ADVANCES IN THE
TREATMENT OF
ISCHEMIC STROKE

Edited by Maurizio Balestrino










Advances in the Treatment of Ischemic Stroke
Edited by Maurizio Balestrino


Published by InTech
Janeza Trdine 9, 51000 Rijeka, Croatia

Copyright © 2012 InTech
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First published February, 2012
Printed in Croatia

A free online edition of this book is available at www.intechopen.com
Additional hard copies can be obtained from


Advances in the Treatment of Ischemic Stroke, Edited by Maurizio Balestrino
p. cm.
ISBN 978-953-51-0136-9









Contents

Preface IX
Part 1 Hypothermia in the Acute Phase 1
Chapter 1 Cerebral Ischemia and Post-Ischemic
Treatment with Hypothermia 3
Kym Campbell, Neville W. Knuckey and Bruno P. Meloni
Chapter 2 Hypothermia as an Alternative for the
Management of Cerebral Ischemia 15
Felipe Eduardo Nares-López, Gabriela Leticia González-Rivera
and María Elena Chánez-Cárdenas
Chapter 3 Timing of Hypothermia (During or After Global
Cerebral Ischemia) Differentially Affects Acute
Brain Edema and Delayed Neuronal Death 37
Masaru Doshi and Yutaka Hirashima
Chapter 4 Molecular Mechanisms
Underlying the Neuroprotective Effect
of Hypothermia in Cerebral Ischemia 43
Yasushi Shintani and Yasuko Terao
Part 2 Brain Regeneration After Stroke:
Spontaneous Events and Stem Cells Therapy 67
Chapter 5 Cortical Neurogensis in Adult Brains
After Focal Cerebral Ischemia 69
Weigang Gu and Per Wester
Chapter 6 Brain Plasticity Following Ischemia:
Effect of Estrogen and Other Cerebroprotective Drugs 89

Edina A. Wappler, Klára Felszeghy, Mukesh Varshney,
Raj D. Mehra, Csaba Nyakas and Zoltán Nagy
VI Contents

Chapter 7 The Promise of Hematopoietic
Stem Cell Therapy for Stroke:
Are We There Yet? 115
Aqeela Afzal and J. Mocco
Chapter 8 Toward a More Effective
Intravascular Cell Therapy in Stroke 141
Bhimashankar Mitkari, Erja Kerkelä, Johanna Nystedt,
Matti Korhonen, Tuulia Huhtala and Jukka Jolkkonen
Part 3 Intravenous Thrombolysis and Intra-Arterial Procedures 161
Chapter 9 Thrombolysis for Ischemic Stroke
in Patients Aged 90 Years or Older 163
M. Balestrino, L. Dinia, M. Del Sette, B. Albano and C. Gandolfo
Chapter 10 Mechanical Embolectomy 169
Jiří Lacman and František Charvát
Chapter 11 Decreased Cerebral Perfusion
in Carotid Artery Stenosis, Carotid Angioplasty
and Its Effects on Cerebral Circulation 183
Antenor Tavares and José Guilherme Caldas
Part 4 Treatment of Intracranial Hypertension 213
Chapter 12 Medical and Surgical Management
of Intracranial Hypertension 215
James Scozzafava, Muhammad Shazam Hussain and Seby John
Chapter 13 An Innovative Technique of Decompressive
Craniectomy for Acute Ischemic Stroke 227
Marcelo M. Valença, Carolina Martins,
Joacil Carlos da Silva, Caio Max Félix Mendonça,

Patrícia B Ambrosi and Luciana P. A. Andrade-Valença










Preface

The last decade or so has witnessed unprecedented advances in the therapy of
ischemic stroke. Intensive preclinical and clinical research in what used to be an
almost incurable disease is finally putting at the clinicians’ disposal powerful
therapeutic tools. While intravenous thrombolysis with recombinant tissue
plasminogen activator has been the first and is still the most used tool, other ways of
interventions have entered the clinical arena, dramatically improving the therapy of
ischemic stroke. As it always happens at times of rapid changes, clinical practice lags
behind research findings. While at times it must be so, since clinical practice must wait
for evidence confirmation, very often the clinician finds it difficult to receive and
process the relevant information in what may appear an overflow of data.
While an all-inclusive review of all available innovations in stroke therapy would
probably be impossible in a single book, this one does provide reviews and updated
information in several hot issues.
Hypothermia is the first such issue. This powerful therapy is finally coming of age, so
far the sole survivor of a host of “neuroprotective” therapies that animal research had
developed. While all other neuroprotective therapies have failed in the clinics,
hypothermia has grown to become now, basically, recommended practice in the rescue

therapy after cardiac arrest, a condition very similar albeit not identical to ischemic
stroke. Its application in stroke is currently not routine practice, because of technical
difficulties, of still significant side effects (let’s not forget that cardiac arrest often
occurs in young people, ischemic stroke in elder persons) and because of limited
clinical trials. However, there is probably sufficient evidence for considering it on a
case-by-case basis in hospitals that have experience in its application. In this book, the
contribution by Campbell et al. provide a fine review of both preclinical and clinical
issues of hypothermia. Both Nares-López et al. and Shintani and Terao convincingly
review the very extensive mechanisms of protection by hypothermia, while Doshi and
Hirashima report results from animal research concerning duration and timing of
hypothermia, results that are relevant to clinical applications of this technique.
Second, brain regeneration is considered. The last decade of the 20th century has
finally rejected the old myth that neurons remain unchanged in number from birth to
death and, if damaged, cannot be replaced. On the contrary, we now know that a
X Preface

lively neuronal regeneration is routinely under way in the brain (for example, new
neurons are continuously generated in the hippocampal dentate gyrus, a fact that is
probably important for memory). Endogenous regeneration is certainly a repair
mechanism that occurs after stroke, although still a poorly understood one. In this
book, two chapters (by Gu and Wester and by Wappler et al.) provide novel
interesting knowledge on the relevance and on the mechanisms of endogenous
regeneration after experimental animal ischemic stroke. Moreover, stem cells
administration has been extensively investigated, in the hope to replace the neurons
that had died after stroke. Unfortunately, human clinical trials in this field have been
surprisingly scarce, a fact that still leaves largely unanswered basic questions like: is
stem cells administration really useful for stroke, does it really work by replacing dead
neurons, or does it rather favor endogenous regeneration and healing, what types of
stem cells are better, what stroke types benefit the most from this therapy. Answer to
these questions is of paramount importance also because several private hospitals are

now offering expensive stem cells transplantation, a legitimate business that however
underlines an urgent need to answer the above questions. In this book the two
chapters by Afzal and Mocco and by Mitkari et al. help the interested professional
navigate this difficult field.
Clot-removal therapies for ischemic stroke (both intravenous thrombolysis and
endovascular techniques) entered the neurological armamentarium at the very end of
the last century, changing forever the way stroke is treated. As we all recall, they were
met with a mix of enthusiasm for their effectiveness and fear for their side effects,
chiefly haemorrage. Fear of haemorrhage caused a long list of exclusion criteria that, at
least in Europe, prevented intravenous thrombolysis from being administered to
many, probably most, patients. In the following years several such criteria were
challenged or revised, for example the maximum acceptable time from onset is
currently no longer considered 3 hours (as it is still stated in the official approval
documents of the therapy) but rather 4.5 hours, following the successful ECASS-III
study, and most centers are now administering intravenous thrombolysis off-label
between 3 and 4.5 hours from symptoms onset. At the time of this writing (January
2012) we are waiting for the results of the IST-3 trial, that will hopefully clarify other
issues in the administration of intravenous thrombolysis (for example, time up to 6
hours from onset, simptoms very mild or too severe, onset with epileptic seizures, and
so on). A major issue is patients’ age, in fact in Europe r-TPA for intravenous
thrombolysis is still officially approved for treatment only in patients younger than 80
y.o. However, this boundary is being strongly challenged, and in this book we
(Balestrino et al.) are reporting our so far successful experience with intravenous
thrombolysis in patients even older than 90 years.
Endovascular therapy has recently raised great interest both in the therapy of acute
stroke and in the therapy of symptomatic or asymptomatic carotid artery stenosis. As
for acute stroke, the only randomized, controlled, multicenter, open-label clinical trial
with blinded follow-up that has been so far completed is the PROACT-II, that
Preface XI


demonstrated superiority of intra-arterial thrombolysis with urokinase plus heparin
compared to heparin alone within 6 hours from onset. Such efficacy occurred at the
expense of an increased rate of cerebral hemorrhages that was of borderline statistical
significance (p=0.06). After that study, several series of patients have been published,
that generally support the effectiveness of this procedure. It is noteworthy, and it
should not be forgot, that intra-arterial thrombolysis is a complex procedure, whose
preliminary activities (angiography, catheterization, etc.) allow it to be started, as an
average, one hour later than intravenous thrombolysis. During this hour brain cells
continue to die, and nobody has ever demonstrated how intra-arterial and intra-
venous thrombolysis compare for safety and effectiveness. At the time of this writing
(January 2012) a pivotal study (“Synthesis-Expansion”, randomizing patients to
intravenous vs. intra-arterial thrombolysis within 4.5 hours from onset) is reaching its
end and will soon provide much needed answers on whether the two treatments have
different efficacy or safety. Waiting for the results of this study, both therapies are
largely practiced. In this book, Lacman and Charvát review a popular technique of
endoscopic (intra-arterial) treatment, i.e. mechanical thrombectomy (not requiring
drugs, only physical disruption of the clot). As we know, this technique is very
interesting, not least because it is supposed (lacking the thrombolytic drug) to
minimize the bleeding risk. For this reason it is often used also as a “rescue” treatment
after failed intravenous thrombolysis.
Another popular application of endovascular techniques is carotid artery stenosis,
both asymptomatic (in a person that never had stroke or TIA) and symptomatic.
Randomized, controlled clinical trials have underlined how carotid “stenting” is more
often loaded with a burden of complications heavier than open-neck conventional
surgery, nevertheless this technique still has specific indications (for example, critical
patients who could not tolerate open-neck surgery), and it is widely practiced. In this
book Tavares and Caldas address relevant technical issues of carotid “stenting”.
Interestingly, they specifically discuss two consequences of this technique that are
often poorly understood. One is the “reperfusion syndrome”, a possible harmful
consequence of carotid artery recanalization, the other is the effects of carotid artery

recanalization on cerebral blood flow and on cognitive defects. Concerning the latter,
we should remember that procedures to reopen a clogged carotid artery are usually
undertaken to prevent a stroke, but restoration of normal cognitive function could in
theory be one more reason to restore carotid artery patency.
Last but not least, research is tackling a fearful complication of ischemic stroke, severe
intracranial hypertension in what is called “malignant” infarction of the middle
cerebral artery, a condition that in most cases ends with death or severe disability.
Hypothermia has been successfully used for this condition, however decompressive
surgery is probably the most largely practiced intervention, perhaps due to its larger
availability. In this book, Scozzafava et al. review the therapy of cerebral edema, while
Valença et al. describe a novel very interesting way (opening the skull “like a
window”) that they invented to improve this surgery.
XII Preface

In the end, I am grateful to the Authors of the above chapters for providing
stimulating and updated reports on many innovative issues in treating ischemic
stroke. I am also indebted to the InTech publisher for having stimulated me to edit this
book and having provided me, in this process, with powerful online tools and with
professional human assistance. In particular, I would like to thank Ms. Ana Pantar for
her skill and determination in starting this project and making it possible, and Ms.
Maja Bozicevic for her kind, extensive and continuous assistance in streamlining the
publishing procedure.

Maurizio Balestrino, MD
Department of Neuroscience,
Ophthalmology and Genetics, University of Genova,
Italy




Part 1
Hypothermia in the Acute Phase