1). Although
post‐stroke dementia rates within 1 year were heterogeneous overall, 93% of the
variance was explained by study methods and case mix; the rates ranged from
7.4% (95% CI = 4.8–10.0) in population‐based studies of first‐ever stroke in which
pre‐stroke dementia was excluded, to 41.3% (95% CI = 29.6–53.1) in h ospital‐
based studies of recurrent stroke in which pre‐stroke dementia was included.
After the first year, the cumulative incidence of dementia per year in h
ospital‐
based studies was a little higher (3.0%, 95% CI = 1.3–4.7) than expected on the
basis of recurrent stroke alone. Medial temporal lobe atrophy, female sex, and a
family history of dementia were strongly associated with pre‐stroke dementia,
whereas the characteristics and complications of the stroke and the presence of
multiple lesions in time and place were more strongly associated with post‐
stroke d ementia. After study methods and case mix are taken into account,
reported estimates of the prevalence of dementia are consistent: 10% of patients
had dementia before first stroke, 10% developed new dementia soon after first
stroke, and more than a third had dementia after recurrent stroke. The strong
association of post‐stroke dementia with multiple strokes and the prognostic
0003172483.INDD 155 8/22/2017 1:18:23 PM

Fig. 13.1 Prevalence of post‐stroke dementia. Pooled prevalence (%) of post‐stroke dementia

up to 1 year after stroke stratified by study setting (hospital‐based study vs population‐based
study), by inclusion or exclusion of pre‐stroke dementia, and by first‐ever stroke vs any (first‐
ever or recurrent) vs recurrent stroke. Mean age of the patients in each study is shown on the
right, together with method of dementia diagnosis. Bars indicate 95% CI. DSM, diagnostic
and statistical manual of mental disorders; MDRS, Mattis dementia rating scale; NINDS—
AIREN, National Institute of Neurological Disorders and Stroke and Association Internationale
pour la Recherché et l’Enseignement en Neurosciences; Records, retrospective review of
medical records. *The study from Gorelick and colleagues excluded patients with “possible
prior Alzheimer disease” but not with prior cognitive impairment associated with stroke, so
actual prevalence rate for this study might have been slightly higher than shown. NA, not
available. Reproduced with permission from reference [10].
value of other stroke characteristics highlight the central causal role of stroke
itself as opposed to the underlying vascular risk factors.
There is a more recent overview that also includes recent data from Asia
[11] (Fig. 13.2). The Asian studies are summarized in Table 13.2. The fre-
quency of cognitive impairment at 3 months after stroke ranged from 21.8%
in Hong Kong to 69.8% in South Korea, with intermediate rates in Chongqing
and Changsha. However, the studies were done at various time‐points, with
different sample sizes and varying tools for diagnosis, making it difficult to
0003172483.INDD 156 8/22/2017 1:18:23 PM

0003172483.INDD 157
Europe
USA Norway Changsha

31% with dementia 3 months 57%, 1 year after 41.8%, 3 months
after stroke; stroke Sweden
19.3% with dementia at 10 years 39%, 1 month South Korea
follow-up Britain after stroke 69.8%, 3 months
24%, 3 months after stroke
after stroke; Chongqing
22%, annually 37.1%, 3 months
after stroke
Netherlands
82%, 1 month after stroke;
France Hong Kong
69%, 6 months after stroke;
47.3%, 3 months 21.8%, 3 months
58%, 1 year after stroke.
after stroke after stroke
India
20%, annually
Caribbean
58.9%, 5 years Singapore
after stroke 44%, 3 months after stroke;
33%, 1 year follow-up
Australia
58%, 3 or 6 months after stroke;
50%, 1 year after stroke
Fig. 13.2 The distribution of post‐stroke cognitive impairment. Reproduced with permission from reference [11].
8/22/2017 1:18:24 PM
Table 13.2 Epidemiology of vascular dementia in Asia. Reproduced with permission from reference [11].
0003172483.INDD 158
Location Population Measured Sample size Outcome measure Results
and year duration
after stroke
Sweden, Patients admitted to a geriatric 38 days Stroke: 74, control: 49 MMSE; 39% with cognitive impairment as measured by
2011 stroke unit at Sahlgrenska neuropsychological test MMSE; 96% with cognitive impairment as measured
University Hospital in Sweden battery by neuropsychological test battery
after a stroke
Britain, Patients from South London 3 months; 271, 817 individuals MMSE; abbreviated 24% with cognitive impairment 3 months after
2013 Stroke Register annual with 63% white, mental test stroke; 22% with cognitive impairment relatively
follow‐up 28% black unchanged and at annual follow‐up
Netherlands, Patients with a first‐ever brain 1 month; 176 MMSE; 10.8% with dementia and 71.1% with MCI at
2004 infarct from cognitive disorders 6 months; neuropsychological test 1 month; 7.7% with dementia and 61.3% with
after stroke 12 months battery MCI at 6 months; 7.7% with dementia and 51.5%
with MCI at 12 months
Norway, Patients with a first‐ever stroke 12 months 206 MMSE, the clock drawing 19.6% with dementia and 37.5% with MCI
2011 or TIA, transient ischemic attack test, TMT A and B,
admitted to the stroke unit of 10‐word test, ADAS‐Cog
Asker and Bærum Hospital
France, Patients with the first‐ever stoke 3 months 220 MMSE; MoCA 47.3% with the post‐stroke cognitive impairment,
2014 and no pre‐stroke dementia including 7.7% with dementia
from Neurology Department of
Dijon, University Hospital
Australia, Patients with and without 1 year Stroke: 99, control: 99 S‐MMSE; IQCODE; IDA; 12.5% with dementia and 37.5% with cognitive
2004 mild‐to‐moderate first‐ever DSM‐IV impairment no dementia at 12 months
stroke from North East
Melbourne Stroke
Incidence Study
8/22/2017 1:18:24 PM
0003172483.INDD 159
Australia, Patients from Sydney Stroke 3–6 months Stroke: 169, MMSE; NART‐IQ; ADL; 21.3% with dementia and 36.7% with MCI
2006 Study control: 103 IADL; IQCODE; SOFAS
United Subjects with stroke and 10 years 212 DSM‐IV 19.3% with dementia at 10 years follow‐up
States, non‐dementia from the
2004 Framingham Study
United Subjects with stroke of 90 days 513 for neurological 3MSE; IQCODE; ADL 31% with dementia
States, Mexican American from Brain outcome; 510 and IADL
2014 Attack Surveillance in Corpus functional outcome;
Christi Project 415 for cognitive
outcome
Martinique, Patients with the first‐ever 5 years 293 MMSE 58.9% with cognitive impairment
2010 stroke from the cohort of
ERMANCIA study
South Patients with the ischemic 3 months 620 MMSE; IQCODE 69.8% with cognitive impairment
Korea, stroke from 12 hospitals
2012
Singapore, Survived patients with TIA Baseline: 6 Baseline: 252; MMSE; vascular Baseline: 40% with cognitive impairment without
2002 or stroke months; follow‐up: 155 dementia battery dementia; 4% with dementia; follow‐up: 29% with
follow‐up: cognitive impairment without dementia; 4% with
1 year dementia
India, 2013 Stroke survivors from the Annual Baseline: 281;1st year: BMSE; ADL Baseline: 13.88% with dementia; 6.05% with MCI;
Kolkata follow‐up 219; 2nd year: 180; 1st year: 10.05% with dementia; 5.48% with MCI;
3rd year: 158 2nd year: 13.89% with dementia; 4.44% with MCI;
3rd year: 17.72% with dementia; 3.16% with MCI
Hong Stroke patients admitted to 3 months Total stroke cases: IQCODE; MMSE; DSM‐IV 21.8% with cognitive impairment in total stroke
Kong, 2006 Acute Stroke Unit of Prince of 179, first‐ever cases; 18% with cognitive impairment in first‐ever
Wales Hospital stroke cases
(Continued )
8/22/2017 1:18:24 PM
0003172483.INDD 160
Location Population Measured Sample size Outcome measure Results
and year duration
after stroke
Chongqing, Patients with ischemic stroke 3 months 434 MMSE; IQCODE 37.1% with the post‐stroke cognitive impairment;
2005 admitted to Daping Hospital of 32.2% with the stroke‐related cognitive impairment;
Chongqing city 29.6% with the cognitive impairment after first‐ever
stroke
Changsha, Patients with ischemic stroke 3 months 706 MMSE; MoCA; FAB; 41.8% with cognitive impairment after ischemic
2014 from the communities WMS; CDR; FAQ; ADL; stroke
CES‐D; SSRS; NINDS;
AIREN
Abbreviations: MCI, mild cognitive impairment; MMSE, mini‐mental state examination; 3MSE, modified mini‐mental state examination; S‐MMSE, standardized Mini‐Mental state
examination; IQCODE, informant questionnaire for cognitive decline in elderly; ADAS‐Cog, Alzheimer’s disease assessment scale‐cognitive; IDA, irritability, depression and anxiety
scale; DSM‐IV, diagnostic and statistical manual of mental disorders criteria, 4th edition; NART‐IQ, national adult reading test‐intelligence quotient; ADL, activities of daily living;
IADL, instrumental activities of daily living; SOFAS, social and occupational functioning assessment scale; BMSE, Bengali version of Hindi mental state examination; MoCA,
Montreal cognitive assessment; fab, frontal assessment battery; WMS, Wechsler memory scale; CDR, clinical dementia rating; FAQ, functional activities questionnaire; CES‐D,
center for epidemiological survey‐depression scale; SSRS, social support rating scale; NINDS, national institute of neurological disorders and stroke; AIREN, association international
pour la Recherché et l’Enseignement en Neurosciences.
8/22/2017 1:18:25 PM
compare the studies. Over time, the prevalence was stable in South London
but decreased in Kolkata.
The frequency of cognitive impairment has been thought to differ based on
whether the stroke is lacunar or not. In a meta‐analysis of 24 studies involving
a total of 7575 patients, including 2860 patients with lacunar stroke, 24% had
mild cognitive impairment (MCI) or post-stroke dementia [12]. Similar propor-
tions of patients with lacunar and non‐lacunar stroke (16 studies, n = 6478) had
MCI or dementia up to 4 years after stroke (odds ratio [OR] = 0.72, 95%
CI = 0.43–1.20). The prevalence of dementia after lacunar stroke (six studies, n =
1421) was 20% (95% CI = 9–33) and the incidence of MCI or dementia
(four studies, n = 275) was 37% (95% CI = 23–53) (Fig. 13.3).
Clinical presentation and diagnosis
To date, all diagnostic criteria to characterize cognitive syndromes associated with

vascular disease should be based on two factors: demonstration of the presence of
a cognitive disorder by neuropsychological testing and history of clinical stroke or
presence of vascular disease by neuroimaging that suggests a link between the
cognitive disorder and vascular disease [13]. The term vascular cognitive impair-
ment (VCI) is used for all forms of cognitive disorder associated with cerebrovas-
cular disease, regardless of the pathogenesis (e.g., cardioembolic, atherosclerotic,
lacunar, ischemic, hemorrhagic, or genetic). VCI is a continuum, and the term
vascular dementia (VaD) is used for the severe grade of VCI. In this context, the
concept of VCI is particularly important for prevention of VaD, not only in the
general population but also in patients with mild vascular cognitive impairment.
Cognitive deficits vary according to the area of the brain affected. Multi‐infarct
dementia [14], referred to as post‐stroke dementia, has stepwise decline in cogni-
tive function with stable periods and some improvement [15]. On the other hand,
VaD due to subcortical small vessel disease (SVD) shows generally gradual onset
and slow progression. VaD has been characterized traditionally as having a patchy
pattern of cognitive deficits [15,16]. This pattern is associated with multi‐infarct
dementia but not necessarily with other types of VaD. Strategic infarct dementia
has a unique pattern of features that reflect the specific brain region affected
[2,16]. Dementia or cognitive impairment due to SVD is often associated with
focal neurological deficits such as lacunar syndrome, small steppage gait,
Parkinsonism, and pseudobulbar palsy [17]. Multi‐infarct dementia is associated
especially with disorders of recognition of words, naming, and repetition in com-
parison with Alzheimer’s disease [18]. The Hachinski Ischemic Score has long been
widely used for the differential diagnosis of VaD, especially multi‐infarct dementia,
and Alzheimer’s disease (AD) [19] (Table 13.3). Disturbance in frontal executive
functions rather than memory is often more pronounced in VaD, and memory
impairment is sometimes even absent despite the presence of evident cognitive
0003172483.INDD 161 8/22/2017 1:18:25 PM

Lacunar Cortical Odds ratio Odds ratio
Study or subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
1.1.1 Assessed under 1 month after stroke
Nys 2007 29 64 47 63 6.5% 0.28 [0.13, 0.60]
Bejot 2011 333 887 289 1960 7.5% 3.48 [2.89, 4.18]
Subtotal (95% Cl) 951 2023 14.0% 1.02 [0.09, 12.01]
Heterogeneity: Tau2 = 3.10; Chi2 = 40.76, df = 1 (P <0.00001); l2 = 98%
Test for overall effect: Z = 0.01 (P = 0.99)
1.1.2 3 months to 1 year after stroke

Klimkowicz-Mrowiec 2006 2 24 35 149 4.7% 0.30 [0.07, 1.32]
de Koning 2005 4 20 17 38 5.2% 0.31 [0.09, 1.10]
Madureira 2001 6 139 5 41 5.3% 0.32 [0.09, 1.13]
Dong 2012 21 106 31 97 6.8% 0.53 [0.28, 1.00]
Censori 1996 2 21 13 83 4.5% 0.57 [0.12, 2.73]
Pohjasvaara 1998 5 21 102 316 5.8% 0.66 [0.23, 1.84]
Sachdev 2006 24 46 74 120 6.7% 0.68 [0.34, 1.35]
Patel 2002 72 218 124 297 7.3% 0.69 [0.48, 0.99]
Tang 2004 33 166 18 90 6.8% 0.99 [0.52, 1.89]
Tatemichi 1994 21 59 59 168 6.8% 1.02 [0.55, 1.90]
Lin 2003 13 136 13 147 6.4% 1.09 [0.49, 2.44]
Subtotal (95% Cl) 956 1546 66.2% 0.70 [0.57, 0.87]
Heterogeneity: Tau = 0.00; Chi = 8.92, df = 10 (P =0.54); l2 = 0%
2 2

1.1.3 Over 1 year after stroke
Tatemichi 1990 25 227 91 499 7.1% 0.55 [0.35, 0.89]
Cordoliani-Mackowiak 2003 8 31 94 101 6.1% 1.12 [0.44, 2.82]
Rasquin 2005 40 57 59 87 6.6% 1.12 [0.54, 2.30]
Subtotal (95% Cl) 315 687 19.8% 0.80 [0.48, 1.34]
Total events 73 174
Heterogeneity: Tau2 = 0.09; Chi2 = 3.42, df = 2 (P = 0.18); l2 = 42%
Total (95% Cl) 2222 4256 100.0% 0.72 [0.42, 1.20]

Heterogeneity: Tau = 0.94; Chi = 174.09, df = 15 (P < 0.00001); l2 = 91%
2 2
0.1 0.2 0.5 1 2 5 10
Test for subgroup differences: Chi2 = 0.30, df = 2 (P = 0.86); l2 = 0% Cortical Lacunar
Fig. 13.3 Odds of cognitive impairment in lacunar stroke vs cortical stroke. Reproduced with
permission from reference [12].
Table 13.3 The Hachinski Ischemic Score. Reproduced

with permission from reference [19].
Item no. Description Value
1 Abrupt onset 2
2 Stepwise deterioration 1
3 Fluctuating course 2
4 Nocturnal confusion 1
5 Preservation of personality 1
6 Depression 1
7 Somatic complaints 1
8 Emotional incontinence 1
9 History of hypertension 1
10 History of stroke 2
11 Associated atherosclerosis 1
12 Focal neurological symptoms 2
13 Focal neurological signs 2
A cut‐off score ≦4 for Alzheimer’s disease and ≧7 for vascular

dementia has a sensitivity of 89% and a specificity of 89% (Moroney JT.
Neurology 1997;49:1096–115).
0003172483.INDD 162 8/22/2017 1:18:25 PM

deficits, which is different from the clinical features in AD [15,20]. In vascular

cognitive disorders, information processing speed may be slow, working memory
poor, and episodic memory rather than retention of memory impaired [15,20].
VaD is commonly associated with mood disorders such as depression and anxiety.
The pattern of VCI cognitive deficits may include all cognitive domains, but
there is likely to be a preponderance of so‐called “executive” dysfunction, such
as slowed information processing, impairments in the ability to shift from one
task to another, and deficits in the ability to hold and manipulate information
(i.e., working memory) [21]. Neuropsychological protocols must therefore be
sensitive to a wide range of abilities, especially for the assessment of executive
function. Timed executive function tests may be particularly sensitive to
VCI‐related impairment because of the slowed information processing noted in
patients with VCI. In order to maximize information obtained from a brief
number of tests, conventional well‐validated tasks should be selected [21].
Table 13.4 shows a proposed 30‐min and 5‐min neuropsychological protocol
[21]. Word list generation cued by category can provide relevant information to
language, activation, speed of processing, set shifting, working memory, and
executive control [20,21]. Frontal executive function tests including Lezak
Tinker Toy, Porteus Maze, Gibson Spiral Maze, Mattis Dementia Rating Scale
Executive Function, Wisconsin Card Sorting Test, and Graphic Sequence Test
demonstrate inferior performance in VaD patients when compared with AD
patients [20]. On the other hand, verbal long‐term memory has been reported
to be relatively spared. Guidelines for the diagnosis of VCI by the American
Heart Association and the American Stroke Association (AHA/ASA) are shown
in Table 13.5 [13].
Table 13.4 Proposed 30‐min and 5‐min neuropsychological protocols.

Reproduced with permission from reference [21].
30‐Minute test protocol

Semantic fluency (animal naming)
Phonemic fluency (controlled oral word association test)
Digit symbol‐coding from the Wechsler Adult Intelligence Scale, Third Edition
Hopkins Verbal Learning Test
Center for Epidemiologic Studies‐Depression Scale
Neuropsychiatric Inventory, Questionnaire Version (NPI‐Q)
Supplemental: MMSE, trail making test
5‐Minute protocol
MoCA subtests:
•• 5‐word memory task (registration, recall, recognition)
•• 6‐item orientation
•• 1‐letter phonemic fluency
Supplemental: Remainder of the MoCA, semantic fluency (animal naming), trail

making test, MMSE (to be administered at least 1 h before or after the above tests).
0003172483.INDD 163 8/22/2017 1:18:25 PM

Table 13.5 Scientific statement for the diagnosis of vascular cognitive impairment
from the American Heart Association/American Stroke Association. Reproduced
with permission from reference [22].
1. The term VCI characterizes all forms of cognitive deficits from VaD to MCI of vascular origin.
2. These criteria cannot be used for subjects who have an active diagnosis of drug or alcohol
abuse/dependence. Subjects must be free of any type of substance for at least 3 months.
3. These criteria cannot be used for subjects with delirium.
Dementia
1. The diagnosis of dementia should be based on a decline in cognitive function from a prior
baseline and a deficit in performance in two cognitive domains that are of sufficient severity to
affect the subject’s activities of daily living.
2. The diagnosis of dementia must be based on cognitive testing, and a minimum of four
cognitive domains should be assessed: executive/attention, memory, language, and visuospatial
functions.
3. The deficits in activities of daily living are independent of the motor/sensory sequelae of the
vascular event.
Probable VaD
1. There is cognitive impairment and imaging evidence of cerebrovascular disease and
a. There is a clear temporal relationship between a vascular event (e.g., clinical stroke) and
onset of cognitive deficits, or
b. There is a clear relationship in the severity and pattern of cognitive impairment and the
presence of diffuse, subcortical cerebrovascular disease pathology (e.g., as in CADASIL).
2. There is no history of gradually progressive cognitive deficits before or after the stroke that
suggests the presence of a non‐vascular neurodegenerative disorder.
Possible VaD
There is cognitive impairment and imaging evidence of cerebrovascular disease but
1. There is no clear relationship (temporal, severity, or cognitive pattern) between the vascular
disease (e.g., silent infarcts, subcortical small vessel disease) and the cognitive impairment.
2. There is insufficient information for the diagnosis of VaD (e.g., clinical symptoms suggest the
presence of vascular disease, but no CT/MRI studies are available).
3. Severity of aphasia precludes proper cognitive assessment. However, patients with documented
evidence of normal cognitive function (e.g., annual cognitive evaluations) before the clinical
event that caused aphasia could be classified as having probable VaD.
4. There is evidence of other neurodegenerative diseases or conditions in addition to
cerebrovascular disease that may affect cognition, such as:
a. A history of other neurodegenerative disorders (e.g., Parkinson’s disease, progressive
supranuclear palsy, dementia with Lewy bodies);
b. The presence of Alzheimer’s disease biology is confirmed by biomarkers (e.g., PET, CSF,
amyloid ligands) or genetic studies (e.g., PS1 mutation); or
c. A history of active cancer or psychiatric or metabolic disorders that may affect cognitive
function.
VaMCI
1. VaMCI includes the four subtypes proposed for the classification of MCI: amnestic, amnestic
plus other domains, non‐amnestic single domain, and non‐amnestic multiple domain.
2. The classification of VaMCI must be based on cognitive testing, and a minimum of four
cognitive domains should be assessed: executive/attention, memory, language, and visuospatial
functions. The classification should be based on an assumption of decline in cognitive function
from a prior baseline and impairment in at least one cognitive domain.
3. Instrumental activities of daily living could be normal or mildly impaired, independent of the
presence of motor/sensory symptoms.
0003172483.INDD 164 8/22/2017 1:18:25 PM

Probable VaMCI
1. There is cognitive impairment and imaging evidence of cerebrovascular disease and
a. There is a clear temporal relationship between a vascular event (e.g., clinical stroke) and
onset of cognitive deficits, or
b. There is a clear relationship in the severity and pattern of cognitive impairment and the
presence of diffuse, subcortical cerebrovascular disease pathology (e.g., as in CADASIL).
2. There is no history of gradually progressive cognitive deficits before or after the stroke that
suggests the presence of a non‐vascular neurodegenerative disorder.
Possible VaMCI
There is cognitive impairment and imaging evidence of cerebrovascular disease but:
1. There is no clear relationship (temporal, severity, or cognitive pattern) between the vascular
disease (e.g., silent infarcts, subcortical small‐vessel disease) and onset of cognitive deficits.
2. There is insufficient information for the diagnosis of VaMCI (e.g., clinical symptoms suggest the
presence of vascular disease, but no CT/MRI studies are available).
3. Severity of aphasia precludes proper cognitive assessment. However, patients with documented
evidence of normal cognitive function (e.g., annual cognitive evaluations) before the clinical
event that caused aphasia could be classified as having probable VaMCI.
4. There is evidence of other neurodegenerative diseases or conditions in addition to
cerebrovascular disease that may affect cognition, such as:
a. A history of other neurodegenerative disorders (e.g., Parkinson disease, progressive
supranuclear palsy, dementia with Lewy bodies);
b. The presence of Alzheimer’s disease biology is confirmed by biomarkers (e.g., PET, CSF,
amyloid ligands) or genetic studies (e.g., PS1 mutation); or
c. A history of active cancer or psychiatric or metabolic disorders that may affect cognitive function.
Unstable VaMCI
Subjects with the diagnosis of probable or possible VaMCI whose symptoms revert to normal
should be classified as having “unstable VaMCI.”
Abbreviations: VCI, vascular cognitive impairment; VaD, vascular dementia; MCI, mild cognitive
impairment; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy; CT/MRI, computed tomography/magnetic resonance imaging; PET, positron
emission tomography; CSF, cerebrospinal fluid; and VaMCI, vascular mild cognitive impairment.
The critical clinical feature of VaD determines the relationship of cerebrovas-

cular disease to the cognitive symptoms [13]. To appropriately diagnose VaD, it
is critical to identify the presence of cortical or subcortical infarcts or other stroke
lesions with neuroimaging, and they should be associated with clinical symp-
tomatology. In this context, neuroimaging is mandatory for the diagnosis of VCI
[15,21]. MRI is more sensitive than CT to detect silent SVD. Neuroimaging is
also important to rule out other diseases such as brain tumor, normal pressure
hydrocephalus, or subdural hematoma, and to differentiate from, or investigate
the coexistence of, degenerative dementias such as AD or frontotemporal
dementia. The NINDS–AIREN criteria [2] require multiple large‐vessel strokes,
single strategic infarct, or multiple basal ganglia and white matter lacunes.
Diffuse extension of a white matter lesion is termed leukoaraiosis [22].
0003172483.INDD 165 8/22/2017 1:18:26 PM

Leukoaraiosis with multiple lacunar infarcts is the diagnostic neuroradiological

finding of Binswanger’s disease [23]. Similar findings can be seen in patients with
cerebral autosomal dominant or recessive arteriopathy with subcortical infarcts
and leukoencephalopathy, CADASIL and CARASIL, respectively. Small subcorti-
cal infarcts or lacunar infarcts and white matter lesions such as periventricular
hyperintensity (PVH) and deep subcortical white matter hyperintensity (DSWMH)
on MRI are well‐known neuroimaging markers for SVD with VCI [13,21]. Other
imaging markers for SVD are cerebral microbleeds (CMBs) [24] and cortical
microinfarcts [25], which have been reported to be associated with VCI. CMBs
can be detected by T2* gradient‐echo imaging or susceptibility‐weighted imaging,
and cortical microinfarcts by high magnetic‐field MRI such as 3 or more Tesla
MRI. Multiple cortical and subcortical microbleeds and superficial siderosis
are likely to be seen in patients with cerebral amyloid angiopathy. Dilated
perivascular spaces and cortical thinning can also be imaging markers for VCI
[26]. DSWMH could be the only neuroimaging finding in younger people with
cognitive deficits secondary to autoimmune disorders [13].
Management
VaD is a potentially preventable dementia [27]. Subclinical (silent) cerebrovas-

cular diseases occur five times as often as symptomatic cerebrovascular diseases
(strokes), and may cause dementia. We need to identify and treat vascular risk
factors for primary and secondary prevention of stroke in patients with VaD. The
common risk factors requiring management for prevention of VaD are hyperten-
sion, diabetes, dyslipidemia, cigarette smoking, heavy alcohol drinking, physical
inactivity, obesity, and atrial fibrillation.
Table 13.6 shows the AHA/ASA guidelines for the prevention of VCI [28].
Evidence exists for the benefit of dietary intake of vitamin E, B vitamins, folate,
and fish oil. These components are prominent in the Mediterranean diet, which
includes fruits, vegetables, fish, nuts, and low fat. Observational studies demon-
strate a beneficial role of physical activity on the risk of VaD. However, a number
of questions remain, including optimal type and frequency of physical activity,
and the period in life when individuals benefit most. Both overweight and
underweight in midlife are associated with an increased risk of VaD. Although
there are no interventional studies examining the effect of targeted weight loss,
weight control may be reasonable to prevent VCI. There is reasonable evidence
from observational studies that in the middle‐aged and young elderly, lowering
blood pressure can be useful for the prevention of late‐life dementia. Diabetes
is associated with an increased risk of VaD. However, there was no significant
treatment difference on any of the cognitive tests. The level of evidence for a
protective effect of intensive glucose lowering with respect to cognitive impair-
ment is very low. Another potentially important aspect is hypoglycemia.
0003172483.INDD 166 8/22/2017 1:18:26 PM

Table 13.6 Recommendations for prevention of vascular cognitive impairment (American
Heart Association/American Stroke Association 2011). Reproduced with permission
from reference [13].
Target Target Recommendation Recommendation

population class and level
of evidence
Lifestyle General Mediterranean‐type dietary pattern has IIb; B

been associated with less cognitive
decline in several studies and may be
reasonable
Vitamin supplementation is not proven IIb; B
to improve cognitive function, even if
homocysteine levels have been
positively influenced, and its usefulness
is not well established
People at Physical activity might be considered IIb; B
risk of VCI for the prevention of cognitive
impairment
Smoking cessation is reasonable IIa; A
The following lifestyle interventions
may be reasonable:
Moderation of alcohol intake IIb; B
Weight control IIb; B
Physical activity IIb; B
The use of antioxidants and B vitamins III; A
are not beneficial, based on current
evidence
Blood pressure Middle‐aged There is reasonable evidence that IIa; B
and young lowering blood pressure can be useful
elderly for the prevention of late‐life dementia
People aged The usefulness of lowering blood IIb; B
>80 y pressure for the prevention of dementia
is not well established
People at Treatment of hypertension is I; A
risk for VCI recommended
Patients Lowering blood pressure is effective for I; B
with stroke reducing the risk of post‐stroke dementia
Hyperglycemia/ General The effectiveness of treating diabetes/ IIb; C
diabetes hyperglycemia for the prevention of
dementia is not well established
People at Treatment of hyperglycemia may be IIb; B
risk for VCI reasonable
Hyperlipidemia General The usefulness of treatment of IIb; C
hyperlipidemia for prevention of
dementia is uncertain
Hypercholesterolemia General Treatment of hypercholesterolemia may IIb; C
be reasonable
Inflammation People at It is uncertain whether treatment of IIb; C
risk for VCI inflammation will reduce the risk of VCI
Antiaggregants General The effectiveness of antiaggregant IIb; B
therapy for VCI is not well established
VCI, vascular cognitive impairment.

Data from reference [13].
See reference regarding recommendation class and level of evidence.
0003172483.INDD 167 8/22/2017 1:18:26 PM

There was an association between hypoglycemic episodes and an increased risk

of dementia in elderly patients with type 2 diabetes. Long‐term epidemiological
studies have found an association between higher midlife serum total choles-
terol levels and subsequent VaD. However, there is no evidence that the use of
statins or other lipid‐lowering drugs has a favorable effect on cognitive function
in the elderly.
Long‐term follow‐up data from a community‐based stroke registry on the
impact of secondary prevention therapies in patients after stroke demonstrated
that protective effects against cognitive impairment were observed in
patients maintained on a combination of antihypertensives, antithrombotics,
and lipid‐lowering drugs [29]. Antiplatelet and anticoagulant therapies may be
useful for preventing VaD by preventing recurrence of non‐cardioembolic and
cardioembolic strokes, respectively, although there is no evidence for signifi-
cantly reducing the risk of VaD with any antithrombotic therapy alone in patients
with prior ischemic stroke.
Specific pharmacotherapy trials targeting VaD have shown consistent,
modest cognitive improvements with donepezil, galantamine, and memantine,
but functional and global benefits have been less consistent. Recommendations
of the AHA/ASA Guidelines are as follows: (i) donepezil can be useful for
cognitive enhancement in patients with VaD; (ii) administration of galantamine
can be beneficial for patients with mixed AD/VaD; and (iii) the benefits of
rivastigmine and memantine are not well established in VaD [13].
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0003172483.INDD 169 8/22/2017 1:18:26 PM

CHAPTER 14
Central nervous system infections

and stroke in Asia
Jeyaraj D. Pandian and Nijasri C. Suwanwela
Introduction
Eighty percent of strokes are caused by modifiable risk factors such as hyper-
tension, diabetes, dyslipidemia, smoking, obesity, unhealthy dietary habits,
etc. However, in low‐ and middle‐income countries central nervous system
(CNS) infections are an important cause of stroke. This chapter will focus on
the common CNS infections and also the emerging infections in Asia that can
lead to stroke. Infections have long been recognized as a potential but uncom-
mon cause of stroke. The role of infection in stroke is complex and can be
divided into four main c ategories. First, infectious illnesses can cause stroke by
direct mechanisms. For example, infective endocarditis is the cause of cardi-
oembolic stroke and intracranial hemorrhage. Other infections in the cranial
region can directly invade the cerebral vessels (e.g., tuberculous meningitis,
fungal sinusitis). Second, chronic viral infection such as HIV can lead to cere-
bral vasculopathy and stroke. Third, preceding acute infections, especially in
the respiratory tract such as influenza, pneumonia, and bronchitis, have been
found to trigger stroke. Lastly, multiple chronic exposures to several common
bacterial and viral infections (infectious burden) have been shown to contrib-
ute to vascular wall inflammation leading to atherosclerosis as well as increased
prothrombotic state, atrial fibrillation, and stroke. Patients with stroke‐related
infections warrant appropriate investigation and management. This chapter
will focus on direct infection and stroke according to the pathogens.
Bacterial infection and stroke
Bacterial infection can directly invade the intracranial blood vessel wall through
different mechanisms. Direct infection from adjacent structures such as the
meninges and sinuses can cause vasculitis, luminal narrowing, or aneurysmal
170
0003172484.INDD 170 8/21/2017 12:33:50 PM

Central nervous system infections and stroke in Asia 171
formation and subsequent stroke. This mechanism is common in tuberculous

and some other forms of bacterial meningitis. Some chronic bacterial infections
such as meningovascular syphilis can also cause vasculopathy. Remote bacterial
infection in endocarditis and septicemia can result in embolic stroke, vasculitis,
and mycotic aneurysm.
Tuberculosis
Burden
According to the World Health Organization (WHO) Global Tuberculosis (TB)
Report 2015, TB then affected 9.6 million people worldwide. CNS involve-
ment occurs in 10% of all patients affected by TB. Tuberculous meningitis
(TBM) is the most common and morbid manifestation of CNS TB in all age
groups. These patients are at a higher risk of stroke. Despite therapy, ensuing
stroke is fatal in nearly 25% of patients and leaves another 25% with neuro-
logical sequelae. Factors associated with an increased risk for TB include
immunocompromise, especially secondary to human immunodeficiency
virus (HIV) infection, and environmental factors such as living in an endemic
area and household contacts.
Patients with TBM typically present with a nonspecific prodrome of fever,
fatigue, malaise, and headache for 7–10 days [1]. If TBM is untreated, stroke
may develop after the second week.
Pathogenesis
Compared with typical forms of stroke, infarctions in TBM develop more insidi-
ously. In some cases, infarction may even be asymptomatic or obscured by symp-
toms of meningitis. Basal arachnoiditis or inflammation and exudate around the
arteries of the circle of Willis can result in ischemic stroke. Cytokines play a key
role in perpetuation of inflammation. They are released when monocytes are acti-
vated by interaction with the mycobacterial cell wall. They release adhesion mol-
ecules that attract more neutrophils and macrophages. These neutrophils then
release several autocoids—platelet activating factor, leukotrienes and prostaglan-
dins, tumor necrosis factor alpha (TNF α)—that propagate inflammation further.
All the inflammatory responses described above cause vasculitis that initiates
thrombus formation. The arteries develop variable degrees of intimal proliferation,
vasospasm, and thrombosis causing arterial occlusion. Infiltration and necrosis of
the vessel wall have been described in autopsy series. Proliferation and thrombosis
leading to stroke is seen more commonly in small arteries while infiltration and
thrombosis is seen in medium‐sized vessels. These may result in partial obstruc-
tion or complete infarcts. Focal weakness is the most frequent presenting sign of
stroke. Most of the strokes in TBM are located in the tubercular zone, consisting of
the caudate, anterior thalamus, anterior limb and genu of the internal capsule,
and are associated with poor outcome [2,3]. Infarcts are easily detected by neuro-
imaging (Figs 14.1, 14.2, and 14.3). Because inflammation is a mechanism in
0003172484.INDD 171 8/21/2017 12:33:50 PM

Infarcts
Exudates
Infarcts
Fig. 14.1 A 5‐year‐old boy with a 5‐day history of headache, fever, and vomiting who
developed right‐sided weakness 5 days after starting antituberculous therapy. Images courtesy
of Jeyaraj D. Pandian.
Infarcts
Tuberculoma
Fig. 14.2 A 13‐year‐old boy presented with a 1‐week history of fever and acute altered
sensorium. He was discharged with a modified Rankin scale of 5. Images courtesy of Jeyaraj
D. Pandian.
0003172484.INDD 172 8/21/2017 12:33:50 PM

Hydrocephalus
Exudates Infarcts
Fig. 14.3 A 60‐year‐old man with a 20‐day history of fever and acute‐onset drowsiness.
Diffusion‐weighted magnetic resonance imaging (DWI MRI) shows infarcts in the posterior
limb of the internal capsule on both sides. Cerebrospinal fluid (CSF) findings were suggestive
of TBM. Images courtesy of Jeyaraj D. Pandian.
stroke, low‐dose aspirin is being tested in a clinical trial to prevent stroke in

patients with TBM (AspirinTBM ClinicalTrials.gov Identifier: NCT02237365).
Treatment
Treatment of TBM with antituberculous drug therapy is mandatory.
Adjunctive corticosteroids should also be administered in patients with
severe basal arachnoiditis with or without stroke, regardless of HIV status. A
randomized controlled trial showed that adjuvant corticosteroid therapy in
patients with TBM was associated with less mortality but not severe disability
[4]. However, another observational study suggested a reduction of strokes
by MRI in patients with corticosteroid treatment [5]. An open‐label study of
aspirin in TBM demonstrated a nonsignificant reduction in stroke and a sig-
nificant reduction in mortality [6]. One of the complications of TB treatment
is the immune reconstitution inflammatory syndrome (IRIS) which is a para-
doxical reaction in which there is clinical worsening after the initiation of
0003172484.INDD 173 8/21/2017 12:33:50 PM

antituberculous medications. In one study from South Africa, stroke was

diagnosed in 10% of TB‐IRIS with neurologic manifestations [7].
Bacterial meningitis
Burden
Vascular complications occur in 15–25% of patients with bacterial meningitis
[8–10]. Mortality in patients with stroke related to bacterial meningitis is high,
and the survivors are often left with severe neurologic sequelae [11].
Pathogenesis
Ischemic arterial disease is the most common stroke subtype, followed by venous
thrombophlebitis and hemorrhagic stroke. Vascular complications may occur
early at the time of presentation together with the symptoms of meningitis
(headache, fever, and neck stiffness) or may occur late, even after antibiotic
treatment [12]. This suggests different mechanisms of stroke: at the initial stage,
direct bacterial invasion and inflammation of the vascular wall result in arterial
narrowing or aneurysm formation, whereas vasospasm or immune mediation
contributes to the delayed vascular complications.
Treatment
Treatment with antibiotic as early as possible has shown to prevent complica-
tions and reduce mortality. Steroid treatment is controversial and is not rou-
tinely recommended to prevent stroke.
Syphilis
Stroke generally occurs as a late manifestation of syphilis. Syphilis can lead to
an obliterative endarteritis of medium‐sized and large arteries. Proliferation of
fibroblasts in the intima, thinning of the media, and adventitial inflammation and
fibrosis result in progressive luminal narrowing and thrombosis leading to ischemic
stroke. Meningovascular syphilis can occur 5–12 years after the primary infection,
with an average of 7 years. Syphilis should be suspected in stroke in young patients,
especially those without traditional risk factors. Another clue for diagnosis is the
preceding prodromal symptoms of headaches, malaise, personality change, and
emotional lability which can occur weeks or months before stroke [13].
Treatment
Aqueous crystalline penicillin G 18–24 million units per day, administered as
3–4 million units intravenously every 4 hours or continuous infusion, for 10–14
days is the recommended treatment for neurosyphilis. However, if compliance
with therapy can be ensured, procaine penicillin G 2.4 million units intramuscu-
larly once daily plus probenecid 500 mg orally 4 times a day, both for 10–14 days,
may be considered.
0003172484.INDD 174 8/21/2017 12:33:50 PM

Fungal infections
Invasive aspergillosis typically affects immunocompromised hosts. CNS involve-

ment is usually secondary via hematogenous spread. Up to 90% of patients with
CNS aspergillosis have evidence of concurrent pulmonary involvement.
However, direct extension from the paranasal sinuses or orbits is common in
developing countries [14,15].
Meningoencephalitis, mycotic aneurysm resulting in subarachnoid or intra-
parenchymal hemorrhage, or vasculopathy complicated by ischemic stroke is
reported in 10–50% of cases of invasive disease [16].
Mucormycosis is an opportunistic infection by ubiquitous fungi from the
Zygomycetes class, including Rhizopus and Mucor. The disease is highly associated
with poorly controlled diabetes mellitus. However, it can also occur in other
immunocompromised patients. The infection typically starts in the paranasal
sinuses or orbits and extends directly into the base of the cerebral hemispheres,
cerebellum, or brainstem. The commonly involved vascular structures are the
cavernous sinus and supraclinoid portion of the internal carotid artery, causing
infarction in the lenticulostriate arteries, anterior choroidal arteries, and fre-
quently watershed infarction due to low perfusion in the internal carotid artery
territory [17]. Diagnosis is typically made by histopathologic examination of tis-
sue from biopsy. Amphotericin B remains the drug of choice against cerebral
mucormycosis.
Cryptococcosis
Cryptococcus is the most common cause of fungal meningitis. Typically, the course
of disease is subacute to chronic with prominent symptoms and signs of high
intracranial pressure. Vascular complications secondary to inflammation in the
subarachnoid space only occur in severe cases and the prevalence of infarction
ranges from 4 to 32% [18].
Viral infections
Human immunodeficiency virus (HIV)

HIV infection provokes a chronic inflammatory response by the body, espe-
cially in the blood vessels (Fig. 14.4). Since the introduction of highly active
antiretroviral therapy (HAART), life expectancy of seropositive individuals has
increased. These individuals are for the first time experiencing the opportunity
to grow old. Advancing age predisposes them to diseases of old age such as
hypertension, diabetes, dyslipidemia, etc. It is now known that HAART causes
accelerated atherosclerosis. Hence, physicians are faced with a situation for the
first time where the medication for HIV is also increasing the risk of stroke.
Stroke occurs in 1–4% of patients with HIV infection but on autopsy higher
0003172484.INDD 175 8/21/2017 12:33:50 PM

HIV infection
Triggers chronic Predisposes to

inflammation opportunistic infections
Leading to vasospasm, thrombosis, and atherosclerosis
STROKE
Age related risk factors:

Alters lipid profile Hypertension
Dyslipidemia
Diabetes
HAART Fig. 14.4 Mechanisms of

stroke in patients with HIV.
percentages have been reported [19]. Stroke clinical features in seropositive

patients are same as in HIV‐negative patients.
Pathogenesis
Many vascular changes occur in seropositive individuals (Table 14.1) and espe-
cially affect children and young adults.
Treatment
Stroke in HIV patients is managed like stroke in seronegative individuals.
Needless to say, these individuals also need treatment for HIV.
Japanese encephalitis
Burden and presentation
Japanese encephalitis (JE) is a preventable cause of encephalitis caused by Culex
mosquitoes, especially Cx. tritaeniorhynchus. There exist five genetically distinct
genotypes of the virus, three of which are associated with the endemic cycle (II,
IV, and V), and the other two (I and III) can cause epidemics. JE primarily affects
children <10 years of age but can affect any age group. It is endemic in south
Asian countries like Nepal, Taiwan, Bangladesh, Burma, Laos, Thailand,
Cambodia, Vietnam, Malaysia, India, Japan, China, the Philippines, and
Indonesia among others. The exact burden is unknown although studies have
reported incidence rates [23,24]. Because it is a vector‐borne disease, incidence
varies widely, depending on the climate.
0003172484.INDD 176 8/21/2017 12:33:50 PM

Table 14.1 Mechanisms of stroke in HIV.
Vascular changes Damage to internal elastic lamina and muscularis layers in the
vessel walls
Hyperplasia of the intima with or without inflammation
Fusiform or saccular aneurysms in circle of Willis
Inflammation and aneurysms predispose to stroke
Direct injury from HIV HIV virus triggers endothelial apoptosis
virus Causes loss of collagen and membrane glycoproteins
Accelerated atherosclerosis
Disrupts the blood–brain barrier
Increases the expression of chemoattractants, adhesion molecules,
and pro‐inflammatory cytokines
Increased leukocyte migration
All culminate in vasospasm, thrombosis, and atherosclerosis [20]
Drugs Protease inhibitors—accelerate atherosclerosis and further damage
vessel wall [21,22]
Opportunistic CNS tuberculosis, varicella zoster, CNS syphilis, neoplasia
infections Immunosuppression increases the susceptibility of reactivation or
acquiring these infections
Varicella zoster virus infection can also cause cerebral vasculitis, even
in the absence of skin manifestations
HIV cardiomyopathy Bacterial and marantic endocarditis
Ischemic heart disease
Mycotic aneurysms
Coagulopathy Relative deficiency of protein C and S
Antiphospholipid antibodies (both of these are currently being
studied)
In infected individuals disease progression is seen in three stages: the prodro-

mal stage is followed by the encephalitis stage and lastly recovery or persistence
of neurological signs. In the prodromal stage there is high‐grade fever with or
without rigors, headache, weakness, nausea, and vomiting. In the encephalitic
stage consciousness drops and patients can also have convulsions, neck stiffness,
muscular rigidity, and abnormal body movements. The third stage is marked by
either recovery or persistence of neurologic signs. Most individuals affected
remain asymptomatic and the virus is estimated to cause clinical disease in <1%
of infected individuals. Among those affected, mortality and neurological seque-
lae are high. Stroke is an uncommon presentation of JE although a few cases
have been reported [25–27].
Diagnosis
Viral load is low, hence antibodies are detected in serum and CSF for diagnosis.
IgM detection using enzyme‐linked immunosorbent assay (ELISA), dipstick
method, JEV‐CheX, and reverse transcriptase PCR are used.
0003172484.INDD 177 8/21/2017 12:33:50 PM

Prevention
Both inactivated and live attenuated vaccines are available:
1 The formalin‐inactivated vaccine against JEV was produced from infected
mouse brain derived tissue soon after the virus was discovered. This type of
vaccine is available in Japan (Biken vaccine [JE‐VAX]) and in Korea (Korean
Green Cross vaccine). It is the only WHO‐recommended vaccine. This vaccine
is expensive and requires multiple doses to maintain efficacy and immunity.
2 The second vaccine is a live attenuated vaccine used in India and China (SA
14‐14‐2). WHO has not approved it for human use because it uses hamster
kidney cells. It is effective with very few reported adverse effects.
Treatment
Treatment is symptomatic.
Chikungunya
Burden
Chikungunya likely originated in Africa. Since then it has caused many out-
breaks (Table 14.2) and deaths.
Chikungunya virus infection is characterized by high fever, exanthema,
weakness, joint pain, and headaches. Chikungunya can also have atypical mani-
festations such as meningoencephalitis, meningoencephalo‐myeloradiculitis,
myeloradiculitis, myelitis, myeloneuropathy, and Guillain–Barré syndrome. It is
an uncommon reason for stroke. The most common symptoms of CHIKV infec-
tion are skin rash (mostly maculopapular), fever, arthralgia, myalgia, headache,
and conjunctivitis. Some epidemics that have recently occurred in French
Polynesia and Brazil reported the most severe conditions, with involvement of
the nervous system (Guillain–Barré syndrome, transverse myelitis, microcephaly,
and meningitis) [28].
Table 14.2 Chikungunya outbreaks.
1952 Makonde Plateau

1960s Bangkok
1963–73 India
1969 Sri Lanka
1975 Vietnam and Myanmar
1982 Indonesia
2002–06 Kenya
2005–06 India
2007 Italy
2008 Singapore and Malaysia
2009 Thailand
2013 America
2014 French Guiana, Brazil, Colombia, USA, Venezuela
2017 India and Pakistan
0003172484.INDD 178 8/21/2017 12:33:50 PM

The treatment is symptomatic and the management for neurological compli-

cations depends on the type of affliction. Intravenous immunoglobulin, plasma-
pheresis, and corticosteroid pulse therapy are currently available options.
Dengue
Dengue fever is the most common arboviral infection, accounting for an estimated
100 million cases per year worldwide. Dengue can present as classical dengue,
dengue hemorrhagic fever, and dengue shock syndrome. Classical dengue patients
present with fever, headache, retrobulbar pain, skin rash, and muscular and joint
pain. Dengue hemorrhagic fever presents with hemorrhagic events and high fever,
as well as hepatomegaly and possibly shock. Dengue shock syndrome is the most
severe form, in which patients present with shock. It is defined as hypovolemia
secondary to capillary plasma leakage with hemodynamic repercussions.
CNS complications of dengue can present as acute encephalitis, acute dis-
seminated encephalomyelitis, transverse myelitis, meningitis, cranial neuropa-
thy, Guillain–Barré syndrome, and myositis. Hemorrhagic stroke has been
reported in a few dengue patients [29] and in pediatric patients [30] (Figs 14.5,
14.6, and 14.7).
Pathogenesis
Dengue patients have thrombocytopenia. Hemorrhage is most likely related to
acute dengue‐associated capillary leakage and thrombocytopenia while ischemia
may be due to vessel inflammation.
(A) (B)
Fig. 14.5 MRI (gradient echo) showing hemorrhage in left parietal and temporal lobes of a
patient with dengue. Reproduced with permission from Mathew S, Pandian JD. J Stroke
Cerebrovasc Dis 2010;19(3):253–6.
0003172484.INDD 179 8/21/2017 12:33:50 PM

(A)
(B)
(C)
Fig. 14.6 Dengue infection. (A) MRI (gradient echo) showing bilateral cerebellar hemorrhages.
(B) MRI (diffusion‐weighted images) showing watershed infarcts. (C) MRI (T1‐weighted
images) showing obstructive hydrocephalus. Reproduced with permission from Mathew S,
Pandian JD. J Stroke Cerebrovasc Dis 2010;19(3):253–6.
0003172484.INDD 180 8/21/2017 12:33:50 PM

Fig. 14.7 Dengue infection. MRI (diffusion‐

weighted images) showing infarct in right
parietal lobe. Reproduced with permission
from Mathew S, Pandian JD. J Stroke
Cerebrovasc Dis 2010;19(3):253–6.
Treatment
Dengue treatment is symptomatic. Stroke in a dengue patient is treated the same
way as in a patient without dengue.
Parasitic infestations
Malaria
Burden
Malaria causes clinical illness in over 300–500 million people globally, and over
1 million people die from it every year. In India the incidence of malaria, since
1982, has been about 2 million cases per year, representing 40% of the total
number of cases outside Africa. Cerebral malaria could be responsible for up to
10% of strokes in endemic regions.
Pathogenesis
Cerebral vessels of infected patients are full of infected red blood cells (RBCs).
Infected RBCs adhere to the endothelial lining. This triggers a cascade where
infected and noninfected RBCs adhere together. This clumping impairs perfu-
sion and leads to hypoxia. The greater the parasite load, the greater the imped-
ance and degree of unresponsiveness. Also, infected RBCs cannot pass easily
through the microvasculature. These then cause stroke in some individuals [31].
Treatment
Treatment consists of quinine dihydrochloride 10 mg (salt)/kg by infusion over
4 hours in 500 ml 5% dextrose, every 8 hours until parasites are less than 1% and
the patient can manage oral intake, then quinine sulfate 600 mg 3 times a day
orally until parasites have cleared, then doxycycline 200 mg daily orally for 7 days.
0003172484.INDD 181 8/21/2017 12:33:50 PM

Cysticercosis
Burden
Cysticercosis is an infection caused by ingesting food or water contaminated
with eggs of the pork tapeworm. Human cysticercosis is found worldwide, espe-
cially in rural areas of developing countries with poor sanitation. Epilepsy is one
of the common presentations of neurocysticercosis. In India, neurocysticercosis
was found to be the cause in one‐third of patients with active epilepsy [32].
Pathogenesis
Various mechanisms are involved in the development of stroke in patients with
cysticercosis. Patients with intraparenchymal cysticercosis can present with stroke‐
like episodes related to focal inflammation surrounding the cyst. However, when
cysts are confined to a focal area and associated with mild arachnoiditis, thrombosis
of superficial cortical vessels due to chronic meningitis or occlusion of small perfo-
rating vessels by endarteritis resulting in lacunar infarction can be found [33,34].
When the subarachnoid cysts are widespread, especially in the basal cistern,
vasculitis and segmental narrowing of the main vessels around the circle of
Willis can result in large territorial infarction [35].
Diagnosis can be made by neuroimaging. Multiple small calcifications in the
brain on CT scan are commonly found (Fig. 14.8). However, MRI is more sensi-
tive for detection of viable intraparenchymal (cystic or colloidal form) and suba-
rachnoid cysts. CSF analysis generally demonstrates mononuclear pleocytosis
with normal or low glucose. Eosinophils can be found in some cases. CSF ELISA
for neurocysticercosis has a sensitivity of 50% and a specificity of 65%.
Treatment
Treatment of neurocysticercosis depends upon the viability of the cyst and its com-
plications. In patients with vasculitis and arachnoiditis, a course of corticosteroid is
recommended in conjunction with use of anticysticercal drugs (albendazole).
Fig. 14.8 CT scan showing multiple calcific spots in the brain parenchyma and evidence of
infarction in the right side of pons and left occipital lobe due to cysticercosis. Images courtesy
of Nijasri C. Suwanwela.
0003172484.INDD 182 8/21/2017 12:33:50 PM

Surgical treatment may be considered in patients with hydrocephalus and patients

with multiple cysts in the subarachnoid space (i.e., the racemose form).
Gnathostomiasis
Burden
Gnathostomiasis is a parasitic infection which is seen mostly in tropical and sub-
tropical regions, especially Thailand and other parts of Southeast Asia.
Pathogenesis
Human gnathostomiasis is caused by ingestion of raw freshwater fish, shellfish, or
other intermediate hosts such as snakes, frogs, and chickens. The third‐stage lar-
vae of the helminth Gnathostoma spp. enter the gastrointestinal tract and then
migrate to the skin through the subcutaneous tissue causing the typical migratory
swellings. They may also penetrate into deeper tissues including the CNS [36].
The hallmark symptoms are an acute onset of excruciating radicular pain and/or
headache related to subarachnoid hemorrhage, with subsequent neurological
deficits. This can be explained by the migratory pathway of the parasite, which
enters the CNS along the nerve roots causing radicular pain followed by mechan-
ical damage to the spinal cord and brain. In some cases, intraparenchymal bleed-
ing with hemorrhagic tracts in different areas may occur due to further migration
of the larva to another location. According to a report from Thailand in 1980, 6%
of subarachnoid hemorrhages in adults and 18% of those in children are due to
gnathostomiasis [37].
The CSF typically shows evidence of subarachnoid hemorrhage and xanthochro-
mia with prominent eosinophils. Elevated opening pressure and protein level are
also found. MRI has also been useful in demonstrating the intraparenchymal bleed-
ing with hemorrhagic tracts in the brain and spinal cord. The migratory nature of
such lesions highly suggests the pathway of the Gnathostoma larva (Fig. 14.9).
Treatment
There is no effective treatment for CNS gnathostomiasis, and surgical excision of
larvae remains the only management.
Acknowledgements
We sincerely thank Dr Akanksha Williams, MD, Clinical Pharmacologist,

Department of Neurology, Christian Medical College, Ludhiana, Punjab, India,
for helping in drafting and editing the chapter.
We also thank Dr Mahesh Kate, MD, DM, Assistant Professor, Department of
Neurology, Department of Neurology, Christian Medical College, Ludhiana,
Punjab, India, and Dr Jency Koshy MD, Associate Professor, Department of
Medicine, Believer’s Church Medical College Hospital, Thiruvalla, Kerala, India,
for sharing patients’ images.
0003172484.INDD 183 8/21/2017 12:33:50 PM

Fig. 14.9 MRI (gradient echo) showing hemorrhagic tracts of CNS gnathostomiasis in the
cerebellum and left occipital lobe. Images courtesy of Nijasri C. Suwanwela.
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Index
activities of daily living (ADL) Alberta Stroke Program Early CT Score

interventions, 127 (ASPECTS), 5–7
acupuncture, 140–141 aneurysms, 62–63
acute admission units, 40–41 ankle foot orthoses, 130
acute complications, after stroke antihypertensive medications, 96, 97
cardiac complications, 79, 84 antihypertensive therapy, 32
due to immobility, 79, 84–86 antiplatelets, stroke prevention
gastrointestinal, 79, 81–82 cilostazol, 113
genitourinary, 79, 82–83 definition, 107
infections, 79–81 evidence based in Western and Asian trials,
long‐term complications, 79, 86 108–113
neurological complications, 78–80 ischemic stroke, secondary prevention,
thromboembolic, 79, 83–84 109–112
acute ischemic lesions, diagnosis of, 16 mechanism of action, 107
acute ischemic stroke (AIS) rationale of treatment, 107
antiplatelet treatment comparison in, 55 recommendations, 113–114
antithrombotics for, 50–56 antithrombotics, 55, 56
blood pressure, 32–33 in Western and Asian countries
brain edema, 33–34 dual antiplatelet therapy, 53–55
complication management single antiplatelet therapy, 51–53
DVT and PTE, 34–35 mechanism of, 50–51
dysphagia, 36 aphasia, dysphasia, apraxia for
fever, 35 speech, 128
gastrointestinal bleeding, 34 apparent diffusion coefficient (ADC), 10
headache, 36 arm, hand/leg weakness and spasticity, 128
seizure, 35 arterial spin labeling (ASL), 15
fluid balance, 33 Asian Stroke Advisory Panel, 23, 24
hemodilution therapy, 36 ASL see arterial spin labeling (ASL)
hyperbaric oxygen therapy, 36 ASPECTS see Alberta Stroke Program Early
nutrition, 33 CT Score (ASPECTS)
respiration, 31–32 aspirin, 50, 54
acute stroke units (ASUs), 41 ASUs see acute stroke units (ASUs)
acute thrombotic occlusion, 12, 13 atrial fibrillation (AF), 80
ADC see apparent diffusion coefficient characteristics, 116
(ADC) nonvitamin K oral anticoagulant (NOAC)
AHA/ASA guidelines, 166, 168 treatment
Akita stroke registry, Japan, 66 clinical trials, 118, 119
187
0003172490.INDD 187 8/23/2017 1:48:15 PM

188 Index
atrial fibrillation (AF) (cont’d ) cysticercosis, 182–183

dose, treatment, 118, 120 gnathostomiasis, 183
perspectives, 119 malaria, 181
prevalence, 116 viral infections and stroke
risk factors and, 116–117 chikungunya, 178–179
stroke and systemic embolism, 117 dengue, 179–181
warfarin‐related bleeding risk and INR HIV infection, 175–176
control, 117–118 Japanese encephalitis, 176–178
ayurveda, 144 cerebellar hemorrhage, 68–69
cerebral blood flow (CBF), 9, 32
bacterial infection and stroke cerebral blood volume (CBV), 9
meningitis, 174 cerebral herniation, deterioration and
syphilis, 174 signs of, 61
tuberculosis cerebral microbleeds (CMBs), 12, 18, 166
pathogenesis, 171–173 cerebrovascular disease, 84
prevalence, 171 CHADS2 score, 116
treatment, 173–174 CHANCE study in China, 53–54
Barrow Rupture Aneurysm Trial (BRAT), chest infections, 80, 81
62–63 chikungunya, 178–179
bleeding, 62–63 Chinese Acute Stroke Trial (CAST), 51, 108
blood pressure (BP), 32–33 Chinese herbal medicine, 142–144
body mass index (BMI), 100, 101 cigarette smoking and stroke
bowel problems, 82 age‐standardized prevalence, 97
brain CT, 4 nicotine dependence treatment, 98
brain edema, 33–34 primary and secondary prevention, 98
brain MRI cilostazol, 51–52
diffusion‐weighted imaging, 10 CLAIR trial, 54, 108
FLAIR imaging, 13 Clinical Research Center for Stroke‐Fifth
GRE imaging, 12, 13 Division (CRCS‐5), 28
magnetic resonance angiography, 15–18 clopidogrel, 50–51, 54
perfusion‐weighted imaging, 13–15 CMBs see cerebral microbleeds (CMBs)
susceptibility‐weighted imaging, 12, 13 cognitive deficits, 154
BRAT see Barrow Rupture Aneurysm Trial cognitive impairment, 129 see also dementia
(BRAT) frequency of, 161
combination antiretroviral therapies
cardiac complications, 79, 84 (cART), 103
cardiovascular disease, 84 combined acute/rehabilitation SUs, 41
CAST see Chinese Acute Stroke Trial complementary and alternative medicine
(CAST) (CAM)
CBF see cerebral blood flow (CBF) acupuncture, 140–141
CE‐MRA see ayurveda, 144
contrast‐enhanced MRA (CE‐MRA) Chinese herbal medicine, 142–144
central nervous system infections and cupping, 142
stroke definition, 139
bacterial infection and stroke homeopathy, 144–145
meningitis, 174 massage, 145–146
syphilis, 174 moxibustion, 142
cryptococcosis, 175 outcomes, 149
fungal infections and stroke, 175 prayer, 148–149
parasitic infestations and stroke reiki, 147–148
0003172490.INDD 188 8/23/2017 1:48:15 PM

Index 189
tai chi, 147 ICD‐10 criteria, 152

utilization, 139–140 ICD‐10 Neurological Adaptation, 154
yoga, 146–147 Informant Questionnaire for Cognitive
comprehensive stroke center (CSC), 24, 31 Decline in the Elderly, 155
computed axial tomography (CAT), 3 management
computed tomography (CT) AHA/ASA guidelines, 166, 168
acute stroke, 3–4 recommendations, 167
advantages and disadvantages, 4 30‐min and 5‐min neuropsychological
brain, 4 protocols, 163
CT angiography, 7–8 NINDS–AIREN criteria, 153, 154, 165
CT perfusion imaging, 8–9 subtypes, 153
goals, 4 dengue
non‐contrast CT scan, 5–7 CNS complications, 179
constipation, 82 MRI, 180, 181
constraint induced movement therapy pathogenesis, 179
(CIMT), 132 treatment, 181
continuous positive airway pressure (CPAP) DESTINY trial, 59–61
ventilation, 32 diabetes mellitus (DM)
contrast‐enhanced MRA (CE‐MRA), 15 behavioral modifications and
coronary heart disease (CHD) risk factors, pharmacological treatment, 94
screening for, 99 definition, 93–94
cryptococcosis, 175 pre‐diabetes level, 94
CSC see comprehensive stroke center (CSC) primary prevention, 94
CT see computed tomography (CT) secondary prevention, 95
CT angiography (CTA), 7–8, 26 diffusion‐weighted imaging (DWI), 10
CT perfusion (CTP) imaging, 8–9 dual antiplatelet therapy, 53–55
cupping, 142 DVT see deep venous thrombosis (DVT)
cysticercosis, 182–183 dynamic susceptibility contrast (DSC), 14
dyslipidemia
DCI see delayed cerebral ischemia (DCI) definition, 98
DECIMAL trial, 59, 60 low‐density lipoprotein cholesterol
decompressive hemicraniectomy, for raised levels, 98
ICP treatment, 64–65 primary prevention, 99–100
deep venous thrombosis (DVT), 34–35, 83 secondary prevention, 100
dehydration, 33 dysphagia, 36, 81–82, 129
delayed cerebral ischemia (DCI), 65–66
dementia EARLY trial, 53, 54
clinical presentation and diagnosis electrolyte imbalance, 33
cerebral microbleeds, 166 electromechanical devices, 132
cognitive deficits, 161 electromyographic biofeedback, 131
Hachinski Ischemic Score, 161, 162 elevated intracranial pressure (ICP), 33
lacunar vs. cortical stroke, 162 embolism, systemic, 117
multi‐infarct dementia, 161 ENCHANTED study, 25
strategic infarct dementia, 161 endovascular treatment (EVT)
vascular cognitive impairment, 161 definition, 25
definitions, 152 endovascular thrombectomy status in
epidemiology Asia, 28
distribution, 157 in Western and Asian countries, 26–28
incidence, 155 rationale of treatment, 26
post‐stroke dementia, prevalence of, 156 recommendation, 28
0003172490.INDD 189 8/23/2017 1:48:15 PM

190 Index
ESCAPE trial, 26, 27 highly active antiretroviral therapy

EVT see endovascular treatment (EVT) (HAART), 175
EXTEND‐IA trial, 26, 27 HIV infection and stroke, 103
external ventricular drain (EVD) see mechanisms of stroke in patients with,
ventriculostomy 176, 177
eyebrows, weakness after stroke, 129–130 pathogenesis, 176
eyes, weakness after stroke, 130 prevalence, 176
treatment, 176
facial weakness after stroke homeopathy, 144–145
eyebrows, 129–130 hydrocephalus, 63–64, 67
eyes, 130 hyperbaric oxygen therapy, 36
nose, 130 hyperglycemia, 33
smiling, 129 hypertension
vowel sounds, 129 blood pressure monitoring, 96
falls and fractures, 85–86 definition, 95
FASTER trial, 53, 54 pharmacologic therapy, 96
fecal incontinence, 82 prevalence, 95
fever, 35 primary prevention, 96
fluid‐attenuated inversion recovery (FLAIR) secondary prevention, 96
imaging, 13 hypothermic treatment, of AIS, 35
fluid balance, in AIS, 33 hypovolemia, 32–33
fungal infections and stroke, 175
ICH see intracerebral hemorrhage (ICH)
gastrointestinal (GI) bleeding, 34 immobility, complications due to, 79
gastrointestinal complications, 79, 81–82 falls and fractures, 85–86
gender pressure sore, 84–85
in Asian women, 92–93 shoulder pain, 86
primary prevention, 93 immune reconstitution inflammatory
secondary prevention, 93 syndrome (IRIS), 173–174
genitourinary complications, 79, 82–83 impairments and limitations after stroke
gnathostomiasis, 183 aphasia, dysphasia, apraxia for speech, 128
GRADE approach, 59 arm, hand/leg weakness and spasticity, 128
gradient‐echo (GRE) imaging, 12–13 cognitive impairment, 129
common types, 128
Hachinski Ischemic Score, 161, 162 dysphagia, 129
hands‐on healing see reiki facial weakness, 129
headache, 36 mobility problems, 130–133
helical CT scanners, 3 infections, 79–81, 102–103
hemicraniectomy bacterial infection, 171–174
in malignant MCA infarction, 58–59 chest, 80, 81
age, 59–60 fungal, 175
cerebral herniation, deterioration and HIV infection, 103, 176–177
signs of, 61 urinary tract infections, 80, 81
timing of surgery, 60 viral infections, 176–181
hemodilution therapy, 36 Informant Questionnaire for Cognitive
hemoglobin A1c (HbA1c), 94, 95 Decline in the Elderly (IQCODE), 155
hemorrhagic stroke, 58, 66, 179 intensive care units (ICUs), 40
detection of, 17–18 International Stroke Trial (IST), 51
hemorrhagic transformation (HT), International Subarachnoid Aneurysm Trial
17–18, 80 (ISAT), 62
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Index 191
intracerebral hemorrhage (ICH), 17 meningoencephalitis, 175

cerebellar hemorrhage, 68–69 mental practice, 132
intraventricular hemorrhage, 67–68 middle cerebral artery (MCA) sign, 5
raised intracranial pressure, 66–67 mixed acute units, 41
intravenous antihypertensive therapy, 32 mobility problems after stroke
intravenous thrombolysis ankle foot orthoses, 130
definition, 22 approach of intervention, 131
dosages, 24–25 electromyographic biofeedback, 131
rationale of treatment, 22–23 intensity of intervention, 131
with recombinant tissue plasminogen muscle strengthening, 131
activator, 22 physical fitness training, 131
recommendations, 25 repetitive task training, 131
in Western and Asian countries, 23–24 treadmill training, 131
intraventricular fibrinolytics, 67 upper limb function
intraventricular hemorrhage (IVH), 67–68 constraint induced movement
ISAT see International Subarachnoid therapy, 132
Aneurysm Trial (ISAT) electromechanical devices, 132
ischemic penumbra, diagnosis of, 16–17 mental practice, 132
ischemic stroke, secondary prevention, mood disturbances and emotional
109–112 behavior, 133
IST see International Stroke Trial (IST) pain, 133
IVH see intraventricular hemorrhage (IVH) post‐stroke spasticity, 132
visual problems, 132
Japan Alteplase Clinical Trial (J‐ACT), 7, 25 mobilization, 127
Japanese encephalitis mood disturbances and emotional behavior, 133
diagnosis, 177 moxibustion, 142
presentation, 176 moyamoya disease, 103
prevention, 178 MR CLEAN study, 26
treatment, 178 MTT see mean transit time (MTT)
mucormycosis, 175
lacunar vs. cortical stroke, 162 multimodality imaging, acute stroke
long‐term complications, 79, 86 clinical application of multimodal MRI in,
16–18
magnetic resonance angiography (MRA), 15 computed tomography, 3–4
magnetic resonance imaging (MRI), 10, 11, CT angiography, 7–8
165, 180–183, CT perfusion imaging, 8–9
malaria, 181 diffusion‐weighted imaging, 10
malignant middle cerebral artery (MCA) FLAIR imaging, 13
infarction GRE imaging/SWI, 12–13
hemicraniectomy in, 58–59 magnetic resonance angiography, 15
age, 59–60 magnetic resonance imaging, 10, 11
deterioration and signs of cerebral non‐contrast CT scan, 5–7
herniation, 61 perfusion‐weighted imaging, 13–15
timing of surgery, 60 multislice CT scanning, 3–4
marma massage, 145–146 muscle strengthening, 131
massage, 145–146
mean transit time (MTT), 9, 14–15 National Center for Complementary and
medical expertise, in stroke care, 46 Alternative Medicine (NCCAM), 139
memory impairment, 154 National Institutes of Health Stroke Scale
meningitis, bacterial, 174 (NIHSS), 51
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192 Index
NCCT scan see non‐contrast CT (NCCT) scan eligibility and admission criteria, 134
NCU see neurovascular care unit (NCU) goals, 125
neuroimaging, 3 impairments and limitations after stroke
neurological complications, 78–80 aphasia, dysphasia, apraxia for
neurovascular care unit (NCU), 41 speech, 128
NIHSS see National Institutes of Health Stroke arm, hand/leg weakness and
Scale (NIHSS) spasticity, 128
non‐contrast CT (NCCT) scan, 5–7 cognitive impairment, 129
nonvitamin K oral anticoagulant (NOAC) common types, 128
treatment dysphagia, 129
clinical trials, 118, 119 facial weakness, 129
dose, treatment, 118, 120 mobility problems, 130–133
perspectives, 119 management and prevention, 125–127
nose, weakness after stroke, 130 outpatient, 133–135
nutrition, 33 recommendations, 126
tertiary stroke care, 124
obesity therapeutic positioning, 127
definition, 100 reiki, 147–148
weight reduction, 101–102 repetitive task training, 131
respiration, 31–32
pain, 133 REVASCAT trial, 28
palm healing see reiki rheumatic heart disease (RHD), 102
parasitic infestations and stroke risk factors
cysticercosis, 182–183 cigarette smoking, 97–98
gnathostomiasis, 183 diabetes mellitus, 93–95
malaria, 181 dyslipidemia, 98–100
perfusion‐weighted imaging (PWI), 13–15 gender, 92–93
physical fitness training, 131 hypertension, 95–96
POINT trial, 54 infection, 102–103
post‐stroke epilepsy, 80 obesity, 100–102
post‐stroke spasticity, 132 rheumatic heart disease, 102
prayer, 148–149 Western and Asian populations, 91–92
pressure sores, 84–85
primary stroke center (PSC), 31 SAH see subarachnoid hemorrhage (SAH)
prophylactic balloon angioplasty, 65 seizures, 35
pulmonary embolism (PE), 83, 84 shoulder pain, 86
pulmonary thromboembolism (PTE), 34–35 shunt‐dependent hydrocephalus, 63–64
SIADH see syndrome of inappropriate
raised intracranial pressure, 80 secretion of antidiuretic hormone
intracerebral hemorrhage, 66–67 (SIADH)
subarachnoid hemorrhage, 64–65 sICH see symptomatic intracranial
Rapid Identification and Treatment of Acute hemorrhage (sICH)
Ischemic Stroke, 50 single antiplatelet therapy, 51–53
rapid stroke management, hospital set‐up for, 24 single slice CT scanners, 3
rebleeding, 62–63 sleep apnea syndrome (SAS), 32
recombinant tissue‐type plasminogen smiling, weakness after stroke, 129
activator (rtPA), 22, 67–68 SOCRATES trial, 52
rehabilitation spiral CT scanners, 3
activities of daily living interventions, 127 statins, 99
early mobilization, 127 STICH trial, 69, 70
0003172490.INDD 192 8/23/2017 1:48:15 PM

Index 193
stroke intensive care unit (SICU), 41 pain, 133

stroke units (SUs), 31, 39, 46–47 post‐stroke spasticity, 132
applicability of, 42–43 visual problems, 132
benefits of, 39, 41–42 urinary incontinence, 82–83
historical landmark evolution of, 40 urinary tract infections (UTIs), 80, 81
in Asia, 45–46 urut, 146
in resource‐limited setting, organize/
develop, 43–45 vascular cognitive impairment (VCI)
subarachnoid hemorrhage (SAH), 61–62 described, 161
bleeding and rebleeding, 62–63 diagnosis of, 164–165
hydrocephalus, 63–64 pattern of, 163
raised intracranial pressure, 64–65 vascular dementia (VaD) see also dementia
vasospasm and DCI, 65–66 critical clinical feature, 165
supratentorial hemorrhage, 69–71 definite, 153–154
SUs see stroke units (SUs) epidemiology, 158–160
susceptibility‐weighted imaging possible and probable, 153
(SWI), 12–13 vasospasm
SWIFT PRIME study, 27–28 subarachnoid hemorrhage, 65–66
symptomatic intracranial hemorrhage venous thrombosis, 83
(sICH), 55 ventricular catheter, 64
syndrome of inappropriate secretion of ventriculostomy, 64
antidiuretic hormone (SIADH), 33 viral infections and stroke
syphilis, 174 chikungunya, 178–179
systemic embolism, stroke and, 117 dengue
CNS complications, 179
tai chi, 147 MRI, 180, 181
Thai massage, 146 pathogenesis, 179
thromboembolic complications, 79, 83–84 treatment, 181
thrombolysis, 39, 54 HIV infection
thrombolytic therapy, 22 mechanisms of stroke in patients with,
ticagrelor, 51 176, 177
time‐of‐flight MRA (TOF‐MRA), 15 pathogenesis, 176
transluminal balloon angioplasty, 65–66 prevalence, 176
treadmill training, 131 treatment, 176
Treat Stroke to Target (TST) trial, 100 Japanese encephalitis
tuberculosis diagnosis, 177
pathogenesis, 171–173 presentation, 176
prevalence, 171 prevention, 178
treatment, 173–174 treatment, 178
visual problems, 132
upper gastrointestinal bleeding, 82 vowel sounds after stroke, 129
upper limb function after stroke
constraint induced movement therapy, 132 warfarin‐related bleeding risk and INR
electromechanical devices, 132 control, 117–118
mental practice, 132 World Stroke Organization, 23
mood disturbances and emotional
behavior, 133 yoga, 146–147
0003172490.INDD 193 8/23/2017 1:48:15 PM

TBC
STROKE IN ASIA
E D I T E D B Y SUWANWELA AND NAVARRO

ASIAN STROKE ADVISORY PANEL
EDITED BY
NIJASRI C. SUWANWELA
JOSE C. NAVARRO
STROKE IN ASIA
EDITION
SECOND
Cover Images: (Map) © redmal/Gettyimages;

(Nerve Cells) © Sergey Nivens/Shutterstock
www.wiley.com
978-4-939028-28-1 SECOND EDITION

Stroke in Asia Book 3

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Stroke in Asia Book 3

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E D I T E D B Y SUWANWELA AND NAVARRO

Cover Images: (Map) © redmal/Gettyimages;

978-4-939028-28-1 SECOND EDITION

0003172485.INDD 1 8/21/2017 11:39:30 AM

Jose C. Navarro, MD, MSc

0003172485.INDD 3 8/21/2017 11:39:31 AM

0003172485.INDD 4 8/21/2017 11:39:31 AM

PART I Acute ischemic stroke management and complications

PART II Long term stroke care and complications

ftoc.indd 5 08/25/2017 11:04:43 AM

12 Alternative and complementary treatments for stroke, 139

ftoc.indd 6 08/25/2017 11:04:43 AM

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This volume covers all aspects of stroke management from prevention

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Sardar M. Alam, FRCP (Edin)

Deepak Arjundas, MD, DM

Ester S. Bitanga, MD, FPNA

Lyna Soertidewi Kiemas, MD

Yohanna Kusuma, MD, Cert. Neurosonology ASN(USA)& WFN‐NSRG

0003172487.INDD 9 08/25/2017 11:33:33 AM

Sun U. Kwon, MD, PhD

Eun‐Jae Lee, MD, PhD

Tsong‐Hai Lee, MD, PhD

Xinyi Leng, MBBS, MMed, PhD

Kazuo Minematsu, MD, PhD

Jose C. Navarro, MD, MSc

Joseph Erroll V. Navarro, MD, FAFN

Jeyaraj D. Pandian, MD, DM, FRACP

0003172487.INDD 10 08/25/2017 11:33:33 AM

N. Venketasubramanian Ramani, MBBS, MMed, FAMS, Cert Neurosonology,

Kay-Sin Tan, MBBS, FRCP, FAMM

Nguyen Huy Thang, MD

Shinichiro Uchiyama, MD, PhD, FAHA, FESO

Lawrence K.S. Wong, MBBS, MHA, MD, MRCP, FHKAM, FRCP

Byung‐Woo Yoon, MD, PhD, FAHA

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0003172487.INDD 12 08/25/2017 11:33:33 AM

Lyna Soertidewi Kiemas

Sze Haur Lee

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Nguyen Huy Thang

Lawrence K.S. Wong

0003172487.INDD 14 08/25/2017 11:33:33 AM

0003172488.INDD 1 8/21/2017 11:45:48 AM

Multimodality imaging in acute

Neuroimaging plays an important role in the diagnosis and management of

Computed tomography (CT)

Computed axial tomography (CAT) or CT scanning was invented in the 1980s.

0003172471.INDD 3 8/22/2017 10:11:20 AM

Table 1.1 Advantages and disadvantages of CT in acute ischemic stroke.

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Non‐contrast CT (NCCT) scan

Estimation of the extent of ischemia with NCCT: ASPECTS

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Fig. 1.1 Non‐contrast CT (NCCT) of a 74‐year‐old female who developed right hemiparesis

0003172471.INDD 6 8/22/2017 10:11:22 AM

Probability of excellent outcome

Fig. 1.3 Baseline Alberta Stroke Program Early CT Score (ASPECTS) as predictor of an

The ASPECTS is a strong predictor of functional outcome. Several studies

0003172471.INDD 7 8/22/2017 10:11:22 AM

CT perfusion (CTP) imaging

CBV = CBF × MTT